NITRIC OXIDE RELEASING PRODRUGS OF THERAPEUTIC AGENTS
Field of the Invention
The present invention relates to nitric oxide releasing prodrugs of known drugs or
therapeutic agents which are represented herein as compounds of formula (I) wherein
the drugs or therapeutic agents contain one or more functional groups independently
selected from the group consisting of a carboxylic acid, an amino, a hydroxyl or a
sulfhydryl group. The invention also relates to processes for the preparation of the nitric
oxide releasing prodrugs [the compounds of formula (I)], to pharmaceutical
compositions containing them and to methods of using the prodrugs. The present
invention also relates to a bio-cleavable linker of formula (IA) capable of forming a
covalent linkage with a drug or a therapeutic agent (designated herein as D) containing
one or more functional groups independently selected from a carboxylic acid, an
amino, a hydroxyl or a sulfhydryl group and also processes for their synthesis.
Background of the Invention:
Many drugs (therapeutic agents) have undesirable properties, for instance, low oral
drug absorption, toxicity, poor patient compliance etc., that may become
pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug
application. Among the various approaches to minimize the undesirable drug
properties, while retaining the desirable therapeutic activity, the chemical approach
using drug derivatisation offers perhaps the highest flexibility and has been
demonstrated as an important means of improving drug efficacy (Hyo-Kyung Han and
Gordon L. Amidon AAPS PharmSci. 2000; 2 (1), 48-58.).
The conventional approach that is adapted to minimize the toxic side effects associated
with the therapeutic agents has been to derivatise one or more functional groups
present in the therapeutic agent or the drug molecule. The derivatives are then
assessed for their therapeutic efficacy as well as toxicity. The carboxylic acid group is
often present as an active functional group for derivatisation in several therapeutic
agents. Non-steroidal anti-inflammatory drugs (NSAIDs) represent the best
characterized class of drugs for therapeutic agents containing a carboxylic acid group
as an active functional group. NSAIDs are also the most commonly used drugs to
relieve pain, symptoms of arthritis and soft tissue inflammation. Most patients with
rheumatoid arthritis receive NSAIDs as first-line treatment which is continued for
prolonged periods. Although, NSAIDs provide anti-inflammatory and analgesic effects,
they also have adverse effects on the upper gastrointestinal (Gl) tract. The occurrence
of Gl toxicity appears to be strictly correlated to the mechanism of action of these
drugs, namely the inhibition of the enzyme cyclooxygenase. In fact, inhibition of platelet
cyclooxygenase, which causes prolonged bleeding time, and inhibition of
cyclooxygenase in gastrointestinal mucosa, which results in a decreased synthesis of
cytoprotective gastric prostaglandins, represent the major cause of serious
gastrointestinal toxicity (Symposium on "New Anti-inflammatory agents: NO-NSAIDs
and COX-2 inhibitors" part of the 11th international conference on "Advances in
prostaglandin and leukotrine research: Basic science and new clinical applications" held
in Florence (Italy), June 4-8, 2000). This problem has been solved by derivatisation of
carboxylic acid group of NSAIDs into its ester and amide derivatives.
Another common approach to minimize adverse effects of the known drugs or
therapeutic agents consists of attaching a carrier group to the therapeutic agents to
alter their physicochemical properties and then subsequent enzymatic or nonenzymatic
mechanism to release the active drug molecule (therapeutic agent). The
therapeutic agent is linked through a covalent linkage with specialized non-toxic
protective groups or carriers or promoieties in a transient manner to alter or eliminate
undesirable properties associated with the parent drug to produce a carrier-linked
prodrug.
Indeed, a more recent strategy for devising a gastric-sparing NSAID involves chemically
coupling a nitric oxide (NO) releasing moiety to the parent NSAID. Nitric oxide is one of
the most important mediators of mucosal defense, influencing such factors as mucus
secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal
immunocytes (Med Inflammation, 1995; 4: 397-405). Compounds that release nitric
oxide in small amounts over a prolonged period of time may also be very useful for the
prevention of gastrointestinal injury associated with shock and with the use of drugs
that have ulcerogenic effects (Muscara M.N.; Wallace J.L. American Journal of
Physiology, Gastrointestinal and liver physiology, 1999;39:G1 3 13-1316). Nitric oxide
has been reported to play a critical role in maintaining the integrity of the
gastroduodenal mucosa and exerts many of the same effects as endogenous
prostaglandins (Drugs Fut 2001 ; 26(5): 485).
Several mechanisms are considered to understand the protective effect of nitric oxide in
the stomach including vasodilation of local mucosal blood vessels, inhibition of
leukocyte adhesion and inhibition of caspase enzyme activity. The inactivation of
caspase(s) appears to be an important factor in the Gl tolerance of nitric oxide
releasing NSAIDs (NO-NSAIDs). Caspases are a family of cysteine proteases that
resemble interleukin-1 (IL- ) converting enzyme (ICE). These enzymes fall into two
broad groups, i.e. caspase-1 -like (including caspase-1 , -4 and -5) and caspase-3-like
enzymes. Caspase-1 is primarily involved in cytokine release, cleaving pro-IL-1 to
produce IL-1 . The ability of a range of NO-NSAIDs to inhibit cytokine formation and
caspase-1 (ICE) activity, thereby reducing the formation of pro-inflammatory IL-1 
provides a possible explanation for the reduced gastric damaging effect of these
compounds (J.E. Keeble and P.K. Moore, British Journal of Pharmacology, 2002;1 37:
295-31 0).
In recent years, several NO-releasing non-steroidal anti-inflammatory drugs (NONSAIDs)
have been synthesized by an ester linkage formed through coupling of a NOreleasing
chemical spacer group to the carboxylic acid moiety of a conventional NSAID.
The use of various aliphatic, aromatic or heterocyclic chemical spacers makes it
possible to alter various physicochemical properties and kinetics of nitric oxide release
[Berguad et al., Ann,. N. Y. Acad. Sci. 1962: 360-371 (2002)]. The first NO-aspirin drug
NCX 4016, which was synthesized relatively recently, consists of an aspirin molecule
linked by an ester bond to a molecular spacer, which in turn, is linked to a nitro-oxy
ester group (Dig Liver Dis 2003; 35 (suppl 2): 9-1 9). A number of NO-NSAID hybrid
compounds, namely NO-naproxen (HCT 301 2), NO-flurbiprofen (HCT 1026), NOibuprofen,
NO-diclofenac and NO-indomethacin have been disclosed in the patent
numbers EP 722434B1 , US 661 3784B1 and US 7220749B2 respectively. European
Patent EP 722434B1 discloses nitric esters of the derivatives of propionic acid, 1-(pchlorobenzoyl)-
5-methoxy-2-methyl-3-indolylacetic acid and 5-benzoyl-1 ,2-dihydro-3Hpyrrolo[
1 ,2-a]pyrrole-1 -carboxylic acid having anti-inflammatory and/or analgesic
activity. U.S. Patent No. 661 3784B1 discloses nitro derivatives of NSAIDs, for instance,
flurbiprofen, indomethacin, aspirin, naproxen and diclofenac. U.S. Patent No.
7220749B2 discloses novel nitrosated and/or nitrosylated derivatives of COX-2
selective inhibitors. U. S. Patent Application Publication no. 20080293781 A 1 describes
O-acyl salicylic acid derivatives bearing a NO donor moiety.
Further, NO releasing COX-2 (cyclooxygenase-2) inhibitors comprising NO-releasing
moieties attached through a chemical linker to the COX-2 inhibitor compounds have
been reported in the art. US Patent No. 7 199154 B2 discloses nitrosated or nitrosylated
prodrugs for COX-2 selective inhibitors that are useful for treating COX-2 mediated
diseases or conditions and which can be administered alone or in combination with lowdose
aspirin. The compounds are effective in treating chronic COX-2 mediated
diseases or conditions, reducing the risk of thrombotic cardiovascular events and
possibly renal side effects and at the same time reduce the risk of Gl ulceration and
bleeding. US Patent Application Publication no. 20060058363 A 1 discloses nitric-oxide
releasing prodrugs of Celebrex and valdecoxib which are useful in the treatment of
COX-2 mediated diseases. The compounds may be used as a combination therapy
with low-dose aspirin to treat COX-2 mediated diseases or conditions while
simultaneously reducing the risk of thrombotic cardiovascular events.
Nitric oxide (NO) also plays an important role in numerous physiological and pathophysiological
conditions, e.g. blood pressure regulation, inflammation, infection, and the
onset and progression of malignant diseases (Lirk, P., Hoffmann, G., and Rieder, J.
Curr. Drug Targets Inflamm. Allergy 2002; 1: 89-108). NO deficiency is recognized to
be a crucial factor in the initiation and progression of many cardiovascular diseases and
delivery of supplementary NO in the form of NO-donor drugs has long been an
attractive therapeutic strategy (Ian L Megson, David J Webb, Expert Opin. Investig.
Drugs, 2002; 11(5): 587-601). In recent years, with the advent of NO-NSAID approach
and because of the beneficial biochemical and pharmacological properties of nitric
oxide, the strategy of linking NO-releasing moieties has been extended to a wide array
of therapeutic agents selected from cardiovascular drugs, for instance, Angiotensin
converting enzyme (ACE) inhibitors, calcium antagonists and beta-blockers, antitumor
agents, antihistamines, glucocorticoids, etc. The aim of this strategy is to synthesize
prodrugs that retain the pharmacological activity of the parent drug molecule coupled
with the benefits of the biological actions of NO in reducing the adverse effects of the
parent drug molecule.
Another class of therapeutic agents which are well-known for their anti-inflammatory
and immunosuppressive effects are glucocorticoids. Due to their beneficial therapeutic
effects, glucocorticoids are useful for the treatment of a variety of inflammation related
disorders and immune system disorders, especially autoimmune diseases such as
rheumatoid arthritis. However, their therapeutic application is limited due to adverse
effects and toxicity associated with their use. The adverse effects caused by
glucocorticoids include hypertension, peptic ulcers, gastrointestinal bleeding, increased
risk for infections, osteoporosis and hyperglycemia (Schacke H et al., Pharmacol Ther
2002;96:23-43).
US Patent Nos 6,610,676 and 7,524,836B2 disclose nitrate esters and nitroxy
derivatives of steroidal compounds having anti-inflammatory, immunodepressive and
angiostatic activity or gastrointestinal activity. The compounds are useful in the
treatment of morbid conditions wherein the steroids are generally used and confer
greater benefit in terms of better tolerability and efficacy. PCT Application Publication
WO2007099548A1 discloses 11p-hydroxyandrosta-4-3-one compounds which possess
useful anti-inflammatory activity whilst having insignificant or no noteworthy side-effects
at efficacious doses. PCT Application Publication WO2008095809A1 discloses
derivatives of known corticosteroids, containing a NO-releasing moiety which are useful
in the treatment of illnesses wherein the known corticosteroid, parent or precursor
steroid, is generally applied, with increased benefit in terms of pharmacological profile
and fewer or milder side effects than those of the parent corticosteroids. The
compounds are useful in the treatment of inflammatory diseases, respiratory diseases,
and autoimmune disorders among other disorders.
The approach and possibility of combining a few classes of drugs bearing different
functional groups susceptible to derivatisation with NO-donating moieties has been
described by Manlio Bolla et al., in Curr. Topic. Med. Chem. 2005; 5: 707-720. The
review paper discloses four chemically different NO-donating linkers hybridized with
different drugs possessing a derivatisable function. Free carboxylic acids, alcohols
(including phenols), thiols, and amines have been demonstrated to be exploitable for
such an approach.
The NO-releasing derivatives and prodrugs of various therapeutic agents known in the
art are in different phases of clinical development and there are reports suggesting that
a few of them have been suspended because of toxicity problems. Therefore, there is a
clear need for new, alternative and better NO-releasing nitrate ester prodrug
compounds which can exhibit improved therapeutic properties. A thorough investigation
by the present inventor led to the discovery of nitric oxide releasing prodrugs or prodrug
compounds which can be obtained through derivatisation of a known drug or a
therapeutic agent containing one or more functional groups independently selected
from carboxylic acid, hydroxyl, amino or sulfhydryl functional groups. The nitric oxide
releasing prodrugs of the present invention are useful in the treatment of diseases or
disorders that is characteristic of the parent drug molecule from which the prodrug is
derived. The nitric oxide releasing prodrugs of the invention exhibit comparable or
superior therapeutic effects compared to the parent drug molecule. The nitric oxide
releasing prodrugs of known drugs or therapeutic agents as described in the present
invention are expected to be safe to administer and have comparable or superior oral
bioavailability compared to the parent drug molecules from which the prodrugs are
derived. Further, owing to the strategy that is used to devise the nitric oxide releasing
prodrugs of the present invention, the prodrugs or at least certain prodrugs
encompassed in the present invention are expected to be devoid of genotoxicity at a
concentration at which the compounds are expected to be used for the treatment of the
medical conditions or diseases for the treatment of which the parent drug molecule is
used.
Moreover, the nitric oxide releasing prodrugs of the invention are expected to overcome
adverse effects, for instance, gastrointestinal (Gl) toxicity and cardiovascular risks
associated with the parent drug molecule.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds of the following formula (I),
which are prodrugs of known drugs or therapeutic agents;
(I)
wherein:
D is a drug containing one or more functional groups independently selected from a
carboxylic acid, an amino, a hydroxyl or a sulfhydryl group capable of forming a
covalent bio-cleavable linkage with a biocleavable linker;
X1 is a bond, oxygen, sulphur or NR3;
X2 is a bond, oxygen or NR3;
R3 is a bond or hydrogen;
=0 or a spacer group selected from:
wherein in the spacer groups of formulae (Ya) to (Y):
R4 is a bond, hydrogen, alkyl or a metal ion selected from sodium, potassium or
calcium;
R5 is hydrogen, C _6 alkyl or phenyl;
R6 is hydrogen or a group (which is a side-chain group of naturally occurring amino
acids) selected from:
-CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C0 2H, -CH2CH2C0 2H, -
CH2OH, -CH(CH3)OH, -CH2SH, -CH2CH2SCH3, -CH2CH2CH2CH2NH2, -C6H5, -
CH2C6H5, -CH2C6H4-p-OH, -CH2CH2CH2NHC(=NH)NH2, -CH2C(=0)NH 2, -
CH2CH2C(=0)NH 2, -CH2-indol-3-yl or -CH2-imidazole;
X3 is oxygen, sulphur, SO, S0 2 or NR3;
R7 is hydrogen or a group selected from acetyl, benzoyl, alkyloxycarbonyl,
benzyloxycarbonyl, 9-fluorenylmethyloxy carbonyl or its pharmaceutically
acceptable ammonium salts;
R is hydrogen or C -6 alkyl;
c is an integer from 0 to 2;
d is an integer from 1 to 5;
e is an integer from 1 to 4.
Z1 is (CH2)a; where a is an integer from 0 to 3;
Z2 is (CH2)b; where b is an integer from 0 to 3;
A is a bond, S, SO, S0 2, S-S, CH=CH, D-isosorbide skeleton, 1,4-anhydroerythritol
skeleton, cycloalkylene, CR R10 , C6-C 0-arylene, a 5- or 6-membered heteroarylene or
a 5- or 6-membered heterocyclylene wherein said arylene, heteroarylene and
heterocyclylene may be unsubstituted or substituted by one or more substituents
independently selected from the group consisting of C -6 alkyl, C -6 alkoxy, hydroxy,
trifluoromethyl, cyano, amino and halogen ;
R and R10 are independently hydrogen or alkyl; or R and R10 taken together with the
carbon atom to which they are attached form a cycloalkyl or a heterocyclic ring;
R1 is hydrogen and R2 is alkyl, cycloalkyl, aryl or aralkyl; or R2 is hydrogen and R1 is
alkyl, cycloalkyl, aryl or aralkyl;
with the proviso that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and mixtures thereof in all ratios or pharmaceutically
acceptable salts thereof.
In another aspect, the present invention provides a bio-cleavable linker of formula (IA)
capable of forming a covalent linkage with a drug (designated herein as D) containing
one or more functional groups independently selected from a carboxylic acid, an amino,
a hydroxyl or a sulfhydryl group:
(IA)
wherein the variables Y, X2, Z1, A, Z2, R1 and R2 are as defined in respect of the
compounds of formula (I). The linker of formula (IA) is non-toxic and facilitates release
of nitric oxide and serves as an important intermediate in the processes for the
PLSPD02J 1 9
synthesis of nitric oxide releasing prodrugs of formula (I) which are the prodrugs of
r therapeutic agents.
In yet another further aspect, the present invention provides processes for the
preparation of the compounds of formula (I).
In yet another further aspect, the present invention provides processes for the
preparation of the bio-cleavable linker of formula (IA).
In yet another aspect, the present invention provides a pharmaceutical composition
comprising the compound of formula (I) as an active ingredient and at least one
pharmaceutically acceptable excipient.
In yet another further aspect, the present invention provides a method for the treatment
of diseases or disorders in a subject by administering a therapeutically effective amount
of the compound of the formula (I) to the subject.
In yet another further aspect, the present invention provides the compounds of formula
(I), which are the prodrugs of known drugs or therapeutic agents, for use in the
treatment of diseases or disorders capable of being treated by the parent drugs or
therapeutic agents from which the prodrugs are derived.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 provides different pathways for oxidation and reduction of nitrate, nitrite and
NO in the human body.
DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses compounds of formula (I), as described herein,
which are nitric oxide releasing prodrugs of known drugs or therapeutic agents useful in
the treatment of diseases or disorders that are characteristic of the drugs from which
the prodrugs of the present invention are derived.
In general, the present invention provides prodrugs of known drugs or therapeutic
agents represented herein by the compounds of formula (I) which primarily constitutes
the following elements:
(a) a drug containing one or more functional groups independently selected from a
carboxylic acid, an amino, a hydroxyl or a sulfhydryl group capable of forming a
covalent bio-cleavable linkage with a linker;
(b) a linker;
(c) optionally a spacer; and
(d) a nitrooxy (ON0 2) group.
The strategy for providing the prodrugs represented herein by the compounds of
formula (I) is applicable to any drug or therapeutic agent which possesses a functional
group such as a carboxylic acid, an amino, a hydroxy or a sulfhydryl group capable of
covalently binding to a linker. The linker is a bi- or multi-functional moiety having the
desired covalent binding properties.
The prodrugs [the compounds of formula (I)] of the present invention would undergo
enzymatic cleavage in a manner such that the parent drugs and effective amounts of
nitric oxide are released in vivo and that the oral bioavailability of the parent drugs is
nearly maintained. The prodrugs [the compounds of formula (I)] of the present invention
are expected to be safe to administer and may have oral bioavailability comparable or
superior to that of the parent drug molecule.
Unless otherwise indicated, the following definitions are set forth to illustrate and define
the meaning and scope of the various terms used to describe the invention herein and
the appended claims. These definitions should not be interpreted in the literal sense as
they are not general definitions and are relevant only for this application.
As used herein, the term "prodrug or prodrugs" refers / refer to a compound/compounds
which upon administration to a subject in need thereof undergoes chemical conversion
by metabolic or chemical processes to release the parent drug in vivo from which the
prodrug is derived.
As used herein, the term "drug" or "drugs" r "therapeutic agents" or "drug molecules"
or "parent drug" or "parent drug molecules" are used interchangeably. The term "drug"
or "drugs" as used herein refers to any compound, substance, medicament or active
ingredient having a therapeutic or pharmacological effect, and which is suitable for
administration to a mammal, e.g., a human. More particularly, in the context of the
present invention all the known drugs or therapeutic agents containing one or more
functional groups independently selected from a carboxylic acid, an amino, a hydroxyl,
or a sulfhydryl group that are capable of forming a covalent bio-cleavable linkage with a
linker. The term "drug" or "drugs" as used herein also encompasses within its scope the
"investigational drug(s)" or "investigational agent(s)" which refer to any new drug or
agent currently under clinical investigation, particularly those investigational drugs or
agents that contain one or more functional groups independently selected from a
carboxylic acid, an amino, a hydroxyl or a sulfhydryl group capable of forming a
covalent bio-cleavable linkage with a linker, which may later be established as
therapeutically active agents by the regulatory bodies of different countries, are also
encompassed within the scope of the term "drugs" or "therapeutic agents" as used
herein. For example, when the drug or the therapeutic agent or the parent drug
molecule contained in the compounds of formula (I) can be selected from ant i
inflammatory and analgesic agents, cardiovascular agents, anti-allergic agents, ant i
cancer agents, anti-depressants, anti-convulsant agents, anti-bacterial agents, ant i
fungal agents, anti-viral agents, anti-malarial agents, anti-diabetic agents, anti-ulcer
agents, anti-oxidants or vitamins.
As used herein, the term "linker" or "linkers" or "bio-cleavable linkers" refers/refer to a
chemical moiety or moieties which forms/form a covalent linkage with the reactive
carboxylic acid, amino, hydroxyl or sulfhydryl group of the drug or therapeutic agent to
obtain a prodrug of the drug. This linker may be cleaved from the prodrug by chemical
means, by enzymatic means, or by both the means. The linker may be
pharmacologically inert or may itself provide added beneficial pharmacological activity.
As used herein, the term "alkyl", alone or as part of a substituent of other groups,
means a branched or straight-chain monovalent alkyl radical, preferably having one to
six carbon atoms such that the alkyl group is designated as C _6-alkyl. This term is
further exemplified by such radicals as methyl, ethyl, n-propyl , isopropyl, n-butyl, sbutyl,
t-butyl. Unless stated otherwise, the "term" alkyl includes unsubstituted alkyl
groups as well as alkyl groups substituted by one or more substituents. A substituted
alkyl refers to an alkyl residue in which one or more hydrogen atoms are optionally
replaced with substituents, for example, halogen, hydroxyl, alkoxyl, carbonyl, amino,
nitro, nitrooxy, alkylthio, sulfhydryl, carbamate, sulphamate, sulphonate or an aryl
group.
As used herein, the term "amino" functional group of drug or therapeutic agent refer to
derivatisable primary and secondary amines (both acyclic and cyclic) which also include
drugs containing derivatisable NH-containing functional groups such as amide-NH,
sulfonamide-NH, carbamate-NH, sulfamate-NH, hydrazide-NH, hydrazone-NH,
semicarbazone-NH, thiosemicarbazone-NH, urea-NH, and also encompass drug
molecules with derivatisable NH-containing heterocyclic sub-structures such as
aziridine, azitidine, dihydropyridine, indole, imidazole, benzimidazole, thiozole,
benzothiozole, oxazole, benzoxazole, pyrrole, pyrrazol, benzopyrrozole, pyrrolidine,
piperidine, triazole, benzotriazoles, tetrazole, and benzotetrazole.
As used herein, the term "hydroxyl" or "hydroxy" functional group of drugs or
therapeutic agents refer to drugs containing derivatisable hydroxyl groups [i.e., these
hydroxyl (OH) groups can be primary, secondary, tertiary or phenolic in nature]
including hydroxyl groups of hydroxamic acids and ketoximes of keto-containing drug
molecules.
As used herein, the term "sulfhydryl" groups of drugs or therapeutic agents refer to
drugs containing derivatisable free sulfhydryl (SH) groups and these can be primary,
secondary, tertiary and thiophenolic in nature.
As used herein, the term "halogen" refers to fluorine, bromine, chlorine or iodine.
As used herein, the term "halide" refers to fluoride, chloride, bromide, and iodide.
As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic
hydrocarbon system having 6 to 14 carbon atoms, preferably 6 to 10 ring carbon atoms,
in which at least one carbocyclic ring is present that has a conjugated pi-electron
system. Examples of (C6-Ci 4) aryl ring system include phenyl, naphthyl, biphenyl or
anthracenyl, particularly preferred aryl ring system include phenyl and naphthyl. Unless
stated otherwise, the aryl ring system, for example, phenyl, naphthyl or anthracenyl,
can be optionally substituted with one or more identical or different substituents
selected from the groups consisting of alkyl, halogen, hydroxyl, alkoxy, nitro, amino,
trihaloalkyl, carbonyl (such as carboxyl, formate, carbamide, ester, ketone, aldehyde),
carbamate, sulphamate, sulphonate, sulphate or a sulfhydryl group. The aryl residue
can be bonded via any desired position and in substituted aryl, the substituents can be
located in any desired position. For instance, in mono-substituted phenyl residue, the
substituent can be present in 2-, 3-, 4- or 5- position. If the phenyl group carries two
substituents, they can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position,
3,4-position or 3,5-position.
As used herein, the term "arylene", by itself or as part of another substituent means,
unless otherwise stated, a divalent aryl radical having 6 to 14 ring carbon atoms,
preferably 6 to 10 ring carbon atoms. The arylene group can have a single ring (e.g.,
phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one
is aromatic, (e.g., 1, 2, 3, 4-tetrahydronaphthyl, naphthyl), which is optionally
substituted with one or more groups selected from, e.g., halogen, alkyl, alkoxy,
trifluoromethyl. Representative arylene groups include, by way of example, 1,2-
phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1 ,5-diyl, naphthalene-2,7-diyl,
and the like.
As used herein, the term "cycloalkyi" refers to a saturated mono-, bi- or polycyclic ring
system containing a specified number of carbon atoms. Unless otherwise stated,
cycloalkyi rings containing 3 to 7 carbon atoms are preferred. Representative cycloalkyi
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Further, unless otherwise stated, the term cycloalkyi includes unsubstituted cycloalkyi
or cycloalkyi which is optionally substituted with any one of the substitutents mentioned
above for aryl and the substitution can be in any desired position. Cycloalkyi group
comprises a saturated cycloalkyi ring system which does not contain any double bond
within the rings and partially unsaturated cycloalkyi ring systems which may contain one
or more double bonds within the ring system that is stable and provided that the double
bonds are not located in a manner that an aromatic system results.
As used herein, the term "cycloalkylene" refers to a divalent saturated carbocyclic
hydrocarbon group. Unless otherwise defined, such cycloalkylene groups typically
contain from 3 to 10 carbon atoms. Representative cycloalkylene groups include, by
way of example, cyclopropane-1 ,2-diyl, cyclobutyl-1 ,2-diyl, cyclobutyl-1 ,3-diyl,
cyclopentyl-1 ,2-diyl, cyclopentyl-1 ,3-diyl, cyclohexyl-1 ,2-diyl, cyclohexyl-1 ,3-diyl,
cyclohexyl-1 ,4-diyl, and the like.
As used herein, the term "aralkyi" refers to an alkyl group substituted with an aryl group,
wherein the term alkyl group is as defined above. Representative aralkyi groups include
-(CH 2)g-phenyl ( wherein g is an integer from 1 to 2) such as benzyl, phenethyl and the
like.
As used herein, the terms "heterocyclyl" or "heterocyclic ring" refer to a saturated,
partially unsaturated or aromatic monocyclic or polycyclic heterocyclic ring system
containing 3 to 14 ring atoms of which 1, 2, 3 or 4 are identical or different heteroatoms
selected from the group consisting of nitrogen, oxygen and sulphur. The heterocyclyl
ring, for example, has 1 or 2 oxygen atoms and/or 1 or 2 sulphur atoms and/or 1 or 2
nitrogen atoms. In monocyclic groups, heterocyclic ring preferably is a 3-membered, 4-
membered, 5-membered, 6-membered or 7-membered ring, more preferably a 5- or 6-
membered ring comprising one to three hetero atoms selected from the group
consisting of nitrogen, oxygen and sulphur. Representative examples of saturated
heterocyclic rings include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl,
oxazolidinyl, dioxanyl and pyranyl. Representative examples of unsaturated
heterocyclic rings are furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl,
isoxazolyl, pyrazolyl, imidazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,
pyrimidinyl, pyrazinyl and pyridazinyl.
In polycyclic groups, the term "heterocycle" or "heterocyclic ring" preferably comprises
two fused rings (bicyclic), one of which is a 5- or a 6-membered heterocyclic ring and
the other is a 5- or 6-membered heterocyclic ring. Representative examples of
polycyclic saturated heterocycle are indolinyl, 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-
tetrahydroisoquinolinyl. Representative examples of polycyclic unsaturated heterocycle
are quinolinyl, isoquinolinyl, benzoxazolyl, benzthiazolyl, benzofuranyl, thionaphthyl and
indolyl. Unless stated otherwise, the heterocycle or heterocyclic group can be
unsubstituted or substituted on the ring carbon atoms with one or more substituents.
Each suitable ring nitrogen atom in the heterocycle or heterocyclic ring can
independently of the other be unsubstituted i.e., carry a hydrogen atom or can be
substituted. Suitable examples of substituents for the heterocyclic ring carbon and/or
the nitrogen atoms are: amino, halo, hydroxyl, alkyl, haloalkyl, cyano, nitro, sulfhydryl
and carboxyl.
As used herein, the term "heteroarylene" refers to a divalent aromatic group having a
single ring or two fused rings containing at least one heteroatom, typically 1 to 3
heteroatoms, selected from the group consisting of nitrogen, oxygen or sulfur in the
ring. Unless otherwise defined, such heteroarylene groups typically contain from 5 to 10
total ring atoms. Representative examples of heteroarylene groups include, divalent
species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole,
isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole,
benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, isoquinoline,
quinazoline, quinoxaline and the like, where the point of attachment is at any available
carbon or nitrogen ring atom.
As used herein, the term "side chain group of naturally occurring amino acids" is
intended to refer to the side chains of o -amino acids selected from the group consisting
of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid,
glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, phenylalanine,
serine, tryptophan, threonine, tyrosine, and valine. The side-chain group of naturally
occurring amino acids being the group represented as R6 in the spacer group of
formula Yc , the sub-group that is defined in the variable Y in respect of the compounds
of formula (I).
As used herein, the term "amino protecting group" is intended to refer to a group that
can be selectively attached to the nitrogen atom by chemical modification of an amino
group so as to selectively inhibit participation of the amino group in chemical reactions.
After the completion of said chemical reactions the amino protecting group may be
selectively removed. Exemplary amino-protecting groups include, carbamates
(urethanes) such as methyl, ethyl, 9-fluorenylmethyl (i.e., Fmoc or 9-
fluorenylmethoxycarbonyl), 2,2,2-trichloroethyl (i.e., Troc or trichloroethoxycarbonyl, 2-
trimethylsilylethyl (i.e., Teoc or trimethylsilylethoxycarbonyl), 2-phenylethyl, 2-
chloroethyl, 1, 1 -dimethyl-2,2,2-trichloroethyl, /-butyl (i.e., BOC or fert-butoxycarbonyl),
benzyl (i.e., Cbz or Z or benzyloxycarbonyl), 1-adamantyl, 2-adamantyl, pmethoxybenzyl,
p-nitrobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-
methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl, 2-methylthioethyl, 2-
methylsulfonylethyl, 4-methylthiophenyl, 4-azidobenzyl, 3,5-dimethoxybenzyl, onitrobenzyl,
2-iodoethyl, phenyl, etc., and amides such as formyl, acetyl, chloroacetyl,
trichloroacetyl, trifuoroacetyl, phenylacetyl, benzoyl, o-nitrophenylacetyl, o-nitrobenzoyl,
bromoacetyl, iodoacetyl, methoxyacetyl, etc., and cyclic imides such as phthalimide,
etc., and N-alkyl and N-aryl amines such as N-methyl, N-t-butyl, N-allyl, N-cyanomethyl,
N-benzyl, N-4-methoxybenzyl, N-2.4-dimethoxybenzyl, N-diphenylmethyl, N-bis(4-
methoxyphenyl)methyl, N-triphenylmethyl (Tr), N-[(methoxyphenyl)diphenylmethyl]
(MMTr), etc., and imine derivatives such as N-1 ,1-dimethylthiomethyleneamine, Nbenzylideneamine,
N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, etc..
Additional examples of amino protecting groups listed in T. W. Greene, "Protective
Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991 are
incorporated herein as a reference. Also, the procedures for the formation and cleavage
of the above mentioned amino protecting groups are based on the known methods and
their relevant references are cited in T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1991 and incorporated herein as a
reference.
As used herein, the term "hydroxyl protecting group" or "hydroxy protecting group", is
intended to refer to a group that can be selectively attached to the oxygen atom by
chemical modification of the hydroxyl group so as to selectively inhibit the participation
of the hydroxyl group in chemical reactions. After said chemical reactions the hydroxy
protecting group may be selectively removed. Examples of hydroxyl and phenolicprotecting
groups include, ether groups such as the alkyl ether group selected from
methyl ether, methoxymethyl ether, methylthiomethyl ether, tert-buylthiomethyl ether,
triphenylmethyl, tetrahydropyranyl (THP), (phenyldimethylsilyl) methoxy methyl ether,
benzyloxymethyl ether, p-methoxybenzyloxy-methyl ether, o-nitrobenzyloxymethyl, pnitrobenzyloxymethyl,
/-butoxymethyl ether, menthoxymethyl ether, 2-
methoxyethoxymethyl ether, siloxymethyl ether, ethoxyethyl ether, 1-(2-chloroethoxy)-
ethyl ether, 2,2,2-trichloroethoxymethyl ether, 2-(trimethylsilyl)ethoxymethyl ether and
isopropyl ether, the aryl ether group is selected from phenyl ether, p-chlorophenyl ether,
p-methoxyphenyl ether, 2,4-dinitrophenyl ether, benzyl ether, p-methoxybenzyl ether, onitrobenzyl
ether, and 2,6-dichlorobenzyl ether, the alkylsilyl ether groups selected from
trimethyl-, triethyl- and triisopropyl- silyl ethers, mixed alkylsilyl ether groups selected
from dimethylisopropylsilyl ether, tert-butyldimethylsilyl ether and diethylisopropylsilyl
ether; and the ester groups selected from acetate ester, formate ester, benzylformate
ester, mono-, di-, and trichloroacetate ester, trifuoroacetate ester, methoxyacetate
ester, triphenylmetoxyacetate ester, benzoate ester, phenylacetate ester, pivalate ester,
phenoxyacetate ester, p-chlorophenoxyacetate, 2-iodobenzoate, 4-azidobutyrate, 4-
nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 4-
(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2-
[(chloroacetoxymethyl)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-
methoxybenzyloxy)ethyl]benzoate, monosuccinate, o-(methoxycarbonyl)benzoate,
nitrate, benzyloxycarbonate, benzyl, ethyl or methyl carbonate, methoxymethyl
carbonate, 9-fluorenylmethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-
(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, 2-
(methylthiomethoxy)ethyl carbonate, 2-(4-nitrophenyl)ethyl carbonate, methyl
dithiocarbonate, 9-fluorenylmethoxycarbonate, /-butoxycarbonate,
trichloroethylcarbonate, 2-danysylethyl carbonate, 2-(4-nitrophenyl)ethyl carbonate, 2-
(2,4-dinitrophenyl)ethyl carbonate, 2-cyano-1-phenylethyl carbonate, S-benzyl
thiocarbonate, 4-ethoxy-1-naphthyl carbonate, borates carbamates, sulfonates and
sulphamate. Examples of protecting groups for 1,2-diols, 1,3-diols, 2-
hydroxybenzenethiols and catechols include, cyclic acetals and ketals such as
methylene acetal, ethylidene acetal, f-butylmethylidene ketal, 1-i-butylethylidene ketal,
1-phenylethylidene ketal, 1-(4-methoxyphenyl)ethylidene acetal, trichloroethylidene
acetal, acrolein acetal, isopropylidene ketal (acetonide), cyclopentylidene ketal,
cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, pmethoxybenzylidene
acetal, 2,4-dimethoxybenzylidene acetal, 3,4-
dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, 4-nitrobenzylidene acetal,
mesitylene acetal, 1-naphthaldehyde acetal, benzophenone ketal, o-xylyl ether,
camphor ketal, cyclic ortho esters such as methoxymethylene acetal, ethoxymethylene
acetal, dimethoxymethylene ortho ester, 1-methoxyethylene ortho ester, 1-
ethoxyethylene ortho ester, methylidne ortho ester, phthalido ortho ester, 2-
oxacyclopentylidene ortho ester, butane-2,3-bisacetal, cyclohexane-1 ,2-diacetal,
dispiroketal, silyl derivatives such as di-i-butylsilylene group, dialkylsilylene groups, 1,3-
( 1 , 1 ,3,3-tetraisopropyldisiloxanylidene group, 1, 1 ,3,3-tetra-i-butoxydisiloxaneylidene
group, cyclic carbonates, cyclic boronates, phenyl boronate and o-acetamidophenyl
boronate. Additional examples of hydroxyl protecting groups are described in T. W.
Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York,
N.Y., 1991 . Also, the procedures for the formation and cleavage of the above
mentioned hydroxyl protecting groups are based on the known methods and their
relevant references are cited in T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1991 and incorporated herein as a
reference.
As used herein, the term "carboxyl protecting group" or "carboxylic acid protecting
group" is intended to refer to a group that selectively blocks the oxygen functionality
within a carboxylic acid group so as to inhibit participation of the carboxylic acid group
in chemical reactions. Examples of such carboxylic acid protecting groups include, for
example unsubstituted and substituted alkyl esters such as methyl, ethyl, /-butyl,
benzyl, 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl,
triisopropylsiliylmethyl, cyanomethyl, acetol (hydroxy acetone), phenacyl, pbromophenacyl,
p-chlorophenacyl, p-methoxyphenacyl, carboxamidomethyl (Cam),
etc., and 2-subtituted ethyl esters such as 2,2,2-trichloroethyl, 2-haloethyl, 2-
(trimethylsilyl)ethyl, 2-methylthioethyl, 2-cyanoethyl, cyclopentyl, cyclohexyl, allyl,
phenyl, etc., and substituted benzyl esters such as triphenylmethyl (trityl),
diphenylmethyl (Dpm), 9-anthrylmethyl, p-methoxybenzyl, etc., and silyl esters such as
trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), /-
propyldimethylsilyl, phenyldimethylsilyl, di-i-butylmethylsilyl (DTBMS), and
triisopropylsilyl (TIPS). Additional examples of carboxylic acid protecting groups are
described in T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and
Sons, New York, N.Y., 1991 . Also, the procedures for the formation and cleavage of the
above mentioned carboxyl protecting groups are based on the known methods and
their relevant references are cited in T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1991 and incorporated herein as a
reference.
As used herein, the term "sulfhydryl protecting group" or "thiol protecting group" is
intended to refer to a group that selectively blocks the thiol (SH) functionality so as to
inhibit participation of the thiol group in chemical reactions. Examples of such thiol
protecting groups include, thioethers such as S-alkyl, S-benzyl, S-p-methoxybenzyl, So-
or p-hydroxy- or acetoxybenzyl, S-p-nitrobenzyl, S-2,4,6-trimethyl/trimethoxybenzyl,
S-4-picolyl, S-2-quinolinomethyl, S-9-Anthrylmethyl, S-9-Fluorenylmethyl, S-xanthenyl,
S-diphenylmethyl, S-substituted diphenylmethyl, S-triphenylmethyl, S-bis(4-
methoxyphenyl)methyl, S-bis(4-methoxyphenyl)phenylmethyl (DMTr), S-i-butyl, S-1-
Adamantyl, S-2-(4'-pyridyl)ethyl, S-2-cyanoethyl, S-2-(trimethylsilyl)ethyl, S-2,2-
bis(carboethoxy)ethyl, etc., and monothio acetals such as S-acetamidomethyl, Strimethylacetamidomethyl,
S-benzamidomethyl, S-allyloxycarbonylaminomethyl, Sphenylacetamidomethyl,
S-phthalimidomethyl, S-methoxymethyl, S-isobutoxymethyl, Sbenzyloxymethyl,
S-2-tetrahydropyranyl, etc., and dithioacetals such as Sbenzylthiomethyl,
S-phenylthiomethyl, etc., and silyl thioethers such as triisopropylsilyl,
etc., and thioesters such S-acetyl, S-benzoyl, S-trifluoroacetyl, etc., and thiocarbonates
such as S-2,2,2-trichloroethoxycarbonyl, S-i-butoxycarbonyl, S-benzyloxycarbonyl, etc.,
and thiocarbamates such as S-(N-ethylcarbamate), S-(N-methoxymethylcarbamate),
etc., and unsymmetrical disulfides such as S-ethyl disulfide, S-t-butyl disulfide,
substituted S-phenyl disulfide, etc., and sulfenyl derivatives such as S-sulfonate, Ssulfenylthiocarbonate,
S-3-nitro-2-pyridinesulfenyl sulfide, etc., and protection of dithiols
as dithio acetals and ketals such as S^-methylene, S,S-isopropylidene and
S,S'benzylidene derivatives. Also, protection of 1,2-aminothiols as thiozolidine
derivatives. The procedures for the formation and cleavage of the above mentioned
sulfhydryl protecting groups are based on the known methods and their relevant
references are cited in T. W. Greene, "Protective Groups in Organic Synthesis", John
Wiley and Sons, New York, N.Y., 1991 and incorporated herein as a reference.
The term "leaving groups" or "LGs" include, but are not limited to, (substituted) alkoxy,
aryloxy, nitrogen containing unsaturated heterocycles such as N-oxybenzotriazole,
imidazolyl, o- or p-nitrophenoxy, pentachloro-phenoxy, N-oxysuccinimide, ,'-
dicyclohexylisoure-O-yl, N-hydroxy-N-methoxyamino, and the like; acetates, formates,
sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, or ptoluenesulfonate,
and the like; and halides such as fluoride, chloride, bromide, or
iodide.
The term "coupling agent" or "carbonyl activating agent" refers to a reagent that
converts the carbonyl of a carboxylic acid group into one that is more susceptible to
nucleophilic attack and includes, but is not limited to, such reagents as those found in
"The Peptides", Gross and Meienhofer, Eds., Academic Press (1979), Ch. 2, and M.
Bodanszky, "Principles of Peptide Synthesis", 2.sup.nd Ed., Springer-Verlag Berlin
Heidelberg, 1993, hereafter referred to as "The Peptides" and "Peptide Synthesis"
respectively. Carbonyl group (i.e., aldehyde or keto group) of the drugs or drug
molecules may be converted first to aldoxime, ketoxime, hydrazone, semicarbazone
and the like, before coupling to the linker. Specifically, carbonyl activating agents
include thionyl bromide, thionyl chloride, oxalyl chloride, and the like; esters of alcohols
such as nitrophenol, pentachlorophenol, and the like; and compounds such as 1,1'-
carbonyldiimidazole (CDI), benzotriazole, imidazole, N-hydroxysuccinimide,
dicyclohexylcarbodiimide (DCC), 1-Ethyl-(3-dimethylaminopropyl)carbodiimide (EDAC),
phosgene or its equivalents, N, N-dimethylaminopyridine (DMAP) and the like.
The terms "phosgene or its equivalents" refer to phosgene or it equivalents such as
diphosgene, triphosgene, ,'-Carbonyldiimidazole (CDI), ,'-
Dicyclohexylcarbodiimide (DSC), 1, 1 -Bis[6-(trifluoromethyl)benzotrazolyl]-carbonate
(BTBC),, alkoxycarbonyl chlorides, o/p-nitrosubstituted phenoxycarbonyl chlorides, and
the like.
The term "suitable solvent" refers to a solvent that is inert to the ongoing reaction and
sufficiently solubilizes the reactants to effect the desired reaction. Examples of suitable
solvents include but are not limited to, dichloromethane, chloroform, 1,2-dichloroethane,
diethyl ether, tert-butylmethyl ether, acetonitrile, ethyl acetate, 1,3-dimethyl-2-
imidazolidinone, tetrahydrofuran, dimethylformamide, benzene, toluene, xylene, N,Ndimethylacetamide,
N-methylpyrrolidine, chlorobenzene, dimethylsulfoxide,
dimethoxyethane, water, methanol, ethanol, isopropanol, pyridine, nitromethane, and
the like or mixtures thereof.
The term "suitable base" refers to a base, which acts as a proton trap for any protons,
which may be produced as a byproduct of the desired reaction, or to a base, which
provides a reversible deprotonation of an acidic proton from the substrate and is
reactive enough to effect the desired reaction without significantly effecting any
undesired reactions. Examples of such bases include, but are not limited to, suitable
metal carbonates, bicarbonates, and hydroxides (e.g., lithium, sodium, potassium,
magnesium, calcium and the like), sodium/potassium/calcium hydride,
sodium/potassium alkoxide (i.e., methoxide, ethoxide, tert-butoxide and the like),
triethylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine,
tetramethylguinidine, or aromatic nitrogen containing heterocycles such as pyridine, 4-
(dimethylamino)pyridine (DMAP), and the like.
The term "suitable oxidizing agent" refers to a suitable agent that causes oxidation of a
molecule. The term "oxidation" in chemistry refers to either elimination of hydrogen or
replacement of hydrogen atom bonded to carbon with another more electronegative
element such as oxygen. A more general definition of oxidation involves an increase in
oxidation state and loss of one or more electrons from an atom or group. Examples of
oxidation include transformations such as conversion of: an alcohol to a carbonyl
compound (i.e., to aldehydes or ketones), aldehydes or ketones to carboxylic acid,
aromatics to phenols, phenols to quinones, alkenes to diols, epoxides or ketones,
sulfides to sulfoxides and sulfones, metals to metal cations and so on. Examples of
"suitable oxidizing agents" include, but not limited to, chromium reagents such as
chromium trioxide, chromium trioxide-pyridine, pyridinium chlorochromate (PCC),
pyridinium dichromate (PDC), oxidations involving dimethyl sulfoxide and an activating
agent such as oxalyl chloride or trifluoroacetic anhydride (Swern oxidation), DCC and
an acid catalyst (Moffat oxidation), acetic anhydride or pyridine-sulfur trioxide, Dess-
Martin Periodinane, Oxone, Oxammonium salts, metal derivatives such as aluminum
triisopropoxide, cyclopentadienyl zirconium reagent (Cp2ZrH2) , manganese dioxide,
silver carbonate, silver (I) oxide, silver (II) oxide, permanganate reagents such as
potassium permanganate, trimethylcetylammonium permanganate and n-butyl
permanganate, molybdenum reagents such as ammonium molybdate
[(4)6724.220], cerium (IV) reagents such as eerie ammonium sulfate and eerie
ammonium nitrate, peroxides such as hydrogen peroxide and t-butyl hydroperoxide
(TBHP), per acids such as peracetic acid, trifluroperacetic acid, perbenzoic acid and mchloroperbenzoic
acid, potassium persulfate, N-bromosuccinimide, osmium tetroxide,
ozone, sodium periodate, ruthinium tetroxide, lead tetraacetate, selenium dioxide, and
so on.
The term "suitable reducing agent" refers to a suitable agent that causes reduction to a
molecule. The term "reduction" in chemistry is generally defined as a decrease in
oxidation state and a gain of one or more electrons. Examples of reduction include
transformations such as conversion of: aldehydes or ketones or acids or esters or
epoxides to alcohols, amides or azides or imides or imines or nitriles or nitro groups or
oximes to amines, alkenes or alkynes to alkanes, sulfonate esters or halocarbons to
alkanes, cations to corresponding metal atoms, disulfide to sulfhydryl and sulfone or
sulfoxide to sulfide. Examples of "suitable reducing agents" include, but not limited to
lithium aluminum hydride, sodium borohydride, potassium borohydride, sodium hydride,
metal trialkoxyaluminum hydrides [LiAIH(OR)3] such as [LiAIH(OMe)3] , [LiAIH(OEt)3]
and [_()3] , Red-AI (sodium k/s(2-methoxyethoxy)aluminum hydride,
diisobutylaluminum hydride (Dibal or DIBAL-H)lithium triethylborohydride (superhydride
™), zinc borohydride, metal/ammonium acyloxyborohydrdes [M BH4_n(0 2R)n]
such as potassium triacetoxyborohydride, sodium triacetoxyborohydride,
tetramethylammonium triacetoxyborohydride, potassium tri-sec-butylborohydride (KSelectride
™), lithium tri-sec-butylborohydride (L-Selectride™), sodium
cyanoborohydride, boranes such diborane (B2H6) , borane complex of dimethylsulfide
(H3B.SMe2), bis(1 ,2-dimethylpropyl)borane (disiamylborane), 9-
borabicyclo[3.3.1]nonane (9-BBN), and catalytic reductions/hydrogenations using metal
catalysts such as platinum oxide, Pt/C. Pd oxide, Pd hydroxide/C, Ni-borides, NiC,
Raney Ni, copper chromite, platinum black, Pt/Rh oxide, Pd/BaC0 3, Pd/C, Rh/C, Ni-Cu,
Raney Ni W 1, Raney Ni W2, Raney Ni W3, Raney Ni W4, Raney Ni W5, Raney Ni W6,
Raney Ni W7, Raney Ni W8 and Raney cobalt, Li - Liq. NH3, Na - Liq. NH3, Zn dust,
ZnCI2, Zinc amalgam [Zn(Hg)], Tin compounds such as tributyltin hydride (Bu3SnH),
SnCI2, Aluminum isopropoxide [AI(0-'Pr) 3] , aluminum amalgam (Al/Hg), silanes such as
Et3SiH, PhMe2SiH, Ph2SiH2 and so on.
The term "pharmaceutically acceptable salts" refers to the salts of the compound of
formula (I) of the invention which are toxicologically acceptable and pharmaceutically
utilisable salts. The compound of formula (I), which contains a basic functionality, can
be used according to the invention in the form of their addition salts of organic or
inorganic acids. The pharmaceutically acceptable acid addition salts of the prodrugs i.e.
the compounds of formula (I) include salts which retain the biological effectiveness and
properties of the free bases and which are not biologically or otherwise undesirable.
Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, phosphoric acid, perchloric acid, boric acid, and other
inorganic acids known in the art. Examples of organic acids include: acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,
succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, sulfanilic acid, 2-acetoxy benzoic acid, toluenesulphonic acid, methane
sulphonic acid, ethane disulphonic acid, isethionic acid, ketoglutaric acid,
benzenesulphonic acid and other organic acids known in the art.
The compound of formula (I), which contains acidic group, can be used according to the
invention as base addition salts. Examples of pharmaceutically acceptable base
addition salts include those salts derived from inorganic bases such as alkali earth
metal salts like sodium, potassium, lithium, alkaline earth metal salts like calcium,
magnesium, aluminium salts or salts of organic bases such as lysine, arginine,
triethylamine, dibenzylamine, piperidine or as salts with ammonia. Particularly preferred
are the ammonium salts of the prodrugs of the present invention i.e. the compounds of
formula (I). The pharmaceutically acceptable salts of the present invention can be
synthesized from the subject compound which contains a basic or acidic moiety by
conventional chemical methods. Generally the salts are prepared by contacting the free
base or acid with stiochiometric amounts or with an excess of the desired salt-forming
inorganic or organic acid or base in a suitable solvent or dispersant or by anion
exchange or cation exchange with other salts. Suitable solvents are, for example, ethyl
acetate, ether, alcohols, acetone, tetrahydrofuran (THF), dioxane or mixtures of these
solvents.
In a first embodiment, the invention relates to compounds of the formula (I), which are
prodrugs of known drugs or therapeutic agents;
(I)
wherein
D is a drug containing one or more functional groups independently selected from a
carboxylic acid, an amino, a hydroxyl or a sulfhydryl group capable of forming a
covalent bio-cleavable linkage with a linker of formula IA (as described herein);
X1 is a bond, oxygen, sulphur, or NR3;
X2 is a bond, oxygen or NR3;
R3 is a bond or hydrogen;
=0 or a spacer group selected from:
where in the spacer groups of formulae (Ya) to (Y) :
R4 is a bond, hydrogen, alkyl or a metal ion;
R5 is hydrogen, C _6 alkyl or phenyl;
R6 is hydrogen or a side-chain group of naturally occurring amino acids selected
from:
-CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C0 2H, -CH2CH2C0 2H, -
CH2OH, -CH(CH3)OH, -CH2SH, -CH2CH2SCH3, -CH2CH2CH2CH2NH2, -C6H5, -
CH2C6H5, -CH2C6H4-p-OH, -CH2CH2CH2NHC(=NH)NH 2, -CH2C(=0)NH 2, -
CH2CH2C(=0)NH 2, -CH2-indol-3-yl or -CH2-imidazole;
X3 is oxygen, sulphur, SO, S0 2 or NR3;
R7 is hydrogen or an amino protecting group selected from: acetyl, benzoyl,
alkyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxy carbonyl or its
pharmaceutically acceptable ammonium salts;
R8 is hydrogen or C _6 alkyl;
c is an integer from 0 to 2;
d is an integer from 1 to 5;
e is an integer from 1 to 4;
Z1 is (CH2)a; where a is an integer from 0 to 3;
Z2 is (CH2)b; where b is an integer from 0 to 3;
A is selected from: a bond, S, SO, S0 2, S-S, CH=CH, D-isosorbide skeleton, 1,4-
anhydroerythritol skeleton, cycloalkylene , CR R10 , C6-C 0-arylene, a 5- or 6-membered
heteroaylene or a 5- or 6-membered heterocyclylene wherein said arylene,
heteroarylene and heterocyclylene may be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of C -6 alkyl, C -6 alkoxy,
hydroxy, trifluoromethyl, cyano, amino and halogen ;
R and R10 are independently selected from: hydrogen or C -6 alkyl; or R and R10 taken
together with the carbon atom to which they are attached form a cycloalkyi or a
heterocyclic ring;
R1 is hydrogen; and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen; and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0; and
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
It would be understood by a person having skill in the art to which this invention relates
that the functional groups namely the carboxylic acid, amino, hydroxyl and sulfhydryl
groups contained in the drug "D" in the compounds of formula (I) participate in the
formation of a linkage with the linker represented herein by the compound of formula IA
through the variable "X1" or Ύ ' which constitute part of the formula (I) represented
herein. In other words, the variable X1 and Y (in part) are derived from the carboxylic
acid or amino or hydroxyl or sulfhydryl functional groups of the drug "D" from which the
nitric oxide releasing prodrugs of the present invention i.e. the compounds of formula
(I), are derived. For instance, the variables X1 and Y in the compound of formula (I)
represents the chemical functionality on the drug "D" represented by carboxylic acid (X1
= bond and Y = C(O)), amino (X1 = NR3 and Y = C(O)), hydroxyl (X1 = oxygen ) and
sulfhydryl (X1 = sulphur) functional groups which are involved in the formation of
covalent linkage with the cleavable linker of formula (IA).
In a second embodiment, the invention encompasses a compound of formula (I),
wherein:
each of D , X1, Z1 and Z2 are as defined in the first embodiment herein above;
Y is C=0;
X2 is oxygen;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkyl or CR R10 ;
where R and R10 are independently selected from hydrogen or C -6 alkyl; or R and
R10 taken together with the carbon atom to which they are attached constitute a
cycloalkyl group or a 5- or 6- membered heterocyclic ring containing one to two hetero
atoms selected from oxygen, sulfur or nitrogen;
R1 is hydrogen and R2 is alkyl, cycloalkyl, aryl or aralkyl; or R2 is hydrogen and R1 is
alkyl, cycloalkyl, aryl or aralkyl;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a third embodiment, the invention encompasses a compound of formula (I), wherein:
each of D, X1, Z1 and Z is as defined in the first embodiment herein above;
each of Y and X2 is as defined in the second embodiment herein above;
A is selected from a bond, CH=CH or CR R10 ; where R and R10 are independently
selected from: hydrogen or C -6 alkyl; or R and R10 taken together with the carbon
atom to which they are attached form a cycloalkyi or a 5- or 6- membered heterocyclic
ring;
R1 and R are as defined in the second embodiment hereinabove;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a fourth embodiment, the invention encompasses a compound of formula (I),
wherein:
each of D, X1, Z1 and Z2 is as defined in the first embodiment herein above;
each of Y and X2 is as defined in the second embodiment herein above;
A is selected from S, SO, S0 2 or S-S; provided that when A is S, then a and b is 3;
R1 and R are as defined in the second embodiment hereinabove;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a fifth embodiment, the invention encompasses a compound of formula (I), wherein:
each of D, X1, Z1 and Z is as defined in the first embodiment herein above;
each of Y and X2 is as defined in the second embodiment herein above;
A is selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine, 3,4-
pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, D-isosorbide skeleton, 1,4-
anhydroerythritol skeleton or cycloalkyi; provided that when A is D-isosorbide skeleton
or 1,4-anhydroerythritol skeleton, then a and b is 0;
R1 and R are as defined in the second embodiment hereinabove;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a sixth embodiment, the invention encompasses a compound of formula (I), wherein:
each of D, X1, Z1 and Z2 is as defined in the first embodiment hereinabove;
each of X2 and Y is as defined in the second embodiment hereinabove;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH or
CR R10 ; where R9 and R10 are independently selected from hydrogen or C -6 alkyl;
provided that when A is S, then a and b is 3;
R1 is hydrogen and R2 is alkyl; or R2 is hydrogen and R1 is alkyl;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a seventh embodiment, the invention encompasses a compound of formula (I),
wherein:
D is a drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker of formula (IA) (as described herein);
X1 is a bond;
X2, Y, Z1, Z2, A, R1 and R2 are as defined in the first embodiment hereinabove;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In an eighth embodiment, the invention encompasses a compound of formula (I),
wherein:
each of D and X1 is as defined in the seventh embodiment hereinabove;
each of X2, Y, Z1, Z2, A, R1 and R2 is as defined in the second embodiment
hereinabove;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a ninth embodiment, the invention encompasses a compound of formula (I), wherein:
D, the drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker, referred to in the first, second, third, fourth, fifth, sixth,
seventh and eighth embodiments, is selected from an anti-inflammatory and analgesic
agent, a cardiovascular agent, an antiallergic agent, an anticancer agent, an
antidepressant, an anticonvulsant agent, an antibacterial agent, an antifungal agent, an
antiviral agent, an antimalarial agent, an antidiabetic agent, an antiulcer agent, a
vitamin or an antioxidant.
In this embodiment, other variables X1, X2, Y, Z1, Z2; A, R1 and R2 in the compounds of
formula (I) are as defined hereinabove; provided that
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a tenth embodiment, the invention encompasses a compound of formula (I), wherein:
D, the drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker, is selected from an anti-inflammatory and analgesic
agent, a cardiovascular agent, an antiallergic agent, an anticancer agent, an
antidepressant, an anticonvulsant agent, an antibacterial agent, an antifungal agent, an
antiviral agent, an antimalarial agent, an antidiabetic agent, an antiulcer agent, a
vitamin or an antioxidant;
X1 is a bond;
Y is C=0;
X2 is O;
Z1 and Z2 are as defined in the first embodiment hereinabove;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkyl or CR R10 ;
where R and R10 are independently selected from hydrogen or C -6 alkyl; or R and
R10 taken together with the carbon atom to which they are attached constitute a
cycloalkyl group or a 5- or 6- membered heterocyclic ring containing one to two hetero
atoms selected from oxygen, sulfur or nitrogen;
R1 is hydrogen and R2 is alkyl, cycloalkyl, aryl or aralkyl; or R2 is hydrogen; and R1 is
alkyl, cycloalkyl, aryl or aralkyl;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In an eleventh embodiment, the invention encompasses a compound of formula (I),
wherein: D, the drug containing a carboxylic acid group capable of forming a covalent
bio-cleavable linkage with a linker, is selected from an anti-inflammatory and analgesic
agent, a cardiovascular agent, an antiallergic agent, an anticancer agent, an
antidepressant, an anticonvulsant agent, an antibacterial agent, an antifungal agent, an
antiviral agent, an antimalarial agent, an antidiabetic agent, an antiulcer agent, a
vitamin or an antioxidant;
each of X1 , Y , X2 , Z1 , Z2 , R1 and R2 are as defined in the tenth embodiment
hereinabove;
A is selected from a bond, CH=CH or CR R10 ;
wherein, R and R10 are independently selected from hydrogen or C -6 alkyl; or R and
R10 taken together with the carbon atom to which they are attached constitute a
cycloalkyl group;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twelfth embodiment, the invention encompasses a compound of formula (I),
wherein:
D, the drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker, is selected from an anti-inflammatory and analgesic
agent, a cardiovascular agent, an antiallergic agent, an anticancer agent, an
antidepressant, an anticonvulsant agent, an antibacterial agent, an antifungal agent, an
antiviral agent, an antimalarial agent, an antidiabetic agent, an antiulcer agent, a
vitamin or an antioxidant;
each of X1, Y, X2, Z1 , Z2 , R1 and R2 is as defined in the tenth embodiment
hereinabove;
A is selected from S, SO, S0 2 or S-S; provided that when A is S, then a and b is 3;
and in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirteenth embodiment, the invention encompasses a compound of formula (I),
wherein:
D. the drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker, is selected from an anti-inflammatory and analgesic
agent, a cardiovascular agent, an antiallergic agent, an anticancer agent, an
antidepressant, an anticonvulsant agent, an antibacterial agent, an antifungal agent, an
antiviral agent, an antimalarial agent, an antidiabetic agent, an antiulcer agent, a
vitamin or an antioxidant;
each of X1, Y, X2, Z1 , Z2 , R1 and R2 is as defined in the tenth embodiment
hereinabove;
A is selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine, 3,4-
pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, D-isosorbide skeleton, 1,4-
anhydroerythritol skeleton or cycloalkyi; provided that when A is D-isosorbide skeleton
or 1,4-anhydroerythritol skeleton, then a and b is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a fourteenth embodiment, the invention encompasses a compound of formula (I),
wherein:
D, the drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker, is selected from an anti-inflammatory and analgesic
agent, a cardiovascular agent, an antiallergic agent, an anticancer agent, an
antidepressant, an anticonvulsant agent, an antibacterial agent, an antifungal agent, an
antiviral agent, an antimalarial agent, an antidiabetic agent, an antiulcer agent, a
vitamin or an antioxidant;
X1 is a bond;
Y is a spacer group as defined in the first embodiment hereinabove;
X2 is O;
Z1 and Z2 are as defined in the first embodiment hereinabove;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkyi or CR R10 ; where R and
R10 are independently selected from hydrogen or C -6 alkyl; or R and R10 taken
together with the carbon atom to which they are attached constitute a cycloalkyi group
or a 5- or 6- membered heterocyclic ring containing one to two hetero atoms selected
from oxygen, sulfur or nitrogen;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyl; or R2 is hydrogen; and R1 is
alkyl, cycloalkyi, aryl or aralkyl;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a fifteenth embodiment, in the compound of formula (I) the anti-inflammatory and
analgesic agent referred to in the ninth, tenth, eleventh, twelfth, thirteenth and
fourteenth embodiments hereinabove is generically selected from an opioid, steroids
(glucocorticoids) or a non-steroidal anti-inflammatory drug (NSAID(s)) and is specifically
selected from aceclofenac, acemetacin, acetamidocaproic acid, acetylsalicylsalicylic
acid, actarit, alclofenac, 3-alminoprofen, amfenac, 3-amino-4-hydroxybutyric acid,
aspirin (acetylsalycilic acid), balsalazide, bendazac, benoxaprofen, bromprofen,
bromfenac, 5-bromosalicylic acid acetate, bucloxic acid, bumadizone, butibufen,
carprofen, cinchophen, cinmetacin, clidanac, clometacin, clonixin, clopirac, diacerein,
diclofenac, diflunisal, dipyrocetyl, enfenamic acid, enoxolone, etodolac, felbinac,
fenbufen, fenclozic acid, fendosal, fenoprofen, fentiazac, flufenamic acid,
flunoxaprofen, fluocortolone-21-acid, flurbiprofen, fosfosal, gentisic acid, ibufenac,
ibuprofen, indomethacin, indoprofen, isofezolac, isoxepac, ketoprofen, ketorolac,
lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, mesalamine, metiazinic
acid, mofezolac, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, pirazolac,
pirprofen, pranoprofen, protizinic acid, salicysulfuric acid, salicylamide o-acetic acid,
salsalate, sulfasalazine, sulindac, suprofen, suxibuzone, tiaprofenic acid, tolfenamic
acid, tolmetin, tropesin, ximoprofen, zaltoprofen or zomepirac.
The representative example of an anti-inflammatory and analgesic agent is a NSAID
that is selected from aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, sulindac or tolmetin.
Further in the fifteenth embodiment, the invention encompasses a compound of formula
(I); wherein the cardiovascular agent referred to in the ninth, tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments hereinabove is generically selected from an
antihypertensive agent such as an angiotensin converting enzyme (ACE) inhibitor, a
beta-blocker, sartan (angiotensin I I blockers), an antithrombotic and vasoactive agent,
an anti-hyperlipidemic drug (including HMG-CoA-reductase inhibitor (statins), fibrate, an
antianginal agent, an antiarrhythmic agent, an antihypotensive agent, a diuretic, a
vasodilator or vasoprotectant and is specifically selected from acifran, acipimox,
acetylsalicylic acid, alacepril, gama-aminobutyric acid, angiotensin, argatroban,
atorvastatin, benazepril, benfurodil hemisuccinate, beraprost, bezafibrate, bumetanide,
candesartan, capobenic acid, captopril, carmoxirole, caronapril, chromocarb, cilazapril,
ciprofibrate, clinofibrate, clofibric acid, dalteparin, daltroban, delapril, dextrothyroxine,
eicosapentaenoic acid, eledoisin, enalapril, enalaprilat, enoxaparin, eprosartan,
ethacrynic acid, fluvastatin, fosinopril, furosemide, gemfibrozil, iloprost, imidapril,
indobufen, isbogrel, heparin, lamifiban, limaprost, lisinopril, lotrafiban, meglutol,
melagatran, mercamphamide, mercaptomerin sodium, mercumallylic acid, mersalyl,
methyldopa, moexipril, moveltipril, nadroparin, omapatrilat, ozagrel, oxiniacic acid,
perindopril, piretanide, privastatin sodium, prostaglandin E-| quinapril, ramipril,
reviparin sodium salt, ridogrel, sampatrilat, saralasin, satigrel, spirapril, taprostene,
telmisartan, temocapril, thyropropic acid, ticrynafen, tinzaparin, tirofiban, trandolapril,
triflusal, valsartan, xanthinol niacinate or xenbucin.
A representative example of the cardiovascular agent is an ACE-inhibitor that is
selected from benazepril, enalapril, enalaprilat, lisinopril, perindopril, quinapril, ramipril,
ramiprilate, trandolapril, alacepril, captopril, ceronapril, cilazapril, delapril, fosinopril,
imidapril, moexipril, moveltipril, omapatrilat, sampatrilat, spirapril or temocapril.
Another representative example of the cardiovascular agent is a sartan that is selected
from candesartan, olmesartan, telmisartan or valsartan.
Yet another representative example of the cardiovascular agent is an antithrombotic
and vasoactive agent that is selected from acetyl salicylic acid, argatroban, beraprost,
dalteparin, daltroban, enoxaparin, iloprost, indobufen, isbogrel, heparin, lamifiban,
lotrafiban, melagatran, nadroparin, ozagrel, reviparin sodium salt, ridogrel, satigrel,
taprostene, tinzaparin, tirofiban or triflusal.
Yet another representative example of the cardiovascular agent is an antihyperlipidemic
agent (statin and fibrate) that is selected from atorvastatin, bezafibrate,
cerivastatin, ciprofibrate, clinofibrate, clofibric acid, fluvastatin, gemfibrozil, pitavastatin,
or pravastatin.
Yet another representative example of the cardiovascular agent is an antianginal agent
such as limaprost.
Yet another representative example of the cardiovascular agent is an antiarrhythmic
agent such as capobenic acid.
Yet another representative example of the cardiovascular agent is an antihypotensive
agent such as angiotensin.
Yet another representative example of the cardiovascular agent is a diuretic that is
selected from bumetanide, ethacrynic acid, furosemide, mercamphamide,
mercaptomerin sodium, mercumallylic acid, mersalyl, piretanide or ticrynafen.
Yet another representative example of the cardiovascular agent is a vasodilator that is
selected from benfurodil hemisuccinate, beraprost, eledoisin, iloprost, prostaglandin E
or xanthinol niacinate.
Yet another representative example of the cardiovascular agent is a vasoprotectant
such as chromocarb.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antiallergic agent referred to in the ninth, tenth, eleventh,
twelfth, thirteenth and fourteenth embodiments hereinabove is generically selected from
a steroidal bronchodilator, a mast cell stabilizer or an antihistamine and is specifically
selected from acrivastine, amlexanox, bepotastine, cetirizine, fexofenadine,
levocetirizine, lodoxamide, montelukast sodium, nedocromil, olopatadine, pentigetide or
tranilast.
A representative example of the antiallergic agent is an antihistamine that is selected
from acrivastine, bepotastine, cetirizine, fexofenadine, levocabastine, levocetirizine or
montelukast sodium.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the anticancer agent referred to in the ninth, tenth, eleventh,
twelfth, thirteenth and fourteenth embodiments hereinabove is selected from acitretin
(etretin), aminolevulinic acid, amsilarotene, butyric acid, eflornithine hydrochloride,
melphalan, methotrexate, minodronate (minodronic acid), retinoic acids (including 13-
cis retinoic and all trans-retinoic acids), sulindac, tamibarotene or valproic acid.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antidepressant (including antimaniacs and antipsychotics)
referred to in the ninth, tenth, eleventh, twelfth, thirteenth and fourteenth embodiments
hereinabove is generically selected from an antimaniac or an antipsychotic agent and
is specifically selected from amineptine, gabapentin, 5-hydroxytryptophan (oxitriptan),
pregabalin, tianeptine, valproic acid or vigabatrin.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the anticonvulsant referred to in the ninth, tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments hereinabove is selected from gabapentin,
pregabalin, tiagabine, valproic acid or vigabatrin.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antibacterial referred to in the ninth, tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments hereinabove is selected from acediasulfone
amdinocillin, p-aminosalicylic acid, amoxicillin, amphomycin, ampicillin, apalcillin
apicycline, aspoxicillin, azidocillin, azlocillin, aztreonam, bacitracin, balofloxacin
benzoylpas, benzylpenicillin, betamipron, biapenem, carbenicillin, carindacillin
carumonam, cefaclor, cefadroxil, cefalexin, cefamandole, cefatiam, cefatrizine
cefazedone, cefazolin, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime
cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid
cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, cefoxitin
cefozopran, cefpimizole, cefpiramide, cefpirome, cefroxadine, cefsulodin, ceftazidime
cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefprozil, cefuroxime
cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine
cephalosporin C, cephalothin, cephapirin sodium, cephradine, cilastatin, cinoxacin
ciproflaxacin, clavulinic acid, clavulanate, clinafloxacin, clometocillin, cyclacillin
dicloxacillin, difloxacin, enoxacin, epicillin, ertapenem, fenbenicillin, fleroxacin, flomoxef
floxacillin, flumequine, fosfomycin, fropenem, fusidic acid, garenoxacin, gatifloxacin
gemifloxacin, grepafloxacin, hetacillin, hydnocarpic acid, imipenem, lomefloxacin
loracarbef, lymecycline, merbromin, meropenem, metampicillin, methicillin, mezlocillin
miloxacin, moxalactam, moxifloxacin, nadifloxacin, nafcillin, nalidixic acid, negamycin
noprysulfamide, norfloxacin, ofloxacin, opiniazide, oxacillin, oxolinic acid, panipenem
pazufloxacin, pefloxacin, penicillin(s), penimepicycline, phenethicillin
phthalylsulfacetamide, phthalylsulfathiazole, pipemidic acid, piperacillin, piromidic acid
propicillin, prulifloxacin, quinacillin, ritipenem, rosoxacin, rufloxacin
salazosulfadimidine, salbactam, sitafloxacin, sparfloxacin, succinylsulfathiazole
succisulfone, sulbenicillin, sulfachrysoidine, sulfaloxic acid, 4-sulfanilamidosalicylic acid
sulfanilic acid, tazobactam, teicoplanin, temocillin, ticarcillin, tigemonam, tosufloxacin
trovafloxacin, tyrocidine or vancomycin.
A representative example of the antibacterial agent is selected from amoxicillin
ampicillin, cefadroxil, cefalexin, cefixime, cefotaxime, cefuroxime, cephalexin
ciproflaxacin, gatifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxacillin
panipenem, salbactam or vancomycin.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antifungal agent referred to in the ninth, tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments hereinabove is selected from amphotericin B,
azaserine, benzoic acid, candicidin, lucensomycin, natamycin, nystatin, propionic acid,
salicylic acid or undecylenic acid (10-undecenoic acid).
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antiviral agent referred to in the ninth, tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments hereinabove is selected from foscarnet sodium
or zanamivir.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antimalarial agent referred to in the ninth, tenth, eleventh,
twelfth, thirteenth and fourteenth embodiments hereinabove is artesumate.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antidiabetic agent referred to in the ninth, tenth, eleventh,
twelfth, thirteenth and fourteenth embodiments hereinabove is selected from mitiglinide,
nateglinide or repaglinide.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antiulcer agent (including proton pump inhibitor) referred to in
the ninth, tenth, eleventh, twelfth, thirteenth and fourteenth embodiments hereinabove
is selected from acetoxolone, arbaprostil, carbenoxolone, cetraxate, ecabet, Smethylmethionine,
proglumide, rebamipide, rosaprostol, rotraxate, sofalcone or
trimoprostil.
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the vitamin referred to in the ninth, tenth, eleventh, twelfth,
thirteenth and fourteenth embodiments hereinabove is selected from biotin (vitamin H
or coenzyme R), folic acid (vitamin M), menadoxime, nicotinic acid (niacin), pantothenic
acid or vitamin B5 (a member of the B complex vitamins).
Still further, in the fifteenth embodiment, the invention encompasses a compound of
formula (I); wherein the antioxidant (including free radical scavengers) referred to in
ninth, tenth, eleventh, twelfth, thirteenth and fourteenth embodiments hereinabove is
selected from o -lipoic acid, L-Carnitine, N-acetyl L-cysteine, N-acetyl carnosine,
raxofelast, tetomilast or SCMC-Lys (S-carboxymethyl-L-cysteine Lysine salt. H20).
For the purpose of this invention, the fifteenth embodiment also encompasses a
compound of formula (I); wherein the drug containing carboxylic acid group is
generically selected from the drugs that fall under several other therapeutic areas
(including those drugs that are classified on the basis of their mechanism of action) and
is specifically selected from an abortifacient/interceptive such as prostaglandin E2; an
anesthetic selected from ecgonidine, ecgonine, hydroxydione sodium or gamahydroxybutyrate
(gama-hydroxybutyric acid); an anthelmintic selected from antimony
sodium thioglycollate, kainic acid or stibocaptate; an antiacne agent selected from
adapalene, isotretinoin or all-frans retinoic acid, an antiamebic agent selected from
thiocarbamizine or thiocarbarsone; an antiarthritic or antirheumatic agent selected from
actarit, bucillamine, diacerein, gold sodium thiomalate, lobenzarit, allocupreide sodium,
clobuzarit or penicillamine; an antiasthmatic agent selected from amiexanox, cilomilast
(ariflo), cromolyn, domitroban, montelukast, nedocromil, ramatroban or seratrodast; an
antigout/ucosuric agent selected from carprofen, probenecid, orotic acid,
oxycinchophen or ticrynafen; an antidiuretic agent such as oxycinchophen; an
antiglaucoma agent such as unoprostone; an antihypothyroid agent selected from
tiratricol or thyroxine; an antiprostatic hypertrophy agent such as epristeride; an
antiprotozoal agent selected from eflornithine or fumagillin; an antipsoriatic agent such
acitretin; an antiseptic agent such as mandelic acid; an anxiolytic agent selected from
calcium n-carbamoylaspartate or clorazepic acid; an astringent such as bismuth
subgallate; a cathartic/laxative such as sennosides; choleretic agents selected from
cholic acid, cicrotoic acid, clanobutin, cyclobutyrol, cynarin(e), dehydrocholic acid,
deoxycholic acid, dimecrotic acid, exiproben, fencibutirol, florantyrone, menbutone, 3-
(o-methoxyphenyl)-2-phenylacrylic acid, sincalide, tocamphyl or trepibutone; an
enzyme cofactor such as pantothenic acid; an estrogen such as methallenestril; a
gastroprokinetic agent selected from alvimopan or loxiglumide; a hemostatic agent
selected from -aminocaproic acid or tranexamic acid; a hepatoprotectant selected from
S-adenosylmethionine, betaine, orazamide, timonacic (thioproline), methionine,
protoporphyrin IX, thioctic acid or tiopronin; an immunomodulator selected from
bucillamine, ubenimex, pidotimod, procodazole, romurtide or thymopentin;
immunosuppressant selected from brequinar or mycophenolic acid; a mucolytic
selected from acetylcysteine, carbocysteine, erdosteine, letosteine or stepronin; a
muscle relaxant selected from baclofen or carisoprodol; a nootropics/Cognitive
enhancer selected from cetylcarnitine, hexacyclonate sodium or leteprinim; a
prostaglandin analog selected from beraprost, carboprost, limaprost, prostacyclin,
prostaglandin E-| , prostaglandin E2, prostaglandin F rosaprostol, sulprostone,
trimoprostil or unoprostone; a sedative/hypnotic chloral selected from betainem or
calcium 2-ethylbutanoate; a dopamine receptor agonist such as carmoxirole; a 5a-
Reductase inhibitor such as epristeride; a reverse transcriptase inhibitor such as
foscarnet sodium.; thromboxane A2-receptor antagonist selected from altroban,
domitroban, ramatroban, ridogrel or seratrodast and a thromboxane A2-synthase
inhibitor selected from isbogrel, ozagrel or ridogrel.
In a sixteenth embodiment, the invention encompasses a compound of formula (I),
wherein D, the drug containing a carboxylic acid group capable of forming a covalent
bio-cleavable linkage with a linker, is a non-steroidal anti-inflammatory drug (NSAID);
X1 is a bond;
Y is C=0 or a spacer group as defined in the first embodiment hereinabove;
X2 is oxygen;
each of Z1, Z2, A , R1 and R2 is as defined in the second embodiment hereinabove; and
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a seventeenth embodiment, the invention encompasses a compound of formula (I),
wherein D, the drug or a therapeutic agent containing a carboxylic acid group capable
of forming a covalent bio-cleavable linkage with a linker, is a non-steroidal ant i
inflammatory drug (NSAID);
X1 is a bond;
Y is C=0;
X2 is oxygen;
each of Z1, Z , R1 and R2 is as defined in the first embodiment hereinabove; and
A is selected from a bond, CH=CH or CR R10 ; where R and R10 are independently
selected from hydrogen or C -6 alkyl; or R and R10 taken together with the carbon atom
to which they are attached constitute a cycloalkyl group;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In an eighteenth embodiment, the invention encompasses a compound of formula (I),
wherein:
wherein D, the drug containing a carboxylic acid group capable of forming a covalent
bio-cleavable linkage with a linker, is a non-steroidal anti-inflammatory drug (NSAID);
each of X1, Y, X2, Z1, Z2, R1 and R2 is as defined in the seventeenth embodiment
hereinabove;
A is selected from S, SO, S0 2 or S-S; provided that when A is S, then a and b is 3;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a nineteenth embodiment, the invention encompasses a compound of formula (I),
wherein:
D, the drug containing a carboxylic acid group capable of forming a covalent biocleavable
linkage with a linker, is a non-steroidal anti-inflammatory drug (NSAID);
each of X1, Y, X2, Z1, Z2, R1 and R2 is as defined in the seventeenth embodiment
hereinabove;
A is selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine, 3,4-
pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, D-isosorbide skeleton, 1,4-
anhydroerythritol skeleton or cycloalkyi; provided that when A is D-isosorbide skeleton
or 1,4-anhydroerythritol skeleton, then a and b is 0; and
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In twentieth embodiment, the invention encompasses a compound of formula (I),
wherein the non-steroidal anti-inflammatory drug (NSAID) referred to in the sixteenth,
seventeenth, eighteenth and nineteenth embodiments is as defined in the fifteenth
embodiment hereinabove. A representative example of the non-steroidal ant i
inflammatory drug (NSAID) is selected from aspirin, diclofenac, naproxen,
indomethacin, sulindac, flurbiprofen, ketoprofen, ibuprofen or mesalamine.
In a twenty-first embodiment, the invention encompasses a compound of formula (I),
wherein: D is a drug containing an amino group capable of forming a covalent biocleavable
linkage with a linker;
X1 is NR3; wherein R3 is a bond or hydrogen;
Y is C=0;
X2; Y, Z1; Z2; A, R1 and R2 are as defined in the second embodiment hereinabove; and
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twenty-second embodiment, the invention encompasses a compound of formula
(I), wherein: each of D and X1 is as defined in the twenty-first embodiment hereinabove;
each of X2, Y, Z1and Z2 is as defined in the second embodiment hereinabove;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH or
CR R10 ; where R and R10 are independently selected from hydrogen, C -6 alkyl;
provided that when A is S, then a and b is 3;
R1 is hydrogen and R is alkyl; or R2 is hydrogen and R1 is alkyl;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twenty-third embodiment, the invention encompasses a compound of formula (I),
wherein: each of D, X1,X2, Y, Z1 and Z2 is as defined in the twenty- second embodiment
hereinabove,
A is selected from a bond, CH=CH or CR R10 ; where R9 and R10 are independently
selected from hydrogen or C -6 alkyl;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twenty-fourth embodiment, the invention encompasses a compound of formula (I),
wherein: each of D, X1,X2, Y, Z1 and Z2 is as defined in the twenty- second embodiment
hereinabove,
A is selected from S, SO, S0 2 or S-S; provided that when A is S, then a and b is 3;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twenty-fifth embodiment, the invention encompasses a compound of formula (I),
wherein: D, the drug containing an amino group capable of forming a covalent biocleavable
linkage with a linker, referred to in the first, second, third, fourth, fifth, sixth,
twenty-first, twenty-second, twenty-third, and twenty-fourth embodiments herein above,
is selected from an antiinflammatory and analgesic drug, a cardiovascular drug, an
antiallergic agent, an anticancer agent, an antidepressant, an anticonvulsant agent, an
antibacterial agent, an antiviral agent, an antifungal agent, an antimalarial agent, an
antidiabetic agent an antiulcer agent, an antioxidant or a vitamin. The twenty-fifth
embodiment also encompasses within its scope a drug containing an amino group
wherein the drug is selected from several other therapeutic areas (including those
drugs that are classified on the basis of their mechanism of action).
In this embodiment, other variables X1; X2, Y, Z1, Z2; A, R1 and R2 in the compounds of
formula (I) are as defined above; provided that
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In twenty-sixth embodiment, the invention encompasses a compound of formula (I),
wherein: the antiinflammatory and analgesic drug referred to in the twenty-fifth
embodiment hereinabove is generically selected from an opioid, a steroid
(glucocorticoid) or a non-steroidal anti-inflammatory drug (NSAID(s)) and is specifically
selected from aceclofenac, acetaminophen, acetaminosalol, actarit, alminoprofen,
amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, ampiroxicam,
aminopropylon, anileridine, antrafenine, benorylate, benzpiperylon, p-bromoacetanilide,
bromfenac, bucetin, bucolome, bufexamac, bumadizone, butacetin, capsaicine,
carprofen, carsalam, celecoxib, clonixin, dezocine, diclofenac, difenamizole,
difenpiramide, enfenamic acid, etersalate, ethenzamide, ethoxazene, etodolac,
etofenamate, fepradinol, flipirtine, floctafenine, flufenamic acid, glafenine, ibuproxam,
isoladol, isonixin, isoxicam, p-lactophenetide, lornoxicam, meclofenamic acid,
mefenamic acid, meloxicam, mesalamine, mofebutazone, nifenazone, niflumic acid,
nimesulide, norlevorphanol, normorphine, oxametacine, paranyline, parecoxib,
parsalmide, phenacetin, phenazopyridine, phenocoll, phenopyrazone, phenylramidol,
piketoprofen, piminodine, piperylone, piroxicam, piritramide, propacetamol,
ramifenazone, salverine, salacetamide, salicylamide, salicylamide o-acetic acid,
sulfasalazine, talniflumate, tenidap, terofenamate, tinoridine, tenoxicam, tolfenamic acid
and valdecoxib. Preferred examples of antiinflammatory drugs include acetaminophen,
bromfenac, celecoxib, diclofenac, etodolac, meloxicam, mesalamine, nimesulide,
paracoxib, phenacetin or valdecoxib.
A representative example of the antiinflammatory and analgesic drug is selected from
acetaminophen, bromfenac, celecoxib, diclofenac, etodolac, meloxicam, mesalamine,
nimesulide, paracoxib, phenacetin or valdecoxib.
Further in the twenty-sixth embodiment, the cardiovascular agent referred to in the
twenty-fifth embodiment hereinabove is generically selected from an antihypertensive
agent such as an angiotensin converting enzyme (ACE) inhibitor, a beta-blocker, a
sartan (angiotensin I I blockers), an antithrombotic and vasoactive agent, an antihyperlipidemic
drug (including HMG-CoA-reductase inhibitor (statins), fibrate, an
antianginal agent, an antiarrhythmic agent, an antihypotensive agent, a calcium
channel blocker, a cardiotonic agent, a cardioprotective agent, a diuretic or a
vasodilator and is specifically selected from acadesine, acebutolol, acecainide,
adenosine, alacepril, alfuzosin, alprenolol, althiazide, amanozine, ambuside, amezinium
methyl sulfate, amiloride, gama-aminobutyric acid, aminometradine, 2-amino-4-picoline,
amisometradine, amlodipine, amosulalol, amrinone, angiotensin, aranidipine,
argatroban, arotinolol, atenolol, azosemide, bamethan, barnidipine, benazepril,
bendazol, bendroflumethiazide, benfluorex, benidipine, benzalbutyramide,
benzylhydrochlorothiazide, benzthiazide, betahistine, bethanidine, betaxolol, bevantolol,
bidisomide, bisoprolol, bopindolol, bosentan, bradykinin, bucindolol, bucladesine,
bucumolol, budralazine, bufeniode, bufetolol, bufuralol, bumetanide, bunazosin,
bunitrolol, bupranolol, butalamine, butazolamide, buthiazide, butidrine, butofilolol,
cadralazine, candesartan, capobenic acid, carazolol, cariporide, carmoxirole,
caronapril, carteolol, carvedilol, celiprolol, cetamolol, chloraminophenamide,
chlorazanil, chlormerodrin, chlorothiazide, chlorthalidone, ciclosidomine, cifenline,
cilazapril, cilnidipine, cilostazol, clofenamide, clonidine, clopamide, cloranolol,
clorexolone, cyclopenthiazide, cyclothiazide, debrisoquin, delapril, denopamine,
diazoxide, dihydralazine, dilevalol, dimetofrine, disopyramide, disulfamide, dobutamine,
docarpamine, dofetilide, dopamine, dopexamine, doxazosin, droprenilamine,
edeserpidine, efonidipine, eledoisin, elgodipine, enalapril, enalaprilat, encainide,
endralazine, enoxaparin, enoximone, epanolol, erythrophleine, esmolol, ethiazide,
ethoxzolamide, etifelmin, etilefrin, etiroxate, fasudil, felodipine, fendiline, fenoldopam,
fenquizone, flecainide, furosemide, gepefrine, guanabenz, guanacline, guanazodine,
guanethidine, guanochlor, guanadrel, guanfacine, guanoxabenz, guanoxan,
heptaminol, hydracarbazine, hydralazine, hydrochlorothiazide, hydroflumethiazide,
ibopamine, imidapril, imolamine, indapamide, indecainide, indenolol, indoramin,
irbesartan, isoxsuprine, isradipine, itramin tosylate, kallidin, ketanserin, labetalol,
lacidipine, lamifiban, landiolol, lercanidipine, levosimendan, lidoflazine, lisinopril,
lofexidine, loprinone, losartan, lotrafiban, manidipine, mebutamate, mecamylamine,
mefruside, melagatran, meobentine, mephentermine, mepindolol, metaraminol,
methazolamide, methoxamine, methyclothiazide, methyldopa, methyl 4-pridyl ketone
thiosemicarbazone, meticrane, metipranolol, metolazone, metoprolol, mexiletine,
mibefradil, midodrine, milrinone, minoxidil, moexipril, molsidomine, monatepil, moprolol,
moricizine, moveltipril, moxonidine, muzolimine, nadolol, nadoxolol, nebivolol,
nicardipine, nicorandil, nifedipine, nifenalol, nilvadipine, nimodipine, nipradilol,
nisoldipine, nitrendipine, norepinephrine, nylidrin, olmesartan, oxprenolol, oxyfedrine,
pamabrom, paraflutizide, penbutolol, pentisomide, perhexiline, perindopril,
pheniprazine, phentolamine, pholedrine, picotamide, pildralazine, pilsicainide,
pimefylline, pimobendan, pinacidil, pindolol, piretanide, plafibride, polythiazide,
practolol, prazosin, prenalterol, prenylamine, procainamide, pronethalol, propafenone,
propranolol, quinapril, quinethazone, ramipril, ranolazine, raubasine, rescimetol,
rescinnamine, reserpiline, reserpine, rilmenidine, roxifiban, sampatrilat, saralasin,
sematilide, sotalol, spirapril, sulfinalol, sulmazole, suloctidil, synephrine, syrosingopine,
talinolol, tasosartan, teclothiazide, temocapril, terazosin, terodiline, tertatolol,
theobromine, tiamenidine, tilisolol, timolol, tinofedrine, tirofiban, tocainide, todralazine,
tolazoline,toliprolol, tolonidine, torsemide, trandolapril, triamterene, trichlormethiazide,
trimazosin, trimetazidine, tripamide, urapidil, valsartan, vesnarinone, viquidil, xamoterol,
xemilofiban, xibenolol, ximelagatran or xipamide.
A representative example of the cardiovascular agent is an ACE inhibitor that is
selected from alacepril, benazepril, ceronapril, cilazapril, delapril, enalapril, enalaprilat,
imidapril, lisinopril, moexipril, moveltipril, omapatrilat, perindopril, quinapril, ramipril,
spirapril, temocapril or trandolapril.
Another representative example of the cardiovascular agent is a beta - blocker that is
selected from atenolol, bupranolol, carvedilol, labetalol, metipranolol, metoprolol,
nadolol, pindolol, propranolol or timolol.
Another representative example of the cardiovascular agent is a sartan (angiotensin I I
blocker) that is selected from Irbesartan, losartan, olmesartan or valsartan;
Yet another representative example of the cardiovascular agent is an antithrombotic
and vasoactive agent that is selected from argatroban, cilostazol, droprenilamine,
enoxaparin, lamifiban, lotrafiban, melagatran, perhexiline, picotamide, plafibride,
roxifiban, suloctidil, tirofiban, xemilofiban or ximelagatran.
Yet another representative example of the cardiovascular agent is an antianginal agent
that is selected from amlodipine, bevantolol, bucumolol, bufuralol, elgodipine,
imolamine, molsidomine, nicardipine, nicorandil, nifedipine, nifenalol, nipradilol,
oxyfedrine, pronethalol, ranolazine, sotalol, terodiline, toliprolol or trimetazidine.
Yet another representative example of the cardiovascular agent is an antiarrhythmic
agent that is selected from acecainide, adenosine, bidisomide, bufetolol, butidrine,
capobenic acid, cifenline, cloranolol, disopyramide, dofetilide, encainide, esmolol,
flecainide, indecainide, landiolol, meobentine, mexiletine, moricizine, nadoxolol,
pentisomide, pilsicainide, practolol, procainamide, propafenone, sematilide, tocainide,
tilisolol or xibenolol.
Yet another representative example of the cardiovascular agent is an antihypotensive
agent that is selected from amezinium methyl sulfate, angiotensin, dimetofrine,
dopamine, etifelmin, etilefrin, gepefrine, heptaminol, mephentermine, metaraminol,
methoxamine, midodrine, norepinephrine, pholedrine or synephrine.
Yet another representative example of the cardiovascular agent is a calcium channel
blocker that is selected from amlodipine, aranidipine, barnidipine, benidipine, cilnidipine,
efonidipine, elgodipine, felodipine, fendiline, isradipine, lacidipine, lercanidipine,
lidoflazine, manidipine, mibefradil, monatepil, nicardipine, nifedipine, nilvadipine,
nimodipine, nisoldipine, nitrendipine, perhexiline, prenylamine or terodiline.
Yet another representative example of the cardiovascular agent is a cardiotonic agent
that is selected from 2-amino-4-picoline, amrinone, bucladesine, denopamine,
dobutamine, docarpamine, dopamine, dopexamine, enoximone, erythrophleine,
ibopamine, levosimendan, loprinone, milrinone, pimobendan, prenalterol, sulmazole,
vesnarinone or xamoterol.
Yet another representative example of the cardiovascular agent is a cardioprotective
agent that is selected from acadesine or cariporide.
Yet another representative example of the cardiovascular agent is a diuretic agent that
is selected from althiazide, amanozine, ambuside, amiloride, aminometradine,
amisometradine, azosemide, bendroflumethiazide, benzthiazide, bumetanide,
butazolamide, buthiazide, chloraminophenamide, chlorazanil, chlormerodrin,
chlorothiazide, chlorthalidone, clofenamide, clorexolone, cyclothiazide, disulfamide,
ethiazide, ethoxzolamide, fenquizone, furosemide, hydrochlorothiazide, mefruside,
methazolamide, methyclothiazide, meticrane, metolazone, muzolimine, pamabrom,
paraflutizide, piretanide, polythiazide, quinethazone, teclothiazide, theobromine,
torsemide, triamterene, trichlormethiazide or xipamide.
Yet another representative example of the cardiovascular agent is a vasodilator that is
selected from bamethan, bendazol, betahistine, bradykinin, butalamine, droprenilamine,
eledoisin, fasudil, fendiline, isoxsuprine, itramin tosylate, kallidin, lidoflazine,
nimodipine, nylidrin, pimefylline, prenylamine, suloctidil, tinofedrine, tolazoline,
trimetazidine or viquidil.
Still further in the twenty-sixth embodiment, the antiallergic agent referred to in the
twenty-fifth embodiment hereinabove is generically selected from a steroidal
bronchodilator, mast cell stabilizer or an antihistamine; and is specifically selected from
amlexanox, antazoline, astemizole, bambuterol, cetoxime, clobenzepam, desloratadine,
epinastine, mizolastine, oxatomide, pemirolast, pentigetide, pifatidine (roxatidine
acetate hydrochloride), repirinast, salbutamol, salmeterol, suplatast, tazanolast,
tranilast, tritoqualine or traxanox.
A representative example of the antiallergic agent is an antihistamine that is selected
from antazoline, astemizole, cetoxime, clobenzepam, desloratadine, epinastine,
mizolastine, pifatidine (roxatidine acetate hydrochloride) or tritoqualine.
Still further in the twenty-sixth embodiment, the anticancer agent referred to in the
twenty-fifth embodiment hereinabove is selected from 9-aminocamptothecin,
aminolevulinic acid, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-ap),3-
aminopyridine-4-methyl-2-carboxaldehyde thiosemicarbazone (3-amp/triapine/ocx-
191/ocx-0191), amsacrine, ancitabine, anthramycin, azacitidine, bicalutamide,
bisantrene, bleomycins, bropirimine, buserelin, carboplatin, carboquone, carmofur,
carmustine, carubicin, chlorozotocin, cisplatin, cladribine, cyclophosphamide,
cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, defosfamide,
demecolcine, diaziquone, 6-diazo-5-oxo-l-norleucine (don), docetaxel, doxorubicin,
ecteinascidins, edatrexate, efaproxiral, eflornithine, eniluracil, epirubicin, erlotinib,
fluorouracil, gefitinib, gemcitabine, goserelin, histamine, hydroxyurea, idarubicin,
ifosfamide, imatinib, improsulfan, lanreotide, leuprolide, liarozole, lobaplatin, lomustine,
lonafarnib, mannomustine, marimastat, melphalan, 6-mercaptopurine, methotrexate,
methyl aminolevulinate, miboplatin, mitoguazone, mitoxantrone, nilutamide, nimustine,
nolatrexed, oxaliplatin, pemetrexed, pentostatin, peplomycin, perfosfamide, phenamet,
pirarubicin, piritrexim, prinomastat, procarbazine, puromycin, raltitrexed, tariquidar,
temozolomide, thiamiprine, thioguanine, tiazofurin, tipifarnib, tirapazamine,
troxacitabine, trimetrexate, uracil mustard (uramustine), vindesine or zorubicin.
A representative example of the anticancer agent is selected from 9-
aminocamptothecin, bicalutamide, carboplatin, cyclophosphamide, cytarabine,
daunorubicin, docetaxel, doxorubicin, fluorouracil, gemcitabine, idarubicin, leuprolide,
melphalan, methotrexate, tirapazamine, troxacitabine, vindesine or zorubicin.
Still further in the twenty-sixth embodiment, the antidepressant referred to in the twentyfifth
embodiment hereinabove also includes an antimaniac and antipsychotic agent and
is specifically selected from S-adenosylmethionine, amineptine, amisulpride,
amoxapine, aripiprazole, benperidol, caroxazone, carpipramine, clocapramine,
clomacran, clospirazine, clozapine, demexiptiline, desipramine, droperidol, duloxetine,
fencamine, fluoxetine, fluspirilene, fluvoxamine, 5-hydroxytryptophan (oxitriptan),
indalpine, indeloxazine hydrochloride, iproclozide, iproniazid, isocarboxazid,
levophacetoperane, maprotiline, metapramine, milnacipran, minaprine, moclobemide,
molindone, mosapramine, nemonapride, nialamide, nomifensine, nortriptyline,
octamoxin, olanzapine, oxypertine, paroxetine, pimozide, pipamperone, protriptyline,
reboxetine, remoxipride, rolipram, roxindole, sertindole, sertraline, spiperone, sulpiride,
sultopride, tianeptine, timiperone, tofenacin, tranylcypromine, viloxazine, benmoxine,
rolicyprine or ziprasidone.
A representative example of the antidepressant is selected from desipramine,
duloxetine, fluoxetine, fluvoxamine, moclobemide, nortriptyline, paroxetine, reboxetine
or sertraline. A representative example of the antidepressant includes an antimanic and
antipsychotic agent that is selected from aripiprazole, clozapine, olanzapine or
ziprasidone.
Still further in the twenty-sixth embodiment, the anticonvulsant agent referred to in the
twenty-fifth embodiment hereinabove is selected from acetylpheneturide, albutoin, 4-
amino-3-hydroxybutyric acid, atrolactamide, n-benzyl-3-chloropropionamide, buramate,
carbamazepine, cinromide, clonazepam, decimemide, dimethadione, doxenitoin,
ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine,
levetiracetam, licarbazepine, mephenytoin, mephobarbital, metharbital, methetoin, 5-
methyl-5-(3-phenanthryl)hydantoin, 3-methyl-5-phenylhydantoin, nitrazepam,
oxcarbazepine, oxicarbamazepine, phenacemide, phenetharbital, pheneturide,
phenobarbital, phenylmethylbarbituric acid, phenytoin, phethenylate sodium,
pregabalin, primidone, progabide, remacemide, rufinamide, suclofenide, sulthiame,
talampanel, tetrantoin, topiramate, valpromide, vigabatrin or zonisamide.
A representative example of the anticonvulsant agent is selected from carbamazepine,
felbamate, gabapentin, lamotrigine, levetiracetam, licarbazepine, oxcarbazepine,
pregabalin, topiramate, valpromide, vigabatrin or zonisamide.
Still further in the twenty-sixth embodiment, the antibacterial agent referred to in the
twenty-fifth embodiment hereinabove is selected from acedapsone, acediasulfone,
acetosulfone sodium, ambazone, amikacin, p-aminosalicylic acid, p-aminosalicylic acid
hydrazide, amoxicillin, amphomycin, ampicillin, apalcillin, apicycline, arbekacin,
aspoxicillin, azidamfenicol, azidocillin, azlocillin, aztreonam, bacampicillin, bacitracin,
balofloxacin, bambermycins, benzoylpas, benzylsulfamide, betamipron, brodimoprim, 5-
bromosalicylhydroxamic acid, butirosin, capreomycin, carbenicillin, carindacillin,
carumonam, cefaclor, cefadroxil, cefamandole, cefatiam, cefatrizine, cefazedone,
cefazolin, cefbuperazone, cefdinir, cefcapene pivoxil, cefclidin, cefditoren, cefepime,
cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid,
cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, cefoxitin,
cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil,
cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime,
ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin,
cephaloridine, cephalosporin c, cephalothin, cephapirin sodium, cephradine,
chloramine-B, chloramine-T, chloramphenicol, chlortetracycline, cilastatin, ciproflaxacin,
clinafloxacin, clindamycin, clometocillin, clomocycline, cloxacillin, colistin, cyacetacide,
cyclacillin, cycloserine, dalfopristin, dapsone, demeclocycline,
deoxydihydrostreptomycin, dibekacin, dicloxacillin, dihydrostreptomycin, dirithromycin,
doxycycline, enoxacin, enviomycin, epicillin, ertapenem, ethambutol, ethionamide,
fenbenicillin, flomoxef, floxacillin, N2- forimicins, formylsulfisomidine, furazolium
chloride, furonazide, garenoxacin, gatifloxacin, gemifloxacin, gentamycin, glyconiazide,
n4-beta-d-glucosylsulfanilamide, gramicidin(s), grepafloxacin, guamecycline, hetacillin,
imipenem, isepamicin, isoniazid, kanamycin(s), lenampicillin, lincomycin, linezolide,
lomefloxacin, loracarbef, lymecycline, mafenide, meclocycline, meropenem,
metampicillin, methacycline, methicillin, 4'-(methylsulfamoyl)sulfanilanilide, mezlocillin,
micronomicin, mikamycin, minocycline, morphazinamide, moxalactam, moxifloxacin,
nafcillin, negamycin, neomycin, netilmicin, nifuradene, nitrofurantoin, noprysulfamide,
norfloxacin, novobiocin, opiniazide, oxacillin, oxytetracycline, panipenem,
paromomycin, pazufloxacin, penamecillin, penethamate hydriodide, penicillin(s),
penimepicycline, pexiganan, phenethicillin, phenyl aminosalicylate,
phthalylsulfacetamide, phthalylsulfathiazole, picloxydine, pipacycline, pipemidic acid,
piperacillin, pivampicillin, pivcefalexin, polymyxin, porfiromycin, primycin, pristinamycin,
protionamide, pyrazinamide, quinacillin, quinupristin, ramoplanin, ribostamycin,
rifabutin, rifalazil, rifamide, rifamycin sv, rifampin, rifapentine, rifaximin, ristocetin,
ritipenem, rolitetracycline, salazosulfadimidine, salinazid, sancycline, sisomicin,
sitafloxacin, solasulfone, sparfloxacin, spectinomycin, streptolydigin, streptomycin,
streptonicozid, subathizone, 4,4'- succinylsulfathiazole, succisulfone, sulbenicillin,
sulfachrysoidine, sulfanilic acid, 2-p-sulfanilylanilinoethanol, sulfinyldianiline, sulfoxone
sodium, 4'-sulfanilylsulfanilamide, sulfoniazide, sulfabenzamide, sulfacetamide,
sulfachlorpyridazine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine,
sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfaloxic acid,
sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,
sulfamethoxazole, sulfamethoxypyridazine, sulfamethylthiazole, sulfametrole,
sulfamidochrysoidine, sulfamoxole, sulfanilamide, 4-sulfanilamidosalicylic acid, psulfanilylbenzylamine,
sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfaperine,
sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfasomizole, sulfasymazine,
sulfathiazole, sulfathiourea, sulfisomidine, sulfisoxazole, sultamicillin, sulfanamide,
talampicillin, taurolidine, teicoplanin, temocillin, tetroxoprim, thiamphenicol,
thiazosulfone, thiacetazone, thiostrepton, ticarcillin, tigemonam, tiocarlide, tobramycin,
tosufloxacin, trimethoprim, trospectomycin, trovafloxacin, tuberactinomycin, tyrocidine,
vancomycin, viomycin or virginiamycin.
A representative example of the anti-bacterial agent is selected from amoxicillin,
ampicillin, cefadroxil, cefalexin, cefixime, cefotaxime, cefuroxime, cephalexin,
chloramphenicol, chlortetracycline, ciproflaxacin, clavulanate, clinafloxacin,
clindamycin, dapsone, doxycycline, ethambutol, gatifloxacin, gentamycin, nadifloxacin,
nalidixic acid, norfloxacin, oflaxacin, oxacillin, panipenem, penicillins, salbactam,
streptomycin, sultamicillin or vancomycin.
Still further in the twenty-sixth embodiment, the antifungal agent referred to in the
twenty-fifth embodiment hereinabove is selected from acrisorcin (9-aminoacrindine
compound with 4-hexylresorcinol ( 1 :1 )), amphotericin B, anidulafungin, azaserine,
bromosalicylchloranilide, buclosamide, candicidin, caspofungin, chlordantoin,
exalamide, flucytosine, loflucarban, lucensomycin, magenta I, mepartricin, micafungin,
natamycin, nystatin, perimycin, pyrrolnitrin, salicylanilide or tubercidin.
Still further in the twenty-sixth embodiment, the antiviral agent referred to in the twentyfifth
embodiment hereinabove is selected from abacavir, acyclovir, adefovir,
amantadine, amidinomycin, amprenavir, atazanavir, atevirdine, capravirine, cidofovir,
delavirdine, didanosine, dideoxyadenosine, efavirenz, emtricitabine, entecavir,
famciclovir, ganciclovir, imiquimod, indinavir, lamivudine, lopinavir, mantadine,
methisazone, 5-(methylamino)-2-deoxyuridine (madu), moroxydine, nelfinavir,
nevirapine, oseltamivir, penciclovir, resiquimod, ribavirin, rimantadine, ritonavir,
saquinavir, stallimycin, tenofovir, tipranavir, trimetazidine, tromantadine, valacyclovir,
valganciclovir, vidarabine, zalcitabine or zanamivir.
A representative example of the antiviral agent is selected from abacavir, acyclovir,
adefovir, amprenavir, cidofovir, didanosine, efavirenz, emtricitabine, famciclovir,
ganciclovir, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, oseltamivir,
penciclovir, ritonavir, saquinavir, trimetazidine, valacyclovir, valganciclovir, vidarabine,
zalcitabine or zanamivir.
Still further in the twenty-sixth embodiment, the antimalarial agent referred to in the
twenty-sixth embodiment hereinabove is selected from amodiaquine, chlorguanide,
chloroquine, chlorproguanil, cycloguanil, hydroxychloroquine, mefloquine, 3-
methylarsacetin, pamaquine, plasmocid, primaquine, pyronaridine, quinocide or
tafenoquine
Still further in the twenty-sixth embodiment, the antidiabetic agent referred to in the
twenty-fifth embodiment hereinabove is selected from acetohexamide, buformin,
carbutamide, chlorpropamide, fidarestat, glibornuride, gliclazide, glimepiride, glipizide,
gliquidone, glisoxepid, glyburide, glybuthiazol(e), glybuzole, glyhexamide, glymidine,
glypinamide, metformin, phenformin, pioglitazone, repaglinide, rosiglitazone,
tolazamide, tolbutamide, tolcyclamide, troglitazone or voglibose.
Still further in the twenty-sixth embodiment, the antiulcer agent referred to in the twentyfifth
embodiment hereinabove includes a proton pump inhibitor and said antiulcer agent
is selected from aldioxa, benexate HCI, carbenoxolone, cetraxate, cimetidine,
ebrotidine, ecabapide, esaprazole, esomeprazole, famotidine, irsogladine, lafutidine,
lansoprazole, leminoprazole, S-methylmethionine, nizatidine, omeprazole,
pantoprazole, pirenzepine, polaprezinc, rabeprazole, ranitidine, rebamipide, rotraxate,
roxatidine, telenzepine or troxipide.
Still further in the twenty-sixth embodiment, the antioxidant referred to in the twentyfifth
embodiment hereinabove includes a free radical scavenger and the antioxidant is
selected from BTX-51 072 (4,4-dimethyl-3,4-dihydro-2H-1 ,2-benzoselenazine),
carnosine, melatonin, (+)-R-pramipexole, SCMC-Lys (S-carboxymethyl-L-cysteine
Lysine salt H20), stobadine or zeatin.
Still further in the twenty-sixth embodiment, the vitamin referred to in the twenty-fifth
embodiment hereinabove is selected from acetiamine (diacethiamine or D.A.T.),
benfotiamine (s-benzoylthiamine monophosphate or BTMP), biotin (vitamin H or
coenzyme R), bisbentiamine (O-benzoylthiamine disulfide), cetotiamine (0,Sdicarbethoxythiamine
or DCET), cobamamide (vitamin B2 coenzyme), cyanocobalamin
(vitamin B 2) , folic acid (vitamin M), fursultiamine (thiamine tetrahydrofurfuryl disulfide),
hydroxocobalamin (vitamin B12a) , nicotinamide, octotiamine, prosultiamine, thiamine
(vitamin B ) or vitamin K5.
As has been indicated hereinabove that the twenty-fifth embodiment also encompasses
within its scope a compound of formula (I) wherein the drug or therapeutic agent
containing an amino group is selected from the drugs belonging to several other
therapeutic areas (including those drugs that are classified on the basis of their
mechanism of action). Thus, for the purpose of this invention, the twenty-sixth
embodiment also encompasses a compound of formula (I); wherein the drug containing
amino group is generically selected from the class of drugs falling under several other
therapeutic areas (including those drugs that are classified on the basis of their
mechanism of action) and is specifically selected from: an abortifacient/interceptive
such as sulprostone; an anesthetic selected from ambucaine, benoxinate, benzocaine,
betoxycaine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, carticaine,
chloroprocaine hydrochloride, dibucaine hydrochloride, dimethocaine, diperodon
hydrochloride, etidocaine, etoxadrol, -eucaine, euprocin, hexylcaine hydrochloride,
hydroxytetracaine, isobutyl p-aminobenzoate, ketamine, lidocaine, leucinocaine
mesylate, mepivacaine, meprylcaine, metabutoxycaine, octacaine, orthocaine,
pentobarbital, piridocaine, prilocaine, procaine, proparacaine, propoxycaine
hydrochloride, pyrrocaine, ropivacaine, tetracaine hydrochloride, thialbarbital, thiamylal,
tolycaine, tricaine, trimecaine or urethan; an anorexic agent selected from aminorex,
chlorphentermine, clobenzorex, cloforex, clortermine, n-ethylamphetamine,
fenfluramine, fenproporex, mefenorex, norpseudoephedrine, pentorex, phenmetrazine,
phentermine, picilorex or methamphetamine; an anthelmintic agent selected from
albendazole, amocarzine, amphotalide, becanthone, cyclobendazole, diphenane,
hycanthone, kainic acid, lucanthone, mebendazole, niridazole, nitazoxanide,
oxamniquine, pelletierine, piperazine, quinacrine, thiabendazole or thymyl Nisoamylcarbamate;
an agent for treating alopecia such as finasteride; an antiamebic
agent selected from carbarsone, dehydroemetine, diphetarsone, emetine,
thiocarbarsone, glycobiarsol or tetracycline; an antiandrogen agent such as flutamide or
nilutamide; an antiarthritic/antirheumatic agent selected from glucosamine, leflunomide
or penicillamine; an antiasthmatic agent selected from domitroban, formoterol,
pranlukast, ramatroban, suplatast tosylate, traxanox, zafirlukast or zileuton; an
antidiarrheal agent selected from alkofanone, racecadotril or zaidaride; an antidiuretic
selected from desmopressin, felypressin, lypressin, ornipressin, terlipressin or
vasopressin; an antiemetic agent selected from alizapride, aprepitant, azasetron,
bromopride, clebopride, dolasetron, domperidone, granisetron, itasetron, methallatal,
metoclopramide, metopimazine, pipamazine, ramosetron, trimethobenzamide or
tropisetron; an antiglaucoma agent selected from acetazolamide, brinzolamide,
dorzolamide, befunolol, bimatoprost, brimonidine or levobunolol; an antigout agent
selected from allopurinol, carprofen, colchicine or orotic acid; an antihyperthyroid agent
selected from propylthiouracil or thiobarbital; an antihypothyroid agent such as
thyroxine; an antimigraine agent selected from almotriptan, alpiropride, eletriptan,
ergotamine, frovatriptan, lisuride, methysergide, naratriptan, rizatriptan, sumatriptan or
zolmitriptan; an antimuscarinic/mydriatic agent selected from ambutonium bromide,
aminopentamide, benzetimide, buzepide, camylofine, darifenacin, fenpiverinium
bromide or isopropamide iodide; an antiosteoporotic agent selected from alendronic
acid, incadronic acid or pamidronic acid; an antiprostatic agent used for treating
hypertrophy selected from doxazosin, epristeride, mepartricin, tamsulosin or terazosin;
an antiprotozoal agent selected from acetarsone, acranil®, aminitrozole, anisomycin,
azanidazole, benznidazole, eflornithine, hydroxystilbamidine, lauroguadine,
melarsoprol, mepartricin, n-methylglucamine, nitazoxanide, oxophenarsine
hydrochloride, pentamidine, propamidine, puromycin, pyrimethamine, quinapyramine,
stilbamidine, suramin sodium, tenonitrozole, trypan red or tryparsamide; an antipsoriatic
agent such as 6-azauridine; an antiseptic agent selected from aminacrine,
aminoquinuride, bisdequalinium chloride, chlorhexidine, chloroazodin, dequalinium
chloride, dibromopropamidine, dodecarbonium chloride, ethacridine, hexamidine,
hexetidine, iodopyrrole, laurolinium acetate, nitroakridin 3582, noxythiolin, oxymethurea
or triclocarban; an antispasmodic agent selected from ambutonium bromide,
aminopentamide, buzepide, camylofine, darifenacin, drotaverine, etomidoline,
fenalamide, fenpiverinium bromide, hydramitrazine, isopropamide iodide, nicofetamide,
octamylamine, phenamacide hydrochloride, pramiverin, proglumide, racefemine or
tiropramide; an antitussive agent selected from alloclamide, benzonatate or fominoben;
an anxiolytic agent selected from abecarnil, azacyclonol, benzoctamine, bromazepam,
calcium /V-carbamoyIaspartate, chlordiazepoxide, clorazepic acid, cloxazolam,
cyclarbamate, emylcamate, ethyl etifoxine, flesinoxan, hydroxyphenamate, loflazepate,
lorazepam, mecloralurea, meprobamate, mexazolam, nordazepam, oxazepam,
oxazolam, tybamate or valnoctamide; a cathartic agent /laxative selected from
bisoxatin acetate or oxyphenisatin acetate; a choleretic agent selected from osalmid or
sincalide; a cholinergic agent selected from bethanechol chloride, eptastigmine,
eseridine, guanidine, dexpanthenol, carbachol or physostigmine; a decongestant
selected from amidephrine, cyclopentamine, ephedrine, epinephrine, fenoxazoline,
indanazoline, naphazoline, nordefrin, octodrine, oxymetazoline, phenylephrine,
phenylpropanolamine, phenylpropylmethylamine, propylhexedrine, pseudoephedrine,
tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline or xylometazoline; an
emetic such as cephaeline; an enzyme cofactor selected from acetiamine,
benfotiamine, bisbentiamine, cetotiamine, dexpanthenol, fursultiamine, octotiamine,
pantothenic acid, prosultiamine, sapropterin, thiamine, thiamine diphosphate or
thiamine disulfide; an agent that acts as an expectorant selected from ambroxol or
bromhexine; a gastroprokinetic agent selected from piboserod, alvimopan, cinitapride,
cisapride, loxiglumide, mosapride, prucalopride, renzapride or tegaserod ; a hemostatic
agent selected from adrenalone, cephalins, aminocaproic acid, carbazochrome sodium
sulfonate, ethamsylate, tranexamic acid, tolonium chloride or vapreotide; a
hepatoprotectant selected from s-adenosylmethionine, citiolone, orazamide, timonacic
(thioproline), methionine, protoporphyrin ix or tiopronin; an immunomodulator selected
from bropirimine, thalidomide, ubenimex, bucillamine, imiquimod, leflunomide,
mitoxantrone, pidotimod, procodazole, romurtide or thymopentin; an
immunosuppressant selected from azathioprine, gusperimus or mizoribine; a mucolytic
agent selected from carbocysteine, erdosteine, letosteine, mecysteine or stepronin; a
muscle relaxant selected from afloqualone, baclofen, carisoprodol, chlorphenesin
carbamate, chlorzoxazone, mephenoxalone, methocarbamol, phenprobamate,
tizanidine, hexacarbacholine bromide, metaxalone or dantrolene; a mydriatic selected
from phenylephrine hydrochloride or yohimbine; a narcotic antagonist such as
amiphenazole; a neuroprotective agent selected from aptiganel, licostinel, repinotan,
riluzole, citicoline or memantine; a drug used as a nootropic/cognitive enhancer
selected from amphetamine, atomoxetine, bemegride, bifemelane, dextroamphetamine,
etifelmin, etryptamine, fencamfamine, fenethylline, fenozolone, ipidacrine, leteprinim,
mefexamide, methylphenidate, modafinil, nebracetam, nefiracetam, oxiracetam,
pemoline, pipradrol, piracetam, posatirelin, pramiracetam, sulbutiamine, tacrine or
velnacrine; a drug which acts as a respiratory stimulant such as almitrine; a drug which
is used as a sedative/hypnotic selected from acecarbromal, allobarbital, amobarbital,
amphenidone, aprobarbital, apronalide, barbital, brallobarbital, bromisovalum,
butalbital, butallylonal, butethal, butoctamide, carbromal, carbubarb, carfimate,
cyclobarbital, cyclopentobarbital, dexmedetomidine, diethylbromoacetamide, ectylurea,
enallylpropymal, ethinamate, febarbamate, 5-furfuryl-5-isopropylbarbituric acid,
glutethimide, haloxazolam, heptabarbital, hexethal sodium, hexobarbital, methitural,
methyprylon, narcobarbital, nealbarbital, niaprazine, pentobarbital, phenallymal,
piperidione, propallylonal, proxibarbal, reposal, rilmazafone, secobarbital sodium,
talbutal, tetrabarbital, valdetamide, vinbarbital sodium or vinylbital; a vulnerary such as
allantoin; a drug that acts as an o -adrenergic agonist selected from adrafinil,
adrenalone, amidephrine, apraclonidine, budralazine, clonidine, cyclopentamine,
dexmedetomidine, dimetofrine, dipivefrin, ecabapide, ephedrine, epinephrine,
fenoxazoline, guanabenz, guanfacine, hydroxyamphetamine, ibopamine, indanazoline,
isometheptene, mephentermine, metaraminol, methoxamine, methylhexaneamine,
midodrine, mivazerol, modafinil, moxonidine, naphazoline, norepinephrine, norfenefrine,
octodrine, octopamine, oxymetazoline, phenylephrine hydrochloride,
phenylpropanolamine, phenylpropylmethylamine, pholedrine, propylhexedrine,
pseudoephedrine, rilmenidine, synephrine, talipexole, tetrahydrozoline, tiamenidine,
tramazoline, tuaminoheptane, tymazoline, tyramine or xylometazoline; a drug that acts
as a -adrenergic agonist selected from albuterol (salbutamol), bambuterol, bitolterol,
carbuterol, clenbuterol, clorprenaline, denopamine, dioxethedrine, dopexamine,
ephedrine, epinephrine, ethylnorepinephrine, fenoterol, formoterol, hexoprenaline,
ibopamine, isoetharine, isoproterenol, mabuterol, metaproterenol, methoxyphenamine,
oxyfedrine, pirbuterol, prenalterol, procaterol, protokylol, reproterol, rimiterol, ritodrine,
salmeterol, soterenol, terbutaline, tretoquinol, tulobuterol or xamoterol; a drug that acts
as an a-adrenergic blocker selected from amosulalol, arotinolol, doxazosin, ergoloid
mesylates, fenspiride, idazoxan, indoramin, labetalol, monatepil, prazosin, tamsulosin,
terazosin, tolazoline, trimazosin or yohimbine; a drug that acts as a -adrenergic
blocker selected from acebutolol, amosulalol, alprenolol, arotinolol, atenolol, befunolol,
betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol,
bunitrolol, bupranolol, butidrine, butofilolol, carazolol, carteolol, carvedilol, celiprolol,
cetamolol, cloranolol, dilevalol, esmolol, indenolol, labetalol, landiolol, levobunolol,
mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivolol, nifenalol,
nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol,
sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol or xibenolol; a dopamine receptor
agonist selected from bromocriptine, cabergoline, carmoxirole, dopexamine,
fenoldopam, ibopamine, pergolide, pramipexole, quinagolide, ropinirole, roxindole or
talipexole; a dopamine receptor antagonist selected from amisulpride, amisulpride,
clebopride, domperidone, metoclopramide or mosapramine; an a-glucosidase inhibitor
selected from acarbose or voglibose; a matrix metalloproteinase inhibitor such as
batimastat; a monoamine oxidase inhibitor selected from iproclozide, iproniazid,
isocarboxazid, lazabemide, moclobemide, mofegiline, octamoxin, phenelzine,
phenoxypropazine, pivalylbenzhydrazine or tranylcypromine; a neutral endopeptidase
inhibitor such as ecadotril; a potassium channel blocker such as fampridine; a prolactin
inhibitor selected from metergoline or terguride; a protease inhibitor selected from
camostat, gabexate, nafamostat or sepimostat; 5a-Reductase inhibitor such as
dutasteride; a reverse transcriptase inhibitor such as stavudine; a serotonin receptor
agonist such as eltoprazine; a serotonin receptor antagonist such as alosetron; and a
thromboxane A2-receptor antagonist such as daltroban.
In a twenty-seventh embodiment, the invention encompasses a compound of formula
(I), wherein: D is a drug containing a hydroxyl group capable of forming a bio-cleavable
covalent linkage with a linker;
X1 is oxygen;
each of X2, Y, Z1; Z2, A, R1 and R2 is as defined in the first embodiment hereinabove;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twenty eighth embodiment, the invention encompasses a compound of formula (I),
wherein: D and X1 are as defined in the twenty seventh embodiment hereinabove;
each X2, Y, Z1, Z2, A, R1 and R2 is as defined in the second embodiment hereinabove;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a twenty ninth embodiment, the invention encompasses a compound of formula (I),
wherein: D and X1 are as defined in the twenty seventh embodiment hereinabove;
each of X2, Y, Z1and Z2 is as defined in the second embodiment hereinabove;
A is selected from 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine, 3,4-
pyridine, 2,4-pyridine, 2,5-pyridine or 2,6-pyridine;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirtieth embodiment, the invention encompasses a compound of formula (I),
wherein: each of D, X1, X2, Y, Z1 and Z2 is as defined in the twenty eighth embodiment
hereinabove,
A is selected from a bond, CH=CH or CR R10 ; where R and R10 are independently
selected from hydrogen or C -6 alkyl;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirty-first embodiment, the invention encompasses a compound of formula (I),
wherein: each of D, X1, X2, Y, Z1 and Z2 is as defined in the twenty eighth embodiment
hereinabove,
A is selected from S, SO, S0 2 or S-S; provided that when A is S, then a and b is 3;
R1 is hydrogen and R2 is alkyl, cycloalkyl, aryl or aralkyl ; or R2 is hydrogen and R1 is
alkyl, cycloalkyl, aryl or aralkyl;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirty-second embodiment, the invention encompasses a compound of formula (I),
wherein: D, the drug containing a hydroxyl group capable of forming a covalent biocleavable
linkage with a linker, referred to in the twenty-seventh, twenty-eighth,
twenty-ninth, thirtieth and thirty-first embodiments, is selected from an antiinflammatory
and analgesic drug, a cardiovascular drug, a glucocorticoid, an antiallergic agent,
anticancer agent, an antidepressant, an anticonvulsant agent, an antibacterial agent, an
antifungal agent, an antiviral agent, an antimalarial agent, an antidiabetic agent, an
antiulcer agent, an antioxidant or a vitamin. The thirty-second embodiment also
encompasses within its scope a drug containing a hydroxyl group is selected from the
drugs that belong to several other therapeutic areas (including those drugs that are
classified on the basis of their mechanism of action). In this embodiment, other
variables X1, X2, Y, Z1 and Z2; A, R1 and R2 in the compounds of formula (I) are as
defined above; with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0; and
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In thirty-third embodiment, the invention encompasses a compound of formula (I),
wherein D, the drug containing a hydroxyl group capable of forming a covalent biocleavable
linkage with a linker, is a glucocorticoid;
X1 is a bond;
X2 oxygen;
Y is spacer group as defined in the first embodiment hereinabove,
Z1, Z2 ,A , R1 and R2 are as defined in the second embodiment hereinabove; and
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirty-fourth embodiment, the invention encompasses a compound of formula (I),
wherein each of D, X1 and X2 is as defined in the thirty-third embodiment hereinabove;
Y is a spacer group selected from:
Z1, Z2, A , R1 and R2 are as defined in the second embodiment hereinabove; and
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirty-fifth embodiment, the invention encompasses a compound of formula (I),
wherein: the glucocorticoid referred to in the thirty-third and thirty-fourth embodiments
hereinabove is selected from 21-acetoxypregnenolone, alclometasone, algestone,
amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone,
ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone,
deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,
difluprednate, enoxolone, fluazacort, flucloronide, fludrocortisone, flumethasone,
flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone,
fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone,
flurandrenolide, fluticasone, formocortal, halcinonide, halobetasol propionate,
halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol
etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone
furoate, paramethasone, prednicarbate, prednisolone, prednisolone 21-
diethylaminoacetate, prednisone, prednival, prednylidene, rimexolone, triamcinolone or
triamcinolone acetonide.
A representative example of the glucocorticoid is selected from betamethasone,
budesonide, dexamethasone, hydrocortisone, fludrocortisone, fluticasone, prednisolone
or triamcinolone.
In a thirty-sixth embodiment, the antiinflammatory and analgesic drug referred to in the
thirty-second embodiment is generically selected from an opioid, a steroid (i.e.,
glucocorticoids) or a non-steroidal anti-inflammatory drug (NSAIDs) and is specifically
selected from acetaminophen, acetaminosalol, 21-acetoxypregnenolone,
alclometasone, alfa-aluminum bis(acetylsalicylate), 3-amino-4-hydroxybutyric acid,
balsalazide, benzylmorphine, bisabolol, bucetin, budesonide, bufexamac,
buprenorphine, butorphanol, capsaicine, chlorobutanol, ciramadol, codeine, deflazacort,
diflorasone, desomorphine, desonide, desoximetasone, dezocine, diflorasone,
diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydromorphine,
dihydroxyaluminum acetylsalicylate, dimepheptanol, ditazol, enoxolone, eptazocine,
ethylmorphine, etofenamate, eugenol, fendosal, fepradinol, floctafenine, fluazacort,
fluocinonide, fluocortin butyl, fluprednidene acetate, gentisic acid, glafenine,
glucametacin, halcinonide, halobetasol propionate, halometasone, halopredone
acetate, hydrocortisone, hydromorphone, hydroxypethidine, ibuproxam, isoladol,
isoxicam, ketobemidone, p-lactophenetide, levorphanol, lornoxicam, loteprednol
etabonate, mazipredone, meloxicam, meptazinol, mesalamine, metazocine, metopon,
mometasone furoate, morphine, nalbuphine, norlevorphanol, normorphine, olsalazine,
oxaceprol, oxametacine, oxycodone, oxymorphone, oxyphenbutazone, pentazocine,
perisoxal, piroxicam, phenazocine, phenoperidine, phenylramidol, phenylsalicylate,
rimexolone, salacetamide, salicin, salicylamide, salsalate, sulfasalazine, tenoxicam,
tixocortol, tramadol, viminol or ximoprofen,
A representative example of the antiinflammatory and analgesic drug (consisting of
glucocorticoids, NSAIDs and opioids) is selected from acetaminophen, balasalazide,
budesonide, codeine, deflazacort, desomorphine, diflunisal, dihydrocodeine,
dihydromorphine, eugenol, glucametacin, halobetasol propionate, halometasone,
hydrocortisone, hydromorphone, levorphanol, meloxicam, mesalamine, mometasone
furoate, morphine, norlevorphanol, normorphine, olsalzine, oxycodone, oxymorphone,
piroxicam, sulfasalazine or tramadol.
Still further in the thirty-sixth embodiment, the cardiovascular agent referred to in the
thirty-second embodiment is generically selected from an antihypertensive agent such
as an angiotesnsin converting enzyme (ACE) inhibitor, a beta-blocker, a sartan (i.e.,
angiotensin I I blockers), an antithrombotic and vasoactive agent, an anti-hyperlipidemic
agent (including HMG-CoA-reductase inhibitors (i.e., statins)), a fibrate, an antianginal
agent, an antiarrhythmic agent, an antihypotensive agent, a calcium channel blocker, a
calcium regulator, a cardiotonic agent, a cardioprotective agent, a diuretic, a vasodilator
or a vasoprotectant; and is specifically selected from acadesine, acebutolol, ajmaline,
alprenolol, ambuside, amosulalol, angiotensin, arotinolol, atenolol, atorvastatin,
bamethan, benzarone, benziodarone, beraprost, betaxolol, bevantolol, bisoprolol,
bosentan, bradykinin, brovincamine, bucindolol, bucumolol, bufeniode, buflomedil,
bufuralol, bunitrolol, bupranolol, butofilolol, cadralazine, calcifediol, calcitriol, canrenone
(hydroxyl of its ketoxime), carazolol, l-carnitine (levocarnitine), carteolol, carvedilol,
celiprolol, cerivastatin, cetamolol, chlorthalidone, chromocarb, cicletanine, clobenfurol,
clobenoside, convallatoxin, cyclandelate, denopamine, deslanoside, digitalin,
dihydrotachysterol, dilevalol, dimetofrine, diosmin, dobesilate calcium, dobutamine,
dopamine, dopexamine, efloxate, eledoisin, enoximone, epanolol, erythrophleine, escin,
etafenone , ethacrynic acid, etilefrin, ezetimibe, fenofibrate, fenoldopam, fluvastatin,
furazabol, gepefrine, gitoxin, guanoxabenz, heptaminol, ibudilast, ifenprodil, iloprost,
indenolol, ipriflavone, isosorbide, isoxsuprine, kallidin, khellin, labetalol, lanatosides,
leucocyanidin, levcromakalim, limaprost, losartan, lovastatin, meglutol, mannitol,
mepindolol, metaraminol, methoxamine, methyldopa, metipranolol, metoprolol,
mevastatin, midodrine, moprolol, nadolol, naftopidil, nebivolol, neriifolin, nicomol,
nicotinyl alcohol, nifenalol, nipradilol, norepinephrine, nylidrin, oleandrin, olmesartan,
oxprenolol, oxyfedrine, penbutolol, pentrinitrol, perhexiline, phenactropinium chloride,
phentolamine, pholedrine, pildralazine, pindolol, pirifibrate, pitavastatin, pravastatin
sodium, prenalterol, probucol, pronethalol, propranolol, proscillaridin, prostaglandin ei
protheobromine, protoveratrines, ouabain, quercetin, ranolazine, rescimetol,
resibufogenin, rutin sampatrilat, scillaren, scillarenin, simvastatin, sotalol,
spironolactone, sulfinalol, suloctidil, synephrine, talinolol, tertatolol, thyropropic acid,
ticrynafen, timolol, tinofedrine, toliprolol, tricromyl, trimazosin, troxerutin, ubiquinones,
vincamine, viquidil, xamoterol, xanthinol niacinate or xipamide.
A representative example of the cardiovascular agent is a beta - blocker that is
selected from atenolol, bupranolol, carvedilol, labetalol, metipranolol, metoprolol,
nadolol, pindolol, propranolol or timolol.
Another representative example of the cardiovascular agent is a sartan selected from
losartan or olmesartan.
Another representative example of the cardiovascular agent is an antithrombotic and
vasoactive agent that is selected from beraprost, clinprost, dalteparin, dipyridamole,
enoxaparin, ifenprodil, iloprost, heparin, lamifiban, nadroparin, reviparin sodium salt,
suloctidil, taprostene, tinzaparin, xanthinol niacinate or ximelagatran.
Yet another representative example of the cardiovascular agent is an anticoagulant that
is selected from acenocoumarol, anisindione, bromindione, clorindione, coumetarol,
dicumarol, diphenadione, ethyl biscoumacetate, ethylidene dicoumarol, fluindione,
heparin, phenindione, phenprocoumon, tioclomarol or warfarin.
Yet another representative example of the cardiovascular agent is an antihyperlipidemic
agent (i.e., statins, fibrates, etc.) that is selected from atorvastatin,
cerivastatin, ezetimibe, fenofibrate, fluvastatin, lovastatin, mevastatin, pirifibrate,
pitavastatin, pravastatin sodium or simvastatin;
Yet another representative example of the cardiovascular agent is an antianginal agent
that is selected from bevantolol, bucumolol, bufuralol, limaprost, nifenalol, nipradilol,
oxyfedrine, pronethalol, ranolazine, sotalol or toliprolol.
Yet another representative example of the cardiovascular agent is an antiarrhythmic
agent that is selected from adenosine, amiodarone, bufetolol, butidrine, cloranolol,
dofetilide, esmolol, hydroquinidine, landiolol, lorajmine, nadoxolol, pirmenol, practolol,
prajmaline, propafenone, pyrinoline, quinidine, tilisolol or xibenolol.
Yet another representative example of the cardiovascular agent is an antihypertensive
agent that is selected from angiotensin, dimetofrine, dopamine, etilefrin, gepefrine,
heptaminol, metaraminol, methoxamine, midodrine, norepinephrine, pholedrine or
synephrine.
Yet another representative example of the cardiovascular agent is a calcium channel
blocker such as etafenone.
Yet another representative example of the cardiovascular agent is a calcium regulator
that is selected from calcifediol, calcitriol, dihydrotachysterol or ipriflavone.
Yet another representative example of the cardiovascular agent is a cardiotonic agent
that is selected from convallatoxin, denopamine, deslanoside, digitalin, dobutamine,
dopamine, dopexamine, enoximone, erythrophleine, gitoxin, lanatosides, neriifolin,
oleandrin, ouabain, prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin,
ubiquinones or xamoterol.
Yet another representative example of the cardiovascular agent is a cardioprotective
agent is acadesine.
Yet another representative example of the cardiovascular agent a diuretic that is
selected from ambuside, canrenone, chlorthalidone, ethacrynic acid, isosorbide,
mannitol, protheobromine, spironolactone, ticrynafen or xipamide.
Yet another representative example of the cardiovascular agent is a vasodilator that is
selected from bamethan, benziodarone, beraprost, bosentan, bradykinin, brovincamine,
bufeniode, buflomedil, clobenfurol, cyclandelate, efloxate, eledoisin, etafenone,
ibudilast, ifenprodil, iloprost, isoxsuprine, kallidin, khellin, nicotinyl alcohol, nylidrin,
pentrinitrol, perhexiline, prostaglandin E suloctidil, tinofedrine, tricromyl, vincamine,
viquidil or xanthinol niacinate.
Yet another representative example of the cardiovascular agent is a vasoprotectant that
is selected from benzarone, chromocarb, clobenoside, diosmin, dobesilate calcium,
escin, leucocyanidin, quercetin, rutin or troxerutin.
Still further in the thirty-sixth embodiment, the antiallergic agent referred to in the thirtysecond
embodiment is generically selected from a steroidal bronchodilator, a mast cell
stabilizer or an antihistamine and is specifically selected from amlexanox, bambuterol,
beclomethasone, cetoxime, ciclesonide, ebastine, fexofenadine, flunisolide, fluticasone
and its approved esters, n-hydroxyethylpromethazine chloride, hydroxyzine, ibudilast,
methyl prednisolone, montelukast sodium, pentigetide, repirinast, roxatidine,
salbutamol, salmeterol, suplatast, terfenadine or tranilast.
A representative example of the antiallergic agent is an antihistamine that is selected
from cetoxime, ciclesonide, ebastine, n-hydroxyethylpromethazine chloride,
hydroxyzine, fexofenadine, roxatidine or terfenadine.
Still further in the thirty-sixth embodiment, the anticancer agent referred to in the thirtysecond
embodiment is selected from aclacinomycins, ancitabine, anthramycin,
arzoxifene, azacitidine, bicalutamide, bleomycins, bropirimine, broxuridine, buserelin,
calusterone, capecitabine, carubicin, CC-1 065 (NSC 298223), chlorozotocin,
chromomycins, cladribine, cytarabine, daunorubicin, decitabine, defosfamide,
diethylstilbestrol, docetaxel, doxifluridine, doxorubicin, droloxifene, dromostanolone,
ecteinascidins, enocitabine, epirubicin, epitiostanol, estramustine, etanidazole,
etoposide, fenretinide, flavopiridol, formestane, fosfestrol, fulvestrant, gemcitabine,
hydroxyurea, idarubicin, irinotecan, leuprolide, marimastat, melengestrol, menogaril, 6-
mercaptopurine, miltefosine, minodronate (minodronic acid), mitobronitol, mitolactol,
mopidamol, nitracrine, nogalamycin, nordihydroguaiaretic acid (masoprocol),
olivomycins, paclitaxel and other known paclitaxel analogs, pentostatin, peplomycin,
perfosfamide, pirarubicin, podophyllotoxin, prinomastat, puromycin, ranimustine,
resveratrol, roquinimex, rubitecan, seocalcitol, streptonigrin, streptozocin, temoporfin,
teniposide, tenuazonic acid, tiazofurin, topotecan, troxacitabine, valrubicin, vinblastine,
vincristine, vindesine, vinorelbine, zorubicin or zosuquidar.
A representative example of the anticancer agent is selected from bicalutamide,
capecitabine, CC-1065 (NSC 298223), cytarabine, daunorubicin, docetaxel,
doxorubicin, estramustine, etoposide, flavopiridol, gemcitabine, idarubicin, irinotecan,
leuprolide, paclitaxel and other active paclitaxel analogs such as docetaxel,
podophyllotoxin, resveratrol, topotecan, vinblastine or vincristine.
Still further in the thirty-sixth embodiment, the antidepressant referred to in the thirtysecond
embodiment is generically selected from an antimanic and antipsychotic agent
and is specifically selected from acetophenazine, S-adenosylmethionine, befloxatone,
bromperidol, bupropion, butaperazine, carphenazine, clopenthixol (c/s-isomer),
clospirazine, dixyrazine, fenpentadiol, fluanisone, flupentixol (c/s-form), fluphenazine,
fluspirilene, haloperidol, 5-hydroxytryptophan (oxitriptan), hypericin, melperone,
moperone, mosapramine, opipramol, penfluridol, pericyazine, perimethazine,
perphenazine, pipamperone, piperacetazine, pipotiazine, pyrisuccideanol, quetiapine,
roxindole, spiperone, sultopride, timiperone, toloxatone, tramadol, trifluperidol or
venlafaxine.
A representative example of the antidepressant is selected from bupropion, tramadol or
venlafaxine.
A representative example of the antidepressant is an antimaniac and antipsychotic
agent that is selected from haloperidol, quetiapine or trifluperidol.
Still further in the thirty-sixth embodiment, the anticonvulsant referred to in the thirtysecond
embodiment is selected from 4-amino-3-hydroxybutyric acid, atrolactamide,
buramate or ganaxolone.
Still further in the thirty-sixth embodiment, the antibacterial agent referred to in the
thirty-second embodiment is selected from amikacin, p-aminosalicylic acid, paminosalicylic
acid hydrazide, amoxicillin, apalcillin, apicycline, arbekacin, aspoxicillin,
azidamfenicol, azithromycin, bambermycins, benzoylpas, biapenem, 5-
bromosalicylhydroxamic acid, butirosin, cefadroxil, cefamandole, cefatrizine,
cefbuperazone, cefdinir, cefminox, cefonicid, cefoperazone, cefoselis, cefpiramide,
cefprozil, chloramphenicol, chloroxylenol, chlorquinadol, chlortetracycline, clofoctol,
clomocycline, cloxacillin, cloxyquin, clarithromycin, clindamycin, colistin, dalfopristin,
demeclocycline, deoxydihydrostreptomycin, diathymosulfone, dibekacin,
dihydrostreptomycin, dirithromycin, doxycycline, enviomycin, ertapenem, erythromycin
and its ester derivatives, ethambutol, flomoxef, forimicins, fropenem, fusidic acid,
gentamycin, glyconiazide, glucosulfone sodium, n4-beta-d-glucosylsulfanilamide,
gramicidin(s), guamecycline, imipenem, isepamicin, josamycin, kanamycin(s),
leucomycins, lincomycin, lymecycline, meclocycline, merbromin, meropenem,
methacycline, micronomicin, midecamycins, mikamycin, minocycline, miokamycin,
moxalactam, nadifloxacin, neomycin, netilmicin, nifurpirinol, nifurtoinol, nitroxoline,
novobiocin, oleandomycin, oxytetracycline, panipenem, paromomycin, phenyl
aminosalicylate, pipacycline, polymyxin, primycin, pristinamycin, quinupristin,
ramoplanin, ribostamycin, rifabutin, rifalazil, rifamide, refampicin, rifamycin sv, rifampin,
rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin, rolitetracycline, rosaramicin,
roxarsone, roxithromycin, salazosulfadimidine, salinazid, sancycline, sisomicin,
spectinomycin, spiramycin, streptolydigin, streptomycin, streptonicozid, sulfaloxic acid,
4-sulfanilamidosalicylic acid, 2-p-sulfanilylanilinoethanol, teicoplanin, telithromycin,
thiamphenicol, thiostrepton, tobramycin, trospectomycin, tuberactinomycin, tyrocidine,
vancomycin, viomycin, virginiamycin, xanthocillin or xibornol.
A representative example of the anti-bacterial agent is selected from amoxicillin,
azithromycin, cefadroxil, cefpiramide, chloramphenicol, clarithromycin, clindamycin,
cloxacillin, doxycycline, ethambutol, nadifloxacin, neomycin, oxytetracycline,
panipenem, refampicin, rifaximin, spiramycin, streptomycin or vancomycin.
Still further in the thirty-sixth embodiment, the antifungal agent referred to in the thirtysecond
embodiment is selected from acrisorcin (9-aminoacrindine compound with 4-
hexylresorcinol ( 1 :1)), amphotericin B, anidulafungin, bromosalicylchloranilide,
buclosamide, candicidin, caspofungin, chlorphenesin, ciclopirox, dermostatin,
griseofulvin, filipin, fluconazole, fungichromin, mepartricin, micafungin, natamycin,
nystatin, lucensomycin, pecilocin, perimycin, posaconazole, ravuconazole, rubijervine,
salicylanilide, siccanin, 2,4,6-tribromo-m-cresol, tubercidin, viridian or voriconazole.
Still further in the thirty-sixth embodiment, the antiviral agent referred to in the thirtysecond
embodiment is selected from abacavir, acyclovir, adefovir, amprenavir,
atazanavir, cidofovir, didanosine, dideoxyadenosine, edoxudine, emtricitabine,
entecavir, floxuridine, ganciclovir, idoxuridine, indinavir, kethoxal, lamivudine, lopinavir,
5-(methylamino)-2-deoxyuridine (madu), nelfinavir, nevirapine, penciclovir,
podophyllotoxin, resiquimod, ribavirin, ritonavir, saquinavir, sorivudine, stavudine,
tenofovir, tipranavir, trifluridine, tromantadine, valganciclovir, vidarabine, zalcitabine,
zanamivir or zidovudine.
A representative example of the antiviral agent is selected from abacavir, acyclovir,
adefovir, amprenavir, cidofovir, didanosine, emtricitabine, ganciclovir, indinavir,
lamivudine, lopinavir, nelfinavir, nevirapine, penciclovir, ritonavir, saquinavir, stavudine,
tenofovir, valganciclovir, vidarabine, zalcitabine, zanamivir or zidovudine.
Still further in the thirty-sixth embodiment, the antimalarial agent referred to in the thirtysecond
embodiment is selected from amodiaquine, arteflene, artemisinin alcohol,
bebeerines, cinchonidine, cinchonine, dihydroartemisinin, fosmidomycin, gentiopicrin,
halofantrine, hydroxychloroquine, lumefantrine, mefloquine, pyronaridine, quinine or
yingzhaosu A.
Still further in the thirty-sixth embodiment, the antidiabetic agent referred to in the thirtysecond
embodiment is selected from acarbose, acetohexamide, miglitol, troglitazone or
voglibose.
Still further in the thirty-sixth embodiment, the antiulcer agent (including proton pump
inhibitors) referred to in the thirty-second embodiment is selected from arbaprostil,
enprostil, misoprostol, ornoprostil, gama-oryzanol A, plaunotol , rebamipide, rioprostil,
rosaprostol, spizofurone (i.e. , hydroxyl of its oxime derivative), telenzepine, teprenone
(i.e. , hydroxyl of its oxime derivative) or trimoprostil.
Still further in the thirty-sixth embodiment, the antioxidant (including free radical
scavengers) referred to in the thirty-second embodiment is selected from N-acetyl
carnosine, ascorbic acid, BN-82451 , L-carnitine (levocarnitine), curcumin, dexanabinol,
edaravone, (-) epigallocatechin gallate, emoxipin , hydroxytyrosol, idebenone, luteolin,
nicanartine, NZ-41 9, oxyresveratrol, probucol (including probucol prodrugs such as
AGI-1 067 and AGI-1 096), quercetin, reductic acid, silybin, SCMC-Lys, tempol (4-
hydroxy-tempo), alfa-tocopherol (vitamin E) or zeatin.
Still further in the thirty-sixth embodiment, the vitamin referred to in the thirty-second
embodiment is selected from ascorbic acid, cobamamide (vitamin B2 coenzyme),
cyanocobalamin (vitamin B 2) , ergosterol (provitamine D), fursultiamine (thiamine
tetrahydrofurfuryl disulfide) , hydroxocobalamin (vitamin B12a) , 1ahydroxycholecalciferol,
( 1oc-hydroxyvitamin D3) , inositol (vitamin B complex) , menadiol
(dihydrovitamin K3) , menaquinones or vitamin K2 (hydroxyl of its ketoxime),
methylcobalamin, octotiamine, pantothenic acid (vitamin B5) , phylloquinone (hydroxyl of
its ketoxime), prosultiamine (dithiopropylthiamine or DTPT or TPD) , pyridoxine
hydrochloride (vitamine B6 hydrochloride) , pyridoxal 5-phosphate, riboflavin (vitamin B2
or vitamin G or lactoflavin), riboflavin monophosphate (vitamin B2 phosphate), vitamin
A, vitamin D2, vitamin D3, vitamin K5, thiamine (vitamin B ) , thiamine disulfide (vitamin
- disulfide) or oc-tocopherol (vitamin E supplement).
As has been indicated hereinabove that the twenty-second embodiment also
encompasses within its scope a compound of formula (I) wherein the drug containing a
hydroxyl group is selected from the group of drugs belonging to several other
therapeutic areas (including those drugs that are classified on the basis of their
mechanism of action). Thus, for the purpose of this invention, the twenty-sixth
embodiment also encompasses a compound of formula (I); wherein the drug containing
hydroxyl group is generically selected from drugs falling under several other therapeutic
areas (including those drugs that are classified on the basis of their mechanism of
action) and is specifically selected from: an abortifacient/interceptive selected from
epostane, gemeprost, mifepristone, prostaglandin E or sulprostone; an anabolic agent
selected from androisoxazole, androstenediol, bolandiol, bolasterone, clostebol,
ethylestrenol, formebolone, mestanolone, methandriol, methenolone, methyltrienolone,
nandrolone, norbolethone, oxabolone, quinbolone or trenbolone; an androgen selected
from boldenone, cloxotestosterone, fluoxymesterone, mesterolone,
methandrostenolone, 17-methyltestosterone, 17oc-methyltestosterone 3-cyclopentyl
enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone,
oxymetholone, stanolone, stanozolol, testosterone or tiomesterone; an anesthetic
selected from biphenamine, chloral hydrate, ecgonine, -hydroxybutyrate (-
hydroxybutyric acid), hydroxytetracaine, ketamine , lidocaine, methohexital sodium,
orthocaine, oxethazaine, pentobarbital, polidocanol, pregnan-3 -ol-20-one, propofol,
propipocaine, salicyl alcohol, thialbarbital, thiamylal or thiobutabarbital; an anorexic
agent selected from diethylpropion, norpseudoephedrine, diphemethoxidine,
metamfepramone or mazindol; an anthelmintic agent selected from aspidin, aspidinol,
becanthone, dichlorophen, 4-hexylresorcinol, ivermectin, niclosamide, oxantel,
triclofenol piperazine, hycanthone, lucanthone, oxamniquine or trichlorfon; an anti-acne
agent selected from algestone acetophenide or cioteronel; an anti-alopecia agent
selected from cioteronel , cioteronel or finasteride; an antiamebic agent selected from
arsthinol, bialamicol, chlorbetamide, chlorphenoxamide, diloxanide, 8-hydroxy-7-iodo-5-
quinolinesulfonic acid, iodoquinol, thiocarbamizine, glycobiarsol, secnidazole or
tetracycline; an antiandrogen agent selected from bicalutamide, bifluranol, cioteronel,
cyproterone, delmadinone acetate, nilutamide, osaterone or oxendolone; an
antiarthritic/antirheumatic agent selected from aurothioglucose, glucosamine,
bucillamine or kebuzone; an antiasthmatic agent selected from beclomethasone,
budesonide, cromolyn, dexamethasone, formoterol, flunisolide, ibudilast, ketotifen,
montelukast, nedocromil, oxatomide, pranlukast, seratrodast, suplatast tosylate,
tiaramide, traxanox, triamcinolone acetonide, zafirlukast or zileuton; an antidiarrheal
agent selected from catechin, loperamide or mebiquine; an antidiuretic drug selected
from desmopressin, lypressin, ornipressin, oxycinchophen, terlipressin or vasopressin;
an antiemetic agent selected from diphenidol, nabilone, ondansetron, oxypendyl or
tetrahydrocannabinols; an antiglaucoma agent selected from bimatoprost, latanoprost,
levobunolol, travoprost or unoprostone; an antigout/uricosuric agent selected from
allopurinol, benzbromarone, colchicine, sulfinpyrazone or oxycinchophen; an
antihyperparathyroid drug selected from doxercalciferol, maxacalcitol or paricalcitol; an
antihyperthyroid drug such as thibenzazoline; an antihypothyroid drug selected from
tiratricol or thyroxine; an antimigraine agent selected from methysergide or
flumedroxone acetate; an antimuscarinic/mydriatic agent selected from atropine,
benactyzine, benzilonium bromide, bevonium methyl sulfate, biperiden, butropium
bromide, n-butylscopolammonium bromide, cimetropium bromide, cinnamedrine,
clidinium bromide, cyclodrine, cyclopentolate, dexetimide, difemerine, eucatropine,
fentonium bromide, flavoxate, flutropium bromide, glycopyrrolate, hexocyclium methyl
sulfate, homatropine, hyoscyamine, ipratropium bromide, mepenzolate bromide,
methscopolamine bromide, oxybutynin, oxyphencyclimine, oxyphenonium bromide,
oxitropium bromide, penthienate bromide, phenglutarimide, pipenzolate bromide,
piperilate, poldine methylsulfate, procyclidine, scopolamine, scopolamine n-oxide,
telenzepine, tiemonium iodide, tiotropium bromide, tolterodine, tridihexethyl iodide,
trihexyphenidyl hydrochloride, tropicamide or trospium chloride; an antiosteoporotic
agent selected from alendronic acid, etidronic acid, ibandronic acid, pamidronic acid,
raloxifene, risedronic acid or zoledronic acid; an antiprostatic hypertrophy agent
selected from gestonorone caproate , mepartricin, osaterone or oxendolone; an
antiprotozoal agent selected from acetarsone, acranil®, anisomycin,
hydroxystilbamidine, melarsoprol, mepartricin, /V-methylglucamine, metronidazole,
nifuroxime, oxophenarsine hydrochloride, puromycin or secnidazole; an antipruritic
agent selected from camphor, dichlorisone, halometasone, 3-hydroxycamphor,
menthol, phenol or polidocanol; an antipsoriatic agent selected from anthralin, 6-
azauridine, calcipotriene, chrysarobin, maxacalcitol, pyrogallol or tacalcitol; an
antiseborrheic agent selected from chloroxine, piroctone, resorcinol or tioxolone; an
antiseptic agent selected from acetomeroctol, benzoxonium chloride, bibrocathol,
broxyquinoline, cethexonium bromide, 4-chloro-m-cresol, dichlorobenzyl alcohol,
ethylhydrocupreine, hexachlorophene, 8-hydroxyquinoline, isopropyl alcohol, mandelic
acid, meralein sodium, mercurophen, 2-naphthyl salicylate, nitroakridin 3582,
noxythiolin, oxymethurea, phenoxyethanol, polynoxylin, pyrocatechol, o -terpineol,
thymol or triclosan; an antispasmodic agent selected from amprotropine phosphate,
benactyzine, benzilonium bromide, bevonium methyl sulfate, butropium bromide, nbutylscopolammonium
bromide, cimetropium bromide, cinnamedrine, clidinium
bromide, difemerine, fentonium bromide, flopropione, glycopyrrolate, hexocyclium
methyl sulfate, hyoscyamine, levomepate, mepenzolate bromide, methscopolamine
bromide, oxyphencyclimine, oxyphenonium bromide, penthienate bromide,
phloroglucinol, pipenzolate bromide, piperilate, poldine methylsulfate, propenzolate,
rociverine, sultroponium, tiemonium iodide, tridihexethyl iodide, tropenzile, flavoxate,
tricromyl or trospium chloride; an antitussive agent selected from chlophedianol,
clobutinol, cyclexanone , dropropizine, drotebanol, eprazinone, pholcodine, zipeprol,
amicibone, morclofone or normethadone; an antiulcerative agent selected from
acetoxolone, aldioxa, carbenoxolone, enprostil, misoprostol, ornoprostil, plaunotol,
rioprostil, rosaprostol, rotraxate, teprenone, trimoprostil, spizofurone or -oryzanol; an
anxiolytic agent selected from azacyclonol, clorazepic acid (enol-form), enciprazine,
ethyl loflazepate (enol-form), flesinoxan, flutazolam, hydroxyphenamate, hydroxyzine,
lorazepam, mecloralurea or oxazepam; an astringent selected from alkannin, baicalein,
bismuth subgallate or tannic acid; a cathartic drug/laxative selected from aloe-emodin,
aloin, bisoxatin acetate, cellulose ethyl hydroxyethyl ether, colocynthin, danthron,
emodin, frangulin, glucofrangulin, oxyphenisatin acetate, phenolphthalein,
phenolphthalol, sennosides or phenoltetrachlorophthalein; a choleretic agent selected
from alibendol, cholic acid, cyclobutyrol, cyclovalone, cynarin(e), dehydrocholic acid,
deoxycholic acid, oc-ethylbenzyl alcohol, exiproben, febuprol, fencibutirol, fenipentol,
hymecromone, menbutone, osalmid, 4,4'-oxydi-2-butanol, 4-salicyloylmorpholine,
taurocholic acid, vanitiolide, trepibutone or metochalcone; a cholinergic agent selected
from muscarine, edrophonium chloride or dexpantheno; a contraceptive or progestogen
drug selected from allylestrenol, anagestone, chlormadinone acetate, delmadinone
acetate, demegestone desogestrel, dienogest, dimethisterone, drospirenone,
dydrogesterone, elcometrine, ethinyl estradiol, ethisterone, ethynodiol, etonogestrel,
flurogestone acetate, gestodene, gestonorone caproate, 17-hydroxy-1 6-methylene-A6-
progesterone, 17oc-hydroxyprogesterone, lynestrenol, medrogestone,
medroxyprogesterone, megestrol acetate, mestranol, norethindrone, norethynodrel,
norgesterone, norgestimate, norgestrel, norgestrienone, norvinisterone, pentagestrone,
progesterone, promegestone or trengestone; a decongestant drug selected from
amidephrine, cafaminol, ephedrine, epinephrine, nordefrin, oxymetazoline,
phenylephrine, phenylpropanolamine or pseudoephedrine; an emetic agent selected
from apocodeine or cephaeline; an enzyme cofactor selected from dexpanthenol,
fursultiamine, octotiamine, pantothenic acid, prosultiamine, pyridoxal 5-phosphate,
pyridoxine hydrochloride, riboflavin, riboflavin monophosphate, sapropterin, thiamine or
thiamine disulfide; an estrogen drug selected from benzestrol , colpormon, dienestrol
trans-trans- ) equilenin, equilin, estradiol, estriol, estrone, ethinyl estradiol,
hexestrol, mestranol, methestrol, moxestrol, mytatrienediol, quinestradiol or quinestrol ;
an expectorant drug selected from ambroxol, guaiacol, iodinated glycerol or
guaifenesin ; a gastroprokinetic drug such as alvimopan ; a hemostatic agent selected
from adrenalone, algin, aminochromes, carbazochrome salicylate, carbazochrome
sodium sulfonate, cephalins, cotarnine, ellagic acid, ethamsylate, oxidized cellulose or
vapreotide ; a hepatoprotective drug selected from S-adenosylmethionine, catechin or
silymarin ; an immunomodulator selected from amiprilose, lisofylline, ubenimex, inosine
pranobex, bropirimine, lentinan, mitoxantrone, romurtide or thymopentin ; an
immunosuppressant selected from everolimus, gusperimus, mizoribine, mycophenolic
acid, rapamycin or tacrolimus; a mucolytic selected from domiodol or sobrerol; a muscle
relaxant drug selected from chlorzoxazone, eperisone, idrocilamide, inaperisone,
mephenesin, methocarbamol, tolperisone or dantrolene; a mydriatic drug such as
yohimbine; a narcotic antagonist agent selected from cyclazocine, levallorphan ,
nalmefene, nalorphine, naloxone or naltrexone; a neuroprotective agent selected from
lubeluzole or citicoline; a nootropics/cognition enhancer drug selected from bemegride,
choline alfoscerate, curcumin, donepezil , ethamivan, exifone, hexacyclonate sodium,
homocamfin , idebenone, nizofenone, oxiracetam , pipradrol, propentofylline pyritinol,
pyrovalerone, sabeluzole, sulbutiamine or velnacrine ; a prostaglandin analog selected
from beraprost, carboprost, clinprost, enprostil, gemeprost, latanoprost, limaprost,
misoprostol, ornoprostil, prostacyclin , prostaglandin E-| , prostaglandin E2,
prostaglandin F rioprostil, rosaprostol, trimoprostil or unoprostone; a respiratory
stimulating agent selected from dimefline, lobeline, mepixanox or pimeclone; a
sedative/hypnotic drug selected from aldol, allobarbital, amobarbital, aprobarbital,
apronalide, barbital, brallobarbital, butabarbital sodium , butalbital, butallylonal, butethal,
butoctamide, carbubarb, chloral formamide, oc-chloralose, cinolazepam, cyclobarbital,
cyclopentobarbital , doxefazepam , ectylurea, enallylpropymal, ethchlorvynol,
febarbamate, 5-furfuryl-5-isopropylbarbituric acid, glutethimide, haloxazolam,
heptabarbital, hexethal sodium, hexobarbital, hexapropymate, homofenazine,
lormetazepam , methyprylon, narcobarbital , nealbarbital, pentaerythritol chloral,
pentobarbital, phenallymal , piperidione, propallylonal , propiomazine proxibarbal,
pyrithyldione reposal, secobarbital sodium, talbutal, temazepam, tetrabarbital, 2,2,2-
trichloroethanol, vinbarbital sodium or vinylbital; a vulnerary drug selected from
allantoin, chitin, dextranome or thioglycerol; an a-adrenergic agonist agent selected
from adrafinil, dipivefrin, hydroxyamphetamine, mivazerol, norfenefrine, octopamine,
pseudoephedrine, pholedrine, synephrine or tyramine; a -adrenergic agonist agent
selected from albuterol (salbutamol), bitolterol, carbuterol, clenbuterol, clorprenaline,
dioxethedrine, etafedrine, ethylnorepinephrine, fenoterol, hexoprenaline, isoetharine,
isoproterenol, mabuterol, metaproterenol, pirbuterol, procaterol, protokylol, reproterol,
rimiterol, ritodrine, soterenol, terbutaline, tretoquinol, tulobuterol or xamoterol; an o -
adrenergic blocker drug selected from labetalol, naftopidil or trimazosin; a dopamine
receptor agonist drug selected from apomorphine, quinagolide or ropinirole; a
dopamine receptor antagonist drug such as iloperidone; a gonad-stimulating agent
selected from epimestrol or LH-RH; a 5-Lipoxygenase inhibiting agent such as tenidap;
a matrix metalloproteinase inhibiting agent selected from batimastat or prinomastat; a
monoamine oxidase inhibiting agent such as toloxatone; a NMDA receptor antagonist
such as licostinel; a prolactin inhibiting agent such as bromocriptine; a reverse
transcriptase inhibiting agent such as zalcitabine; a serotonin receptor agonist such as
ergotamine; a serotonin receptor antagonist selected from dolasetron or ketanserin
and a topoisomerase I inhibitor such as 9-aminocamptothecin.
In a thirty-seventh embodiment, the invention encompasses a compound of formula (I),
wherein: D is a drug containing a sulfhydryl group capable of forming a bio-cleavable
covalent linkage with a linker;
X1 is sulphur;
Y is C=0;
each X2; Z1; Z2; A, R1 and R2 is as defined in the first embodiment hereinabove;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0; and
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirty-eighth embodiment, the invention encompasses a compound of formula (I),
wherein: each of D and X1 is as defined in the thirty-seventh embodiment hereinabove;
Each of X2; Y, Z1; Z2; A, R1 and R2 is as defined in the second embodiment
hereinabove;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a thirty-ninth embodiment, the invention encompasses a compound of formula (I),
wherein: each of D and X1 is as defined in the thirty-seventh embodiment hereinabove;
each of X2; Y, Z1; Z is as defined in the second embodiment hereinabove;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH or
CR R10 ; where R and R10 are independently selected from hydrogen or C -6 alkyl;
provided that when A is S, then a and b is 3;
R1 is hydrogen and R2 is alkyl; or R2 is hydrogen and R1 is alkyl;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a fortieth embodiment, the invention encompasses a compound of formula (I),
wherein: each of D, X1, X2, Y, Z1 and Z2 is as defined in the thirty-eighth embodiment
hereinabove,
A is selected from a bond, CH=CH or CR R10 ; where R9 and R10 are independently
selected from hydrogen or C _6 alkyl;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a forty-first embodiment, the invention encompasses a compound of formula (I),
wherein: each of D, X1, X2, Y, Z1 and Z2 is as defined in the thirty-eighth embodiment
hereinabove,
A is selected from S, SO, S0 2 or S-S; provided that when A is S, then a and b is 3
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyi; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyi;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In forty-second embodiment, the invention encompasses a compound of formula (I),
wherein D, the drug containing a sulfhydryl group referred to in the thirty-seventh, thirtyeighth,
thirty-ninth, fourtieth and forty-first embodiments, is selected from cardiovascular
agents or glucocorticoids. The forty-second embodiment also encompasses within its
scope a drug containing a sulfhydryl selected from the drugs that belong to several
other therapeutic areas (including those drugs that are classified on the basis of their
mechanism of action). In this embodiment, other variables X1, X2, Y, Z1, Z2, A, R1 and
R2 in the compounds of formula (I) are as defined above; with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In forty-third embodiment, the cardiovascular agent referred to in the forty-second
embodiment is selected from captopril or omapatrilat. Further, in this embodiment the
glucocorticoid referred to in the forty-second embodiment is selected from tixocortol.
For the purpose of this invention, the forty-second embodiment also encompasses a
compound of formula (I); wherein the drug containing sulfhydryl group is generically
selected from the group of drugs falling under several other therapeutic areas (including
those drugs that are classified on the basis of their mechanism of action) and is
specifically selected from an anesthetic selected from buthalital sodium hydroxydione
sodium, thialbarbital (Intranarcon), thiamylal, thiobutabarbital or thiopental sodium; an
antiarthritic/antirheumatic agent selected from bucillamine or penicillamine; an
antihyperthyroid drug selected from methimazole, propylthiouracil or thiobarbital; an
antiseborrheic agent such as pyrithione; an antiseptic drug selected from noxythiolin or
thiocresol; a hepatoprotective agent such as tiopronin; an immunomodulator such as
bucillamine or a vulnerary drug such as thioglycerol.
In a specific embodiment, the invention encompasses a bio-cleavable linker
represented herein by the compounds of formula (IA) which is capable of forming biocleavable
covalent linkage with a drug having a carboxylic acid, hydroxyl, amino or
sulfhydryl group:
R 2 N0 2
X2 is a bond, oxygen or NR3;
R3 is a bond or hydrogen;
=0 or a spacer group selected from:
where in the spacer groups of formulae (Ya) to (Y) :
R4 is a bond, hydrogen, alkyl or a metal ion;
R5 is hydrogen, methyl or phenyl;
R6 is hydrogen or a side-chain group of naturally occurring amino acids selected
from:
-CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C0 2H, -CH2CH2C0 2H, -
CH2OH, -CH(CH3)OH, -CH2SH, -CH2CH2SCH3, -CH2CH2CH2CH2NH2, -C6H5, -
CH2C6H5, -CH2C6H4-p-OH, -CH2CH2CH2NHC(=NH)NH2, -CH2C(=0)NH 2, -
CH2CH2C(=0)NH 2, -CH2-indol-3-yl or -CH2-imidazole;
X3 is oxygen, sulphur, SO, S0 2 or NR3;
R7 is hydrogen or an amino protecting group selected from: acetyl, benzoyl,
alkyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or its
pharmaceutically acceptable ammonium salts;
R8 is hydrogen or methyl;
c is an integer from 0 to 2;
is an integer from 1 to 5;
e is an integer from 1 to 4;
Z1 is (CH2)a; where a is an integer from 0 to 3;
Z2 is (CH2)b; where_b is an integer from 0 to 3;
A is selected from: bond, S, SO, S0 2, S-S, CH=CH, D-isosorbide skeleton, 1,4-
anhydroerythritol skeleton, cycloalkylene , CR R10 , C6-C 0-arylene, a 5- or 6-membered
heteroarylene or a 5- or 6-membered heterocyclylene wherein said arylene,
heteroarylene and heterocyclylene may be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of C -6 alkyl, C -6 alkoxy,
hydroxy, trifluoromethyl, cyano, amino and halogen ;
R and R10 are independently selected from: hydrogen or C _6 alkyl; or R and R10 taken
together with the carbon atom to which they are attached form a cycloalkyi or a
heterocyclic ring;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyl; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyl;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In an embodiment of the specific embodiment, the invention encompasses a compound
of formula (IA), wherein:
X2 is oxygen;
Y is C=0;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkyi or CR R10 ;
where R9 and R10 are independently selected from hydrogen or C -6 alkyl; or R9 and
R10 taken together with the carbon atom to which they are attached constitute a
cycloalkyi group or a 5- or 6- membered heterocyclic ring containing one to two hetero
atoms selected from oxygen, sulfur or nitrogen;
R1 is hydrogen and R2 is alkyl, cycloalkyi, aryl or aralkyl; or R2 is hydrogen and R1 is
alkyl, cycloalkyi, aryl or aralkyl;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In a further embodiment of the specific embodiment, the invention encompasses a
compound of formula (IA), wherein:
X2 is oxygen;
Y is C=0;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkyi or CR R10 ;
where R and R10 are independently selected from hydrogen or C -6 alkyl; or R and
R10 taken together with the carbon atom to which they are attached constitute a
cycloalkyi group or a 5- or 6- membered heterocyclic ring containing one to two hetero
atoms selected from oxygen, sulfur or nitrogen;
R1 is hydrogen and R2 is alkyl; or R2 is hydrogen and R1 is alkyl;
with the provisos that:
a) when A is S, then a and b is 3; or
b) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In yet another embodiment of the specific embodiment, the invention encompasses a
compound of formula (IA), wherein
X2 is oxygen;
Y is C=0;
A is selected from a bond, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridine,
3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, S, SO, S0 2, S-S, CH=CH or
CR R10 ; where R9 and R10 are independently selected from hydrogen or C -6 alkyl;
provided that when A is S, then a and b is 3.
R1 is hydrogen and R2 is alkyl; or R2 is hydrogen and R1 is alkyl;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
In yet another further embodiment of the specific embodiment, the invention
encompasses a compound of formula (IA), wherein
X2 is oxygen;
Y is C=0;
A is selected from a bond, CH=CH or CR R10 ; where R and R10 are independently
selected from hydrogen or C _6 alkyl;
R1 is hydrogen and R2 is alkyl; or R2 is hydrogen and R1 is alkyl;
in all its stereoisomeric forms and pharmaceutically acceptable salts thereof.
It would be understood by a person of skill in the art that in the compounds of formula
(IA) when Y is "CO" or designate any other group that contain a "CO", then the "CO"
must have been derived from a carboxyl-containing drug D.
In specific embodiments, the invention encompasses a compound of formula (I) from
the following compounds:
(a) Compounds of formula (I) whererin D is a drug containing a carboxylic acid group:

I-CD1 -L1 4-R1
(Mixture of diastereomers)
(Mixture of diastereomers)
(Mixture of diastereomers)
(b) Compounds of formula (I) whererin D is a drug containing an amino group :
I-AD7-L2-R1
(c) Compounds of formula (I) whererin D is a drug containing a hydroxy group :

In a specific embodiment, the invention encompasses linker compounds of formula (IA)
from the following group of representative linkers:
1A-L1 0-R1 IA-L1 1-R1
IA-L1 4-R1 IA-L1 5-R1
Mixture of diastereomers) (Mixture of diastereomers)
* Point of attachment to a suitable drug residue.
The compound of formula (I) and the bio-cleavable linker of formula (IA) contain
asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. In
the structures shown herein, where the stereochemistry of any particular chiral atom is
not specified, then all stereoisomers are contemplated and included as the compounds
of the invention. The term "chiral" refers to molecules which have the property of nonsuperimposability
of the mirror image cohort, while the term "achiral" refers to
molecules which are superimposable on their mirror image partner. It is intended that all
stereoisomeric forms of the compounds of the invention, including but not limited to,
diastereomers and enantiomers, as well as mixtures thereof such as racemic mixtures,
form part of the present invention. Thus, compound of formula (I) and the linker of
formula (IA) according to the present invention which can exist as enantiomers can be
present in enantiomerically pure form, both as levorotatory and as dextrorotatory
antipodes, in the form of racemates and in the form of mixtures of the two enantiomers
in all ratios. In the case of cis/trans isomerism the compound of formula (I) and the biocleavable
linker of formula (IA) includes both cis and trans form as well as mixtures of
these forms in all ratios, preferably exists in cis form. The preparation of individual
stereoisomers of the compounds of the present invention i.e. the compound of formula
(I) and the bio-cleavable linker of formula (IA), can be carried out, if desired, by
separation of a mixture by methods known in the art. For instance, the racemic forms
can be resolved by physical methods, such as fractional crystallisation or separation by
chiral column chromatography. The individual optical isomers can be synthesised in the
optically pure form by the use of enzymes or through asymmetric synthesis. If, for
instance, a particular enantiomer of the compound of formula (I) of the present
invention is desired, it may be prepared by derivatisation with a chiral auxiliary whereby
the resulting diastereomeric mixture is separated and the auxiliary group cleaved to
provide the pure desired enantiomer. In case, the compound of formula (I) contains a
basic functional group such as amino or an acidic functional group such as carboxyl,
diastereomeric salts are formed with an appropriate optically active acid or base,
respectively. Consequently, compounds of formula I can exist in enantiomeric or
diastereomeric forms or in mixtures thereof. The processes for preparation can utilize
racemates, enantiomers or diastereomers as starting materials. When diastereomeric
or enantiomeric products are prepared, they can be separated by conventional methods
for example, chromatographic techniques or fractional crystallization.
The present invention also relates to processes for the preparation of the compounds of
formula (I) or pharmaceutically acceptable salts thereof. The compound of formula (I)
may be prepared by any of the general schemes 1-21 as outlined herein below. Unless
otherwise specified, the groups A, Z1, Z2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 , X1, X2,
X3, a, b, c, d, e are as defined in respect of formula (I) and/or formula (IA) above. The
starting materials and reagents employed in the processes for preparation of
compounds of formula (I) may be commercially available or may be prepared by
processes known in the art.
The symbols as used herein with particular reference to the processes for the
preparation of the compounds of formula (I) as illustrated in the following schemes 1 -
2 1 , are as described herein below:
> The drug containing carboxylic acid group is designated as Da (D-COOH) and its
derivatives are designated as Da i and Da respectively.
> The drug containing an amino group (D -Y- X1H, wherein Y is a bond, C=0, S0 2 or
O(CO); X1 = NR3 wherein R3 is a bond or H) is designated in general as Db. Further,
the drug containing a hydroxyl or sulfhydryl group (D - X1H, wherein X1 = O or S) is
designated herein as Dc. The derivatives of the drug Db are designated herein as Dbi
and Db2 respectively. The derivatives of the drug Dc are designated herein as Dci ,
DC2, DC3, DC4, Dc5, Dc6, Dc7, Dc8, Dc9, Dc10, Dc1 1, Dc12, Dc13, Dc14, Dc15, Dc16, Dc17, Dc18,
Dci9, Dc2o, Dc2i , Dc22, Dc 23, Dc 24, Dc25 and Dc26 respectively.
> The starting material or the precursors to the linker are denoted herein by the
symbols La, Lb, La , a2 a3 Lbi a C Lf and Lg, respectively.
> The linker is denoted herein by the symbol l and its derivative is denoted herein by
the symbol Le.
> The aldehyde, R1C(=0)R 2 (wherein, R1 and R2 are as defined above), the starting
material for the preparation of the o -chloroformate of formula (X) is denoted herein
by the symbol Sa.
> The precursor for the spacer groups are denoted herein by the symbols Sb, Sc, Sd,
Se, Sf, Sg, Sh, Si, Sj , Sk and Si, respectively.
> The derivative of the spacer group precursor Sb is denoted herein by the symbol Sb .
> The linker group obtained by coupling the linker with the spacer group precursor
or its derivatives (Sbi , Sc, Sd, Sh, S,, Sj and Sk) are denoted herein by the symbols
Lg , Lh, Li, Lk, Li, Lmand Ln, respectively.
> The linker group obtained by coupling the spacer group precursor Si and the linker
derivative Le is denoted herein by the symbol Ln.
> The intermediates obtained by coupling the drug, D (as defined herein) with the
a) linker precursors (as defined above), b) linker (as defined above), c) linker
derivatives d) spacer precursors (as defined above); and e) linker groups obtained
by coupling spacer precursors or its derivatives and the linker L 1 (as defined above)
are denoted by the symbols la, lb, lc, , le, If, lg, lh, i, l i , lj, lji, Ik, li, lm and ln,
respectively.
In one embodiment, the processes for the preparation of the compounds of formula (I),
wherein D is a drug containing a carboxylic acid functional group is provided herein
below. One such process for the preparation of the compound of formula (I), wherein D
is a drug containing a carboxylic acid group, consists of the following reaction steps as
outlined in the following Scheme 1:
Scheme 1
X
Step 1'
OR LG = Br B
H 0 \ / A \ / 0 H
L H
Z z Z1' R = H Z
(LG = a halide or tosylate, mesylate, etc.;
R = H or a hydroxy1 protecting group)
Step 2
Step 3
(I)
Step 1
This process step involves reacting an aldehyde represented by formula (Sa) (wherein,
R1 and R2 are as defined in any of the embodiments of the present invention), with
triphosgene (or phosgene or diphosgene or any other phosgene substitutes known to
those skilled in the art) in the presence of a suitable organic base for example, pyridine
at -10° to 40°C according to the method described in M.J. Coghlam and B. A. Caley,
Tetrahedron Letters, 1989, 2033-2036, to obtain the chloroformate of formula (X).
Step V
In this step, the linker La is converted to La wherein one of the hydroxyl group is
converted to a leaving group (LG) such as a halide or tosylate or mesylate and the
other hydroxyl group is either left unprotected or is protected by a suitable hydroxyl
protecting group and the processes used for the said conversions are generally known
to those skilled in the art of organic synthesis.
Step 2
In this step, the drug containing carboxylic acid group Da (D-COOH) is treated with
carbonyl chloride, for example oxalyl chloride, in the presence of an organic solvent, for
example, dichloromethane and dimethylformamide in catalytic amount to form a
reactive carbonyl derivative such as the acid chloride of formula Da i . Also, the
carboxylic acid group of the drug Da is converted to its carboxylate metal salt (Da2) , for
example, to a cesium salt. The drug containing carboxylic acid group (Da) or its reactive
acid chloride (Da ) is then directly coupled with the compound of formula (La) in the
presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC) and an
organic base, for example, triethylamine to form a compound intermediate (la) . The
reaction of the drug containing carboxylate metal salt (Da2) with linker intermediate La
(as obtained in step 1' above) in the presence of an organic solvent, for example
dimethylformamide (DMF) to obtain a compound of formula (la) .
Step 3
The compound intermediate (la) as obtained in step 2 above is further reacted with the
chloroformate (X) obtained in step 1 above in the presence of an organic base, for
example, pyridine and an organic solvent, for example, dichloromethane (DCM) to
obtain the intermediate compound (la ) . The resulting compound (la ) is subjected to
nitration using silver nitrate in the presence of an organic solvent, for example,
acetonitrile to form the compound of formula (I), and if desired, the compound of
formula (I) is converted to its pharmaceutically acceptable salt.
In scheme 1, the variables D, R1, R2, Z1, Z2 and A are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing carboxylic acid group.
Alternatively, the compounds of formula (I), wherein D is a drug containing a carboxylic
acid group, can be prepared in accordance with a process involving the reaction steps
depicted in the following Scheme 2.
Scheme 2
Step 1: Synthesis of linker Intermediates L and L
Step 2: Synthesis of Drug-acid chloride
D— COOH D— COCI
Dal
Step 3:
Method A :
M
Step 1
In this step, the linker (l_ ) containing ON0 2 group is produced by: (i) reacting -
chloroformate (X) (as obtained in step 1 of Scheme 1) with a compound of formula (La)
in the presence of a base, for example, pyridine and a solvent, for example,
dichloromethane (DCM) to obtain the compound of formula (La ) ; and (ii) subjecting the
resultant compound of formula (La i ) to nitration using silver nitrate in the presence of an
organic solvent, for example, acetonitrile.
Step 2
In this step, the drug containing carboxylic acid group Da is converted to its reactive
carbonyl derivative such as an acid chloride of formula (Da i ) as depicted in Step 2,
Scheme 1.
Step 3
Method A:
The drug Da is directly coupled with the linker of formula (La i ) , as obtained in step 1
above, in the presence of a coupling agent, for example, N,N-dicyclohexylcarbodiimide
(DCC) and an organic base, for example, 4-dimethylaminopyridine (DMAP) to form the
compound of formula (la i ) . Alternatively, treatment of the acid chloride (Da ) with the
linker of formula (La ) in the presence of a base, for example triethylamine also gives
the compound of formula (la i ) . Finally, the resulting compound (la ) is subjected to
nitration using silver nitrate in the presence of an organic solvent, for example
acetonitrile to form the compound of formula (I), and if desired, the compound of
formula (I) is converted to its pharmaceutically acceptable salt.
Method B:
In this method, the drug (Da) is directly coupled with the linker of formula ( ), as
obtained in step 1 above, in the presence of a coupling agent, for example, N,Ndicyclohexylcarbodiimide
(DCC) and an organic base, for example, 4-
dimethylaminopyridine (DMAP) to form the compound of formula (I). Alternatively,
treatment of acid chloride (Da ) with the linker of formula ( ) in the presence of a base,
for example triethylamine also gives the compound of formula (I) , and if desired, the
compound of formula (I) is converted to its pharmaceutically acceptable salt.
In scheme 2, the variables D, R1, R2, Z1, Z2 and A are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing carboxylic acid group.
Another process for the preparation of compound of formula (I), wherein D is a drug
containing a carboxylic acid group, can be prepared in accordance with a process
involving the reaction steps depicted in the following Scheme 3.
Scheme 3
Step 1
La: X2 = O x =o
Lh: X2 = NR3 L 1: X2 = NR3
Step 2
+ = Na+, K+, Cs+ or Ca2+) La2: X2 = O
Lbl : X2 = NR3
O
o
Step 1
In this step, the linkers of formula La (X2 = O) and Lb (X2 = NR3, wherein R3 is as defined
above) is reacted with a-chloro acetyl chloride (ACAC) in the presence of a base, for
example, triethylamine and a solvent, for example, dichloromethane (DCM), to obtain
the respective compounds of formula La2 (X2 = O) and Lb i (X2 = NR3, wherein R3 is as
defined above).
Step 2
The drug Da is treated with a metal carbonate, for example, cesium carbonate or
calcium carbonate, in the presence of an organic solvent, for example, N,Ndimethylformamide
(DMF), to form the corresponding cesium or calcium salt of the drug
(designated as Da2) . The resultant cesium or calcium salt of the drug (Da2) is directly
coupled with the compounds of formula a and Lbi as obtained in the above step 1, in
the presence of an organic solvent, for example DMF, to obtain an intermediate
compound (lb) (wherein X2 = O or NR3, wherein R is as defined above).
Step 3
The compound of formula (lb) as obtained in step 2 above is further reacted with the
chloroformate (X) (as obtained in step 1 of Scheme 1) to obtain another intermediate
compound (lbi ) . The intermediate compound (lbi ) is further subjected to nitration in the
presence of silver nitrate and acetonitrile to obtain the compound of formula (I).
In scheme 3, the variables D, R1, R2, Z1, Z2 and A are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing carboxylic acid group.
Another process for the preparation of compound of formula (I), wherein D is a drug
containing a carboxylic acid group, can be prepared in accordance with a process
involving the reaction steps depicted in the following Scheme 4.
Scheme 4
Step 1
Step 3
Step 1
In this step, the drug Da or its reactive carbonyl chloride derivative (Da i ) (as obtained in
step 2 of Scheme 1) is coupled with the compound of formula (Lc) in the presence of a
coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC) or an organic base,
for example, triethylamine to obtain an intermediate compound (lc) .
Step 2
The intermediate compound (lc) as obtained in step 1 above is subjected to reduction
using sodium borohydride in the presence of a solvent, for example, methanol, to form
intermediate compound ( lc i ) .
Step 3
The compound intermediate (lc i ) is further reacted with the chloroformate (X) (as
obtained in step 1 of Scheme 1) in the presence of an organic solvent, for example,
dichloromethane (DCM), and an organic base, for example, pyridine, to obtain an
intermediate compound (lC2). The intermediate compound (lC2) is subjected to nitration
using silver nitrate and in the presence of an organic solvent, for example, acetonitrile
to form a compound of formula (I).
In scheme 4, the variables D, R1, R2, Z1, Z2 and A are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing carboxylic acid group.
An alternative process for the preparation of compound of formula (I), wherein D is a
drug containing a carboxylic acid group and the variable A is D-isosorbide skeleton, can
be prepared in accordance with a process involving the reaction steps depicted in the
following Scheme 5.
Scheme 5
Step 1
(I)
Step 1
In this step, the reactive carbonyl derivative i.e. the acid chloride Da i of the drug Da (as
obtained in step 2 of Scheme 1) is reacted with isosorbide-5-mononitrate (Ld) in the
presence of an organic base, for example, triethylamine and an organic solvent, for
example, toluene at a temperature of 0° -15 °C for a period of 24 hours according to
the method described in the reference J. F. Gilmar et al., Eur J Pharm Sci 2001 , 14,
221-227, to form the intermediate compound (ld) . The cited reference is incorporated
herein by reference.
Step 2
The intermediate compound (ld) as obtained in step 1 above is further subjected to
reduction using a hydrogenation catalyst, 10% palladium/carbon ( 10 % Pd on C) in the
presence of an organic solvent selected from methanol or ethyl acetate according to the
procedure described in the reference L M Moriarty et al., J Med Chem 2008, 5 1, 7991 -
7999, to obtain another intermediate compound (ldi ) . The cited reference is
incorporated herein by reference.
Step 3
The compound intermediate (ldi ) , as obtained in step 2 above, is further reacted with o -
chloroformate (X) (as obtained in step 1 of scheme 1) in the presence of an organic
solvent, for example, dichloromethane (DCM) and an organic base, for example,
pyridine to produce the intermediate compound (ld2)- The intermediate compound (ld2)
is subjected to nitration using silver nitrate and in the presence of an organic solvent,
for example, acetonitrile to obtain the compound of formula (I).
In scheme 5, the variables D, R1, R2, Z1 and Z2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing a carboxylic acid group.
Another process for the preparation of compound of formula (I), wherein D is a drug
containing a carboxylic acid group and the variable A is S, SO or S0 2, can be carried
out in accordance with the reaction steps depicted in the following Scheme 6.
Scheme 6
Step 1
(I) (I)
[A = S(O)] [A = S(0) ]
Step 1
In this step, the drug Da or its reactive carbonyl chloride derivative Da i (as obtained in
step 2 of Scheme 1) is coupled with the compound of formula (La') (wherein, A is S) in
the presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), an
organic base, for example, dimethylaminopyridine (DMAP) and a solvent selected from
dichloromethane (DCM) or tetrahydrofuran (THF) to obtain the intermediate compound
) (wherein, A is S).
Step 2
The compound intermediate (la ) as obtained in step 1 above is reacted with the
chloroformate (X) (as obtained in step 1 of Scheme 1) in the presence of a base, for
example, pyridine and a solvent, for example, dichloromethane (DCM) to obtain an
intermediate compound (la i ) . The intermediate compound (la i ) is subjected to nitration
using silver nitrate, in the presence of an organic solvent, for example, acetonitrile, to
obtain the compound of formula (I) (wherein A = S).
Step 3
The compound of formula (I) (wherein A = S) as obtained in step 2 above is subjected
to oxidation in the presence of an oxidising agent, for example, sodium periodate in
water in the presence of an organic solvent selected from methanol or acetone, to
obtain the compound of formula (I) (wherein A = SO). Alternatively, the compound of
formula (I) (wherein A = S) is treated with oxone in the presence of an organic solvent,
for example, methanol, to obtain the compound of formula (I) (wherein A = S0 2) .
In scheme 6, the variables D, R1, R2, Z1 and Z2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing carboxylic acid group.
A process for the preparation of the compound of formula (I), wherein D is a drug
containing one or more functional groups independently selected from an amino, a
hydroxy or a sulfhydryl group, can be carried out in accordance with the reaction steps
depicted in the following Scheme 7.
Scheme 7
Step 1
Step 2
D-Y— X H ► D—Y—X -C— LG
Db, Y = a bond, C=0 or S(0) 2; D l , Y = a bond, C=0 or S(0) 2;
X1 = NR3 (R3 = a bond); X1 = NR3 (R3 = a bond);
D , Y = abond; X1 = O or S; D 4, Y = abond; X1 = O or S;
LG = a leaving group.
D-Y— X1H — D—Y—N=C=0
Db, Y = a bond, C=0 or S(0) 2; Db2, Y = a bond, C=0 or S(0) 2;
X1 = NR3 (R3 = H)
Step 3
Step 1
In this step, the linker (L^ (as obtained in step 1 of Scheme 2) is reacted with phosgene
or its equivalent selected from diphosgene, triphosgene, N, N'- carbonyldiimidazole
(CDI), N, N'- disuccinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the
presence of a base, for example, pyridine or triethylamine and a solvent, for example,
dichloromethane (DCM) to obtain the corresponding alkoxycarbonyl derivative of the
linker L designated herein as Le, wherein LG is a suitable leaving group selected from
halide, imidazole, N-hydroxysuccinimide or 4-nitrophenyl group.
Step 2
The drug containing an amino group Db (D-Y-X 1H, wherein Y = a bond, C=0 or S(0) 2;
X1 = NR3, wherein R3 is a bond) or the drug containing a hydroxyl or sulfhydryl group Dc
(D-Y-X 1H, wherein Y = a bond; X1 = O or S) is reacted with phosgene or its equivalent
selected from: diphosgene, triphosgene, N, N'- carbonyldiimidazole (CDI), N, N'-
disuccinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a
base, for example, triethylamine and a solvent, for example, dichloromethane (DCM) to
obtain the corresponding reactive carbonyl derivative of the drug Db or Dc designated
herein as Dbi and Dc4 respectively wherein LG is a suitable leaving group selected from
halide, imidazole, N-hydroxysuccinimide or 4-nitrophenyl group.
Similarly, the drug containing an amino group Db (D-Y-X 1H, wherein Y = a bond, C=0
or S(0) 2; X1 = NR3, wherein R3 is H) is converted to its reactive isocyanate derivative
Db2 by methods known to those skilled in the art i.e., either by the reaction of
corresponding primary amine-containing drug Db (D-Y-X1H, wherein Y = a bond; X1 =
NR3, wherein R3 is H) with phosgene or its equivalent (Reference: Shriner, R. L. et al.,
Org. Synth. Coll. Vol. 2, ( 1943), 453) or by the reaction of corresponding
amide/sulfonamide-containing drug Db (D-Y-X1H, wherein Y = C(=0) or S(0) 2; X1 =
NR3, wherein R3 is H) with oxalyl chloride (Reference: Speziale, A. J. et al., J. Org.
Chem. 1962, 27, 3742 and Speziale, A. J. et al., J. Org. Chem. 1963, 28, 1805-1 8 11) .
Step 3
The drug containing an amino group Db (D-Y-X 1H, wherein Y = a bond, C=0 or S(0) 2;
X1 = NR3, wherein R3 is a bond or H) or the drug containing a hydroxyl or sulfhydryl
group Dc (D-Y-X 1H, wherein Y = a bond; X1 = O or S) is reacted with the compound (Le)
(as obtained in step 1 above) or the reactive carbonyl derivative Db or Dc4 (as obtained
in Step 2 above) of the drugs Db and Dc respectively is reacted with the linker (L^ in the
presence of a base, for example, triethylamine and a solvent, for example,
dichloromethane (DCM) to obtain the compound of formula (I).
Alternatively, the reactive isocyanate derivative Db2 (as obtained in Step 2 above) of the
drug Db is reacted with the linker in the presence of a base, for example,
triethylamine and a solvent, for example, dichloromethane (DCM) to obtain the desired
compound of formula (I).
In scheme 7, the variables D, A, R1, R2, Z1and Z2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing a hydroxyl, a sulfhydryl or an amino group.
A process for the preparation of the compound of formula (I), wherein D is a drug
containing one or more functional groups independently selected from an amino, a
hydroxyl or a sulfhydryl group, can be carried out in accordance with the reaction steps
depicted in the following Scheme 8.
Scheme 8
Step 1
D-Y— X H D—Y—X -C— LG
Db, D i D 4
a bond, C=0 or S(0) 2
Db l , Y = a bond, C=0 or S(0) 2;
= NR3 (R3 = a bond); X1 = NR (R = a bond);
a bond; X1 = O or S; D 4, Y = a bond; X O or S;
LG = a leaving group.
D-Y— X H D—Y—N=C = 0
Db, Y = a bond, C=0 or S(0) 2; D , Y = a bond, C=0 or S(0) 2
10
X1 = NR3 (R3 = H);
Step
L a: X2 = O
Step 3 L : X2 = NR3
(Y = a bond, C(O) or S0 )
Step 1
The drug containing an amino group Db (D-Y-X 1H, wherein Y = a bond, C=0 or S(0) 2;
X1 = NR3, wherein R3 is a bond) or the drug containing a hydroxyl or sulfhydryl group Dc
(D-Y-X 1H, wherein Y = a bond; X1 = O or S) is converted to its corresponding reactive
carbonyl derivative designated herein as Db i and Dc4 respectively (as depicted in Step
2, Scheme 7). Similarly, the drug containing an amino group Db (D-Y-X 1H, wherein Y =
a bond, C=0 or S(0) 2; X1 = NR3, wherein R3 is H) is converted to its reactive
isocyanate derivative Db2 (as depicted in Step 2, Scheme 7).
Step 2
In this step, the reactive carbonyl derivative Db i [of the drug containing an amino group
Db (D-Y-X1H, wherein Y = a bond, C=0 or S(0) 2; X1 = NR3, wherein R3 is a bond)] or
Dc4 [of the drug containing a hydroxyl or a sulfhydryl group Dc (D-Y-X1H, wherein Y = a
bond; X1 = O or S)] as obtained in Step 1 above, is reacted with the compound of
formula (La) (X2 = O) or the compound of formula (Lb) (X2 = NR3, wherein R3 is as
defined above) to obtain the intermediate compound (le) . Similarly, the reactive
isocyanate derivative Db2 0 f the drug containing an amino group Db (D-Y-X1H, wherein
Y = a bond, C=0 or S(0) 2; X1 = NR3, wherein R3 is H) is reacted with the compound of
formula La (X2 = O) or the compound of formula Lb (X2 = NR3, wherein R3 is as defined
above) to obtain the intermediate compound ( le) .
Step 3
The intermediate compound (le) as obtained in step 2 above is then reacted with the
chloroformate (X) (as obtained in step 1 of Scheme 1) to obtain the intermediate
compound (le ) , which is subjected to nitration using silver nitrate, in the presence of an
organic solvent, for example, acetonitrile, to obtain the compound of formula (I).
Alternatively, the reactive isocyanate derivative Db2 of the drug containing an amino
group Db (D-Y-X1H, wherein Y = a bond, C=0 or S(0) 2; X1 = NR3, wherein R3 is H) as
obtained in Step 1 above, is reacted with the compound of formula La i in the absence
or presence of a base, for example, triethylamine and a solvent, for example,
dichloromethane (DCM) to obtain the compound of formula (le i ) which is finally nitrated
using silver nitrate in the presence of an organic solvent, for example acetonitrile to
form the compound of formula (I).
In scheme 8, the variables D, A, R1, R2, Z1and Z2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing hydroxyl, sulfhydryl or amino group.
A process for the preparation of the compound of formula (I), wherein D is a drug
containing one or more functional groups independently selected from an amino, a
hydroxyl or a sulfhydryl group, can be prepared in accordance with a process involving
the reaction steps depicted in the following Scheme 9.
Scheme 9
Step 1
HO A ^OH HO .O. LG. ^O. A O
Z Z2 ► z 2 PG ► Z Z PG
a L ,
Step 1
In this step, one of the hydroxyl groups of the linker diol (La) is selectively protected by
a suitable hydroxyl protecting group by a standard method to obtain the corresponding
monoprotected compound of formula (La2) . The resultant compound of formula (La2) is
further treated with phosgene or its equivalents: diphosgene, triphosgene, N, N'-
carbonyldiimidazole (CDI), N, N'- disuccinimidyl carbonate (DSC) or 4-nitrophenyl
chloroformate in the presence of a base, for example, pyridine or triethylamine and a
solvent, for example, dichloromethane (DCM) to obtain the compound of formula (La 3) .
Step 2
In this step, the drug containing an amino group Db (D-Y-X1H, wherein Y = a bond, C=0
or S(0)2; X1 = NR3, wherein R3 is a bond or H) or the drug containing a hydroxyl or
sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1 = O or S) is reacted with the
compound of formula (La3) as obtained in step 1 above in the presence of a suitable
base, for example, triethylamine and a solvent, for example, dichloromethane (DCM) to
form the intermediate compound (lf) . Removal of hydroxyl protecting group from the
intermediate compound (If) is carried out using a standard procedure in the art to obtain
the intermediate compound (I ).
Step 3
In this step, the intermediate compound ( lf ) is reacted with the chloroformate (X) (as
obtained in step 1 of Scheme 1) to obtain the intermediate compound ( lf2) . The
intermediate compound (lf2) is further subjected to nitration using silver nitrate in the
presence of an organic solvent, for example, acetonitrile, to form the compound of
formula (I).
In scheme 9, the variables D, A, R1, R2, Z1 and Z2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing a hydroxyl, a sulfhydryl or an amino group.
An alternative process for the preparation of the compound of formula (I), wherein D is
a drug containing one or more functional groups independently selected from a
hydroxyl or a sulfhydryl group and the variable A is selected from the groups consisting
of 1,2-, 1,3-, and 1,4-phenylene and both, Z1 and Z2 represent bond, can be prepared in
accordance with the process involving the reaction steps depicted in the following
Scheme 10.
Scheme 10
Step 1
Step 1
In this step, the drug containing hydroxyl or sulfhydryl functional group Dc (D-Y-X1H,
wherein Y = a bond; X1 = O or S) is directly coupled with the compound of formula (Lf)
(wherein A = 1,2-, 1,3-, or 1,4-phenylene and Z1 and Z2 = bond) in the presence of a
coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC) and in the presence
of an organic base, for example, dimethylaminopyridine (DMAP) and a solvent, for
example, dichloromethane (DCM) to obtain an intermediate compound (lg) . The
intermediate compound (lg) is further subjected to reduction in the presence of a
reducing agent, for example, sodium borohydride and in a solvent, for example,
methanol to obtain another intermediate compound (l
Step 2
The intermediate compound (lg ) is further reacted with the chloroformate (X) (as
obtained in step 1 of Scheme 1) to obtain another intermediate compound (lg2) . The
intermediate compound (lg2) is further subjected to nitration using silver nitrate in the
presence of an organic solvent, for example, acetonitrile, to form the compound of
formula (I).
In scheme 10, the variables D, R1, R2 are as defined in any of the embodiments of the
present invention with reference to the compounds of formula (I) wherein D constitutes
a drug containing a hydroxyl or a sulfhydryl group. It has already been indicated
hereinabove that A = 1,2-, 1,3-, and 1,4-phenylene and Z1 and Z2 = bond.
An alternative process for the preparation of the compound of formula (I), wherein D is
a drug containing carboxylic acid group and the variable Y is a spacer group Yb
o 5
0 (wherein R is as defined above), can be prepared in accordance with a
process involving the reaction steps depicted in the following Scheme 11.
Scheme 11
Step 1
Step 1
In this step, the compound of formula (Sb) is reacted with phosphorous pentachloride or
sulphonyl chloride to obtain the compound of formula (Sbi).
Step 2
The compound (Sbi ) as obtained in step 1 above is further reacted with the compound
of formula (La) or the linker ( ) in the presence of a base, for example, triethylamine
and a solvent, for example, dichloromethane (DCM) to obtain the respective compound
of formula (Lg) or (Lg ) .
Step 3
In this step, the metallic salt Da2 (wherein M+ = Na+, K+, Ca + or Cs+) of the drug
containing carboxylic acid group Da is directly coupled with the compound of formula
(Lg) as obtained in step 2 above in the presence of an organic solvent, for example,
,-dimethylformamide (DMF) to obtain an intermediate compound (lh) . The
intermediate compound ( l ) is further reacted with the chloroformate (X) (as obtained in
step 1 of Scheme 1) to obtain another intermediate compound (l i ) . The intermediate
compound (l i ) is then subjected to nitration using silver nitrate in the presence of an
organic solvent, for example, acetonitrile, to form the compound of formula (I).
Alternatively, the metallic salt Da2 (wherein M+ = Na+, K+, Ca + or Cs+) of the drug
containing carboxylic acid group Da is reacted with the compound of formula (Lg ) in the
presence of an organic solvent, for example, ,-dimethylformamide (DMF) to obtain
the compound of formula (I).
In scheme 11, the variables D, Z1, Z2, A, R1 and R2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing carboxylic acid group or its metallic salt as
specified above.
A process for the preparation of the compound of formula (I), wherein D is a drug
containing one or more functional groups independently selected from hydroxyl or
sulfhydryl group and Y is a spacer group, Yc = R 0 (wherein R is as defined above)
can be prepared in accordance with a process involving the reaction steps depicted in
the following Scheme 12.
Scheme 12
Step 1
Step 1
In this step, the compound of formula (Sc) (wherein PG is an amino protecting group
as defined above and R6 is as defined above) is reacted with the linker (Li) in the
presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC) and in
the presence of an organic base, for example, dimethylaminopyridine (DMAP), and an
organic solvent, for example, dichloromethane (DCM) to obtain the compound of
formula (Lh) . The removal of the amino protecting group PG in the compound of
formula (Lh) is carried out by a standard procedure known in the art to form compound
of formula ( i ).
Step 2
In this step, the drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y
= a bond; X1 = O or S) is reacted with the compound of formula (Sc) in the presence of
a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base,
for example, dimethylaminopyridine (DMAP) and an organic solvent, for example,
dichloromethane (DCM) to obtain a reactive drug derivative of formula (Dci). Removal
of the amino protecting group PG from the reactive drug derivative (Dci ) is carried out
using a standard procedure known in the art to obtain another reactive compound
intermediate (DC2). The drug derivative (DC2) is further treated with phosgene or its
equivalent selected from diphosgene, triphosgene, ,'- carbonyldiimidazole (CDI), N,
N'- disuccinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a
base, for example, triethylamine and a solvent, for example, dichloromethane (DCM) to
obtain another reactive isocyanate intermediate (DC3).
Step 3
In this step, the drug derivative (DC2) as obtained in step 2 above is reacted with the
compound (Le) (as obtained in step 1 of Scheme 7) in the presence of a base, for
example, triethylamine and a solvent, for example, dichloromethane (DCM) to obtain
the intermediate compound (I,). Removal of the protecting group from the intermediate
compound (I,) is carried out using a standard procedure known in the art to form the
compound of formula (I). Alternatively, the drug derivative DC3 as obtained in Step 2
above is reacted with the linker ( ) to form the compound of formula (I) after removal of
the protecting group from the protected intermediate of the formula (I,) thus obtained.
Alternatively, the drug derivative Dc4, as obtained in Step 2, Scheme 7 (wherein, Y = a
bond; X1 = O or S) is reacted with the compound ( i ) produced in reaction step 1
above to form a compound intermediate (In). The removal of protecting group PG in the
compound intermediate (In) is carried out using any standard procedure known in the
art to form the compound of formula (I).
In scheme 12, the variables D, A, Z1, Z2, R1 and R2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing hydroxyl or sulfhydryl group.
An alternative process for the preparation of the compound of formula (I), wherein D is
a drug containing one or more functional groups independently selected from hydroxyl
or sulfhydryl group and Y is a spacer group selected from
O |_|
Yf = d o (wherein d is as defined above) can be carried out in accordance with the
reaction steps as depicted in the following Scheme 13.
Scheme 3
Step 1
Step 3
Step 1
In this step, the compound of formula (Sd) (wherein PG is an amino protecting group
as defined above) is reacted with the linker ( ) in the presence of a coupling agent, for
example, ,-dicyclohexylcarbodiimide (DCC) and in the presence of an organic base,
for example, dimethylaminopyridine (DMAP), and organic solvent, for example,
dichloromethane (DCM) to obtain the compound of formula (L,). Removal of the amino
protecting group PG in compound of formula (!_,) is carried out by a standard
procedure known in the art to form the compound of formula (_ ) .
Step 2
The drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1
= O or S) is reacted with the compound of formula (Sd) in the presence of a coupling
agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain the corresponding derivative of the drug (Dcs). Removal of the amino
protecting group PG from the drug derivative (Dcs) is carried out using a standard
procedure known in the art to form another reactive free amine drug derivative (Dce).
The resulting free amine derivative (Dce) is further treated with phosgene or its safe
equivalent selected from diphosgene, triphosgene, ,- carbonyldiimidazole (CDI), N,
N'- disuccinimidyl carbonate (DSC), 4-nitrophenyl chloroformate in the presence of a
base, for example, triethylamine and a solvent, for example, dichloromethane to form
another reactive compound i.e. the intermediate isocyanate compound (Dc7) .
Step 3
The resulting drug derivative (Dce) is reacted with the compound of formula (Le) (as
obtained in step 1 of Scheme 7) in a solvent, for example, dichloromethane (DCM) to
obtain the compound of formula (I). Alternatively, the drug isocyanate derivative (DC7)
as obtained in step 2 above is reacted with the linker ( ) in a solvent, for example,
dichloromethane (DCM) to form the nitrate ester prodrug of formula (I). In an alternative
synthesis, the drug derivative (Dc4) (as obtained in Step 2, scheme 7, wherein Y = a
bond) is reacted with the compound (Ln ) as obtained in step 1, to form the nitrate ester
prodrug of formula (I).
In scheme 13, the variables D, Z1, Z2, A, R1 and R2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing a hydroxyl or a sulfhydryl group.
Another process for the preparation of the compound of formula (I), wherein D is a drug
containing one or more functional groups independently selected from a hydroxyl or a
9
sulfhydryl group and Y is a spacer group selected from = (wherein c is as
defined above) can be carried out in accordance with the reaction steps as depicted in
Scheme 14.
Scheme 4
Step 2
Step 1
In this step, the drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y
= a bond; X1 = O or S) is reacted with the compound of formula Se (wherein R7 is an
amino protecting group (PG ) as defined above) in the presence of a coupling agent,
for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain a reactive drug derivative (Dc8) and/or a reactive drug derivative (Dc9) .
Step 2
The reactive drug derivative of formula Dcs or the reactive drug derivative of formula Dcg
(as obtained in step 1 above) is directly coupled with the nitrate ester containing linker
(L^ (formed in reaction step 1 of Scheme 2) in the presence of a coupling agent, for
example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain the intermediate compound (lj) and the intermediate compound (lj )
respectively. Removal of the amino protecting group R7 from each of the intermediate
compounds (lj) and (lj ) is carried out by a standard procedure known in the art to obtain
the respective compounds of formula (I).
In scheme 14, the variables D, Z1, Z2, A, R1 and R2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing hydroxyl or sulfhydryl group.
Another process for the preparation of the compound of formula (I), wherein D is a drug
containing one or more functional groups selected from a hydroxyl or a sulfhydryl group
o o
and Y is a spacer group selected from " (wherein d is as defined above) can be
carried out in accordance with the reaction steps as depicted in the following Scheme
15.
Scheme 5
Ste l
Step 1
In step 1, the drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a
bond; X1 = O or S) is reacted with a dicarboxylic acid compound of formula (Sf) in the
presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a
suitable base, for example, dimethylaminopyridine (DMAP) and an organic solvent, for
example, dichloromethane (DCM) to obtain the corresponding reactive drug derivative
(Ddo).
Step 2
The reactive drug derivative (Dcio) as obtained in step 1 above is further coupled with
the linker compound of formula (La) in the presence of a coupling agent, for example,
,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) to obtain the intermediate compound (lk) . The resulting
intermediate compound (lk) is further reacted with the chloroformate (X) (as obtained in
step 1 of Scheme 1) to obtain another intermediate compound of formula (lki). The
intermediate compound of formula (lki ) is then subjected to nitration using silver nitrate
in the presence of an organic solvent, for example, acetonitrile, to obtain the compound
of formula (I). Alternatively, the drug derivative (Dcio) is coupled directly with the linker
(Lai) (as obtained in Step 1' , Scheme 1) to obtain the intermediate chloro compound of
formula (lki) which is converted to the nitrate compound of the formula (I) as described
above. In a more direct approach, the drug derivative (Dcio) is coupled directly with the
nitrate containing linker (as obtained in Step 1, Scheme 2) to obtain the final
compound of formula (I). In another approach, the chloro compound of the formula (Lai )
is coupled first with a dicarboxylic acid of the formula (Sf) in the presence of a coupling
agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain the corresponding derivative (Lar). This compound of formula (Lar) is
further coupled with a drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X 1H,
wherein Y = a bond; X1 = O or S) in the presence of a coupling agent, for example,
,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain the corresponding reactive drug derivative (lki). The intermediate
compound of the formula ( lk ) is coverted to the final compound of formula (I) as
described above. In yet another approach, the nitrate linker of formula ( ) is coupled
with dicarboxylic acid of the formula (Sf) followed by the drug containing a hydroxyl or
sulfhydryl group Dc (D-Y-X 1H, wherein Y = a bond; X1 = O or S) in the presence of a
coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for
example, dimethylaminopyridine (DMAP) and an organic solvent, for example,
dichloromethane (DCM) to obtain the final nitrate compound of formula (I).
In scheme 15, the variables D, Z1, Z2, A, R1 and R2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing a hydroxyl or a sulfhydryl group.
Alternative process for the preparation of the compound of formula (I), wherein D is a
drug containing one or more functional groups independently selected from a hydroxyl
o o
or a sulfhydryl group and Y is a spacer group selected from Yh = (wherein X
is as defined above) can be carried out in accordance with the reaction steps as
depicted in the following Scheme 16.
Scheme 6
Step 1
The drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1
= O or S) is reacted with the compound of formula (Sg) in the presence of a suitable
base, for example, dimethylaminopyridine (DMAP) and a solvent, for example,
dichloromethane (DCM) to form the reactive drug derivative (Dcn). Similarly, reactions
of the linkers of formula (Lai ) or ( ) with cyclic anhydride compound of formula (Sg) in
the presence of a suitable base, for example, dimethylaminopyridine (DMAP) and an
organic solvent, for example, dichloromethane (DCM) afforded the respective linker
intermediates of formula (La ) and (L ) respectively.
Step 2
The reactive drug derivative (Dcn ) as obtained in step 1 above is then coupled with the
linker of formula (La) in the presence of a coupling agent, for example, N,Ndicyclohexylcarbodiimide
(DCC), a suitable base, for example, dimethylaminopyridine
(DMAP) and an organic solvent, for example, dichloromethane (DCM) to form the
compound intermediate ( ) . The compound intermediate ( ) is further reacted with the
chloroformate (X) (as obtained in step 1 of Scheme 1) to obtain another intermediate
compound of formula (In). The intermediate compound of formula (In) is then subjected
to nitration using silver nitrate in the presence of an organic solvent, for example,
acetonitrile, to obtain the compound of formula (I). In another approach, the compound
of formula (Dcn ) is reacted with the linker intermediate of formula (La ) in the presence
of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base,
for example, dimethylaminopyridine (DMAP) and an organic solvent, for example,
dichloromethane (DCM) to form the compound intermediate (In), which is converted to
the final compound of formula (I) as described above. Alternatively, the compound of
formula (Dcn) is reacted with the linker intermediate of formula ( ) in the presence of a
coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for
example, dimethylaminopyridine (DMAP) and an organic solvent, for example,
dichloromethane (DCM) to directly afford the compound of formula (I). In another
approach, the drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y =
a bond; X1 = O or S) is coupled with the linker compound of formula (La ) in the
presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a
suitable base, for example, dimethylaminopyridine (DMAP) and an organic solvent, for
example, dichloromethane (DCM) to form the compound intermediate (In), which is
finally converted to the compound of formula (I) as described above. In yet another
approach, reaction of the drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H,
wherein Y = a bond; X1 = O or S) with the linker compound of formula (Lr) in the
presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a
suitable base, for example, dimethylaminopyridine (DMAP) and an organic solvent, for
example, dichloromethane (DCM) directly afforded the final compound formula (I).
In scheme 16, the variables D, Z Z2, A, R1 and R2 are as defined in any of the
embodiments of the present invention with reference to the compounds of formula (I)
wherein D constitutes a drug containing hydroxyl or sulfhydryl group.
An alternative process for the preparation of the compound of formula (I) , wherein D is
a drug containing one or more functional groups independently selected from a
hydroxyl a sulfhydryl group and Y is a spacer group selected from Ye = (wherein
R7 and R8 is as defined above) can be carried out in accordance with the reaction steps
as depicted in Scheme 17.
Step 1
The compound of formula (Sh) (wherein PG is a hydroxyl protecting group defined
above and R7 and R8 are as defined above) is reacted with the linker ( ) in the
presence of a coupling agent, for example, ,-dicyclohexylcarbodiimide (DCC), a
suitable base, for example, dimethylaminopyridine (DMAP), and organic solvent, for
example, dichloromethane (DCM) to form the compound of formula (Lj). Removal of the
protecting group PG in the compound of formula (Lj) is carried out by a standard
procedure known in the art to afford compound of formula (Lj ).
Step 2
The drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1
= O or S) is reacted with the compound of formula (Sh) in the presence of a coupling
agent, for example, ,-dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain a reactive drug derivative of formula DC12 (wherein R7 is hydrogen or an
amino protecting group as defined in the first embodiment herein above). Removal of
the protecting group PG from the drug derivative (DC12) is carried out using a standard
procedure known in the art to obtain another reactive drug derivative of formula (Dc i 3 ) .
The resulting drug derivative (DC13) is further treated with phosgene or its equivalent
selected from diphosgene, triphosgene, ,'- carbonyldiimidazole (CDI), ,'-
disuccinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a
base, for example, triethylamine and a solvent, for example, dichloromethane (DCM) to
afford another reactive drug derivative of formula (Dc 4 ) .
Step 3
The drug derivative (DC13) as obtained in step 2 above is reacted with the compound
(l_e) (as obtained in reaction step 1 of Scheme 7) in the presence of a base, for
example, triethylamine and a solvent, for example, dichloromethane (DCM) to obtain
the compound of formula (I) (wherein Y is a spacer of formula Ye and R7 is an amino
protecting group as defined above). Alternatively, the drug derivative (Dc i 4 ) is reacted
with the linker (L^ in the presence of a base, for example, triethylamine and a solvent,
for example, dichloromethane (DCM) to obtain the compound (I) (wherein Y is a spacer
group of formula Ye and R7 is an amino protecting group as defined above). The
compound of formula (I), (wherein Y is a spacer group of formula Ye and R7 is an amino
protecting group as defined above) can alternatively be obtained by reacting the drug
derivative (Dc4) as obtained in Step 2, Scheme 7 (wherein Y = a bond; X1 is O or S, LG
= Leaving group) with the compound (L^) as obtained in reaction step 1 above, in the
presence of a suitable base, for example, triethylamine and a solvent, for example,
dichloromethane (DCM). Removal of the amino protecting group R7 in the compound of
formula (I), (wherein Y is a spacer group of formula Ye and R7 is an amino protecting
group as defined above) is carried out using any standard procedure known in the art to
obtain the compound of formula (I) (wherein R7 = hydrogen).
An alternative process for the preparation of the compound of formula (I), wherein D is
a drug containing one or more functional groups selected from a hydroxyl or a
sulfhydryl group (Db ) and Y is a spacer group selected from Y, = (wherein c is
as defined above) can be carried out in accordance with the reaction steps as depicted
in Scheme 18.
Scheme 18
D 17 1 Step 3
Step 1
In this step, the compound of formula (S,) (wherein PGC is a suitable carboxyl protecting
group and PG is a suitable amino protecting group as defined above and c is as
defined above) is reacted with the linker (L^ in the presence of a coupling agent, for
example, dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain the compound of formula (Lk) . Removal of the protecting group PG in
the compound of formula (Lk) is carried out by a standard procedure known in the art to
get the compound of formula (Lk ) .
Step 2
The drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X 1H, wherein Y = a bond; X1
= O or S) is reacted with the compound of formula (S,) in the presence of a coupling
agent, for example, dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to get the corresponding reactive drug derivative of formula DC15, wherein PGC is
a carboxylic acid protecting group as defined above). The removal of the protecting
group PGC from the drug derivative (Dcis) is carried out using a standard procedure
known in the art to obtain another reactive drug derivative of formula (D e) The drug
derivative (Dci6) is further treated with phosgene or its safe equivalent selected from
diphosgene, triphosgene, ,'- carbonyldiimidazole (CDI), ,'-disuccinimidyl
carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a base, for example,
triethylamine and a solvent, for example, dichloromethane(DCM) to afford another
reactive drug derivative of formula (DC17)-
Step 3
The drug derivative (Dcie) is reacted with the compound of formula (Le) (as obtained in
step 1 of Scheme 7) in the presence of a base, for example, triethylamine and a
solvent, for example, dichloromethane (DCM) or alternatively, the drug derivative (DC 17)
is reacted with the linker (l_i) in the presence of a base, for example, triethylamine and
a solvent, for example, dichloromethane (DCM) to get the compound intermediate (lm ).
Alternatively, the drug derivative (Dc4) as obtained in Step 2, Scheme 7 (wherein Y = a
bond; X1 is O or S, LG = Leaving group) is coupled with the compound of formula Lk
(as obtained in Step 1 above) to obtain an intermediate compound ( lm) . Removal of the
carboxylic acid protecting group PGC in the intermediate compound (lm) or the
compound intermediate (lm ) is carried out using a standard procedure known in the art
to obtain the compound of formula (I).
An alternative method for obtaining the compound of formula (I), wherein D is a drug
containing one or more functional groups selected from a hydroxyl or a sulfhydryl group
NHR7
and Y is a spacer group selected from Yj = o o (wherein the group R is an amino
protecting group as defined above and e is also defined above) involves the reaction
steps depicted in the following Scheme 19.
Scheme 19
Step 1
In this step, the compound of formula (Sj) (wherein R7 and PG are suitable amino
protecting groups) is reacted with the linker ( ) in the presence of a coupling agent, for
example, dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to yield the compound of formula (Lr). Selective removal of the protecting group
PG in compound of formula (Lv) is carried out by a standard procedure known in the
art to afford the compound of formula (L ) .
Step 2
The drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X 1H, wherein Y = a bond; X1
= O or S) is reacted with the compound of formula (Sj ) in the presence of a coupling
agent, for example, dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to form a reactive drug derivative of formula (Dcis)- Selective removal of the
protecting group PG from the drug derivative (Dcis) is carried out using a standard
procedure known in the art to give another reactive drug derivative of formula (Dci9) .
The drug derivative (Dcig) is further treated with phosgene or its equivalent selected
from diphosgene, triphosgene, ,'- carbonyldiimidazole (CDI), ,'-disuccinimidyl
carbonate (DSC) or 4-nitrophenyl chloroformate in the presence of a base, for example,
triethylamine and a solvent, for example, dichloromethane to afford another reactive
drug isocyanate derivative of formula (DC2o)-
Step 3
The drug derivative (Dcig) as obtained in step 2 above is reacted with the compound of
formula (Le) (as obtained in step 1 of Scheme 7) in the presence of a base, for
example, triethylamine and a solvent, for example, dichloromethane (DCM) or the drug
derivative (DC2o) is reacted with the linker (L^ in the presence of a base, triethylamine
for example, and a solvent, for example, dichloromethane (DCM) to yield the compound
of formula (I") (wherein Y is a spacer group of formula Yj , wherein R7 is an amino
protecting group as defined above). Alternatively, the drug derivative (Dc4) as obtained
in Step 2, Scheme 7 (wherein Y = a bond; X1 is O or S; LG = Leaving group) is coupled
with the compound of formula L (as obtained in Step 1 above) to obtain a compound
of formula ( ) (wherein Y = Yj , wherein R7 is an amino protecting group as defined
above). Removal of the amino protecting group R7 in the compounds of formulae ( )
and (I") (wherein Y is a spacer of formula Yj , wherein R7 is an amino protecting group
as defined above) is carried out using a standard procedure known in the art to obtain
the respective compounds of formula (I) (wherein R7 = hydrogen as defined above).
An alternative process for the preparation of the compound of formula (I), wherein D is
a drug containing one or more functional groups independently selected from a
hydroxyl or a sulfhydryl group and Y is a spacer group selected from Yk
(wherein R7 is as defined above) can be carried out in accordance with the reaction
steps as depicted in the following Scheme 20.
Scheme 20
Step 1
Dc21
Step 1
In this step, the compound of formula (Sk) (wherein PG is a suitable hydroxyl
protecting group and R7 is a suitable amino protecting group) is reacted with the linker
(L^ in the presence of a coupling agent, for example, dicyclohexylcarbodiimide (DCC),
a suitable base, for example, dimethylaminopyridine (DMAP) and an organic solvent,
for example, dichloromethane (DCM) to obtain the compound of formula (Lm) . Removal
of the protecting group PG in compound of formula (Lm) is carried out by a standard
procedure known in the art to obtain the compound of formula (Lm ) .
Step 2
The drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1
= O or S) is reacted with the compound of formula (Sk) in the presence of a coupling
agent, for example, dicyclohexylcarbodiimide (DCC), a suitable base, for example,
dimethylaminopyridine (DMAP) and an organic solvent, for example, dichloromethane
(DCM) to obtain the corresponding reactive derivative of the drug represented by
formula (Dc2i ) . Removal of the protecting group PG from the drug derivative (DC2i ) is
carried out using a standard procedure known in the art to obtain another reactive drug
derivative of formula (DC22)- The drug derivative (Dc 22) is further treated with phosgene
or its equivalent selected from diphosgene, triphosgene, ,'-carbonyldiimidazole
(CDI), ,'-disuccinimidyl carbonate (DSC) or 4-nitrophenyl chloroformate in the
presence of a base, for example, triethylamine and a solvent, for example,
dichloromethane (DCM) to obtain another reactive drug derivative of formula (DC23)-
Step 3
The drug derivative (DC22) is reacted with the compound of formula (Le) (as obtained in
reaction step 1 of Scheme 7) in the presence of a base, for example, triethylamine and
a solvent, for example, dichloromethane (DCM) or alternatively, the drug derivative
(Dc23) is reacted with the linker ( ) in the presence of a base, for example,
triethylamine and a solvent, for example, dichloromethane (DCM) to obtain a compound
of formula (I") (wherein Y is a spacer group of formula Yk, wherein R7 is as defined
above). Alternatively, the drug derivative (Dc4) as obtained in Step 2, Scheme 7
(wherein Y = a bond; X1 is O or S; LG = Leaving group) is coupled with the compound
of formula Lm (as obtained in Step 1 above) to obtain the compound of formula ( )
(wherein Y is a spacer group of formula Yk, wherein R7 is an amino protecting group as
defined above). Removal of the amino protecting group R7 in the compounds of
formulae ( ) and (I") (wherein Y is a spacer group of formula Yk) is carried out using a
standard procedure known in the art to yield the nitrate ester prodrug of formula (I)
(wherein R7 = hydrogen as defined above).
An alternative method for the preparation of the compound of formula (I), wherein D is a
drug containing one or more functional groups selected from a hydroxyl or a sulfhydryl
group and Y is a spacer group selected from Y involves the reaction
steps as depicted in the following Scheme 2 1.
Scheme 2 1
Step 1
In this step, the compound of formula (Si) (wherein PG is a suitable hydroxyl protecting
group and PGC is a suitable carboxylic acid protecting group) is reacted with the linker
Le (as obtained in Stepl , Scheme 7) in the presence of a coupling agent, for example,
dicyclohexylcarbodiimide (DCC), a suitable base, for example, dimethylaminopyridine
(DMAP) and an organic solvent, for example, dichloromethane (DCM) to obtain the
compound of formula (Ln) . Selective removal of the protecting group PG in the
compound of formula (Ln) is carried out by a standard procedure known in the art to
obtain the compound of formula (Ui).
Step 2
The drug derivative Dc4 as obtained in Step 2, Scheme 7 (wherein Y = a bond; X1 is O
or S; LG = Leaving group) is reacted with the compound of formula (Si) in the presence
of a suitable base, for example, triethylamine and an organic solvent, for example,
dichloromethane (DCM) to obtain a reactive drug derivative of formula (Dc24) . Removal
of the protecting group PG from the drug derivative (DC24) is carried out using a
standard procedure known in the art to obtain another reactive derivative of the drug
represented by formula (Dc25)- The drug derivative (DC2s) is further treated with
phosgene or its safe equivalent selected from diphosgene, triphosgene, ,'-
carbonyldiimidazole (CD I), ,'-disuccinimidyl carbonate (DSC) or 4-nitrophenyl
chloroformate in the presence of a base, for example, triethylamine and a solvent, for
example, dichloromethane (DCM) to form another reactive drug derivative of formula
(Dc26) .
Step 3
The drug derivative (DC2s) as obtained in step 2 above is reacted with the compound of
formula (Le) (as obtained in step 1 of Scheme 7) in the presence of a base,
triethylamine and a solvent, for example, dichloromethane (DCM) or alternatively, the
drug derivative (DC2e) is reacted with the linker ( ) in the presence of a base, for
example, triethylamine and a solvent, for example, dichloromethane (DCM) to obtain
an intermediate compound (lni). Similarly, the drug derivative Dc4 as obtained in Step 2,
Scheme 7 (wherein Y = a bond ; X1 is O or S; LG = Leaving group), is reacted with the
compound of formula Lni (as obtained in Step 1 above) to get another intermediate
compound (ln) . Removal of the carboxylic acid protecting group PGC in the intermediate
compound (ln) or in the intermediate compound (lni) is carried out using a standard
procedure known in the art to obtain the respective compounds of formula (I) .
Although not specified in the above general synthetic schemes, it is understandable to
any person skilled in the art that if the said drugs or therapeutic agents contain one or
more additional derivatizable functional groups such as amino, carboxyl, hydroxyl
(including phenolic), or sulfhydryl groups, those functional groups may need to be
selectively protected, if it is necessary, by any widely used suitable protecting groups
and subsequently deprotected, if it is necessary, at appropriate stages of the processes
for the preparation of the compound of formula (I), which are the nitric oxide releasing
prodrugs of known drugs or therapeutic agents, and such selective protection and
deprotection reactions are carried out as described in Theodora W. Greene and Peter
G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, John Wiley and Sons,
Inc. New York ( 1999), the disclosure of the relevant portion is incorporated herein by
reference. To illustrate this feature, conversion of a drug containing two or more types
of functional groups, for example atorvastatin, to the corresponding nitric oxidereleasing
prodrug of atorvastatin (NO-Atorvastatin) of formula (I) via selective protection
and if necessary, deprotection of the hydroxyl groups of the drug at appropriate stages
of their synthesis as shown in Scheme 22.
cheme 22
(PG or PG2 = a suitable hydroxyl protecting group)
Method A:
In Step A two hydroxyl groups of the drug, for example Atorvastatin (D-C0 2H) are
protected by a suitable protecting group, for example as an acetonide, by a generally
known procedure, to obtain the partially protected drug (Da ) . In Step A2, the partially
protected drug (Da ) as obtained in step above is coupled with a linker diol (La) by a
method described in Step 2 of Scheme 1, to afford the intermediate alcohol (lar). In
Step A3, the acetonide protecting group in the intermediate (lar ) is removed by a
method generally known to those skilled in the art to obtain the intermediate triol (la) . In
Step A4, the intermediate alcohol (la) as obtained in step A3 above is further reacted
with a-chloroformate (X) in the presence of an organic base, for example, pyridine and
an organic solvent, for example, dichloromethane (DCM) to obtain the selectively
acylated intermediate compound (la ) . In the final Step, the intermediate chloride (la ) is
subjected to nitration using silver nitrate in the presence of an organic solvent, for
example, acetonitrile to form the compound of formula (I), and if desired, the compound
of formula (I) is converted to its pharmaceutically acceptable salt.
Method B1/B2/B3:
In Step 1, the two hydroxyl groups of the drug, for example Atorvastatin (D-C0 2H) are
protected by any suitable hydroxyl protecting groups that are likely to be cleaved in vivo
(i.e., under biological conditions), by a method generally known to those skilled in the
art, to obtain a partially protected drug (Da ) , which can be converted to the compounds
of formula (I) by any of the following methods:
Method B 1 : In Step 2, the partially protected drug (Da ) , as obtained in step 1 above, is
coupled with a linker diol (La) by a method described in Step 2 of Scheme 1, to afford
the intermediate alcohol (la ) . In Step 3, the intermediate alcohol (lar ) as obtained in
step 2 above is further reacted with -chloroformate (X) in the presence of an organic
base, for example, pyridine and an organic solvent, for example, dichloromethane
(DCM) to obtain the intermediate compound (la i ) . In the final Step, the intermediate (la i )
is also converted to the compound of formula (I) as described in the final step of
Method A.
Method B2: In Step 2, the partially protected carboxyl-containing drug (Da ) as obtained
in step 1 above is coupled with a linker intermediate (La ) by a method described in
Step 3 (i.e., Method A) of Scheme 2, to afford the intermediate chloride (la ) , which is
finally converted to the compound of formula (I) as described in the Final step of
Method A.
Method B3: In Step 2, the partially protected Atorvastatin (Dai ) as obtained in step 1
above is directly coupled with the nitrate containing linker ( ) by a method described in
Step 3 (i.e., Method B) of Scheme 2, to afford the compound of formula (I), and if
desired, the compound of formula (I) is converted to its pharmaceutically acceptable
salt.
Method C: In Step 1, sodium or calcium salt of the atorvastain (D-C0 2 , wherein, R =
Na+ or Ca +) is reacted with linker bromide (Lar ) in the presence of an organic solvent,
for example DMF to afford the intermediate alcohol of the formula (la) . The resulting
intermediate alcohol ( la) is converted to the compound of formula (I), as already
described above in Method A. If desired, the compound of formula (I) thus obtained is
converted to its pharmaceutically acceptable salt.
The organic base, used in any reaction steps of the processes for the preparation of the
compound of formula (I) as depicted in the aforementioned schemes, may be selected
from but not limited to triethylamine, diisopropylethylamine, 4-(dimethylamino) pyridine
(DMAP), pyridine or mixtures thereof.
The organic solvent used in any reaction steps of the processes for the preparation of
the compound of formula (I) may be selected from but not limited to dichloromethane
(DCM), chloroform, dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, ethyl
acetate, diethyl ether or mixtures thereof.
The coupling agent used in a reaction step involving coupling for the preparation of the
compound of formula (I) may be selected from but not limited to ,'-
dicyclohexylcarbodiimide (DCC), 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), benzotriazol-1-yl-oxy-fr/ s(dimethylamino)phosphonium
hexafluorophosphate (BOP), 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), N,N'-dicyclohexylcarbodiimide/ N-hydroxybenzotriazole
(DCC/ HOBT), 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.
HCI) and benzotriazol-1-yl-oxy-fr/ s(dimethylamino)phosphonium hexafluorophosphate
(BOP) and EDAC. HCI/HOBT,
The present invention also relates to the process of resoluting the racemic mixture of
the compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein D, X1, Y, X A, Z1, Z2 R1 and R2 are as defined above, the process of
resoluting the racemic mixture comprises reacting the racemic compound of formula (I)
with a chiral auxiliary in the presence of a solvent, crystallising out the required
diastereoisomeric salt and subsequently treating it with a base to obtain the desired
enantiomer of the compound of formula (I)
It has been indicated herein that the prodrugs [the compounds of formula (I)] of the
present invention would undergo enzymatic cleavage in a manner such that the parent
drugs and effective amounts of nitric oxide are released in vivo. On this basis, the
inventor provides herein a plausible mechanism of cleavage of nitric oxide-releasing
prodrugs (the compound of formula I). The plausible mechanism by which the parent
drug(s) designated herein as D and nitric oxide (i.e., possibly in nitrate form) can be
released in vivo from the NO-Prodrugs as shown in Scheme M 1. In the scheme that
depicts plausible mechanism of cleavage of nitric oxide-releasing prodrugs (the
compound of formula I), disulfide linker (Ll)-containing NO-Prodrug is used for
illustrative purpose only.
An aldehyde except formaldehyde
Bioreduction
NO
Nitric Oxide
Scheme Ml: Plausible Mechanism of Drug and NO release
Understandably, the release of parent drug and nitric oxide (i.e., in the form of
nitrate/nitrite) from NO-prodrugs containing non-disulfide linkers as found in many other
examples of formula I is expected to occur via enzymatic cleavage of linkages between
the drug and linker as shown in the following Scheme M2.
NO-Prodrug of Formula I
(Drug is an amino/carboxyl/hydroxyl/sulfydryl containing drug)
[X1 = NR3, a bond, O or S] f R = Hydrogen, then R2 =Alkyl;
Drug-X1 or Drag-C0 2H +
[Released free drugs]
(when X1 = a bond)
reduction
NO
Nitric Oxide
Scheme M2: Plausible Mechanism of Drug and NO release
The nitrate ion (N0 3
~) thus released from the NO-prodrug would get reduced to nitrite in
vivo by the action of oral bacteria (i.e., by bacterial nitrate reductase) or Xanthine
Oxidase in tissues as shown in the following equation:
Bacterial Nitrate reductase
N(V + 2e + 2 H+ N0>2 + H20
Nitrate Xanthine Oxidases in tissue Nitrite
Further reduction of nitrite to nitric oxide (NO) would readily occur in many different
ways. Under non-enzymatic acidic conditions in the human body (in stomach or tissue)
or by Xanthine Oxidase in tissues or by Cytochromes in liver/tissues nitrite would get
converted to nitrous acid which would further dissociateto water and dinitrogen trioxide
which in turn would dissociate further to nitrogen dioxide and NO as shown in the
following equations:
N0 2- + H+ HN0 2
Nitrite
Dehydro Ascorbic acid Ascorbic acid 2 N 2 N2 0 3 H 0
+ NO + H Dinitrogen 20 trioxide
Nitric oxide
NO, + NO
Nitrogen Nitric oxide
dioxide
As shown in the above equation, in the presence of vitamin C (Ascorbic acid) and
polyphenols, nitrous acid thus generated is directly reduced to NO without yielding
nitrogen dioxide (Green L C, et al., Nitrate biosynthesis in man. Proc Natl Acad Sci USA
1981 , 78, 7764-8).
The released NO has an extremely short half-life (less then 1 s) in circulating blood
(Kelm M. Nitric oxide metabolism and breakdown, Biochim Biophys Acta 1999, 141 1,
273-289). NO and nitrite react with oxyhemoglobin to yield nitrate and methemoglobin
(Doyle M P, et al., Oxidation of nitrogen oxides by bound dooxygen in hemoproteins. J
Inorg Biochem 1981 , 14, 351-358; Dyle M P, et al., Kinetics and mechanism of the
oxidation of human deoxyhemoglobin in nitrites. J Biol Chem 1981 , 256, 12393-8). The
half-life of nitrite in blood is 20-30 minutes (Dejam A. et al., Nitrite infusion in humans
and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation,
Circulation 2007, 116, 1821-31) whereas nitrate has a circulating half-life of several
hours (Tannenbaum SR. Nitrate and nitrite: origin in humans. Science 1979, 205, 1332,
1334-7; Green L C, et al., Nitrate biosynthesis in man. Proc Natl Acad Sci USA 1981 ,
78, 7764-8).
As mentioned in the above equations, there are several pathways for oxidation and
reduction of nitrate, nitrite and NO in the body and some of them are summarized in the
following Figure (Joel Petersson, 2008. Nitrate, Nitrite and Nitric oxide in Gastric
Mucosal Defense, Doctoral Dissertation, 2008, pages 17-18 and the relevant
references cited therein):
It is reported that most of the circulating plasma nitrate is excreted through the kidneys
(Green L C, et al., Nitrate biosynthesis in man. Proc Natl Acad Sci USA 1981, 78, 7764-
8), but about 25% of the plasma nitrate is recycled in the human body to yield nitrite
and NO (Tannenbaum S R, et al., The effect of nitrate intake on nitrate formation in
human saliva. Food Cosmet Toxicol 1976, 14, 549-52) as shown in the above figure.
The present invention furthermore relates to a pharmaceutical composition containing
an effective amount of the compound of formula (I) which is a nitric oxide releasing
prodrug of a known drug or a therapeutic agent or its physiologically tolerable salts,
along with a pharmaceutically acceptable carrier, and to a process for the production of
the pharmaceutical composition, which comprises converting the compound of formula
(I) into a suitable administration form using an appropriate pharmaceutically acceptable
and physiologically tolerable excipient, and if appropriate, using further suitable active
compounds, additives or auxiliaries.
The compound of formula (I), which are the nitric oxide releasing prodrugs of known
drugs or therapeutic agents, can be administered to a subject in need thereof in a
variety of routes such as oral, for example in the form of pills, tablets, coated tablets,
capsules, granules or elixirs. Administration, however, can also be carried out rectally,
for example in the form of suppositories, or parentally, for example, intravenously,
intramuscularly or subcutaneously, in the form of injectable sterile solutions or
suspensions, or topically, for example in the form of solutions or transdermal patches,
or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical composition according to the invention is prepared in a manner
known per se, and by utilizing methods well-known to one skilled in the art.
Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can
be used in addition to the prodrug compound of formula (I) and/or its pharmacologically
acceptable salts. For the production of pills, tablets, coated tablets and hard gelatin
capsules it is possible to use, for example, lactose, corn starch or derivatives thereof,
gum arabic, magnesia or glucose, etc. Carriers for soft gelatin capsules and
suppositories are, for example, fats, wax, natural or hardened oils, etc. Suitable carriers
for the production of solutions, for example, injection solutions, or of emulsions or
syrups are, for example, water, physiological sodium chloride solution or alcohols, for
example, ethanol, propanol, or glycerol, sugar solutions, such as glucose solutions or
mannitol solutions, or a mixture of the various solvents which have been mentioned.
The pharmaceutical composition of the invention also contains additives such as, for
example, antioxidants, emulsifiers, preservatives, colouring agents and flavouring
agents. The pharmaceutical composition may also contain two or more prodrug
compounds of formula (I) and/or their physiologically tolerable salts. Furthermore, in
addition to at least one prodrug compound of formula (I) or (II) and/or its physiologically
tolerable salts, the pharmaceutical composition can also contain one or more other
therapeutically or prophylactically active ingredients.
It would be understood by persons skilled in the art that the amount of the compound of
formula I (prodrugs of known drugs or therapeutic agents) that is contained in the
pharmaceutical composition will depend upon the amount of the parent drug molecule
included therein. Generally, the amount of the prodrug used in the treatment methods is
that amount which effectively achieves the desired therapeutic effect in subjects being
treated for a particular disease. Naturally, the dosages of the various prodrugs
encompassed in the compounds of formula (I) will vary somewhat depending upon the
parent drug molecule, rate of in vivo drug hydrolysis etc.
The pharmaceutical composition contains about 1 to 99-, preferably about 1 to 80 %
and most preferably from about 10 to 70% by weight of the prodrug compound of
formula (I) and/or the physiologically tolerable salts of prodrug compound of formula (I).
The effective amount of the active ingredient of prodrug compound of formula (I) and/or
its physiologically tolerable salts in the pharmaceutical composition in order to obtain a
desired therapeutic effect varies from 1 to 5000 mg. The desirable dosage of the
pharmaceutical composition to be administered can vary over a wide range. The
selected dosage level can be readily determined by a skilled medical practitioner in the
light of the relevant circumstances, including the condition (diseases or disorder) to be
treated, the chosen route of administration depending on a number of factors, such as
age, weight and physical health and response of the individual patient,
pharmacokinetics, severity of the disease and the like, factors known in the medical art.
However, in order to obtain desirable effects, it would be recommended to administer
the pharmaceutical composition in the form of oral tablets (tablets, capsules) for a day/
week/ month and in a dosage ranging from 1 mg to 5000 mg, preferably 1 mg to 2000
mg, in a single dosage form or a multi-dosage form.
The range set forth above is illustrative and those skilled in the art will be able to
determine the optimal dosing of the prodrugs, the compounds of formula (I) of the
present invention selected based on clinical experience and the medical indication or
disease to be treated in a subject in need of the treatment.
Another aspect of the present invention is to provide methods for the treatment of
various medical conditions or diseases or disorders in a subject comprising
administering to a subject in need thereof a therapeutically effective amount of a
compound of formula (I). It has already been indicated herein above that the
compounds of formula (I) of the present invention are prodrugs of known drugs or
therapeutic agents containing a functional group independently selected from a
carboxylic acid, an amino, a hydroxyl or a sulfhydryl group. The specific class of
therapeutic agents encompassed within the scope of the invention are described herein
above.
Accordingly, in one aspect the present invention is related to a method of treating a
disease or disorder where a chronic, sustained and selective release of the constituent
drug or therapeutic agent D or nitric oxide contained in the compounds of formula (I) is
beneficial; comprising administering to a mammal or a human in need of the treatment
a therapeutically effective amount of the compound of formula (I).
In another aspect, the present invention also relates to a method of treating a disease
in a human or mammal where a chronic, sustained and selective release of the
constituent drug or therapeutic agent D or nitric oxide contained in the compounds of
formula (I) is beneficial; comprising administering to said mammal a therapeutically
effective amount of the pharmaceutical composition comprising the compounds of
formula (I).
In another aspect, the present invention relates to the compounds of formula (I) which
are the prodrugs of known drugs or therapeutic agents for use in the treatment of a
disease or disorder where a chronic, sustained and selective release of the constituent
drug or therapeutic agent D or nitric oxide contained in the compounds of formula (I) is
beneficial.
In another aspect, the present invention relates to the pharmaceutical composition
comprising the compounds of formula (I), which are the prodrugs of known drugs or
therapeutic agents, for use in the treatment of a disease or disorder where a chronic,
sustained and selective release of the constituent drug or therapeutic agent D or nitric
oxide contained in the compounds of formula (I) is beneficial.
In another aspect, the present invention relates to use of the compounds of formula (I),
which are the prodrugs of known drugs or therapeutic agents, for the treatment of a
disease or disorder where a chronic, sustained and selective release of the constituent
drug or therapeutic agent D or nitric oxide contained in the compounds of formula (I) is
beneficial.
In another aspect, the present invention relates to use of the pharmaceutical
composition comprising the compounds of formula (I), which are the prodrugs of known
drugs or therapeutic agents, in the treatment of a disease or disorder where a chronic,
sustained and selective release of the constituent drug or therapeutic agent D or nitric
oxide contained in the compounds of formula (I) is beneficial.
In another aspect, the present invention relates to use of the compounds of formula (I),
which are the prodrugs of known drugs or therapeutic agents, for the manufacture of
medicaments for the treatment of a disease or disorder where a chronic, sustained and
selective release of the constituent drug or therapeutic agent D or nitric oxide contained
in the compounds of formula (I) is beneficial.
In another aspect, the present invention relates to use of the pharmaceutical
composition comprising the compounds of formula (I), which are the prodrugs of known
drugs or therapeutic agents, for the manufacture of medicaments for the treatment of a
disease or disorder where a chronic, sustained and selective release of the constituent
drug or therapeutic agent D or nitric oxide contained in the compounds of formula (I) is
beneficial.
According to the present invention, the diseases or disorders or the medical conditions
for the treatment of which the compounds of formula (I) of the present invention are
used or are adapted for use, are those for which the parent drug molecule (represented
by the variable D which encompasses specific therapeutic agents) is conventionally
used by a medical practitioner. For instance, when the drug or the parent drug molecule
contained in the compounds of formula (I) is an anti-inflmmatory and analgesic agent
which are known for their use in the treatment of inflammatory disorders or
inflammatory conditions, the compounds of formula (I) of the present invention can be
used for the treatment of inflammatory conditions or disorders selected from:
inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenile rheumatoid
arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic nonrheumatoid
arthritis, osteoporosis/bone resorption, Crohn's disease, gout,
atherosclerosis, vasculitis, amyloidosis, chronic recurrent uveitis, ulcerative colitis,
cachexia, psoriasis, plasmocytoma, endometriosis, Behcet's disease, Wegenrer's
granulomatosis, autoimmune disease, immune deficiency, common variable
immunodeficiency (CVID), chronic graft-versus-host disease, trauma and transplant
rejection, adult respiratory distress syndrome, pulmonary fibrosis, ankylosing
spondylitis, skin delayed type hypersensitivity disorders, Alzheimer's disease, systemic
lupus erythematosus or allergic asthma. Further, for instance, when the drug or the
parent drug molecule contained in the compounds of formula (I) is a cardiovascular
agent which is known for its use in the treatment of cardiovascular diseases such as the
coronary artery diseases, atheroscerosis, angina, rheumatic heart disease and other
related disorders such as hypertension, the compounds of formula (I) of the present
invention can also be used for the treatment of similar diseases or conditions.
Thus, the diseases or disorders that can be treated using the compounds of formula (I)
of the present invention include but are not limited to inflammatory conditions or
disorders, cardiovascular diseases, cancer, allergies, psychological disorders,
neurological disorders, cerebrovascular disorders, convulsions, eye diseases, ear
diseases, nose and oropharynx diseases, diseases of respiratory system, diseases of
gastrointestinal tract system, diseases of genito-urinary system, skin diseases,
musculo-skeletal diseases, endocrinal disorders, metabolism disorders such as
diabetes, infectious diseases such as bacterial infections and fungal infections, viral
infections etc.
Moreover, the compounds of formula (I), which are the prodrugs of known drugs or
therapeutic agents, in all likelihood are advantageous over the parent drug molecules or
prodrugs of the parent molecule known hitherto in the prior art in terms of increased
bioavailability, reduced adverse effect, for instance, gastric irritability caused by
NSAIDS etc. Moreover, representative compounds encompassed in the compounds of
formula (I) have been found to be devoid of genotoxicity at a concentration at which the
compounds are expected to be used for the treatment of the medical conditions or
diseases for the treatment of which the parent drug molecule is used.
It is understood that modifications that do not substantially affect the activity of the
various embodiments of this invention are included within scope of the invention
disclosed herein. Accordingly, the following examples are intended to illustrate but not
to limit scope of the present invention.
Experimental
The abbreviations and terms that are used herein:
BOP: Benzotriazol-1 -yl-oxy-fr/ s(dimethylamino)phosphonium hexafluorophosphate
DMF: N,N-Dimethylformamide
DSC: ,'-Disuccinimidyl carbonate
CDI: N,N'-Carbonyldiimidazole
DCC: N,N'-Dicyclohexylcarbodiimide
DMAP: 4-Dimethylaminopyridine
EDAC. HCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
HBTU: 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
TBTU: 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
EtOH: Ethanol
LAH: Lithium Aluminum Hydride
Et20 : Diethyl ether
THF: Tetrahydrofuran
DMSO: Dimethyl sulfoxide
TEA: Triethylamine
DIPEA: N,N-Diisopropylethylamine
DCM: Dichloromethane
EtOAc or EA: Ethyl acetate
DME: Dimethoxyethane
MeOH: Methanol
PE: Petroleum ether
RT: Room temperature
TFA: Trifluoroacetic acid
HOBT: N-Hydroxybenzotriazole
HPLC: High Performance Liquid Chromatography
TLC: Thin Layer Chromatography
RT: Room Temperature
Examples of the compounds of formula I which are the prodrugs of the drugs
containing an carboxylic acid group :
Example 1:
(2S)-2-((2-((1-(nitrooxy)ethoxy)carbonyloxy)ethyl)disulfanyl)ethyl 2-(6-
methoxynaphthalen-2-yl)propanoate (I-CD1-L1-R1)
This compound was synthesized in 3 steps as shown in Scheme 1 and the
experimental procedure is described below:
Step 1: Preparation of (S)-2-((2-hydroxyethyl)disulfanyl)ethyl 2-(6-methoxynaphthalen-
2-yl) propanoate [NO-Naproxen (CD1-L1-OH)]
A solution of DCC ( 13.0 g, 62.6 mmol) in DCM (25 mL) was added drop-wise over 5
minutes to a stirred solution of naproxen (CD1 , 12.0 g, 52.2 mmol), bis(2-hydroxyethyl)
disulfide (HO-L1-OH, 13.4 g, 104.3 mmol) and DMAP ( 1 .3 g, 10.4 mmol) in 250 mL of
DCM at 0 °C and the mixture was stirred for 3 h when TLC analysis of the mixture
indicated completion of the reaction. The mixture was filtered and the filtrate was
washed with water (2 x 100 mL) and brine ( 1 x 100 mL). The organic layer was
separated, dried over Na2S0 4 and concentrated in vacuo to give the crude product
which was purified by column chromatography (600 g of silica gel, 150-300 mesh). The
expected bis-naproxen derivative (i.e., CD1-L1-CD1), which was formed as a minor
undesired product, was eluted with 10 % EtOAc in petroleum ether. The desired monoacylated
title compound, which was eluted with 20 % EtOAc in petroleum ether, was
obtained as a white solid. Yield: 12.0 g (63.1 %); 1H NMR (CDCI3, 300 MHz): 1.58 (d,
J = 7.2 Hz, 3H), 2.77 (t, J = 5.7 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H), 3.77 (t, J = 5.7 Hz,
2H), 3.87 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.28 - 4.42 (m, 2H), 7.08 - 7.1 7 (m, 2H), 7.40
(dd, J = 8.4, 1.5 Hz, 1H), 7.64 - 7.73 (m, 3H); MS m/z: 384.1 [M+NH4]+.
Step 2 : Preparation of (2S)-2-((2-((1 -chloroethoxy)carbonyloxy)ethyl) disulfanyl)ethyl 2-
(6-methoxynaphthalen-2-yl)propanoate (CD1 -L1 -R1 -CI)
a-chloroethyl chloroformate (CI-R1-CI, 1. 1 mL, 11.5 mmol) was added drop-wise to a
solution of (S)-2-((2-hydroxyethyl)disulfanyl)ethyl 2-(6-methoxynaphthalen-2-yl)-
propanoate (CD1-L1-OH, 3.5 g, 9.6 mmol) in 30 mL of DCM at 0 °C under nitrogen
atmosphere. To this stirred mixture was added a solution of pyridine ( 1 .2 mL, 14.3
mmol) in 5 mL of DCM over 5 minutes. The mixture was stirred at 0 °C under nitrogen
atmosphere for 30 minutes when TLC analysis of the mixture indicated completion of
the reaction. The mixture was diluted with DCM (~ 65 mL), washed with 1N HCI (3 x
100 mL), saturated sodium bicarbonate ( 1 x 100 mL) and brine (2 x 50 mL). The
organic layer was dried over anhydrous Na2S0 and concentrated in vacuo to afford a
yellow oily residue which was purified by column chromatography (200 g silica gel, 200-
400 mesh, eluted with 10 % EtOAc in petroleum ether) to afford the title compound,
CD1-L1-R1-CI as a slight greenish yellow colored oil. Yield: 3.2 g (70.8 %); 1H NMR
(CDCI3, 300 MHz): 1.58 (d, J = 6.9 Hz, 3H), 1.82 (d, J = 5.7 Hz, 3H), 2.83 - 2.93 (m,
4H), 3.87 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.27 - 4.43 (m, 4H), 6.41 (q, J = 6.0 Hz, 1H),
7.1 0 - 7.1 8 (m, 2H), 7.40 (dd, J = 8.4, 1.5 Hz, 1H), 7.67 (br s, 1H), 7.71 (d, J = 8.4 Hz,
2H); MS m/z: 491 .25 [M + NH4]+.
Step 3 : Preparation of (2S)-2-((2-((1 -(nitrooxy)ethoxy)carbonyloxy) ethyl)disulfanyl)-
ethyl 2-(6-methoxynaphthalen-2-yl)propanoate (I-CD1-L1-R1)
Silver nitrate ( 1 .4 g, 8.1 mmol) was added to a solution of (2S)-2-((2-((1-
chloroethoxy)carbonyloxy)ethyl)disulfanyl)ethyl 2-(6-methoxynaphthalen-2-
yl)propanoate (CD1-L1-R1-CI, 3.2 g, 6.8 mmol) in 35 mL of ACN and the mixture was
refluxed in dark at 85 - 90 °C for 30 minutes when TLC analysis of the mixture indicated
complete conversion. The mixture was cooled and filtered through celite. The filtrate
was concentrated and the residue (~ 3.5 g) was purified by column chromatography
( 150 g of silica gel, 200-400 mesh, eluted with 10 % EtOAc in petroleum ether) to afford
2.3 g of slightly impure product which was purified again by column chromatography
[100 g of silica gel, 200-400 mesh, eluted with petroleum ether/ DCM (2:3)] to afford the
pure title compound (I-CD1-L1-R1) as greenish oil. Yield: 1.8 g (84 %); 1H NMR (CDCI3,
300 MHz): 1.56 - 1 .61 (m, 6H), 2.81 - 2.90 (m, 4H), 3.87 (q, J = 7.2 Hz, 1H), 3.91 (s,
3H), 4.30 - 4.38 (m, 4H), 6.91 (q, J = 5.7 Hz, 1H), 7.10 - 7.1 7 (m, 2H), 7.40 (dd, J = 8.4,
1.8 Hz, 1H), 7.65 - 7.73 (m or distorted t , 3H); 1 C NMR (CDCI3, 75.47 MHz): 17.5,
18.6, 30.5, 30.8, 45.5, 55.4, 64.1 , 67.4, 96.4, 105.7, 119.2, 126.1 , 126.3, 127.3, 129.0,
129.4, 133.8, 135.5, 152.6, 157.8, 174.5; MS m/z: 522.1 [M+Na] +; HRMS ESI (m/z):
[M+Na] + calculated for 21 5 Nai0 9S2: 522.0863; Found: 522.0869 (Mass Accuracy:
1. 15 ppm).
Example 2 :
2-((2-((1-(nitrooxy)butoxy)carbonyloxy)ethyl)disulfanyl)ethyl 2-acetoxybenzoate
[NO-Aspirin/Salicylic acid (I-CD2-L1-R2)]
This compound was synthesized in 3 steps as shown in Scheme 1 and the
experimental procedure is described below:
Step 1: Synthesis of 2-((2-hydroxyethyl)disulfanyl)ethyl 2-acetoxybenzoate (CD2-L1-
OH)
A solution of aspirin acid chloride (CD2-CI, 7.0 g, 35.3 mmol, freshly prepared from
aspirin by using oxalyl chloride/ DMF/ DCM method) in 20 mL of DCM was added dropwise
to a stirred solution of 2-hydroxyethyl disulfide (HO-L1-OH, 10.9 g, 70.5 mmol)
and Triethylamine (7.35 mL, 52.89 mmol) in 50 mL of DCM at 0 °C under nitrogen
atmosphere and the mixture was stirred at RT for overnight, when TLC analysis of the
mixture indicated completion of the reaction. The mixture was diluted with 25 mL of
water and 100 mL of DCM. The organic layer was separated and washed with aqueous
sodium bicarbonate (2 x 100 mL) and brine ( 1 x 100 mL), dried over Na2S0 4 and
concentrated in vacuo to give 10.0 g of crude oil which was purified by column
chromatography (225.0 g of silica gel, 150-300 mesh, eluted with 5 - 30% ethyl acetate
in petroleum ether) to afford the title compound (CD2-L1-OH) as yellow oil. Yield: 5.2 g
(46.6 %); 1H NMR (CDCI3, 300 MHz): 2.26 (bt, J = 4.2 Hz, 1H), 2.38 (s, 3H), 2.90 (t, J
= 6.0 Hz, 2H), 3.05 (t, J = 6.6 Hz, 2H), 3.69 (distorted q or m, 2H), 4.57 (t, J = 6.6 Hz,
2H), 7.13 (dd, J = 8.1 , 0.9 Hz, 1H), 7.34 (dt, J = 7.8 Hz, 1H), 7.60 (dt, J = 7.8, 1.5 Hz,
1H), 8.06 (dd, J = 7.8, 1.5 Hz); MS m/z: 339.0 [M+Na]+.
Step 2 : Synthesis of 2-((2-((1-chlorobutoxy)carbonyloxy)ethyl)disulfanyl)ethyl 2-
acetoxybenzoate (CD2-L1-R2-CI)
Pyridine (73.0 _, 0.9 mmol) followed by diphosgene ( 1 . 1 mL, 9.3 mmol) were added to
a stirred solution of butyraldehyde ( 1 .0 g, 13.9 mmol) in 3 mL of dry DCM at RT under a
nitrogen atmosphere and the mixture was stirred at RT for 3 h. About 50 % of the
solvent was distilled off in vacuo and kept the mixture under nitrogen atmosphere. To
this stirred mixture at 0 °C under nitrogen was added a solution of 2-((2-
hydroxyethyl)disulfanyl)ethyl 2-acetoxybenzoate (CD2-L1-OH, 1.5 g, 4.6 mmol) in 4 mL
of dry DCM followed by pyridine ( 1 . 1 mL, 13.9 mmol) and the mixture was stirred at 0
°C for 30 minutes when TLC analysis of the mixture indicated completion of the
reaction. The mixture was diluted with 10 mL of DCM, washed with 1N HCI (3 x 15 mL),
saturated sodium bicarbonate (3 x 15 mL) and brine (2 x 10 mL). The organic layer was
dried over anhydrous Na2S0 4 and concentrated in vacuo to give a oily residue (2.5 g)
which was purified by column chromatography (40.0 g of silica gel, 200-400 mesh;
eluted with 5-8 % of EtOAc in petroleum ether) to afford the title compound as yellow
oil. Yield: 1.6 g (80 %); 1H NMR (CDCI3, 300 MHz): 0.98 (t, J = 7.5 Hz, 3H), 1.47 -
1.62 (m, 2H), 1.96 -2.17 (m, 2H), 2.38 (s, 3H), 3.00 (t, J = 6.6 Hz, 2H), 3.06 (t, J= 6.6
Hz, 2H), 4.48 (t, J = 6.6 Hz, 2H), 4.56 (t, J = 6.6 Hz, 2H), 6.32 (t, J = 6.0 Hz, 1H), 7.1 3
(dd, J = 7.8, 0.9 Hz, 1H), 7.34 (dt, J = 7.8, 0.9 Hz, 1H), 7.59 (dt, J = 7.8, 1.5 Hz, 1H),
8.06 (dd, J =7.8, 1.5 Hz, 1H); MS m/z: 474.0 [M+Na]+.
Step 3 : Synthesis of 2-((2-((1-(nitrooxy)butoxy)carbonyloxy)ethyl)disulfanyl)ethyl 2-
acetoxybenzoate (I-CD2-L1-R2)
Silver nitrate (0.9 g, 5.0 mmol) was added to a solution of 2-((2-((1 -chlorobutoxy)-
carbonyloxy)ethyl) disulfanyl)ethyl 2-acetoxybenzoate (CD2-L1-R2-CI, 1.5 g, 3.3 mmol)
in 15 mL of ACN at RT under a nitrogen atmosphere (covered the reaction flask with
aluminum foil to minimize exposure of reaction mixture to light) and the mixture was
stirred at RT for overnignt ( 16 h). HPLC analysis of the mixture indicated complete
conversion. The mixture was diluted with 10 mL of DCM and filtered through a small
pad of celite to remove the insoluble salts. The filtrate was concentrated to give 2.0 g of
oily residue which was purified by column chromatography (50.0 g of silica gel, 200-400
mesh, eluted with 8 % EtOAc in petroleum ether) to afford the title compound as yellow
oil. Yield: 0.4 g (27 %). (Note: additional ~ 0.35 g (-1 9 %) of impure product (-80 %
pure by HPLC) was also obtained); 1H NMR (CDCI3, 300 MHz): 1.00 (t, J = 7.5 Hz,
3H), 1.43 - 1 .58 (m, 2H), 1.83 - 1.92 (m, 2H), 2.38 (s, 3H), 2.99 (t, J = 6.6 Hz, 2H), 3.05
(t, J = 6.6 Hz, 2H), 4.47 (t, J = 6.6 Hz, 2H), 4.55 (t, J = 6.6 Hz, 2H), 6.85 (t, J = 6.0 Hz,
1H), 7.13 (dd, J = 7.8, 0.9 Hz, 1H), 7.34 (dt, J = 7.8, 0.9 Hz, 1H), 7.59 (dt, J = 7.8, 1.5
Hz, 1H), 8.05 (dd, J = 7.8, 1.8 Hz); 1 C NMR (CDCI3, 75.47 MHz): 12.9, 16.2, 20.6,
32.7, 36.2, 36.6, 62.3, 65.8, 97.9, 122.4, 123.3, 125.6, 13 1 .3, 133.6, 150.3, 152.3,
163.6, 169.1 ; MS m/z: 477.1 [M+H] +, 500.1 [M+Na] +.
Example 3 :
(2S)-((Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl) 2-(6-methoxynaphthalen-
2-yl)propanoate [NO-Naproxen (I-CD1-L2-R1)]
This compound was synthesized in 4 steps as shown in Scheme 1 and the
experimental procedure is described below:
Step 1: Preparation of (S)-2-6-methoxynaphthalen-2-yl)propanoyl chloride (CD1-CI)
DMF (- 3 - 4 drops) followed by oxalyl chloride ( 1 1.0 mL, 130.4 mmol) were added
drop-wise to a stirred solution of naproxen (DC1 , 25.0 g, 108.7 mmol) in 200 mL of
DCM at RT under a nitrogen atmosphere over 10 minutes. The mixture was stirred at
RT under nitrogen atmosphere for 3 h. The mixture was concentrated in vacuo to afford
crude naproxen acid chloride as a yellow solid, which was used as such in the next
step. Yield: 27.0 g (quantitative).
Step 2 : Preparation of (S,Z)-4-hydroxybut-2-enyl 2-(6-methoxynaphthalen-2-yl)-
propanoate (CD1-L2-OH):
A solution of naproxen chloride (5.0 g, 20.0 mmol) in 10 mL of DCM was added to a
stirred solution of cis-2-butene-1 ,4-diol (HO-L2-OH, 5.3 mL, 60.0 mmol) in 100 mL of
DCM at 0 °C under a nitrogen atmosphere. To this stirred mixture was added
triethylamine (4.2 mL, 30.0 mmol) drop-wise over 15 minutes and the resulting mixture
was stirred at 0 °C for 30 minutes and at RT for overnight (-12 h), when TLC analysis
of the mixture indicated formation of two product spots (i.e., mono and bis-acylated
products). The mixture was washed with saturated sodium bicarbonate (3 x 100 mL),
brine (3 x 100 mL), dried over anhydrous Na2S0 4 and concentrated to afford 7.0 g of
crude oily residue which was purified by column chromatography ( 150.0 g of silica gel,
200-400 mesh, eluted with 10 % EtOAc in petroleum ether to isolate the bis-acylated
compound and with 20 % EtOAc in petroleum ether to isolate the desired monoacylated
product). The title compound was obtained as a white solid. Mp: 69 - 7 1 °C;
Yield: 4.5 g (75 %); 1H NMR (CDCI3, 300 MHz): 1.57 (d, J = 6.9 Hz, 3H), 1.99 (br s,
1H), 3.85 (q, J = 6.9, 7.2 Hz, 1H), 3.91 (s, 3H), 4.18 (t, J = 4.8 Hz, 2H), 4.60 - 4.73 (m,
2H), 5.50 - 5.62 (m, 1H), 5.75 - 5.85 (m, 1H), 7.09 - 7.17 (m, 2H), 7.38 (dd, J = 8.4, 1.5
Hz, 1H), 7.65 (br s, 1H), 7.70 (d, J = 8.7 Hz, 2H); MS m/z: 323.1 [M+Na] +.
Step 3 : Preparation of (2S)-((Z)-4-((1-chloroethoxy)carbonyloxy)but-2-enyl) 2-(6-
methoxynaphthalen-2-yl)propanoate (CD1-L2-R1-CI):
o -chloroethyl chloroformate (CI-R1-C1 , 1.6 mL, 16.4 mmol) was added drop-wise to a
stirred solution of (S,Z)-4-hydroxybut-2-enyl 2-(6-methoxynaphthalen-2-yl)propanoate
(CD1-L2-OH, 4.1 g, 13.7 mmol) in 50 mL of DCM at 0 °C under a nitrogen atmosphere.
To this stirred mixture was added a solution of pyridine ( 1 .7 mL, 20.4 mmol) in 5 mL of
DCM over 5 minutes. The mixture was stirred at 0 °C under nitrogen for 30 minutes and
at RT for 3 h when TLC analysis of the mixture indicated completion of the reaction. The
mixture was diluted with DCM (-75 mL), washed with 1N HCI (3 x 100 mL), saturated
sodium bicarbonate ( 1 x 100 mL) and brine (2 x 100 mL). The organic layer was dried
over anhydrous Na2S0 4 and concentrated in vacuo to give a greenish oily residue which
was used as such in the next step as its purity was > 90 % (by HPLC) and its proton
NMR and mass spectral data was consistent with the expected structure. Yield: 5.0 g
(89.9 %); 1H NMR (CDCI3, 300 MHz): 1.57 (d, J = 7.5 Hz, 3H), 1.81 (d, J = 5.1 Hz, 3H),
3.86 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.61 - 4.82 (m, 4H), 5.66 - 5.79 (m, 2H), 6.39 (dq,
J = 1.2, 6.0 Hz, 1H), 7.10 - 7.17 (m, 2H), 7.38 (dd, J = 8.4, 1.5 Hz, 1H), 7.65 (d, J = 1.2
Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H); MS m/z: 429.1 [M+Na] +.
Step 4 : Preparation of (2S)-((Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 2-(6-
methoxynaphthalen-2-yl)propanoate (I-CD1-L2-R1):
Silver nitrate (3.1 g, 18.8 mmol) was added to a solution of (2S)-((Z)-4-((1-
chloroethoxy)carbonyloxy)but-2-enyl) 2-(6-methoxynaphthalen-2-yl)propanoate (CD1 -
L2-R1-CI, 5.0 g, 12.3 mmol) in 50 ml of ACN and the mixture was refluxed in dark at
85 - 90 °C for -40 min when TLC analysis of the mixture indicated complete
conversion. The mixture was cooled, diluted with DCM (-70 ml.) and filtered through
celite. The filtrate was concentrated and the residue was re-dissolved in DCM (-50 ml.)
and the separated silver salt was filtered again through celite. The filtrate was
concentrated to give 7.0 g of residue which was purified by column chromatography
( 150.0 g of silica gel 200-400 mesh, eluted with 7 - 10 % EtOAc in petroleum ether) to
afford the title compound as a white solid. Mp: 76 - 78 °C; Yield: 5.0 g (93.7 %); 1H
NMR (CDCI3, 300 MHz): 1.55 - 1.62 (m, 6H), 3.86 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H),
4.65 - 4.72 (m, 4H), 5.65 - 5.79 (m, 2H), 6.89 (q, J = 5.7 Hz, 1H), 7.10 - 7.18 (m, 2H),
7.40 (dd, J = 8.4, 1.8 Hz, 1H), 7.64 - 7.74 (m or distorted t , 3H); 1 C NMR (CDCI3, 75.47
MHz): 17.5, 18.6, 45.5, 55.4, 60.3, 64.1 , 96.3, 105.7, 119.2, 126.1 , 126.3, 126.7,
127.4, 129.0, 129.3, 129.4, 133.9, 135.5, 152.6, 157.8, 174.4; MS m/z: 456.1 [M+Na] +;
HRMS ESI (m/z): [M+Na] + calculated for C2i H23NiNai0 9: 456.1265; Found: 456.1266
(Mass Accuracy: 0.88 or -0.22 ppm).
Example 4 :
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl nicotinate [NO-Niacin (I-CD3-L2-
R1)]
The title compound was synthesized in 3 steps as shown in Scheme 2 and the
experimental procedure is described below:
Step 1: Preparation of (Z)-l -chloroethyl 4-hydroxybut-2-enyl carbonate (HO-L2-R1-CI)
o -Chloroethyl chloroformate (CI-R1-CI, 20.0 ml_, 187.0 mmol) was added drop-wise to
a stirred solution of cis-2-butene-1 ,4-diol (HO-L2-OH, 15.0 g, 170.2 mmol) and pyridine
(27.0 mL, 340.0 mmol) in 200 mL of DCM at 0 °C over a period of 10 minutes and the
mixture was stirred at 0 °C for 1 h. TLC analysis of the mixture indicated completion of
the reaction. The mixture was diluted with 100 mL of DCM and washed with 1N HCI (2
x 200 mL), water (2 x 150 mL), and brine (2 x 150 mL). The organic layer was dried
over Na2S0 4 and concentrated in vacuo to obtain an oil which was purified by column
chromatography (silica gel 100-200 mesh, eluted with 5 % EtOAc in petroleum ether) to
afford the title compound as a colorless oil. Yield: 16.0 g (48.5 %); 1H NMR (CDCI3, 300
MHz): 1.85 (d, J = 5.7 Hz, 3H), 4.30 (d, J = 6.3 Hz, 2H), 4.75 - 4.90 (m, 2H), 5.65 -
5.76 (m, 1H), 5.90 - 5.99 (m, 1H), 6.43 (q, J = 5.7 Hz, 1H); 1 C NMR (CDCI3, 125.77
MHz): 25.2, 58.4, 64.1 , 84.7, 124.1 , 134.7, 152.9; MS m/z: 2 17.1 [M+Na] +.
Step 2 : Preparation of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1)
Silver nitrate ( 15.7 g, 92.5 mmol) was added to a solution of (Z)-l -chloroethyl 4-
hydroxybut-2-enyl carbonate (HO-L2-R1-CI, 12.0 g, 6 1.7 mmol) in acetonitrile ( 120 mL)
and the mixture was stirred at 80 °C for 2 h. HPLC analysis of the mixture indicated
completion of conversion. The mixture was cooled to RT and filtered through celite. The
filtrate was concentrated to give the residue which was re-dissolved in 200 mL of DCM
and filtered through celite to remove the separated silver chloride. The filtrate was
washed with water (2 x 100 mL) and brine (2 x 100 mL), dried over Na2S0 4 and
concentrated in vacuo to give the crude product as yellow oil, which was used as such
in the next step. Yield: 8.9 g (65.3 %); 1H NMR (CDCI3, 300 MHz): 1.60 (d, J = 6.0 Hz,
3H), 1.99 (s, 1H), 4.28 (t, J = 6.3 Hz, 2H), 4.80 (d, J = 7.2 Hz, 2H), 5.64 - 5.75 (m, 1H),
5.90 - 5.98 (m, 1H), 6.93 (q, J = 5.7 Hz, 1H).
Step 3 : Preparation of (Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl nicotinate (ICD3-
L2-R1)
A solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1 , 0.6 g, 2.8
mmol) and pyridine (0.5 mL, 5.6 mmol) in 4 mL of DCM was added drop-wise to a
stirred suspension of nicotinoyl chloride hydrochloride (CD3-CI. HCI, 0.5 g, 2.8 mmol) in
6 mL of DCM at 0 °C under a nitrogen atmosphere over 10 minutes and the resulting
mixture was stirred at RT for 2 h when TLC analysis of the mixture indicated completion
of the reaction. The mixture was diluted with 20 mL of DCM, washed with water (2 x 20
mL), dried over Na2S0 4 and concentrated to give the crude residue which was purified
by column chromatography (silica gel, eluted with 30-50 % EtOAc in petroleum ether) to
afford the title compound as colorless oil. Yield: 0.6 g (60 %); 1H NMR (CDCI3, 300
MHz): 1.62 (d, J = 5.7 Hz, 3H), 4.69 - 4.80 (m, 1H), 4.87 - 4.93 (m, 2H), 4.99 (d, J =
6.6 Hz, 1H), 5.83 - 6.13 (m, 2H), 6.95 (q, J = 5.7 Hz, 1H), 7.42 (dd, J = 8.1 , 5.1 Hz, 1H),
8.30 - 8.37 (m, 1H), 8.81 (d, J = 4.8 Hz, 1H), 9.23 - 9.28 (m, 1H); MS m/z: 327.1
[M+H]+.
Example 5 :
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl2-(2-(4-((4-chlorophenyl)
(phenyl)methyl)piperazin-1-yl)ethoxy)acetate [NO-Cetirizine (I-CD4-L2-R1)]
This compound was synthesized as shown in Scheme 2 and the experimental
procedure is described below:
Triethylamine (TEA, 0.9 mL, 4.5 mmol) followed by a solution of (Z)-4-hydroxybut-2-
enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1 , 0.5 g, 2.3 mmol) in DCM (5 mL) was
added to a stirred suspension of cetirizine dihydrochloride (CD4. 2 HCI, 1.0 g, 2.3
mmol) in 15 mL of DCM. To this stirred mixture was added DCC (0.6 g, 2.7 mmol)
followed by DMAP (50 mg, -0.4 mmol) and the resulting mixture was stirred for 2 h
when TLC analysis of the mixture indicated formation of a new product. The mixture
was diluted with 10 mL of DCM and filtered. The filtrate was washed with saturated
sodium bicarbonate (10 mL) and brine ( 10 mL). The organic layer was dried over
Na2S0 4 and concentrated on rotavap to give a crude residue which was purified by
column chromatography (silica gel, eluted with EtOAc/petroleum ether gradient) to
afford the title compound as a yellow gum/ highly viscous oil. Yield: 0.4 g (32.6 %); 1H
NMR (CDCI3, 300 MHz): 1.61 (d, J = 5.7 Hz, 3H), 2.35 - 2.64 (m, 8H), 2.68 (t, J = 5.7
Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H), 4.13 (s, 2H), 4.22 (s, 1H), 4.64 - 4.83 (m, 4H), 5.80 -
5.93 (m, 2H), 6.91 - 6.98 (m, 1H), 7.1 6 - 7.41 (m, 9H); MS m/z: 592 [M+H]+.
The compounds of the examples 6 - 11 were prepared by following the experimental
procedure for the compound exemplified in example 5. The characterization data for the
compounds of examples 6 - 11 is described below:
Example 6 :
(2R)-((Z)-4-((1 -(nitrooxy)ethoxy)carbonyloxy)but-2-enyl) 2-((1 S,4S)-4-isopropylcyclohexanecarboxamido)-
3-phenylpropanoate [NO-Nateglinide (I-CD5-L2-R1)]
The title compound was obtained as a pale yellow gum. Yield (last step): 22.0 %; 1H
NMR (CDCI3, 300 MHz): 0.87 (d, J = 6.9 Hz, 6H), 1.62 (d, J = 5.7 Hz, 3H), 0.89 - 2.09
(m, 11H), 3.06 - 3.22 (m, 2H), 4.62 - 4.97 (m, 5H), 5.72 - 5.95 (m, 3H), 6.94 (q, J = 5.7
Hz, 1H), 7.07 - 7.13 (m, 2H), 7.23 - 7.35 (m, 3H); MS m/z: 521 .2 [M+H]+, 543.2
[M+Na] +.
Example 7 :
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 2-(2-(2,6-dichlorophenylamino)
phenyl)acetate [NO-Diclofenac (I-CD6-L2-R1)]
The title compound was obtained as light red oil. Yield (last step): 89.9 %; 1H NMR
(CDCI3, 300 MHz): 1.61 (d, J = 5.7 Hz, 3H), 3.85 (s, 2H), 4.79 (distorted t , J = 6.0 Hz,
4H), 5.74 -5.92 (m, 2H), 6.57 (d, J = 7.8 Hz, 1H), 6.86 (br s, 1H), 6.94 (q, J = 5.7 Hz,
1H), 6.99 (q, J = 8.1 Hz, 2H), 7.1 6 (dt, J = 7.8, 1.5 Hz, 1H), 7.25 (dd, J = 7.5, 1.5 Hz,
1H), 7.37 (d, = 8.1 Hz, 2H).
Example 8 :
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 2-(1-(4-chlorobenzoyl)-5-
methoxy-2-methyl-1 H-indol-3-yl)acetate [NO-lndomethacin (I-CD7-L2-R1 )]
The title compound was obtained as yellow viscous oil. Yield (last step): 92.7 %; 1H
NMR (CDCI3, 300 MHz): 1.60 (d, J = 5.4 Hz, 3H), 2.41 (s, 3H), 3.70 (s, 2H), 3.85 (s,
3H), 4.75 (distorted dd, J = 10.2, 5.4 Hz, 4H), 5.73 - 5.88 (m, 2H), 6.69 (dd, J = 9.0, 2.4
Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H), 6.93 (q merged with adjacent doublets, J = 5.7 Hz,
1H), 6.96 (d, J = 2.4 Hz, 1H), 7.49 (distorted d, J = 8.4 Hz, 2H), 7.69 (distorted d, J =
8.7 Hz, 2H);
MS m/z: 561 . 1 [M+H]+, 583.1 [M+Na] +, 599 [M+K] +.
Example 9 :
4-((1-(nitrooxy)ethoxy)carbonyloxy)butyl 2-(6-methoxynaphthalen-2-
yl)propanoate [NO-Naproxen (I-CD1-L3-R1)]
The title compound was also obtained as oil. Yield (last step) : 86.9 %; 1H NMR (CDCI3,
300 MHz) : 1.56 - 1.62 (m, 6H), 1.64 - 1.72 (m, 4H), 3.87 (q, J = 7.2 Hz, 1H), 3.94 (s,
3H) , 4.09 - 4.18 (m, 4H), 6.92 (q, J = 5.7 Hz, 1H), 7.11 - 7.19 (m, 2H) , 7.41 (dd, J = 8.4,
1.5 Hz, 1H), 7.68 (br s, 1H), 7.72 (d, J = 8.4Hz, 2H) ; MS m/z: 458. 1 [M+Na] +, 474. 1
[M+K] +; HRMS ESI (m/z) : [M+Na] + calculated for C2iH25N1Na 0 9: 458. 1422; Found:
458. 1431 (Mass Accuracy: - 1 .96 ppm).
Example 10:
(2S)-3-((1-(nitrooxy)ethoxy)carbonyloxy)propyl 2-(6-methoxynaphthalen-2-yl)
propanoate [NO-Naproxen (I-CD1-L4-R1)]
The title compound was also obtained as oil. Yield (last step) : 68.0 %; 1H NMR (CDCI3,
300 MHz) : 1.53 - 1.64 (m, 6H), 1.91 - 2.02 (m, 2H), 3.86 (q, J = 7.2 Hz, 1H), 3.92 (s,
3H), 4.13 - 4.2 1 (m, 4H), 6.85 - 6.93 (m, 1H), 7.10 - 7.18 (m, 2H), 7.41 (d, J = 8.4 Hz,
1H) , 7.66 (br s, 1H), 7.70 (d, J = 8.4 Hz, 2H) ; MS m/z: 444. 1 [M+Na] +.
Example 1 1 :
(2S)-2,2-dimethyl-3-((1-(nitrooxy)ethoxy)carbonyloxy)propyl 2-(6-methoxynaphthalen-
2-yl) propanoate [NO-Naproxen (I-CD1-L5-R1)]
The title compound was also obtained as yellow oil. Yield (last step) : 96.0 %; 1H NMR
(CDCI3, 300 MHz) : 0.86 (s, 3H), 0.90 (s, 3H), 1.53 - 1.64 (m, 6H), 3.83 - 3.97 (m
buried under -OCH3 singlet, 5H), 3.95 (s, 3H), 6.83 - 6.94 (m, 1H), 7.11 - 7.19 (m, 2H),
7.42 (bd, J = 8.7 Hz, 1H), 7.68 (br s, 1H) , 7.72 (d, J = 8.7 Hz, 2H) ; MS m/z: 472. 1
[M+Na] +.
Example 12:
(3/?,5/7)-((Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl) 7-(2-(4-fluorophenyl)-
5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)-3,5-
dihydroxyheptanoate [NO-Atorvastatin (I-CD8-L2-R1)]
This compound was synthesized in 5 steps as shown in Scheme 22 (via method A) and
the experimental procedure is described below:
Step 1: 2-((4f?,6f?)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-
1H-pyrrol-1 -yl)ethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetic acid [CD8(PG )]
To a stirred suspension of atorvastatin calcium salt ( 10.0 g, 8.7 mmol) and 2,2-
dimethoxypropane (5.3 mL, 43.3 mmol) in acetone (500 mL) at 0 °C was added
concentrated sulfuric acid (-0.5 mL added drop wise) and the mixture was stirred at 0
°C for 3 h and at RT for additional 2 h. TLC of the mixture indicated -90 % conversion
to the acetonide. The mixture was concentrated in vacuo and about half of the residue
(-7.0 g) was used as such in the next step. The remaining half of the crude product (-
8.0 g) was purified by column chromatography on silica gel (200-400 mesh) using 5 %
acetone in DCM to yield the pure title compound as white solid; Purity by HPLC: 99.29
% at 210 nm. 1H NMR (CDCI3, 300 MHz): 1.34 (s, 3H), 1.39 (s, 3H), 1.25 - 1.42 (m,
2H), 1.54 (d, J =7.2 Hz, 6H), 1.63 - 1 .73 (m, 2H), 2.47 (dq, J =15.9, 10.0, 6.6 Hz, 2H),
3.45 - 3.65 (m, 1H), 3.67- 3.75 (m, 1H), 3.80 - 3.93 (m, 1H), 4.05 - 4.25 (m, 2H), 6.89
(br s, 1H), 6.98 - 7.21 (m, 14H); MS m/z: 599.3 [M+H]+, 621 .3 [M+Na] +.
Step 2 : (Z)-4-hydroxybut-2-enyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)ethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate
[CD8(PG )-L2-OH]
1, 1 '-Carbonyldiimidazole (CDI, 3.4 g, 2 1.0 mmol) was added as solid (in one lot) to a
solution of 7.0 g ( 1 1.7 mmol) of 2-((4f?,6f?)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)ethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetic
acid [CD8(PG )] in DCM ( 100 mL) at RT and the mixture was stirred at RT for 1.5 h
when TLC analysis indicated formation of the corresponding CDI intermediate. This
mixture was added to a suspension of cis-2-butene-1 ,4-diol (HO-L2-OH, 4.2 g, 48.0
mmol) in DCM ( 150 mL) at 0 °C over a period of 20 minutes and the mixture was stirred
at 0 °C for 4 h and at RT for 2 days. TLC analysis of the mixture indicated completion of
the reaction. The mixture was washed with water (3 x 200 mL), brine (2 x 100 mL),
dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6.5 g of a
crude semisolid which was purified by column chromatography on silica gel (150-300
mesh) using 2 % acetone in DCM as eluent. The pure title compound was obtained as
a white solid, Yield: 4.7 g (58.8 %); 1H NMR (CDCI3, 300 MHz): 1 .31 (s, 3H), 1.37 (s,
3H), 1.30 - 1 .45 (m, 2H), 1.54 (d, J = 6.9 Hz, 6H), 1.62 - 1.73 (m, 2H), 2.42 (dq, J = 15.6,
8.7, 6.0 Hz, 2H), 3.50 - 3.65 (m, 1H), 3.66 - 3.77 (m, 1H), 3.78 - 3.92 (m, 1H), 4.05 -
4.23 (m, 3H), 4.26 (d, J = 6.6 Hz, 2H), 4.70 (d, J = 6.9 Hz, 2H), 5.57 - 5.68 (m, 1H),
5.83 - 5.93 (m, 1H), 6.88 (br s, 1H), 6.98 - 7.19 (m, 14H); MS m/z: 669.3 [M+H] +, 691 .3
[M+Na] +.
Step 3 : (3f?,5f?)-((Z)-4-hydroxybut-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoyl)-l H-pyrrol-1 -yl)-3,5-dihydroxyheptanoate (CD8-L2-OH)
Montmorillonite Clay K-1 0 powder ( 1 .8 g) was added to a solution of (Z)-4-hydroxybut-
2-enyl 2-((4f?,6f?)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-
1H-pyrrol-1 -yl)ethyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate [CD8(PG )-L2-OH] (4.5 g, 6.7
mmol) in 150 mL of methanol and the mixture was stirred at RT for 10 days when TLC
analysis of the mixture indicated -90 % conversion. The mixture was filtered through
celite and the filtrate was concentrated and the crude residue (-4.0 g) thus obtained
was used as such in the next step. For obtaining analytical sample, a small amount
(-100 mg) of this crude product was purified by column chromatography on silica gel
(200-400 mesh) using 2 % acetone in DCM as eluent. The pure title compound was
obtained as a white solid. 1H NMR (CDCI3, 300 MHz): 1.22 - 1.32 (m, 2H), 1.55 (d, J =
6.9 Hz, 6H), 1.65 - 1.72 (m, 2H), 2.20 (br s, 2H), 2.43 (d, J = 6.0 Hz, 2H), 3.01 (br s,
1H), 3.54 - 3.65 (m, 1H), 3.70 - 3.80 (m, 1H), 3.90 - 4.03 (m, 1H), 4.06 - 4.22 (m, 2H),
4.27 (d, J = 6.6 Hz, 2H), 4.73 (d, J = 6.9 Hz, 2H), 5.60 - 5.70 (m, 1H), 5.82 - 5.95 (m,
1H), 6.87 (br s, 1H), 6.97 - 7.26 (m ,14H); MS m/z: 629.3 [M+H] +, 651 .3 [M+Na] +.
Step 4 : (3fl,5fl)-((Z)-4-((1-chloroethoxy)carbonyloxy)but-2-enyl) 7-(2-(4-fluorophenyl)-
5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)-3,5-dihydroxyheptanoate
(CD8-L2-R1-CI)
o -Chloroethyl chloroformate (CI-R1-CI, 0.8 mL, 7.2 mmol) was added drop-wise to a
solution of (3f?,5f?)-((Z)-4-hydroxybut-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoyl)-1 H-pyrrol-1 -yl)-3,5-dihydroxyheptanoate (CD8-L2-OH, 3.8
g, 6.0 mmol) in 100 mL of DCM at 0 °C under a nitrogen atmosphere. To this stirred
mixture was added pyridine (6.2 mL, 76.4 mmol) and the mixture was stirred at 0 °C
under nitrogen for 1 h and at RT for overnight. TLC analysis of the mixture indicated
-30 % completion. Additional amounts of oc-Chloroethyl chloroformate (0.8 mL) and
pyridine (0.9 mL) were added to the mixture at RT and mixture was stirred at RT for 1h
when TLC analysis of the mixture indicated about 40 % conversion. Another 1.6 mL of
oc-Chloroethyl chloroformate (total added: 3.2 mL) and 1.8 mL of pyridine (total amount
of pyridine added: 3.6 mL) were added and the mixture was stirred for additional 3 h
when TLC analysis of the mixture indicated -70 % product formation. The mixture was
washed with 1N HCI (3 x 100 mL), aqueous sodium bicarbonate (3 x 100 mL) and brine
(2 X 100 mL). The organic layer was dried over Na2S0 4 and concentrated in vacuo to
afford the crude product as a sticky semisolid which was purified by column
chromatography on silica gel (200-400 mesh) using 2 % acetone in DCM as eluent. The
pure title compound was obtained as a light blue colored semisolid. Yield: 2.0 g (45.4
%); 1H NMR (CDCI3, 300 MHz): 1 .25 - 1.60 (m, 2H), 1.56 (d, J = 6.9 Hz, 6H), 1.60 -
1.80 (m, 2H), 1.88 (d, J = 8.4 Hz, 3H), 2.20 (s, 1H), 2.44 (d, J = 6.0 Hz, 2H), 3.50 - 3.67
(m, 1H), 3.72 - 3.82 (m, 1H), 3.90 - 4.05 (m, 1H), 4.10 - 4.30 (m, 2H), 4.73 (d, J = 4.5
Hz, 2H), 4.82 (d, J = 4.8 Hz, 2H), 5.82 (t, J = 4.5 Hz, 2H), 6.43 (q, J = 5.7 Hz, 1H),
6.88 (s, 1H), 6.97 - 7.27 (m, 15H); MS m/z: 735.3 [M+H]+
.
Step 5 : (3fl,5fl)-((Z)-4-((1 -(nitrooxy)ethoxy)carbonyloxy)but-2-enyl) 7-(2-(4-
fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1 H-pyrrol-1-yl)-3,5-
dihydroxyheptanoate [NO-Atorvastatin (I-CD8-L2-R1)]
Silver nitrate (0.7 g, 3.9 mmol) was added to a solution of (3f?,5f?)-((Z)-4-((1-
chloroethoxy)carbonyloxy)but-2-enyl) 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoyl)-1 H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (CD8-L2-R1-CI, 1.9 g, 2.6
mmol) in 50 mL of ACN and the mixture was refluxed in dark at 85-90 °C for 3 h when
HPLC analysis of the mixture indicated complete conversion (Note: Retention time (TR)
of starting material and product were the same and there was no precipitation of silver
chloride in the reaction mixture!. It was for that reason that the mixture was refluxed for
3 h long). The mixture was cooled and filtered over celite. The filtrate was concentrated
and the residue thus obtained was purified by column chromatography on silica gel
(200-400 mesh) by using 4 % acetone in DCM to afford the title compound as light
yellow semisolid which solidified on standing. Mp: 56-58 °C; Yield: 1.5 g (76.0 %); 1H
NMR (CDCI3, 300 MHz): 1.25 - 1 .35 (m, 2H), 1.56 (d, J = 7.2 Hz, 6H), 1.61 (d, J = 5.4
Hz, 3H), 1.45 - 1.80 (m, 3H), 2.44 (d, J = 6.0 Hz, 2H), 3.50 - 3.67 (m, 2H), 3.72 - 3.82
(m, 1H), 3.90 - 4.20 (m, 1H), 4.08 - 4.25 (m, 2H), 4.74 (d, J = 5.1 Hz, 2H), 4.80 (d, J =
5.1 Hz, 2H), 5.80 - 5.85 (m, 2H), 6.88 (br s, 1H), 6.93 (q, J = 5.7 Hz, 1H), 6.98 - 7.22
(m, 14H); MS m/z: 762.3 [M+H]+, 784.3 [M+Na] +.
Example 13:
(2S)-2-(3-((1 -(nitrooxy)ethoxy)carbonyloxy)propoxy)-2-oxoethyl 2-(6-
methoxynaphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L6-R1)]
This compound was prepared in four steps as shown in Scheme 3 and the
experimental procedure is described below:
Step 1: Preparation of linker 3-hydroxypropyl 2-chloroacetate (CI-L6-OH):
2-Chloroacetyl chloride (5.0 g, 44.2 mmol) followed by TEA (9.2 mL, 66.4 mmol) were
added drop-wise to a stirred solution of propane-1 ,3-diol (10.0 g, 132.7 mmol) in 150
mL of DCM at 0 °C under nitrogen over 15 min and the mixture was stirred at RT for 4 h
when TLC analysis (H2S0 4 spray) of the mixture indicated formation of a new product
CI-L6-OH as the major product. The mixture was concentrated and the crude product
thus obtained was used as such in the next step.
Step 2 : Preparation of (S)-2-(3-hydroxypropoxy)-2-oxoethyl 2-(6-methoxynaphthalen-2-
yl)propanoate (CD1-L6-OH)
A solution of 3-hydroxypropyl 2-chloroacetate (CI-L6-OH, crude product obtained from
the first step, ~ 44.0 mmol) in 75 mL of DMF was added to naproxen cesium ( 10.0 g,
65.7 mmol, freshly prepared by treating naproxen with equimolar amount of cesium
carbonate) in 25 mL of DMF and the mixture was stirred at RT for overnight (~ 16 h)
when TLC analysis of the mixture indicated formation of a new product. The mixture
was diluted with DCM (-200 mL), washed with cold water (4 x 100 mL), 1N sodium
bicarbonate (3 x 100 mL), and brine (2 x 100 mL). The organic layer was dried over
Na2S0 4 and concentrated to give the crude product as yellow oil which was purified by
column chromatography (silica gel 200-400 mesh, eluted with 20 % EtOAc in petroleum
ether) to afford the title compound as yellow oil. Yield: 8.0 g (52.5 %); 1H NMR (CDCI3,
300 MHz): 1.62 (d, J = 7.2 Hz, 3H), 1.73 - 1.83 (m, 2H), 3.56 (t, J = 6.0 Hz, 2H), 3.91
(s, 3H), 3.97 (q, =7.2 Hz, 1H), 4.25 (t, J = 6.0 Hz, 2H), 4.59 (q, J = 20.4, 15.9 Hz, 2H),
7.09 - 7.1 7 (m, 2H), 7.42 (dd, J = 8.4, 1.8 Hz, 1H), 7.69 (s, 1H), 7.72 (s, 1H), 8.00 (s,
1H); MS m/z: 369.1 [M+Na] +.
Step 3 : Preparation of (2S)-2-(3-((1-chloroethoxy)carbonyloxy)propoxy)-2-oxoethyl 2-
(6-methoxynaphthalen-2-yl)propanoate (CD1-L6-R1-CI)
o -Chloroethyl chloroformate (CI-R1-CI, 2.7 mL, 27.7 mmol) followed by pyridine (2.8
mL, 34.5 mmol) were added drop-wise to a stirred solution of 2-(3-hydroxypropoxy)-2-
oxoethyl 2-(6-methoxynaphthalen-2-yl)propanoate (CD1-L6-OH, compound from step b
above, 8.0 g, 23.0 mmol) in 50 mL of HPLC grade DCM at 0 °C under nitrogen over 10
minutes and the mixture was stirred for -40 minutes when TLC analysis of the mixture
indicated completion of the reaction. After the usual aqueous work-up as described in
analogues experimental step above, the crude product was used as such in the next
reaction. Yield: 10.0 g (96.0 %); 1H NMR (CDCI3, 300 MHz): 1.62 (d, J = 6.9 Hz, 3H),
1.82 (d, J = 5.7 Hz, 3H), 1.87 - 1.98 (m, 2H), 3.91 (s, 3H), 3.97 (q, J = 7.2 Hz, 1H), 4.1 3
- 4.26 (m, 4H), 4.59 (q, J = 2 1.3, 15.9 Hz, 2H), 6.40 (q, J = 5.7 Hz, 1H), 7.09 - 7.19 (m,
2H), 7.42 (dd, J = 8.4, 1.8 Hz, 1H), 7.70 (s, 1H), 7.71 (d mixed with singlet, J = 8.1 Hz,
2H); MS m/z: 475.1 [M+Na] +.
Step 4 : Preparation of (2S)-2-(3-((1 -(nitrooxy)ethoxy)carbonyloxy)propoxy)-2-oxoethyl
2-(6-methoxynaphthalen-2-yl)propanoate (I-CD1 -L6-R1 )
Silver nitrate (5.3 g, 3 1 .5 mmol) was added to a stirred solution of 2-(3-((1-
chloroethoxy)carbonyloxy)propoxy)-2-oxoethyl 2-(6-methoxynaphthalen-2-
yl)propanoate (CD1-L6-R1 -CI, compound from step 3 above, 9.5 g, 20.9 mmol) in 70
mL of ACN and the mixture was refluxed gently (at 85-90 °C) for 40 minutes when
HPLC analysis of the mixture indicated completion of the reaction. The mixture was
cooled and diluted with DCM (-200 mL) and filtered over celite. The filtrate was
concentrated and the residue was re-dissolved in DCM (-1 00 mL) and filtered to
remove the precipitated silver salt. This process was repeated twice to remove most of
the silver salt from the crude product. The residue thus obtained was purified by column
chromatography (300.0 g silica gel, 200-400 mesh, eluted with 15-20 % EtOAc in
petroleum ether) to afford the title compound as light yellow oil. Yield: 7.3 g (72.5 %);
1H NMR (CDCI3, 300 MHz): 1.60 (d, J = 5.4 Hz, 3H), 1.64 (d, J = 7.2 Hz, 3H), 1.89 -
1.98 (m, 2H), 3.94 (s, 3H), 3.99 (q, J = 7.2 Hz, 1H), 4.16 (t, J = 6.3 Hz, 2H), 4.21 (t, J =
6.3 Hz, 2H), 4.63 (dq, J = 2 1 .0, 15.9, 1.2 Hz, 2H), 6.93 (q, J = 5.7 Hz, 1H), 7.12 - 7.1 9
(m, 2H), 7.45 (dd, J = 8.4, 1.8 Hz, 1H), 7.72 (s, 1H), 7.73 (d mixed with singlet, J = 8.4
Hz, 2H); MS m/z: 502.1 [M+Na] +, 518.1 [M+K] +; HRMS ESI (m/z): [M+Na] + calculated
for C22H25N1Na O : 502.1320; Found: 502.1 330 (Mass Accuracy: - 1 .99 ppm).
The compounds of examples 14 and 15 were prepared by following the experimental
procedure described for preparing the compound of example 13. The characterization
data for the compounds of examples 14 and 15 is described below:
Example 14:
(2S)-2-(4-((1-(nitrooxy)ethoxy)carbonyloxy)butoxy)-2-oxoethyl 2-(6-
methoxynaphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L7-R1)]
The title compound was obtained as colorless viscous oil. Yield (last step): 5 1.0 %; 1H
NMR (CDCI3, 300 MHz): 1.55 - 1.68 (m, 10H), 3.91 (s, 3H), 3.97 (q, J = 7.2 Hz, 1H),
4.07 - 4.17 (m, 4H), 4.59 (dd, J = 2 1.0, 15.9 Hz, 2H), 6.92 (q, J = 5.7 Hz, 1H), 7.1 0 -
7.1 7 (m, 2H), 7.43 (dd, J =8.4, 1.5 Hz, 1H), 7.70 (s, 1H), 7.71 (d mixed with singlet, J =
8.1 Hz, 2H); MS m/z: 493.1 [M+H]+, 516.1 [M+Na] +.
Example 15:
(2S,3aS,6aS)-2-(nitrooxy)-4,13-dioxo-3,5,12-trioxa-8,9-dithiatetradecan-14-yl 1-
((S)-2-((S)-1-ethoxy-1-oxo-4-phenylbutan-2-ylamino)propanoyl)octahydrocyclopenta[
b]pyrrole-2-carboxylate [NO-Ramipril (I-CD9-L8-R1)]
The title compound was obtained as colorless oil. Yield (last step): 36.0 %; 1H NMR
(CDCI 3, 500 MHz): 1.20 - 1.32 (m, 6H), 1.60 (d, J = 5.5 Hz, 3H), 1.50 - 2.1 7 (m, 10H),
2.40 - 2.52 (m, 1H). 2.60 - 2.76 (m, 2H), 2.78 - 2.88 (m, 1H), 2.91 - 2.98 (m, 4H), 3.1 8
(t, J = 6.5 Hz, 1H), 3.65 (q, J = 6.5 Hz, 1H), 4.18 (q, J = 7 Hz, 2H), 4.31 (q, J = 7.5 Hz,
1H), 4.39 - 4.47 (m, 4H), 4.56 (d, J = 16.0 Hz, 1H), 4.65 - 4.71 (m, 1H), 4.80 (d, J =
16.0 Hz, 1H), 6.93 (q, J = 5.5 Hz, 1H), 7.14 - 7.29 (m, 5H); MS m/z: 744.1 [M+H]+.
Example 16:
3-(((1 -(nitrooxy)ethoxy)carbonyloxy)methyl)phenyl 2-acetoxybenzoate [NOAspirin/
Salicylic acid (I-CD2-L9-R1)]
The title compound was synthesized in four steps as shown in Scheme 4 and the
experimental procedure is described below:
Step 1: Synthesis of 3-formylphenyl 2-acetoxybenzoate (CD2-L9-CHO)
A solution of 3-hydroxybenzaldehyde (HO-L9-CHO, 5.0 g, 40.9 mmol) and triethylamine
( 12.4 g/14.4 mL, 122.8 mmol) in 50 mL of DCM was added drop-wise to a stirred
solution of aspirin acid chloride (freshly prepared from 14.7 g (81 .9 mmol) of aspirin by
using oxalyl chloride/ DMF method) in 100 mL of DCM at 0 °C and the mixture was
stirred at RT for overnight when TLC analysis of the mixture indicated completion of the
reaction. The mixture was diluted with 100 mL of DCM and washed with water ( 100 mL)
and brine (100 mL), dried over anhydrous Na2S0 4 and concentrated in vacuo to give a
solid residue which was purified by column chromatography (silica gel 100-200 mesh,
eluted with a gradient of EtOAc in petroleum ether and finally with DCM) to afford the
title compound as a white solid. Yield: 7.0 g (60.1 %); 1H NMR (DMSO-d 6, 300 MHz): 
2.26 (s, 3H), 7.35 (dd, J = 8.1 , 0.9 Hz, 1H), 7.52 (dt, J = 7.8, 0.9 Hz, 1H), 7.58 - 7.63
(two m, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.77 - 7.84 (m, 2H), 7.89 (distorted d, J = 7.5 Hz,
1H), 8.21 (dd, J = 7.8, 1.5 Hz, 1H), 10.05 (s, 1H).
Step 2 : Synthesis of 3-(hydroxymethyl)phenyl 2-acetoxybenzoate (CD2-L9-OH)
Sodium borohydride (79 mg, 2.1 mmol) was added to a solution of 3-formylphenyl 2-
acetoxybenzoate (CD2-L9-CHO, 2.8 g, 9.9 mmol) in 30 mL of THF/ MeOH (9:1) at 0
°C, and the mixture was stirred at that temperature for 20 minutes when TLC analysis
of the mixture indicated completion of the reaction. The mixture was slowly poured into
10 mL of ice cold 1N HCI and extracted with ethyl acetate (2 x 100 mL). The organic
layer was washed with brine ( 1 x 100 mL), dried over anhydrous Na2S0 4 and
concentrated in vacuo to give a solid residue which was purified by column
chromatography (silica gel 100-200 mesh, eluted with a gradient of EtOAc in petroleum
ether and finally with DCM) to afford the title compound as a white solid. Yield: 2.2 g
(78.0 %); 1H NMR (DMSO-d 6, 300 MHz): 2.25, (s, 3H), 4.54 (d, J = 5.7 Hz, 2H), 5.34
(t, J = 5.7 Hz, 1H Exchangeable with D20), 7.08 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.25
(d, J = 7.5 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz,
1H), 7.77 (t, J = 7.8 Hz, 1H), 8.1 5 (distorted dd, J = 7.2, 1,5 Hz, 1H).
Step 3 : Synthesis of 3-(((1-chloroethoxy)carbonyloxy)methyl)phenyl 2-acetoxybenzoate
(CD2-L9-R1-CI)
A solution of o -chloroethyl chloroformate (C-R1-CI, 0.18 mL, 1.3 mmol) in 1 mL of DCM
was added drop-wise to a stirred solution of 3-(hydroxymethyl)phenyl 2-
acetoxybenzoate (CD2-L9-OH, 0.3 g, 1. 1 mmol) and pyridine (0.1 mL, 1.3 mmol) in
dichloromethane (3 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes when
TLC analysis of the mixture indicated completion of the reaction. The mixture was
diluted with DCM (-10 mLI), washed with water ( 1 x 10 mL) and brine ( 1 x 10 mL). The
organic layer was dried over Na2S0 4 and concentrated in vacuo to give an oily crude
product which was purified by column chromatography on silica gel by eluting with a
gradient of EtOAc in petroleum ether to afford the title compound as colorless viscous
oil. Yield: 0.4 g (93.7 %); 1H NMR (CDCI3, 300 MHz): 1.85 (d, J = 5.7 Hz, 3H), 2.33 (s,
3H), 5.26 (AB q, J = 12.3 Hz, 2H), 6.45 (q, J = 5.7 Hz, 1H), 7.1 6 - 7.27 (m, 3H), 7.38 -
7.51 (d, J = 7.5 Hz, 1H), 7.38 - 7.50 (m, 2H), 7.67 (dt, J = 7.8, 1.5 Hz, 1H), 8.23 (dd, J =
7.8, 1.5 Hz, 1H). MS m/z: 410.1 [M+NH4]+
, 4 15.0 [M+Na] +.
Step 4 : Synthesis of 3-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)phenyl 2-
acetoxybenzoate (I-CD2-L9-R1)
Silver nitrate (0.2 g, 0.9 mmol) was added in one lot to a stirred solution of 3-(((1 -
chloroethoxy)carbonyloxy)methyl)benzyl 2-acetoxybenzoate (CD2-L9-R1-CI, 1.4 g, 3.5
mmol) in ACN (20 mL) at RT and the mixture was stirred at 60-70 °C for 2 h when TLC
analysis of the mixture indicated completion of the reaction The mixture was cooled to
RT, diluted with 10 mL of DCM and filtered over celite pad. The filtrate was
concentrated and the residue thus obtained was purified by column chromatography on
silica gel and eluted with a gradient of EtOAc in petroleum ether to afford the title
compound as yellow viscous oil. Yield: 0.3 g (81 .2 %); 1H NMR (CDCI3, 300 MHz): 
1.62 (d, J = 5.7 Hz, 3H), 2.33 (s, 3H), 5.24 (AB q, J = 12.3 Hz, 2H), 6.97 (q, J = 5.7 Hz,
1H), 7.1 8 - 7.27 (m, 3H), 7.31 (d, J = 7.8Hz, 1H), 7.37 - 7.53 (m, 2H), 7.67 (t, J = 7.8,
1H), 8.24 (dd, J = 7.8, 1.5 Hz, 1H); MS m/z: 437.1 [M+NH4]+, 442.1 [M+Na] +.
Example 17:
3-(((1 -(nitrooxy)ethoxy)carbonyloxy)methyl)benzyl 2-acetoxybenzoate [NOAspirin/
Salicylic acid (I-CD2-L10-R1)]
The title compound was synthesized in three steps as shown in Scheme 1 and the
experimental procedure is described below:
Step 1: Synthesis of 3-(hydroxymethyl)benzyl 2-acetoxybenzoate (CD2-L10-OH)
A solution of aspirin acid chloride (3.0 g, 16.7 mmol, freshly prepared from aspirin using
oxalyl chloride/ DMF method) in dichloromethane ( 15 mL) was added to a stirred
solution of 1,3-benzenedimethanol (HO-L10-OH, 2.3 g, 16.6 mmol) and triethylamine
(6.96 mL, 49.9 mmol) in dichloromethane (12 mL) at 0 °C. The mixture was stirred at
RT for 8 h when TLC analysis of the mixture indicated completion of the reaction. The
mixture was concentrated and the residue was partitioned between ethyl acetate (100
mL) and water (50 mL). The organic layer was separated, washed with brine ( 1 x 50
mL), dried over anhydrous Na2S0 4 and concentrated in vacuo to give the crude oily
residue which was purified by column chromatography (silica gel, 150.0 g, 200-400
mesh, 30 % EtOAc in hexane) to afford the title compound as colorless oil. Yield: 1.9 g
(38.2 %); 1H NMR (CDCI3, 300 MHz): 1.99 (t, J = 5.7 Hz, 1H), 2.14 (s, 3H), 4.73 (d, J
= 5.4Hz, 2H), 5.33 (s, 2H), 7.10 (d, J = 8.1 Hz, 1H), 7.30 - 7.43 (m, 5H), 7.58 (dt, J =
7.8, 1.5 Hz, 1H), 8.08 (dd, J = 7.8, 1.5 Hz, 1H); MS m/z: 301 . 1 [M+H]+, 323.1 [M+Na]+.
Step 2 : Synthesis of 3-(((1-chloroethoxy)carbonyloxy)methyl)benzyl 2-acetoxybenzoate
(CD2-L10-R1-CI)
o -Chloroethyl chloroformate (CI-R1-CI, 0.5 mL, 4.6 mmol) was added drop-wise to a
stirred solution of 3-(hydroxymethyl)benzyl 2-acetoxybenzoate (CD2-L10-OH, 1. 1 g, 3.8
mmol) and pyridine (0.6 mL, 7.6 mmol) in dichloromethane (12 mL) at 0 °C. The mixture
was stirred at 0 °C for 30 minutes when TLC analysis of the mixture indicated
completion of the reaction. The mixture was concentrated in vacuo and the residue was
partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was
separated and washed with brine ( 1 x 50 mL), dried over anhydrous Na2S0 4 and
concentrated in vacuo to give an oily crude product which was purified by column
chromatography (silica gel, 60.0 g, 200-400 mesh, 30 % EtOAc in hexane) to afford the
title compound as colorless oil. Yield: 1.4g (91 .0 %); 1H NMR (CDCI3, 300 MHz): 1.84
(d, J = 5.7 Hz, 3H), 2.18 (s, 3H), 5.26 (d, J = 2.1 Hz, 2H), 5.33 (s, 2H), 6.45 (q, J = 5.7
Hz, 1H), 7.1 1 (dd, J = 8.1 , 0.6 Hz, 1H), 7.34 (dt, J = 7.8, 0.9 Hz, 1H), 7.37 - 7.48 (m,
4H), 7.58 (dt, J = 7.8, 1.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H); MS m/z: 407.1 [M+H]+,
429.1 [M+Na] +.
Step 3 : Synthesis of 3-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)benzyl 2-
acetoxybenzoate (I-CD2-L10-R1)
Silver nitrate (0.9 g, 5.2 mmol) was added in one lot to a stirred solution of 3-(((1 -
chloroethoxy)carbonyloxy)methyl)benzyl 2-acetoxybenzoate (CD2-L10-R1-CI, 1.4 g,
3.5 mmol) in ACN (20 ml.) at RT and the mixture was stirred at 80 °C for 1.5 h. The
mixture was cooled to RT and filtered over celite pad. The filtrate was concentrated and
the residue thus obtained was partitioned between EtOAc (75 ml.) and water (75 ml_).
The organic layer was washed with brine ( 1 x 75 ml_), dried over anhydrous Na2S0 4
and concentrated to give an oily crude residue which was purified by column
chromatography (silica gel, 40.0 g, 200-400 mesh 30 % EtOAc in hexane) to afford the
title compound as yellow oil. Yield: 1. 1 g (74.0 %); 1H NMR (CDCI3, 300 MHz): 1.63
(d, J = 6.0 Hz, 3H), 2.1 7 (s, 3H), 5.24 (s, 2H), 5.32 (s, 2H), 6.96 (q, J = 6.0 Hz, 1H),
7.1 1 (d, J = 9.0 Hz, 1H), 7.31 - 7.44 (m, 5H), 7.58 (dt, J = 6.0 Hz, 1H), 8.07 (dd, J = 1.8
Hz, 1H); MS m/z: 434.2 [M+H]+, 456.1 [M+Na] +.
The compounds of examples 18 - 20 were prepared by following the experimental
procedure described for preparing the compound of example 17. The characterization
data for the compounds of examples 18 - 20 is described below:
Example 18:
(6-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)pyridin-2-yl)methyl 2-
acetoxybenzoate [NO-Aspirin/Salicylic acid (I-CD2-L1 1-R1)]
The title compound was also obtained as yellow oil. Yield (last step): 68.0 %; 1H NMR
(CDCI3, 300 MHz): 1.64 (d, J = 5.7 Hz, 3H), 2.27 (s, 3H), 5.29 - 5.34 (distorted AB
quartet or m, 2H), 5.44 (s, 2H), 6.98 (q, J = 5.7 Hz, 1H), 7.14 (dd, J = 8.1 , 0.9 Hz, 1H),
7.31 - 7.42 (m, 3H), 7.61 (dt, J = 7.8, 1.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 8.12 (dd, J =
7.8, 1.8 Hz, 1H); MS m/z: 435.1 [M+H] +, 457.1 [M+Na] +.
Example 19:
(4-(((1 -(nitrooxy)ethoxy)carbonyloxy)methyl)cyclohexyl)methyl 2-(2-(2,6-
dichlorophenylamino)phenyl)acetate [NO-Diclofenac (I-CD6-L12-R1)]
The title compound was obtained as pale yellow gum. Yield (last step): 54.0 %; 1H NMR
(CDCI3, 300 MHz): 0.85 - 1.98 (m, 10H), 1.61 (d, J = 5.7 Hz, 3H), 3.83 (s, 2H), 3.97 -
4.1 6 (m, 4H), 6.57 (d, J = 7.8 Hz, 1H), 6.91 - 7.04 (m, 4H), 7.14 (dt, J = 7.8, 1.2 Hz,
1H), 7.25 (dd, J = 7.5, 1.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H); MS m/z: 555.1 [M+H] +,
577.1 [M+Na] +.
Example 20:
4-((1-(nitrooxy)ethoxy)carbonyloxy)cyclohexyl 2-(2-(2,6-
dichlorophenylamino)phenyl)acetate [NO-Diclofenac (I-CD6-L13-R1)]
The title compound was obtained as pale yellow gum. Yield (last step): 66.0 %; 1H NMR
(CDCI3, 300 MHz): 1.63 (d, J = 5.7 Hz, 3H), 1.67 - 2.00 (m, 8H), 3.82 (s, 2H), 4.73 -
4.83 (m, 1H), 4.89 - 4.98 (m, 1H), 6.57 (d, J = 7.8 Hz, 1H), 6.89 - 7.04 (m, 4H), 7.14 (dt,
J = 7.8, 1.5 Hz, 1H), 7.25 (dd, J = 7.5, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H); MS m/z:
527.6 [M+H] +.
Example 2 1 :
(2S)-4-((1-(nitrooxy)ethoxy)carbonyloxy)tetrahydrofuran-3-yl 2-(6-
methoxynaphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L14-R1-A & I-CD1-L14-
R1-B)] (Mixture of diastereomers)
The title compound was synthesized in 3 steps as shown in Scheme 1 and the
experimental procedure is described below:
Step 1: Synthesis of (2S)-4-hydroxytetrahydrofuran-3-yl 2-(6-methoxynaphthalen-2-
yl)propanoate (CD1-L14-OH)
A solution of naproxen acid chloride (CD1-1 , freshly prepared from 10.0 g (43.4 mmol)
of naproxen using oxalyl chloride/ DMF method) in 20 mL of DCM was added to a
stirred solution of 1,4-anhydroerythritol (HO-L14-OH, 9.1 g (-7.1 mL), 86.9 mmol) and
TEA ( 18.0 mL, 130.0 mmol) in 20 mL of DCM at 0 °C over a period of 30 minutes and
the mixture was stirred at 0 °C for 1.5 h when TLC analysis of the mixture indicated
formation of a major mono adduct along with the expected minor bis-adduct. The
mixture was diluted with saturated sodium bicarbonate (-100 mL) and the organic layer
was separated. The aqueous layer was extracted with DCM (2 x 100 mL). The organic
extracts were combined, dried over anhydrous Na2S0 4, filtered and concentrated to
give 12.0 g of crude residue which was purified by column chromatography (silica gel
150-300 mesh, the bis-adduct and other non-polar impurities were eluted with 5-1 0 %
EtOAc in petroleum ether and the desired mono-adduct was eluted with 13-1 5 % EtOAc
in petroleum ether) to afford the title compound as a white solid. Yield: 8.0 g (58.2 %);
1H NMR (CDCI3, 300 MHz) (Mixture of diastereomers): 1.609, 1.614 (two overlapping
doublets, J = 6.9, 7.2 Hz, 3H), 3.52 - 3.72 (m, 2H), 3.77 - 4.10 (m, 5H), 3.91 (s, 3H),
4.30 (q, J = 5.7, 5.4 Hz, 0.5H), 4.40 (q, J = 5.7, 5.4 Hz, 0.5H), 5.07 - 5.1 9 (m, 1H), 7.09
-7.20 (m, 2H), 7.37 - 7.44 (m or distorted doublet, 1H), 7.66 - 7.76 (m, 3H); MS m/z:
3 17.1 [M+H] +, 339.1 [M+Na] +, 355.1 [M+K]+.
Step 2 : Synthesis of (2S)-4-((1-chloroethoxy)carbonyloxy)tetrahydrofuran-3-yl 2-(6-
methoxynaphthalen-2-yl)propanoate (CD1-L14-R1-CI-A & CD1-L14-R1-CI-B) (Mixture
of diastereomers A & B)
o -Chloroethyl chloroformate (CI-R1-CI, 1.0 g (0.8 mL), 7.6 mmol, 1.2 eqs.) followed by
pyridine (0.8 mL, 9.5 mmol, 1.5 eqs.) were added drop-wise to a stirred solution of (2S)-
4-hydroxytetrahydrofuran-3-yl 2-(6-methoxynaphthalen-2-yl)propanoate (CD1-L14-OH,
2.0 g, 6.3 mmol, 1.0 eq.) in 20 mL of DCM at 0 °C under nitrogen and the mixture was
stirred at 0 °C for 2 h and at RT for 1 h when TLC analysis of the mixture indicated
completion of the reaction. The mixture was diluted with 20 mL of DCM and washed
with 1N HCI (3 x 40 mL), aqueous sodium bicarbonate (3 x 40 mL), dried over
anhydrous Na2S0 4 and concentrated to give 2.0 g of crude product as slightly yellow
colored oil. Although TLC analysis of the crude product indicated two major new spots
or products (CD1-L14-R1-CI-A and CD1-L14-R1-CI-B), HPLC analysis of the same
crude product revealed 4 peaks. The crude product was purified by column
chromatography (80.0 g of silica gel, 200^100 mesh, eluted with 10 % EtOAc in
petroleum ether) and the following two products were separated:
Less polar CD1-L14-R1-CI-A: HPLC analysis of this isolated product (single spot on
TLC) was shown to contain two diastereomers with retention times (TR) of 9.414 &
9.508 min (peak ratio: 42:54); Obtained as an oil. Yield: 1. 1 g (43.0 %). 1HNMR (CDCI3,
300 MHz, (mixture of diastereomers)): 1.42 (d, J = 6.0 Hz, 1.5H), 1.57 (t, J = 7.2 Hz,
3H), 1.74 (d, J = 6.0 Hz, 1.5 Hz), 3.71 - 3.87 (m, 2H), 3.87 - 3.94 (m or q buried under
methoxy singlet, 1H), 3.91 (s, 3H), 4.01 - 4.1 5 (m, 2H), 5.1 5 - 5.40 (m, 2H), 5.83, 6.35
(two q in 1:1 , = 5.7 Hz, 1H (i.e., 0.5H each)), 7.15 - 7.1 9 (m, 2H), 7.38 (d, J = 8.7 Hz,
1H), 7.64 (d, J = 6.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H); MS m/z: 445.1 [M+Na] +.
More polar CD1-L14-R1-CI- B: HPLC analysis of this isolated product (single spot on
TLC) was shown to contain two diastereomers with retention times (TR) of 9.386 and
9.476 min (43:56); Obtained as an oil. Yield: 1.0 g (38.5 %). 1HNMR (CDCI3, 300 MHz,
(mixture of diastereomers)): 1.59 (d, overlapping with the doublet at 1.61 ppm, J = 7.2
Hz, 1.5H) 1.61 (d, overlapping with the doublet at 1.59 ppm, J = 7.2 Hz, 1.5H), 1.73 (d,
J = 5.7 Hz, 3H), 1.85 (d, J = 6.0 Hz, 3H), 3.61 - 4.17 (m, 5H), 3.93 (s, 3H), 5.24 - 5.34
(m, 2H), 6.30-6.45 (m, 1H), 7.1 0 -7.1 8 (m, 2H), 7.42 (dt, J = 1.5, 8.4 Hz, 1 H), 7.66 -
7.77 (m, 3H); MS m/z: 445.1 [M+Na] +.
Step 3 : Synthesis of (2S)-4-((1-(nitrooxy)ethoxy)carbonyloxy)tetrahydrofuran-3-yl 2-(6-
methoxynaphthalen-2-yl)propanoate (I-CD1-L14-R1- A or B) (Mixture of diastereomers
A & B)
Silver nitrate (0.5 g, 3.2 mmol, 1.2 eqs.) was added to a solution of (2S)-4-((1-
chloroethoxy)carbonyloxy)tetrahydrofuran-3-yl 2-(6-methoxynaphthalen-2-
yl)propanoate (CD1-L14-R1-CI-A, Less polar product A, 1. 1 g, 2.6 mmol, 1.0 eq.) in 10
mL of ACN and the mixture was refluxed at 85 - 90 °C for 2 h when TLC analysis of
the mixture indicated completion of the reaction with the formation of two product spots
(i.e., less polar (spot) product l-CD1-L14-R1-Aa and more polar (spot) product I-CD1-
L14-R1-Ab). The reaction mixture was diluted with 10 mL of DCM, filtered over celite
and the filtrate was concentrated and the residue was dissolved again in 20 mL of DCM
and washed with water (3 x 20 mL), brine ( 1 x 20 mL), dried over anhydrous Na2S0 4
and concentrated to give an oily residue which was purified by column chromatography
(40.0 g of silica gel, 200-400 mesh, eluted with 5-8 % EtOAc in petroleum ether) to
afford the title compound as the following diastereomeric mixtures:
Less polar (spot) product l-CD1-L14-R1-Aa: HPLC analysis of this product was shown
to contain two diastereomers with retention times (TR) of 9.44 & 9.53 min (peak ratio:
43:56); obtained as a viscous oil. Yield: 0.2 g (14.4 %); 1HNMR (CDCI3, 300 MHz,
(mixture of diastereomers in -43:56)): 1.21 - 1.28 (m, 3H), 1.51 - 1.62 (m, 3H), 3.91
(s, 3H), 3.83 - 3.89 (m, 3H), 4.00 - 4.13 (m, 2H), 5.1 8 - 5.34 (m, 2H), 6.65 (q, J = 5.7
Hz, 0.5H), 6.86 (q, J = 5.7 Hz, 0.5H), 7.1 1 - 7.1 6 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.65
- 7.71 (m, 3H); MS m/z: 472.1 [M+Na] +.
More polar (spot) product l-CD1-L14-R1-Ab: HPLC analysis of this product was shown
to contain two diastereomers with retention times (TR) of 9.39 & 9.48 min (peak ratio:
43:56); Obtained as a green viscous oil. Yield: 0.7 g (55.9 %); 1HNMR (CDCI3, 300
MHz, (mixture of diastereomers in -45:55)): 1.47 - 1.62 (m, 6H), 3.61 - 3.82 (m, 3H),
3.91 (s, 3H), 3.85 - 3.91 (m, buried under OCH3 signal, 1H), 4.15 - 3.95 (m, 2H), 5.19 -
5.33 (m, 2H), 6.80 (q, J = 5.7 Hz, 0.5H), 6.95 (q, J = 5.7 Hz, 0.5H), 7.1 2 - 7.1 6 (m, 2H),
7.31 - 7.42 (m, 1H), 7.67 -7.72 (m, 3H); MS m/z: 472.1 [M+Na] +.
The following isomers were obtained by following the same procedure involving the
treatment of (2S)-4-((1 -chloroethoxy)carbonyloxy)tetrahydrofuran-3-yl 2-(6-
methoxynaphthalen-2-yl)propanoate (CD1-L14-R1-CI-B, the more polar product B, 1.0
g, 2.4 mmol, 1.0 eq.) with 0.5 g (2.8 mmol, 1.2 eqs.) of silver nitrate:
Less polar (spot) product l-CD1-L14-R1-Ba: HPLC analysis of this product was shown
to contain two diastereomers with retention times (TR) of 9.44 & 9.53 min (peak ratio:
43:56); Obtained as a viscous oil. Yield: 0.6 g (64.0 %); 1HNMR (CDCI3, 300 MHz,
(mixture of two diastereomers in -47:53)): 1.21 - 1.28 (m, 3H), 1.51 - 1.62 (m, 3H),
3.76 - 3.89 (m, 3H), 3.91 (s, 3H), 4.00 - 4.13 (m, 2H), 5.1 8 - 5.36 (m, 2H), 6.56 (q, J =
5.7 Hz, 0.5H), 6.86, (q, J = 5.7 Hz, 0.5H), 7.1 1 - 7.16 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H),
7.65 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H); MS m/z: 472.1 [M+Na] +.
More polar (spot) product l-CD1-L14-R1-Bb: HPLC analysis of this product was shown
to contain two diastereomers with retention times (TR) of 9.39 & 9.48 min (peak ratio:
43:56); Obtained as a green viscous oil. Yield: 0.3 g (25.0 %); 1HNMR (CDCI3, 300
MHz, (mixture of two diastereomers in -39:45)): 1.42 - 1.61 (m, 6H), 3.61 - 3.89 (m,
3H), 3.91 (s, 3H), 3.86 - 4.1 5 (m, 4H), 5.21 - 5.35 (m, 2H), 6.80 (q, J = 5.7 Hz, 0.5H),
6.95 (q, J = 5.7 Hz, 0.5H), 7.12 - 7.1 5 (m, 2H), 7.37 - 7.42 (m, 1H), 7.66 - 7.72 (m, 3H);
MS m/z: 472.1 [M+Na] +.
The compound of example 22 was prepared by following the experimental procedure
described for preparing the compound of example 2 1. The characterization data of the
compound is described below:
Example 22:
4-((1 -(nitrooxy)ethoxy)carbonyloxy)tetrahydrof uran-3-yl 2-acetoxybenzoate [NOAspirin/
Salicylic acid (I-CD2-L14-R1-A & I-CD2-L14-R1-B)] (Mixture of
diastereomers)
As expected, the title compound was obtained as mixture of diastereomers, I-CD2-L14-
R1-A or I-CD2-L14-R1-B and they were isolated and characterized as described
below:
Less polar diastereomer I-CD2-L14-R1-A: Obtained as oil. Yield: 0.3 g (24.4 %); TR =
3.95 min (HPLC Method: Isocratic at 1: 1 ACN/ water); 1HNMR (CDCI3, 300 MHz): 
1.43 (d, J = 5.7 Hz, 3H), 2.35 (s, 3H), 3.91 - 4.02 (m, 2H), 4.07 - 4.23 (m, 2H), 5.38 (q, J
= 5.4 Hz, 1H), 5.56 (q, J = 5.4 Hz, 1H), 6.84 (q, J = 5.7 Hz, 1H), 7.1 2 (d, J = 8.1 Hz,
1H), 7.33 (distorted dt, J = 7.8, 0.9 Hz, 1H), 7.59 (dt, J = 7.8, 1.5 Hz, 1H), 8.02 (dd, J =
7.8, 1.5 Hz, 1H), MS m/z: 422.1 [M+Na] +.
More polar diastereomer I-C2-L14-R1-B: Obtained as oil. Yield: 0.2 g (20.3 %); TR =
3.56 min (HPLC Method: Isocratic at 1: 1 ACN/ water); 1HNMR (CDCI3, 300 MHz): 
1.57 (d, J = 5.7 Hz, 3H), 2.35 (s, 3H), 3.88, 3.92 (two doublets, -4:5, J = 5.7, 5.4 Hz,
respectively, 1H), 3.97, 4.00 (two doublets, -2:3, J = 3.9 Hz each, 1H), 4.12, 4.1 6 (two
doublets, -3:2, J = 5.4 Hz each, 1H), 4.1 8, 4.22 (two doublets, -5:4, J = 6.3 Hz each,
1H), 5.38 (q, J = 5.4 Hz, 1H), 5.53 (q, J = 5.7 Hz, 1H), 6.87 (q, J = 5.7 Hz, 1H), 7.1 1
(dd, J = 8.1 , 0.6 Hz, 1H), 7.33 (dt, J = 7.8, 1.2 Hz, 1H), 7.59 (dt, J = 7.8, 1.5 Hz, 1H),
8.02 (dd, J = 7.8, 1.5 Hz, 1H), MS m/z: 422.1 [M+Na] +.
Example 23:
(3S,6/?)-6-((1-(nitrooxy)ethoxy)carbonyloxy)hexahydrofuro[3,2-b]furan-3-yl 2-
acetoxybenzoate [NO-Aspirin/Salicylic acid (I-CD2-L15-R1) (Mixture of
diastereomers)
The title compound was synthesized in 4 steps as shown in Scheme 5 and the
experimental procedure is described below:
Steps 1 and 2 : Synthesis of (3S,6ft)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 2-
acetoxybenzoate (CD2-L15-OH)
This known compound (CD2-L15-OH) was synthesized according to the method
described by Moriarty et al., J. Med. Chem. 5 1, 7991 -7999, 2008. Thus, 6.0 g of 10 %
Pd/C was added to a solution of (3S,6f?)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl 2-
acetoxybenzoate (CD2-L15-ON0 2, 6.3 g, 17.8 mmol; This known compound was
prepared according to the method described by Gilmer et al., Eur. J. Pharm. Sci. 14,
221-227, 2001) in 100 mL of 1:1 MeOH and EtOAc and the mixture was stirred under
one atmosphere of hydrogen for 16 h when TLC analysis of the mixture indicated
completion of the reaction. The mixture was passed through a small pad of celite and
solids were washed with 100 mL of fresh 1:1 mixture of MeOH and EtOAc. The used
catalyst was disposed off carefully. The filtrate was concentrated to give 6.0 g of oily
residue which was purified by column chromatography (60.0 g of silica gel, 200-400
mesh, eluted with DCM followed by 5 % MeOH in DCM). The title compound (CD2-L15-
OH) was obtained as colorless viscous oil. Yield: 5.4 g (98.0 %); 1HNMR (CDCI3, 300
MHz) (Mixture of diastereomers): 2.36 (s, 3H), 3.59, 3.62 (two doublets in ratio of
-4:5, J = 6.0, 5.7 Hz, respectively, 1H), 3.90, 3.93 (two doublets in ratio of -5:4, J = 6.0,
5.7 Hz, respectively, 1H), 4.06, 4.09 (two doublets in ratio of -3:7, J = 3.3 Hz, 3.6 Hz,
respectively, 1H), 4.14, 4.18 (two singlets in ratio of -7:3, 1H), 4.33 (q, J = 11.7, 5.7 Hz,
1H), 4.57 (unsymmetrical d, J = 4.2 Hz, 1H), 4.68 (t, J = 4.8 Hz, 1H), 5.44 (d, J = 3.3
Hz, 1H), 7.1 1 (dd, J = 8.1 , 0.6 Hz, 1H), 7.32 (dt, J = 7.8, 0.9 Hz, 1H), 7.55-7.63 (m, 1H),
7.99 (dd, J = 7.8, 1.8 Hz, 1H); MS m/z: 331 . 1 [M+Na] +.
Step 3 : Synthesis of (3S,6f?)-6-((1 -chloroethoxy)carbonyloxy)hexahydrofuro[3,2-
b]furan-3-yl 2-acetoxybenzoate (CD2-L15-R1-CI- A or CD2-L15-R1-CI- B) (Mixture of
diastereomers)
o -Chloroethyl chloroformate (CI-R1-CI, 0.4 mL, 3.9 mmol, 1.2 eqs.) followed by pyridine
(0.4 mL, 4.9 mmol, 1.5 eqs.) were added drop-wise to a stirred solution of (3S,6f?)-6-
hydroxyhexahydrofuro[3,2-b]furan-3-yl 2-acetoxybenzoate (CD2-L15-OH, 1.0 g, 3.2
mmol, 1.0 eq.) in 5 mL of DCM at 0 °C under nitrogen (over -10 minutes) and the
mixture was stirred at 0 °C for 30 minutes and at RT for 1 h when TLC analysis of the
mixture indicated completion of the reaction. The mixture was diluted with 20 mL of
DCM and 30 mL of 1N HCI. The layers were separated. The organic layer was washed
with 1N HCI ( 1 x 20 mL), aqueous sodium bicarbonate (3 x 25 mL), brine (2 x 20 mL),
dried over anhydrous Na2S0 4 and concentrated to give 1.2 g of crude product as a
gum. TLC analysis of the crude product indicated two major new spots or products
(CD2-L15-R1-CI- A and CD2-L15-R1-CI- B). The crude product was purified by column
chromatography (30.0 g of silica gel, 200^100 mesh, eluted with 15-20 % EtOAc in
petroleum ether) and the following two products were separated:
Less polar CD2-L15-R1-CI- A : HPLC analysis of this isolated less polar product
showed single peak with retention time (TR) of 4.546 min (HPLC Method: isocratic at
1: 1 ACN/ water); Obtained as a sticky solid. Yield: 0.6 g (42.4 %); 1HNMR (CDCI3, 300
MHz): 1.85 (d, J = 2.4 Hz, 3H), 2.35 (s, 3H), 3.85 - 4.1 8 (m, 4H), 4.57 (d, J = 4.8 Hz,
1H), 4.95 (t, J = 5.1 Hz, 1H), 5.14 (q, J = 9.0, 4.5 Hz, 1H), 5.42 (d, J = 3.0 Hz, 1H), 6.45
(q, = 11.4, 5.7 Hz, 1H), 7.1 0 (dd, J = 8.1 , 0.9 Hz, 1H), 7.31 (dt, J = 7.5, 0.9 Hz, 1H),
7.55 (dt, J = 7.8, 1.5 Hz, 1H), 7.98 (dd, J = 8.1 , 1.8 Hz, 1H); MS m/z: 437.0 [M+Na] +.
More polar CD2-L15-R1-CI- B: HPLC analysis of this isolated more polar product
showed single peak with retention time (TR) of 4.317 min (HPLC Method: isocratic at
1: 1 ACN/ water); Obtained as a sticky solid. Yield: 0.4 g (32.7 %); 1HNMR (CDCI3,300
MHz): 1.84 (d, J = 6.0 Hz, 3H), 2.35 (s, 3H), 3.88 - 4.1 6 (m, 4H), 4.56 (d, J = 4.8 Hz,
1H), 4.95 (t, J = 5.1 Hz, 1H), 5.14 (q, J = 9.0, 4.5 Hz, 1H), 5.42 (d, J = 3.0 Hz, 1H), 6.43
(q, J = 12.0, 6.0 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.58 (dt, J =
7.8, 1.5 Hz, 1H), 7.99 (dd, J = 7.8, 1.5 Hz, 1H); MS m/z: 437.0 [M+Na] +.
Step 4 : Synthesis of (3S,6f?)-6-((1-(nitrooxy)ethoxy)carbonyloxy)hexahydrofuro[3,2-
b]furan-3-yl 2-acetoxybenzoate (I-CD2-L15-R1- A or I-CD2-L15-R1-B) (Mixture of
diastereomers)
Silver nitrate (0.3 g, 1.7 mmol, 1.2 eqs.) was added to a solution of (3S,6f?)-6-((1-
chloroethoxy)carbonyloxy)hexahydrofuro[3,2-b]furan-3-yl 2-acetoxybenzoate (CD2-
L15-R1-CI-A, Less polar product A, 0.6 g, 1.4 mmol, 1.0 eq.) in 15 mL of ACN and the
mixture was refluxed at 85-90 °C for 3 h when TLC analysis of the mixture indicated
completion of the reaction with the formation of the desired compound I-CD2-L15-R1-A
as the major product. The reaction mixture was filtered and the filtrate was
concentrated. The residue was diluted with 40 mL of DCM and washed with water (3 x
40 mL), brine (2 x 40 mL), dried over anhydrous Na2S0 4 and concentrated to give a
sticky solid residue which was purified by column chromatography (25.0 g of silica gel,
200-400 mesh, eluted with 20-25 % EtOAc in petroleum ether) to afford the title
compound as a sticky solid. HPLC analysis of this product has shown single peak with
retention time (TR) of 4.538 min (HPLC method: isocratic at 1: 1 ACN/ water); Yield: 0.3
g (43.3 %); 1HNMR (CDCI3, 300 MHz): 1.61 (d, J = 5.7 Hz, 3H), 2.36 (s, 3H), 3.87,
3.91 (two doublets in ratio of 1:2, J = 5.4, 5.1 Hz, respectively, 1H), 3.95 - 4.17 (m,
3H), 4.54 (d, J = 4.8 Hz, 1H), 4.94 (t, J = 5.1 Hz, 1H), 5.00 (q, J = 9.3, 1.2 Hz, 1H), 5.42
(d, J = 3.0 Hz, 1H), 6.94 (q, J = 5.7 Hz, 1H), 7.1 0 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 7.8 Hz,
1H), 7.57 (dt, J = 7.8, 1.5 Hz, 1H), 8.00 (dd, J = 7.8, 1.5 Hz, 1H); MS m/z: 464.0
[M+Na]+.
The other diastereomer isomer I-CD2-L15-R1-B was also obtained by following the
same experimental procedure involving treatment of (3S,6f?)-6-((1-
chloroethoxy)carbonyloxy)hexahydrofuro[3,2-b]furan-3-yl 2-acetoxybenzoate (CD2-
L15-R1-CI - B, the more polar product B, 0.4 g, 1. 1 mmol, 1.0 eq.) with 0.2 g ( 1.2
mmol, 1.2 eqs.) of silver nitrate. HPLC analysis of this product has shown single peak
with retention time (TR) of 4.792 min (HPLC method: isocratic at 1: 1 ACN/ water); this
product was obtained as a sticky solid. Yield: 0.3 g (59.8 %); 1HNMR (CDCI3, 300 MHz):
1.61 (d, J = 5.7 Hz, 3H), 2.35 (s, 3H), 3.89, 3.92 (two doublets in ratio of ~ 1 :3, J = 5.4
Hz each, 1H), 3.96, 4.00 (two doublets in ratio of -3:1 , J = 3.9 Hz each, 1H), 4.03, 4.06
(two doublets in ratio of - 1:3, J = 3.3 Hz each, 1H), 4.10, 4.13 (two singlets in ratio of
-3:1 , 1H), 4.55 (d, J = 4.8 Hz, 1H), 4.94 (t, J = 5.1 Hz, 1H), 5.1 1 (distorted q, J = 9.3,
3.9 Hz, 1H), 5.42 (d, J = 3.0 Hz, 1H), 6.94 (q, J = 5.7 Hz, 1H), 7.1 0 (dd, J = 8.1 , 0.6 Hz,
1H), 7.31 (dt, J = 7.8, 0.9 Hz, 1H), 7.58 (dt, J = 7.8, 1.5 Hz, 1H), 7.98 (dd, J = 7.8, 1.5
Hz, 1H); MS m/z: 464.1 [M+Na] +.
Example 24:
(2S)-2-(2-((1-(nitrooxy)ethoxy)carbonyloxy)ethylsulfinyl)ethyl 2-(6-methoxy
naphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L16-R1)]
The above compound was synthesized in 4 steps as shown in Scheme 6 and the
experimental procedure is described below:
Step 1: Preparation of (S)-2-(2-hydroxyethylthio)ethyl 2-(6-methoxynaphthalen-2-
yl)propanoate (CD1-L16S-OH)
A solution of freshly prepared naproxen acid chloride (CD1-CI, 16.0 g, 64.0 mmol) in
DCM (-50 mL) was added to a stirred solution of 2,2'-thiodiethanol (HO-L16S-OH, 26.0
g, 256.0 mmol, 3.3 eqs.) in 100 mL of DCM at 0 °C under nitrogen. To this stirred
mixture was added triethylamine (TEA, 13.0 mL, 92.9 mmol, 1.5 eqs.) drop-wise over
30 minutes and the mixture was stirred at RT under nitrogen for overnight. TLC analysis
of the mixture indicated completion of the reaction. The mixture was washed with
saturated sodium bicarbonate (3 x 100 mL) and brine (2 x 100 mL) to remove the
remaining un-reacted water-soluble linker. The organic layer was dried over anhydrous
Na2S0 4 and concentrated in vacuo to give 22.0 g of crude product which was purified
by column chromatography (300.0 g of silica gel, 200-400 mesh). The expected bisderivative
was eluted with 10 % EtOAc in petroleum ether. The desired compound was
eluted with 15-25 % EtOAc in petroleum ether. The pure title compound (CD1-L16SOH)
was obtained as light yellow oil which solidified at low temperature (< 0 °C). Yield:
17.4 g (81 .3 %); 1H NMR (CDCI3, 300 MHz): 1.60 (d, J = 6.9 Hz, 3H), 2.63 (t, J = 6.0
Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H), 3.88 (q, J = 7.2 Hz, 1H), 3.93
(s, 3H), 4.26 (t, J = 6.9 Hz, 2H), 7.10 - 7.20 (m, 2H), 7.41 (dd, J = 8.4, 1.5 Hz, 1H), 7.67
- 7.77 (m, 3H); MS m/z: 357.1 [M+Na] +. This intermediate was also synthesized in good
yields by the reaction of naproxen with the corresponding diol in the presence of
coupling agents such as DCC, DMAP in a suitable solvent such as DCM or DMF.
Step 2 : Preparation of (2S)-2-(2-((1-chloroethoxy)carbonyloxy)ethylthio)ethyl 2-(6-
methoxynaphthalen-2-yl)propanoate (CD1 -L1 6S-R1 -CI)
-Chloroethyl chloroformate (CI-R1-CI, 6.0 mL, 6 1.0 mmol) was added drop-wise to a
solution of 2-(2-hydroxyethylthio)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate (CD1-
L16S-OH, 17.0 g, 50.9 mmol) in 100 mL of DCM at 0 °C under nitrogen. To this stirred
mixture was added a solution of pyridine (6.2 mL, 76.4 mmol) in 50 mL of DCM over 5
minutes. The mixture was stirred at 0 °C under nitrogen for 1 h. TLC analysis of the
mixture indicated completion of the reaction. The mixture was washed with 1N HCI (3 x
100 mL) and brine (2 x 100 mL). The organic layer was dried over Na2S0 4 and
concentrated in vacuo to afford the title compound (CD1-L16S-R1-CI) as yellow oil of
sufficient purity to be used as such in the next step. Yield: 2 1 .0 g (93.6 %); 1H NMR
(CDCI3, 300 MHz): 1.58 (d, J = 6.6 Hz, 3H), 1.82 (d, J = 6.0 Hz, 3H), 2.64 - 2.77 (m,
4H), 3.86 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.20 (t, J = 6.9 Hz, 2H), 4.24 (t, J = 6.9 Hz,
2H), 6.40 (q, J = 5.7 Hz, 1H), 7.10 - 7.1 8 (m, 2H), 7.39 (dd, J = 8.4, 1.5 Hz, 1H), 7.65 -
7.74 (m, 3H); MS m/z: 463.1 [M + Na]+.
Step 3 : Preparation of (2S)-2-(2-((1-(nitrooxy)ethoxy)carbonyloxy)ethylthio)ethyl 2-(6-
methoxynaphthalen-2-yl)propanoate (CD1 -L1 6S-R1 )
Silver nitrate ( 1 2.1 g, 7 1.3 mmol) was added to a solution of 2-(2-((1-
chloroethoxy)carbonyloxy)ethylthio)ethyl 2-(6-methoxynaphthalen-2-yl)-propanoate
(CD1-L16S-R1-CI, 2 1.0 g, 47.6 mmol) in 175 mL of ACN and the mixture was refluxed
in dark at 85-90 °C for -45 minutes when HPLC analysis of the mixture indicated
complete conversion. The mixture was cooled and filtered through celite. The filtrate
was concentrated and the residue was re-dissolved in DCM (-1 00 mL) and filtered
through celite to remove the precipitated silver chloride. The filtrate was concentrated in
vacuo and the residue thus obtained was purified by column chromatography (400.0 g
of silica gel, 200-400 mesh, eluted with 13 % EtOAc in petroleum ether) to afford the
title compound as yellow oil. Yield: 20.0 g (89.8 %); 1H NMR (CDCI3, 300 MHz): 1.55-
1.63 (m, 6H), 2.64 - 2.77 (m, 4H), 3.86 (q, J = 7.2 Hz, 1H), 3.91 (s, 3H), 4.1 9 (t, J = 6.9
Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 6.90 (q, J = 5.7 Hz, 1H), 7.10 - 7.1 8 (m, 2H), 7.39 (dd,
J = 8.4, 1.5 Hz, 1H), 7.65 - 7.74 (m or distorted t , 3H); 1 C NMR (CDCI3, 75.47 MHz): 
17.5, 18.6, 30.5, 30.8, 45.5, 55.4, 64.1 , 67.4, 96.4, 105.7, 119.2, 126.1 , 126.3, 127.3,
129.0, 129.4, 133.8, 135.5, 152.6, 157.8, 174.5; MS m/z: 490.1 [M+Na] +; HRMS ESI
(m/z): [M+Na] + calculated for C H NiNaiOgSi : 490.1 142; Found: 490.1 147 (Mass
Accuracy: - 1 .02 ppm).
Step 4 : Preparation of (2S)-2-(2-((1-(nitrooxy)ethoxy)carbonyloxy)ethylsulfinyl)ethyl 2-
(6-methoxynaphthalen-2-yl)propanoate (I-CD1-L16-R1)
A solution of sodium periodate (Nal0 4, 5.5 g, 25.6 mmol) in 25 mL of water was added
drop-wise to a stirred solution of CD1-L16S-R1 (8.0 g, 17.0 mmol) in 100 mL of 3:1
methanol/ acetone over 15 minutes and the resulting turbid mixture was stirred at RT
for ~4 h when TLC analysis of the mixture indicated >90 % conversion. The mixture
was concentrated and the residue thus obtained was diluted with 100 mL of DCM and
washed with water (3 x 100 mL) and brine ( 1 x 100 mL). The organic layer was dried
over anhydrous Na2S0 4 and concentrated to give a crude product (-9.0 g) which was
triturated and sonicated with 40 % EtOAc in petroleum ether to afford the title
compound (I-CD1-L16-R1) as a white solid. Mp: 112-1 15 °C; Yield: 1.6 g ( 19.0 %); 1H
NMR (CDCI3, 300 MHz): 1.53-1 .63 (m, 6H), 2.52 - 3.1 0 (m, 4H), 3.87 (q, J = 6.9 Hz,
1H), 3.91 (s, 3H), 4.09 - 4.67 (m, 4H), 6.86 - 6.94 (m, 1H), 7.1 2 (s, 1H), 7.1 5 (d, J = 9.0
Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H); 1 C NMR
(CDCI3, 75.47 MHz): 16.9, 17.7, 44.9, 50.2, 50.3, 50.6, 50.8, 5 1. 1 , 54.9, 56.3, 56.4,
56.5, 60.5, 95.9, 96.0, 105.2, 118.8, 118.9, 125.7, 126.9, 128.4, 128.8, 133.3, 134.62,
151 .7, 157.4, 157.4, 173.6; MS m/z: 484.0 [M+H]+, 506.0 [M+Na] +; HRMS ESI (m/z):
[M+Na] + calculated for C2i H25N1NaiOioSi: 506.1 091 ; Found: 506.1 109 (Mass
Accuracy: -3.56 ppm).
Example 25:
(2S)-2-(2-((1-(nitrooxy)ethoxy)carbonyloxy)ethylsulfonyl)ethyl 2-(6-methoxy
naphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L17-R1)]
The title compound was synthesized as shown in Scheme 6 and the experimental
procedure is described below:
A solution of oxone (4.7 g, 7.7 mmol) in -20 mL of water was added to a stirred solution
of CD1-L16S-R1 (7.5 g, 16.0 mmol) in 75 mL of 2:1 methanol/ acetone at 0 °C over 10
minutes and the resulting turbid solution was stirred for overnight when TLC analysis of
the mixture indicated formation of the intermediate sulfoxide. Additional 8.0 g (-1 3.0
mmol) of oxone as solution in water (-35 mL) was added to the mixture and the
resulting turbid mixture was diluted with -80 mL of methanol and stirring was continued
at RT for 1 h when TLC analysis of the mixture indicated formation of the sulfone
product. The mixture was concentrated on rotavap and the residue thus obtained was
dissolved in -300 mL of DCM and washed with water (3 x 100 mL) and brine (2 x 100
mL). The organic layer was dried over anhydrous Na2S0 4 and concentrated on rotavap
to give - 10.0 g of yellow oil which was purified by column chromatography (300.0 g of
silica gel, 200-400 mesh). The residual sulfide intermediate was eluted with 10-15 %
EtOAc in petroleum ether. Elution with 1: 1 MeOH/ DCM afforded the title compound as
a slightly yellow colored solid. Mp: 98-100 °C; Yield: 5.0 g (62.5 %); 1H NMR (CDCI3,
300 MHz): 1.55-1 .63 (m, 6H), 2.43 - 2.74 (m, 2H), 3.10 - 3.33 (m, 2H), 3.82 - 3.95 (m,
2H), 3.92 (s, 3H), 4.05 - 4.16 (m, 1H), 4.38 - 4.48 (m, 1H), 4.51 - 4.62 (m, 1H), 6.83 -
6.94 (m, 1H), 7.1 0 (d, J = 2.1 Hz, 1H), 7.1 6 (dd, J = 9.0, 2.4 Hz, 1H), 7.33 (dd, J = 8.4,
1.2 Hz, 1H), 7.63 (s, 1H), 7.65-7.75 (m, 2H); 1 C NMR (CDCI3, 75.47 MHz): 16.9,
17.7, 44.9, 52.0, 53.4, 54.9, 57.9, 58.0, 60.7, 96.0, 105.1 , 119.2, 125.5, 125.8, 127.1 ,
128.3, 128.7, 133.3, 134.5, 134.6, 151 .4, 157.6, 173.2; MS m/z: 498.8 [M-H]; HRMS
ESI (m/z): [M+Na] + calculated for C2iH25N1Na O S : 522.1041 ; Found: 522.1 063
(Mass Accuracy: -4.21 ppm).
The compounds of the examples 26 and 27 were prepared by following the
experimental procedure described for preparing the compound of example 25 except
that 3,3'-thiodipropanol [CAS #: 10595-09-2] was used as the starting diol linker. The
characterization data of the compounds of examples 26 and 27 is provided below.
Example 26:
(2S)-3-(3-((1-(nitrooxy)ethoxy)carbonyloxy)propylthio)propyl 2-(6-methoxy
naphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L18-R1)]
The title compound (I-CD1-L18-R1) was obtained as yellow oil. Yield (last step): 96.0
%; 1H NMR (CDCI3, 300 MHz): 1.60 (d, J = 7.2 Hz, 3H), 1.61 (d, J = 5.7 Hz, 3H), 1.75
- 1 .91 (m, 4H), 2.40 (t, J = 7.2 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 3.87 (q, J = 7.2 Hz, 1H),
3.94 (s, 3H), 4.1 0 - 4.26 (m, 4H), 6.94 (q, J = 5.7 Hz, 1H), 7.1 2 - 7.19 (m, 2H), 7.41 (dd,
J = 8.4, 1.5 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.72 (unsymmetrical d, J = 8.7 Hz, 2H);
1 C NMR (CDCI3, 75.47 MHz): 16.9, 17.9, 27.6, 27.7, 27.8, 28.1 , 45.0, 54.8, 62.6,
66.7, 95.7, 105.1 , 118.5, 125.4, 125.7, 126.6, 128.4, 128.7, 133.2, 135.2, 152.1 , 157.2,
174.0; MS m/z: 495.1 . 1 [M+H] +, 518.1 [M+Na] +; HRMS ESI (m/z): [M+Na] + calculated
for C23H29NiNai0 9Si: 518.1455; Found: 5 18.1465 (Mass Accuracy: - 1 .93 ppm).
Example 27:
(2S)-3-(3-((1-(nitrooxy)ethoxy)carbonyloxy)propylsulfinyl)propyl 2-(6-
methoxynaphthalen-2-yl)propanoate [NO-Naproxen (I-CD1-L19-R1)]
The title compound (I-CD1-L19-R1) was obtained as yellow oil. Yield (last step): 1.4 g
(70.0 %). 1H NMR (CDCI3, 300 MHz) (Mixture of diastereomers): 1.60 (dd, J = 5.7, 1.5
Hz, 6H), 1.92 - 2.1 1 (m, 4H), 2.23 - 2.55 (m, 4H), 3.87 (q, J = 7.2 Hz, 1H), 3.93 (s, 3H),
4.09 - 4.37 (m, 4H), 6.94 (q, J = 5.7 Hz, 1H), 7.13 (distorted d, J = 2.4 Hz, 1H), 7.1 8
(dd, J = 8.7, 2.4 Hz, 1H), 7.40 (dd, J = 7.2, 1.2 Hz, 1H), 7.67 (br s, 1H), 7.71 (d, J = 8.4
Hz, 2H); 1 C NMR (CDCI3, 75.47 MHz) (Mixture of diastereomers): 16.9, 17.6, 2 1.5,
2 1 .6, 2 1 .8, 44.9, 47.8, 48.3, 54.8, 62.2. 62.3, 66.4, 66.5, 95.8, 105.1 , 118.7, 125.4,
125.7, 126.7, 128.3, 128.7, 133.2, 135.1 , 135.2, 152.0, 157.3, 173.9; MS m/z 512.2
[M+H] +, 534.1 [M+Na] +. HRMS ESI (m/z): [M+H] + calculated for C23H30N O 10S 1:
5 12.1585; Found: 5 12.1598 (Mass Accuracy: -2.1 7 ppm). Purity by HPLC @210 nm:
96.39 %.
Examples of the compounds of formula I which are the prodrugs of the drugs
containing an amino group :
Example 28:
(Z)-3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2-(15-(nitrooxy)-6,13-dioxo-
2,7,1 2,1 4-tetraoxa-5-azahexadec-9-enyl)-1,4-dihydropyridine-3,5-dicarboxylate
[NO-Amlodipine (I-AD1-L2-R1)]
This compound was synthesized in 2 steps as shown in Scheme 8 and the
experimental procedure is described below:
Step 1: Preparation of (Z)-3-ethyl 5-methyl 2-(1 5-chloro-6,1 3-dioxo-2,7,1 2,14-tetraoxa-
5-azahexadec-9-enyl)-4-(2-chlorophenyl)-6-methyl-1 ,4-dihydropyridine-3,5-
dicarboxylate (AD1-L2-R1-CI)
A solution of triphosgene (0.5 g, 1.7 mmol) in 4 mL of DCM was added to a stirred
solution of amlodipine besylate (2.9 g, 5.1 mmol) and triethylamine ( 1 .5 mL, 10.1 mmol)
in 26 mL of DCM at RT and the mixture was stirred for 1.5 h to get the crude isocyanate
intermediate AD1-IM1 . To this stirred mixture was added a solution of (Z)-l-chloroethyl
4-hydroxybut-2-enyl carbonate (HO-L2-R1-CI, 1.0 g, 5.1 mmol, freshly prepared as
described in Example 4) in 4 mL of DCM and the mixture was stirred at RT for 12 h
when TLC analysis of the mixture indicated formation of a new product. The mixture
was diluted with DCM (40 mL), washed with 0.5 N HCI ( 1 x 40 mL) & brine ( 1 x 50 mL).
The organic layer was dried over MgS0 4 and concentrated on rotavap to give a residue
which was purified by column chromatography on silica gel by eluting with 30 % EtOAc
in hexane to afford the title compound AD1-L2-R1-CI as yellow oil. Yield: 1.5 g (47.0
%); 1H NMR (CDCI3, 300 MHz): 1. 18 (t, J = 4.2 Hz, 3H), 1.82 (d, J = 3.6 Hz. 3H), 2.36
(s, 3H), 3.42 - 3.51 (m, 2H), 3.59 - 3.68 (m, 5H), 4.01 -4.08 (m, 2H), 4.64 - 4.78 (m, 4H),
4.82 (d, J = 3.6 Hz, 2H), 5.05 (br s, 1H), 5.40 (s, 1H), 5.74 - 5.87 (m, 2H), 6.42 (q, J =
3.6 Hz, 1H), 7.04 (t, J = 4.5 Hz, 1H), 7.14 (t, J = 6.0 Hz, 1H), 7.20 - 7.28 (m, 2H), 7.37
(d, J = 4.5 Hz, 1H); MS m/z: 628.2 [M+H]+ , 651 .2 [M+Na] +.
Step 2 : Preparation of the title compound NO-Amlodipine (I-AD1-L2-R1)
Silver nitrate (0.6 g, 3.3 mmol) was added to a stirred solution of the intermediate AD1-
L2-R1-CI ( 1 .4 g, 2.2 mmol) in 25 mL of ACN at RT and the mixture was stirred at -90
°C for 1.5 h when HPLC analysis of the mixture indicated completion of the reaction.
The mixture was cooled and filtered through celite pad. The filtrate was concentrated
and the residue obtained was partitioned between EtOAc (75 mL) and water (75 mL).
The EtOAc layer was separated, washed with brine ( 1 x 75 mL), dried over anhydrous
Na2S0 4 and concentrated in vacuo to give the crude product which was purified by
column chromatography on silica gel by eluting with 20 % EtOAc in hexane to afford the
title compound as yellow oil. Yield: 1.2 g (81 .0 %); 1H NMR (CDCI3, 300 MHz): 1.20 (t,
J = 7.2 Hz, 3H), 1.60 (d, J = 5.4 Hz, 2H), 2.38 (s, 2H), 2.67 (s, 1H), 3.33 - 3.70 (m, 7H),
3.98 - 4.1 6 (m, 2H), 4.64 - 4.87 (m, 6H), 5.05 (br s, 0.7H), 5.32 (s, 0.37H), 5.42 (s,
0.7H), 5.55 - 5.63 (m, 0.25H), 5.70 - 5.90 (m, 2H), 6.94 (q, J = 5.7 Hz, 1H), 7.02 -7.47
(m, 5H); MS m/z: 654.2 [M-H] .
Example 29:
Ethyl 2-(1 -(1 4-(nitrooxy)-3,1 2-dioxo-4,1 1,13-trioxa-7,8-dithia-2-
azapentadecyl)cyclohexyl)acetate [NO-Gabapentin ethyl ester (I-AD2-L1-R1)]
This compound was synthesized in 4 steps as shown in Scheme 9 and the
experimental procedure is described below:
Step 1: Preparation of ethyl 2-(1-(3,12-dioxo-4,1 1-dioxa-7,8-dithia-2-
azatridecyl)cyclohexyl)acetate (AD2-L1 -OAc)
To a stirred solution of diphosgene ( 1 .4 mL, 12.0 mmol) in 4 mL of dry DCM at 0 °C
under nitrogen was added a solution of 2-((2-hydroxyethyl)disulfanyl)ethyl acetate (HOL1-
OAc, 0.8 g, 4.0 mmol, freshly prepared by mono-acetylation of 2-hydroxyethyl
disulfide (HO-L1-OH)) and diisopropylethylamine (DIPEA, 3.5 mL, 19.9 mmol) in 4 mL
of DCM over 20 minutes and the mixture was stirred at the same temperature for 40
minutes. The mixture was concentrated at RT to give the crude formyl chloride CI-L1-
OAc. A mixture of gabapentin ethyl ester hydrochloride (0.9 g, 4.0 mmol, freshly
prepared from gabapentin using thionyl chloride/ ethanol method) and DIPEA ( 1 .4 mL,
8.0 mmol) in 4 mL of DCM was added to the intermediate formyl chloride CI-L1-OAc at
0 °C under nitrogen and the mixture was stirred at RT for overnight (-1 2 h). The mixture
was concentrated and the residue was re-dissolved in 25 mL of ethyl acetate and
washed with water ( 1 x 10 mL) and brine ( 1 x 10 mL). The organic layer was dried over
Na2S0 4 and concentrated in vacuo to get 2.9 g of crude product as yellow oil which was
purified by column chromatography (silica gel, 90.0 g, 200-400 mesh, eluted with 30 %
EtOAc in hexane) to afford the title compound as colorless oil. Yield: 1.2 g (73.0 %); 1H
NMR (CDCI3, 300 MHz): 1.22 (t, J = 7.3 Hz, 3H), 1.27 - 1.68 (m, 10H), 2.06 (s, 3H),
2.27 (s, 2H), 2.91 (t, J = 6.6 Hz, 4H), 3.19 (d, J = 6.7 Hz, 2H), 4.1 2 (q, J = 7.2 Hz, 2H),
4.31 (q, J = 6.4 Hz, 4H), 5.40 (br s, 1H); MS m/z: 422 [M+H]+, 444 [M+Na] +.
Step 2 : Preparation of ethyl 2-(1 -(((2-((2-hydroxyethyl)disulfanyl)ethoxy)-
carbonylamino)methyl)cyclohexyl)acetate (AD2-L1-OH)
To a stirred solution of AD2-L1-OAc ( 1 .2 g, 2.8 mmol) in 10 mL of methanol at 0 °C
was added an ice-cold solution of K2C0 3 (0.6 g, 4.3 mmol) in 2 mL of water over a
period of 30 minutes when TLC analysis of the mixture indicated consumption of all the
starting material. The mixture was filtered and the solid residue was washed with
methanol ( 10 mL). The filtrate was concentrated and the residue was re-dissolved in 30
mL of ethyl acetate and washed with water ( 1 x 10 mL) and brine ( 1 x 10 mL). The
organic layer was dried over Na2S0 4 and concentrated to give 0.9 g of crude product
which was purified by column chromatography (silica gel, 30.0 g, 200-400 mesh, eluted
with DCM) to afford the title compound (AD2-L1-OH) as yellow oil. Yield: 0.4 g (32.0
%); 1H NMR (CDCI3, 300 MHz): 1.25 (t, = 12. Hz, 3H), 1.30 - 1.71 (m, 10H), 2.87 -
2.94 (m, 4H), 2.27 (s, 2H), 3.1 8 (d, J = 6.6 Hz, 2H), 3.87 (t, J = 5.7 Hz, 2H), 4.09 - 4.1 6
(q, J = 7.1 Hz, 2H), 4.31 (t, J = 6.6 Hz, 2H), 5.44 (br s, 1H); MS m/z: 380 [M+H]+, 402
[M+Na]+.
Step 3 : Preparation of ethyl 2-(1 -(14-chloro-3,12-dioxo-4,1 1, 1 3-trioxa-7,8-dithia-2-
azapentadecyl)cyclohexyl)acetate (AD2-L1 -R1 -CI)
oc-Chloroethyl chloroformate (CI-R1-CI, 0.2 mL, 2.1 mmol) was added drop-wise to a
stirred solution of AD2-L1-OH (0.4 g, 1. 1 mmol) and pyridine (0.2 mL, 2.1 mmol) in 10
mL of DCM at 0 °C under nitrogen and the mixture was stirred at RT for 45 minutes
when TLC analysis of the mixture indicated formation of the desired product. The
mixture was washed with 0.5 N HCI ( 1 x 10 mL) and brine ( 1 x 10 mL), dried over
MgS0 4 and concentrated in vacuo to give a residue which was purified by column
chromatography (silica gel, 15.0 g, 200-400 mesh eluted with 20 % EtOAc in hexane) to
afford the title compound (AD2-L1-R1-CI) as yellow oil. Yield: 0.4 g (83.0 %); 1H NMR
(CDCI3, 300 MHz): 1.28 (t, J = 7.2 Hz, 3H), 1.34 - 1.60 (m, 10H), 1.85 (d, J = 6.0 Hz,
3H), 2.30 (s, 2H), 2.92 - 3.03 (m, 4H), 3.22 (d, J = 6.9 Hz, 2H), 4.1 5 (q, J = 7.2 Hz, 2H),
4.30 - 4.38 (m, 2H), 4.48 (t, J = 6.6 Hz, 2H), 5.42 (t, J = 7.5 Hz, 1H), 6.44 (q, J = 6.0 Hz,
1H); MS m/z: 508.1 [M+Na]+.
Step 4 : Preparation of NO-Gabapentin ethyl ester/Ethyl 2-(1-(14-(nitrooxy)-3,1 2-dioxo-
4,1 1, 1 3-trioxa-7,8-dithia-2-azapentadecyl)cyclohexyl)acetate (I-AD2-L1-R1)
Silver nitrate (0.2 g, 1.2 mmol) was added as a solid to a stirred solution of AD2-L1-R1-
Cl (0.4 g, 0.8 mmol) in 10 mL of ACN at RT and the mixture was stirred at 85-90 °C for
1.5h. The mixture was allowed to attain RT, filtered through celite, the celite bed was
washed with fresh ACN ( 15 mL). The filtrate and washings were combined and
concentrated in vacuo to get a residue which was purified by column chromatography
(silica gel, 15.0 g, 200-400 mesh, 20 % EtOAc in hexane) to afford the title compound
as yellow oil. Yield: 0.2 g (48.0 %); 1H NMR (CDCI3, 300 MHz): 1.26 (t, J = 4.2 Hz,
3H), 1.34 - 1.58 (m, 10H), 1.60 (d, J = 3.3 Hz, 3H), 2.29 (s, 2H), 2.90 - 2.99 (m, 4H),
3.20 (d, J = 3.9 Hz, 2H), 4.13 (q, J = 4.2 Hz, 2H), 4.31 (t, J = 3.9 Hz, 2H), 4.45 (t, J =
3.9 Hz, 2H), 5.37 - 5.48 (m, 1H), 6.93 (q, J = 3.3 Hz, 1H); MS (ESI ) m/z: 534.8
[M+Na] +.
Example 30:
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl (S)-2-(2-oxopyrrolidin-1-
yl)butanoylcarbamate [NO- Levetiracetam (I-AD3-L2-R1)]
This compound was synthesized as shown in Scheme 8 and the experimental
procedure is described below:
Oxalyl chloride ( 1 .2 mL, 14.0 mmol) was added to a solution of (S)-2-(2-oxopyrrolidin-1-
yl)butanamide (AD3, levetiracetam, 2.0 g, 11.7 mmol) in 10 mL of 3:1 mixture of DCE/
DCM and the mixture was refluxed for 8 h to yield the corresponding isocyanate AD3-
IM1 . To this cooled and stirred mixture was added drop-wise a solution of (Z)-4-
hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1 , 2.5 g, 11.7 mmol, freshly
prepared as described in Example 4) in 10 mL of DCM over 5 minutes and the mixture
was stirred at RT for 12 h when TLC analysis of the mixture showed completion of the
reaction. The mixture was concentrated to give a residue which was purified by column
chromatography (silica gel 150-300 mesh, eluted with 40 % EtOAc in petroleum ether)
to afford the title compound (I-AD3-L2-R1) as yellow oil. Yield: 1.5 g (30.6 %); 1H NMR
(CDCI3, 300 MHz): 0.90 (t, J = 7.2 Hz, 2.25H), 0.94 (t, J = 7.2 Hz, 0.75H), 1.61 (d, J =
5.4 Hz, 3H), 1.80 - 2.1 5 (m, 4H), 2.38 - 2.50 (m, 2H), 3.03 - 3.15 (m, 0.75H), 3.31 - 3.41
(m, 0.25H), 3.48 - 3.58 (m, 0.25H), 3.64 - 3.77 (m, 0.75H), 4.09 (m, 1H), 4.68 - 4.76 (m,
2H), 4.78 - 4.86 (m, 2H), 5.73 - 5.92 (m, 2H), 6.94 (q, J = 5.4 Hz, 5.7 Hz, 1H), 8.04 (br
s, 1H); MS m/z: 440.1 [M+Na] +.
The compounds of examples 3 1 - 33 were prepared by following the procedure as
indicated in example 30. The characterization data for the compounds of examples 3 1 -
33 is provided below:
Example 3 1 :
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl (Z)-5H-dibenzo[b,f]azepine-5-
carbonylcarbamate [NO-Carbamazepine (I-AD4-L2-R1)]
The title compound (I-AD4-L2-R1) was obtained as an off-white gum. Yield: 0.6 g (55.4
%); 1H NMR (CDCI3, 300 MHz): 1.59 (d, J = 5.4 Hz, 3H), 4.72 (d, J = 5.4 Hz, 2H),
4.77 (mixed d, J = 5.1 Hz, 2H), 5.70 - 5.85 (m, 2H), 6.68 (br s, 1H), 6.93 (q, J = 5.4 Hz,
1H), 6.98 (s, 2H), 7.37 - 7.45 (m, 4H), 7.47 - 7.53 (m, 4H); MS () m/z: 484.1 [M+H]+,
506.1 [M+Na] +.
Example 32:
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 10-oxo-10,11-dihydro-5Hdibenzo[
b,f]azepine-5-carbonylcarbamate [NO-Oxcarbazepine (I-AD5-L2-R1 )]
The title compound (I-AD5-L2-R1) was obtained as an off-white gum. Yield: 30.6 %; 1H
NMR (CDCI3, 300 MHz): 1.60 (d, J = 5.7 Hz, 3H), 3.89 (d, J = 14.7 Hz, 1H), 4.45 (d, J
= 14.4 Hz, 1H), 4.75 - 4.79 (m, 4H), 5.76 - 5.83 (m, 2H), 6.92 (q, J = 5.7 Hz, 1H), 7.07
(br s, 1H), 7.37 - 7.52 (m, 5H), 7.57 - 7.68 (m, 2H), 8.13 (d, J = 7.5 Hz, 1H); MS ()
m/z: 500.1 [M+H] +, 522.1 [M+Na] +.
Example 33:
(Z)-5-((4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyloxy)-carbonylcarbamoyl)-
10,11-dihydro-5H-dibenzo[b,f]azepin-10-yl acetate [NO-O-Acetyl-licarbazepine (IAD6-
L2-R1)]
The title compound (I-AD6-L2-R1) was obtained as an off-white gum. Yield: 48.8 %; 1H
NMR (CDCI3, 300 MHz): 1.59, 1.60 (mixed doublets, J = 5.4 Hz, 5.7 Hz, 3H), 2.09 (d,
J = 12.6 Hz, 3H), 3.05 - 3.26 (m, 1H), 3.58 - 3.68 (m, 1H), 4.65 - 4.87 (m, 4H), 5.72 -
6.07 (m, 3H), 6.38 - 6.45 (m, 0.5H), 6.92 (q, J = 5.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H),
7.22 -7.54 (m, 8.5H); MS () m/z 544.2 [M+H]+, 566.2 [M+Na] +.
Example 34:
(Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 6-methoxy-2-((4-methoxy-3,5-
dimethylpyridin-2-yl)methylsulfinyl)-1 H-benzo[d]imidazole-1-carboxyla [NOOmeprazole
(I-AD7-L2-R1)]
This compound was synthesized as shown in Scheme 7 and the experimental
procedure is described below:
Diphosgene (0.2 g, 1.3 mmol) was added drop-wise to a stirred solution of (Z)-4-
hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1 , 0.5 g, 2.3 mmol, freshly
prepared as described in Example 4) and triethylamine (0.1 ml_,1 .4 mmol) in 5 mL of
dry DCM at 0 °C under nitrogen and the mixture was stirred for 30 minutes. The
reaction mixture was concentrated to get the corresponding formyl chloride, CI-L2-R1 ,
as yellow residue. This residue was re-dissolved in DCM (5 mL) and the resulting
solution was added to a stirred mixture of omeprazole (AD7, 0.4 g, 1. 1 mmol) ) and
DMAP (0.3 g, 2.3 mmol) in DCM (5 mL) at 0 °C and the mixture was stirred for 1 h
when TLC analysis of the mixture indicated formation of a major new product.. The
reaction mixture was diluted with DCM (15 mL), washed with water, dried over
anhydrous Na2S0 4, concentrated and purified by column chromatography on silica gel
by eluting with methanol/ dichloromethane gradient to afford the title compound I-AD7-
L2-R1 as a brown gum. Yield: 0.3 g (45.0 %); 1H NMR (CDCI 3, 300 MHz, mixture of
diastereomers, -0.55:0.45): 1.61 (d, J = 5.7, 3H), 2.21 (s, 3H), 2.37 (s, 3H), 3.76
(unsymmetrical d, J = 1.2 Hz, 3H), 3.88, 3.92 (two singlets, 3H), 4.65 - 4.94 (m, 4H),
5.02 - 5.21 (m, 2H), 5.90 - 6.1 0 (m, 2H), 6.93 (q, J = 5.7 Hz, 1H), 7.03 (dd, J = 2.4, 9.0
Hz, 0.5H), 7.09 (dd, J = 2.4, 9.0 Hz, 0.5H), 7.33 (d, J = 2.4 Hz, 0.45H), 7.49 (d, J = 1.8
Hz, 0.55H), 7.75 (d, J = 9.0 Hz, 0.55H), 7.83 (dd, J = 9.0, 1.8 Hz, 0.45H), 8.06 (br s,
1H); MS () m/z 593.2 [M+H] +, 6 15.1 [M+Na] +.
Examples of the compounds of formula I which are the prodrugs of the drugs
containing hydroxyl group :
Example 35:
NO-Paclitaxel Prodrug (I-HD1-L2-R1)
This compound was synthesized as shown in Scheme 7 and the experimental
procedure is described below:
A solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1 , 0.1 g, 0.5
mmol, freshly prepared as described in Example 4) and DIPEA (0.3 ml_, 1.8 mmol) in 3
ml of DCM was added drop-wise to a stirred solution of diphosgene (0.1 ml_, 0.9 mmol)
in 1 ml of DCM at 0 °C under nitrogen over 10 minutes and the resulting mixture was
stirred for 45 minutes. The mixture was concentrated in vacuo and the corresponding
dry formyl chloride, CI-L2-R1 , thus obtained was re-dissolved in 3 ml of DCM and
cooled to 0 °C under nitrogen. To this stirred solution was added drop-wise a solution of
paclitaxel (0.08 g, 0.1 mmol) and diisopropylethylamine (0.03 ml_, 0.2 mmol) in 2 ml of
DCM and the mixture was stirred for 2 h when TLC analysis of the mixture indicated
completion of the reaction. The mixture was diluted with 10 mL of DCM and washed
with water ( 1 x 10 mL) and brine ( 1 x 10 mL). The organic layer was dried over MgS0 4
and concentrated in vacuo to give a residue which was purified by column
chromatography on silica gel by eluting with 10 % ACN in DCM to afford the title
compound I-HD1-L2-R1 as a white solid. Mp: 141 -143 °C; Yield: 0.07 g (75.0 %); 1H
NMR (CDCI3, 300 MHz): 1. 1 6 (s, 3H), 1.31 (s, 3H), 1.41 - 1.43 (m, 1H), 1.58 - 1.64 (m,
2H), 1.71 (s, 3H), 1.81 - 1.94 (m, 2H), 1.95 (s, 3H), 2.02 - 2.08 (m, 2H), 2.25 (s, 3H),
2.37 - 2.65 (m, 3H), 2.49 (s, 3H), 2.58 - 2.61 (m, 1H), 3.83 (d, J = 7.2 Hz, 1H), 4.04 -
4.1 9 (m, 1H), 4.22 (d, J = 8.4 Hz, 1H), 4.34 (d, J = 8.4 Hz, 1H), 4.42 - 4.52 (m, 1H),
4.62 - 4.84 (m, 4H), 4.92 - 5.05 (m, 2H), 5.44 (s, 1H), 5.71 (d, J = 7.2 Hz, 1H), 5.76 -
5.86 (m, 1H), 5.91 (s, 1H), 6.01 (d, J = 8.7 Hz, 1H), 6.26 - 6.36 (distorted t or m, 2H),
6.50 - 6.68 (m, 2H), 7.35 - 7.68 (m, 11H), 7.76 (d, J = 7.5 Hz, 2H), 8.1 7 (d, J = 7.2 Hz,
2H) ; MS m/z 1123.4 [M+Na] +.
Example 36:
NO-Metronidazole Prodrug (I-HD2-L2-R1)
The title compound was synthesized in 3 steps as shown in Scheme 8 and the
experimental procedure is described below:
Step 1: Synthesis of (Z)-4-hydroxybut-2-enyl 2-(2-methyl-5-nitro-1 H-imidazol-1-yl)ethyl
carbonate (HD2-L2-OH)
CDI (3.1 g, 19.3 mmol) was added to a stirred suspension of metronidazole (3.0 g, 17.5
mmol) in 50 mL of DCM at RT under nitrogen and the mixture (after the addition of CDI,
the suspension slowly dissolved to form a clear solution in about 30 minutes) was
stirred at RT for 2.5 h when TLC of the mixture indicated formation of a new product.
The mixture was cooled to 0 °C. To this stirred mixture was added a solution of 2-
butene-1 ,4-diol (HO-L2-OH, 4.3 mL, 52.6 mmol) in DCM (25 mL) and the mixture was
stirred at RT for overnight and at 70 °C for 3 h when TLC analysis of the mixture
indicated formation of a new product. The mixture was diluted with 50 mL of DCM,
washed with water (2 x 30 mL), dried over anhydrous Na2S0 4 and concentrated on
rotavap to give 5.0 g of crude product which was purified by column chromatography
(50.0 g silica gel, 150-300 mesh, eluted with 2-5 % MeOH in DCM to afford the title
intermediate HD2-L2-OH as greenish oil. Yield: 4.2 g (84.3 %); 1H NMR (CDCI3, 300
MHz): 2.36 (t, J = 3.6 Hz, 1H), 2.50 (s, 3H), 4.23 (t, J = 3.6 Hz, 2H), 4.50 (t, J = 3.0
Hz, 2H), 4.60 (t, J = 3.0 Hz, 2H), 4.68 (d, J = 4.2 Hz, 2H), 5.57 - 5.66 (m, 1H), 5.87 -
5.94 (m, 1H), 7.96 (s, 1H); MS m/z. 286.1 [M+H] +, 308.1 [M+Na] +.
Step 2 : Synthesis of intermediate HD2-L2-R1-CI
o -Chloroethyl chloroformate (CI-R1-C1 , 0.8 mL, 7.7 mmol) was added drop-wise to a
solution of the intermediate HD2-L2-OH (2.0 g, 7.0 mmol) in 20 mL of DCM at 0 °C
under nitrogen. To this stirred mixture was added pyridine (0.8 mL, 9.6 mmol) over 5
minutes. The mixture was stirred under nitrogen for 1 h while allowing it to attain RT.
TLC analysis of the mixture indicated completion of the reaction. The mixture was
washed with water ( 1 x 20 mL) and dried over Na2S0 4 and concentrated on rotavap to
afford 2.9 g of the crude product as red oil which was purified by column
chromatography (34.0 g of silica gel, 150-300 mesh, eluted with DCM) to afford the title
intermediate HD2-L2-R1-CI as red oil. Yield: 2.3 g (83.2 %); 1H NMR (CDCI3, 300
MHz): 1.85 (d, J = 5.7 Hz, 3H), 2.53 (s, 3H), 4.51 (t, J = 4.8 Hz, 2H), 4.62 (t, J = 4.8
Hz, 2H), 4.74 (d, J = 5.7 Hz, 2H), 4.80 (s, 1H), 4.82 (d, J = 2.1 Hz, 1H), 5.75 - 5.93 (m,
2H), 6.43 (q, J = 6.0 Hz, 1H), 7.99 (s, 1H); MS () m/ 392.1 [M+H] +, 414.1 [M+Na] +.
Step 3 : Synthesis of NO-Metronidazole (I-HD2-L2-R1)
Silver nitrate (12.1 g, 7 1.3 mmol) was added to a solution of the intermediate HD2-L2-
R1-CI ( 1 .5 g, 3.8 mmol) in 30 ml of ACN and the mixture was refluxed in dark at -90
°C for 2 h and at RT for overnight. HPLC analysis of the mixture indicated complete
conversion. The mixture was cooled and filtered through celite. The filtrate was
concentrated and the residue was re-dissolved in DCM (-100 ml.) and filtered through
celite to remove the precipitated silver chloride. The filtrate was concentrated in vacuo
and the residue thus obtained was purified by column chromatography (50.0 g of silica
gel, 150-300 mesh, eluted with 20-80 % EtOAc in petroleum ether) to afford the title
compound (I-HD2-L2-R1) as red oil. Yield: 1.0 g (63.1 %); 1H NMR (CDCI3, 300 MHz): 
1.62 (d, J = 5.7 Hz, 3H), 2.53 (s, 3H), 4.51 (t, J = 4.8 Hz, 2H), 4.63 (t, J = 4.8 Hz, 2H),
4.73 (d, J = 5.4 Hz, 2H), 4.79 (d, J = 5.4 Hz, 2H), 5.75 - 5.95 (m, 2H), 6.94 (q, J = 5.7
Hz, 1H), 7.99 (s, 1H); MS () m/z 441 . 1 [M+Na]+.
Example 37:
NO-Zidovudine (I-HD3-L2-R1)
The above compound was synthesized as shown in Scheme 7 and the experimental
procedure is described below:
Diphosgene (0.1 g, 0.5 mmol) was added drop-wise to a stirred solution of (Z)-4-
hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1 , 0.2 g, 0.9 mmol, freshly
prepared as described in Example 4) and triethylamine (0.3 ml_, 1.8 mmol) in 5 ml of
DCM at 0 °C under nitrogen and the mixture was stirred for 30 minutes. The mixture
was concentrated in vacuo and the crude and dry CI-L2-R1 thus obtained was redissolved
in 5 ml of DCM and cooled to 0 °C under nitrogen. This cold solution was
added to a stirred solution of zidovudine (0.2 g, 0.9 mmol) and triethylamine (0.3 ml_,
1.8 mmol) in 5 ml of DCM at 0 °C and the mixture was stirred for 3 h when TLC
analysis of the mixture indicated formation of the product. The mixture was diluted with
10 mL of DCM and washed with water ( 1 x 10 ml.) and brine ( 1 x 10 ml_). The organic
layer was dried over Na2S0 4 and concentrated in vacuo to give a residue which was
purified by column chromatography on silica gel by eluting with MeOH/ DCM gradient to
afford the title compound I-HD3-L2-R1 as yellow oil. Yield: 0.1 g (42.0 %); 1H NMR
(CDCI3, 300 MHz): 1.63 (d mixed with water peak, J = 5.1 Hz, 3H), 1.93 (s, 3H), 2.35 -
2.57 (m, 2H), 4.05 - 4.12 (m, 1H), 4.29 (q, J = 5.7, 5.4 Hz, 1H), 4.44 (dq, J = 12.0, 2.7
Hz, 2H), 4.65 - 4.88 (mixed m, 4H), 5.83 - 6.05 (mixed m, 2H), 6.23 (t, J = 6.0 Hz, 1H),
6.95 (q, J = 5.7 Hz, 1H), 7.36 (s, 1H), 8.40 (br s, 1H); MS (El ) mlz 513.1 [M-H] .
The compound of example 38 was prepared by following the experimental procedure
described for preparing the compound of example 37. The characterization data for the
compound of example 38 is described below:
Example 38:
NO-Budesonide prodrug (I-HD4-L2-R1)
The title compound (I-HD4-L2-R1) was obtained as yellow semisolid. Yield: 8.2 %; 1H
NMR (CDCI3, 300 MHz): 0.83 - 1.08 (mixed m, 7H), 1.09 - 1.21 (m, 2H), 1.23 - 1.33
(m, 2H), 1.36 - 1.50 (m, 5H), 1.62 (d, 3H), 1.74 - 1.86 (m, 2H), 2.04 - 2.26 (mixed m,
4H), 2.32 - 2.38 (m, 1H), 2.53 - 2.64 (m, 1H), 4.48 - 4.66 (mixed m, 2H), 4.71 (s, 3H),
4.76 -5.05 (mixed m, 3H), 5.13 - 5.20 (m, 1H), 5.80 - 5.99 (mixed m, 2H), 6.04 (s, 1H),
6.29 (d, J = 10.2Hz, 1H), 6.95 (q, J = 5.7 Hz each, 1H), 7.24 (d, J = 3.6 Hz, 1H); MS
m/z: 678.3 [M+H] +
, 700.3 [M+Na] +
.
Example 39:
NO-Budesonide Prodrug (I-HD4-L20-R1)
The above compound was synthesized in 4 steps as shown in Scheme 10 and the
experimental procedure is described below:
Step 1: Synthesis of Intermediate HD4-L20-CHO
4-Formylbenzoic acid (HO2C-L20-CHO, 0.2 g, 1.4 mmol) followed by DCC (0.3 g, 1.4
mmol) and DMAP (0.056 g, 0.5 mmol) were added to a stirred solution of budesonide
(HD4, 0.5 g, 1.2 mmol) in dichloromethane (30 ml.) and the mixture was stirred at RT
for overnight. The mixture was filtered and the filtrate was washed with water ( 1 x 2
ml_), 1N HCI solution ( 1 x 2 ml_), brine ( 1 x 2 ml_), dried over anhydrous Na2S0 4 and
concentrated in vacuo to give 0.8 g of crude product as a semisolid which was purified
by column chromatography (40.0 g of silica gel, 200-400 mesh, eluted with 10-50 % of
ethyl acetate in petroleum ether) to afford the title Intermediate HD4-L20-CHO as a
white gum. Yield: 0.6 g (93.0 %); 1H NMR (CDCI3, 300 MHz): 0.97 (t, J = 7.5 Hz, 3H),
1.05 (d, J = 12.0 Hz, 3H), 1. 1 1 - 1.33 (m, 4H), 1.38 - 2.32 (m, 13H), 2.35 (d, J = 2.7 Hz,
-0.4H), 2.40 (d, J = 2.7 Hz, -0.6H), 2.60 (dt, J = 13.5, 12.6, 5.1 , 4.2 Hz, 1H), 4.56 (br s,
1H), 4.72 (t, J = 4.5 Hz, 0.5H), 4.89 (d, J = 4.5 Hz, 0.5H), 5.05 (d, J = 13.2 Hz, -0.2H),
5.1 1 (d, J = 12.9 Hz, -0.8H), 5.1 5 - 5.25 (m, 2H), 6.06 (br s, 1H), 6.30 (t, J = 1. 8 Hz,
-0.5H), 6.33 (t, J = 2.1 Hz, -0.5H), 7.29 (d, J = 9.9 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H),
8.26 (d, J = 8.4 Hz, 2H), 10.14 (s, 1H).
Step 2 : Synthesis of intermediate HD4-L20-OH
Sodium borohydride (0.008 g, 0.2 mmol) was added to a stirred solution of aldehyde
intermediate HD4-L20-CHO (0.3 g, 0.5 mmol) in 3 mL of THF at 0 °C and the mixture
was stirred at 0 °C for 30 minutes. The reaction mixture was poured into 5 mL of ice
cold 1N HCI solution (5 mL) and extracted with ethyl acetate (2 x 5 mL). The organic
layer was washed with brine ( 1 x 2 mL), dried over anhydrous Na2S0 4 and
concentrated in vacuo to give 0.45 g of crude product as yellow oil which was purified
by column chromatography (25.0 g of silica gel, 150-300 mesh, eluted with 10-60 %
ethyl acetate in petroleum ether) to afford the title HD4-L20-OH as white gum. Yield:
0.3 g (94.0 %); 1H NMR (CDCI3, 300 MHz): 0.97 (t, J = 7.2 Hz, 3H), 1.05 (d, J = 12.0
Hz, 3H), 1. 1 1 - 1 .35 (m, 3H), 1.27 (s, 3H), 1.38 - 1.53 (m, 2H), 1.48 (s, 3H), 1.55 - 2.42
(m, 8H), 2.60 (dt, J = 13.8, 5.1 Hz, 1H), 4.55 (br s, 1H), 4.71 (t, J = 4.8 Hz, 0.5H), 4.81
(unsymmetrical d, J = 5.1 Hz, 2H), 4.90 (unsymmetrical d, J = 4.2 Hz, 0.5H), 4.98 (d, J
= 13.2 Hz, -0.3H), 5.04 (d, J = 12.9 Hz, -0.7H), 5.12 - 5.25 (m, 2H), 6.05 (s, 1H), 6.29
(t, J = 1 .8 Hz, -0.5H), 6.32 (t, J = 1.8 Hz, -0.5H), 7.29 (d buried under chloroform
singlet, J = 8.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 8.08 (d, J = 8.1 Hz, 2H); MS m/z:
565.3 [M+H] +.
Step 3 : Synthesis of intermediate HD4-L20-R1-CI
o -Chloroethyl chloroformate (CI-R1-CI, 0.063 g, 0.44 mmol) was added drop-wise to a
stirred solution of the alcohol intermediate HD4-L20-OH (0.250 g, 0.44 mmol) and
pyridine (0.035 g, 0.44 mmol) in 2 mL of DCM at 0 °C under nitrogen. The mixture was
stirred under nitrogen for 30 minutes while allowing it to attain RT. TLC analysis of the
mixture indicated completion of the reaction. The mixture was diluted with 5 mL of DCM
and washed with water ( 1 x 2 mL) and brine ( 1 x 2 mL) and dried over Na2S0 4 and
concentrated in vacuo to afford 0.370 g of the crude product which was purified by
column chromatography (20.0 g of silica gel, 150-300 mesh, eluted with 5-30 %of
EtOAc in petroleum ether) to afford the title intermediate HD4-L20-R1-CI as colorless
oil. Yield: 0.246 g (82.0 %); 1H NMR (CDCI3, 300 MHz): 0.97 (t, J = 7.2 Hz, 3H), 1.05
(d, J = 12.0 Hz, 3H), 1. 1 1 - 1.33 (m, 4H), 1.38 - 1.83 (m, 9H), 1.86 (d, J = 5.7 Hz, 3H),
1.89 - 2.43 (m, 5H), 2.60 (dt, J = 13.8, 5.1 Hz, 1H), 4.56 (br s, 1H), 4.70 (t, J = 4.5 Hz,
0.5H), 4.89 (unsymmetrical d, J = 4.5 Hz, 0.5H), 5.00 (d, J = 12.6 Hz, -0.3H), 5.06 (d, J
= 12.3 Hz, -0.7H), 5.1 2 - 5.24 (m, 2H), 5.31 (d, J = 5.4 Hz, 2H), 6.05 (s, 1H), 6.29 (t, J
= 1.8 Hz, -0.5H), 6.33 (t, J = 1.8 Hz, -0.5H), 6.46 (q, J = 5.7 Hz, 1H), 7.29 (d buried
under chloroform singlet, J = 7.2 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 8.1 1 (d, J = 8.1 Hz,
2H); MS m/z: 671 .3 [M+H]+.
Step 4 : Synthesis of NO-Budesonide (I-HD4-L20-R1)
Silver nitrate (0.8 g, 0.4 mmol) was added to a stirred solution of the chloro intermediate
HD4-L20-R1-CI (0.2 g, 0.3 mmol) in 2 mL of ACN and the mixture was refluxed in dark
at -70-75 °C for 2 h. HPLC analysis of the mixture indicated complete conversion. The
mixture was cooled, diluted with 5 mL of DCM and filtered through celite. The filtrate
was concentrated and the residue thus obtained (-0.3 g) was purified by column
chromatography (20.0 g of silica gel, 150-300 mesh, eluted with 5-30 % EtOAc in
petroleum ether) to afford the title compound (I-HD4-L20-R1) as white gum. Yield: 0.2 g
(88.0 %); 1H NMR (CDCI3, 300 MHz): 0.97 (t, J = 7.5 Hz, 3H), 1.05 (d, J = 12.0 Hz,
3H), 1. 1 1 - 1.33 (m, 3H), 1.38 - 1.54 (m, 3H), 1.48 (s, 3H), 1.55 - 2.27 (m, 11H), 2.35 (d,
J = 3.3 Hz, -0.4H), 2.39 (d, J = 2.7 Hz, -0.6H), 2.60 (dt, J = 13.5, 12.6, 5.1 , 4.2 Hz,
1H), 4.56 (br s, 1H), 4.71 (t, J = 4.8 Hz, 0.5H), 4.89 (d, J = 4.5 Hz, 0.5H), 5.00 (d, J =
12.6 Hz, -0.2H), 5.06 (d, J = 12.6 Hz, -0.8H), 5.12 - 5.24 (m, 2H), 5.28 (s, 2H), 6.05 (br
s, 1H), 6.29 (t, J = 1.8 Hz, -0.45H), 6.33 (t, J = 1.8 Hz, -0.55H), 6.96 (q, J = 5.7 Hz
each, 1H), 7.30 (d, overlapped with chloroform singlet, 1H), 7.48 (d, J = 8.4 Hz, 2H),
8.1 1 (d, J = 8.1 Hz, 2H); MS m/z 698.3 [M+H]+.
The compounds of examples 40 - 42 were prepared by following the experimental
procedure described for example 39. The characterization data for the compounds of
examples 40-42 is described below:
Example 40:
NO-Paclitaxel prodrug (I-HD1-L20-R1)
The title compound (I-HD1-L20-R1) was obtained as a yellow solid. Mp: 117-1 19 °C;
Yield (last step): 63.0 %; 1H NMR (300 MHz, CDCI3) : 1. 16 (s, 3H), 1.20 (s, 3H), 1.27
(s, 1H), 1.62 (d, overlapped with water signal, 3H), 1.68 (s, 3H), 1.94 (s, 3H), 2.02 (s,
1H), 2.1 1 - 2.23 (m, 1H), 2.20 (s, 3H), 2.29 - 2.43 (m, 3H), 2.54 (s, 3H), 3.72 (dd, J =
11.4, 3.3 Hz, 1H), 3.94 (d, J = 7.5 Hz, 1H), 4.37 - 4.40 (m, 2H), 4.72 (d, J = 11.4 Hz,
1H), 4.95 (dd, J = 9.0, 3.6 Hz, 1H), 5.28 (s, 2H), 5.72 - 5.80 (m, 2H), 6.08 (dd, J = 9.0,
3.9 Hz, 1H), 6.25 (t, J = 7.5 Hz, 1H), 6.84 (s, 1H), 6.96 (q, J = 5.7 Hz, 1H), 7.07 (d, J =
9.3 Hz, 1H), 7.32 - 7.58 (m, 12H), 7.61 - 7.69 (m, 1H), 7.77 (d, J = 7.2 Hz, 2H), 8.00 (d,
J = 8.1 Hz, 2H), 8.1 6 (d, J = 7.2 Hz, 2H); MS m/z 112 1 .4 [M+H] +, 1138.4 [M+NH4]+,
1143.4 [M+Na] +
Example 4 1 :
4-Acetamidophenyl 4-(((1-(nitrooxy)ethoxy)carbonyloxy)methyl)benzoate [NOParacetamol
(HD5-L20-R1)]
The title compound (HD5-L20-R1) was obtained as a white solid. Mp: 149-152 °C; Yield
(last step): 65.0 %; 1H NMR (300 MHz, CDCI3) : 1.63 (d, J = 5.4 Hz, doublet partially
overlapped with water signal, 3H), 2.20 (s, 3H), 5.31 (s, 2H), 6.97 (q, J = 5.7 Hz, 1H),
7.1 8 (d, J = 8.7 Hz, 2H), 7.37 (br s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.7 Hz,
2H), 8.22 (d, J = 8.4 Hz, 2H); MS m/z: 4 17.1 [M-H] , 4 19.1 [M+H] +.
Example 42:
(1-((2'-(1 H-Tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1 H-imidazol-5-
yl)methyl 4-(((1 -(nitrooxy)ethoxy)carbonyloxy)methyl)benzoate [NO-Losartan
(HD6-L20-R1)]
The title compound (HD6-L20-R1) was obtained as a pale yellow solid. Mp: 107-109
°C; Yield (last step): 64.0 %; 1H NMR (300 MHz, CDCI3) : 0.88 (t, J = 7.5 Hz, 3H), 1. 15
- 1 .35 (m, 4H), 1.57 (d, J = 5.7 Hz, 3H), 2.47 (t, J = 7.8 Hz, 2H), 4.96 (s, 4H), 5.10 (s,
2H), 6.56 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 7.8 Hz, 2H), 6.91 (q, J = 5.7 Hz, 1H), 7.12 (d,
J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.30 - 7.38 (m, 2H), 7.39 - 7.60 (m, 2H), 7.1 7
(d, J = 8.7 Hz, 2H); MS m/z 688.1 [M-H] , 690.2 [M+H]+.
Example 43
Pharmacokinetic data for the compounds of the invention
Representative compounds of formula (I) of the present invention that are the nitric
oxide releasing prodrugs of known drugs or therapeutic agents, were subjected to
pharmacokinetic study and the method and results of the study are presented herein
below:
General Procedures:
The oral pharmacokinetic profile of the compounds of the invention was studied in
male Sprague-Dawley rats. For the purpose of the study, the nitric oxide releasing
prodrugs of a drug containing a carboxylic acid functional group, e.g. naproxen that is
encompassed in the compounds of formula (I), was selected. The release profile of
naproxen from said nitric oxide releasing prodrugs was analysed using a HPLC
system.
Animals:
Male Sprague-Dawley rats weighing 150-220 g were used in the study. The rats were
fed normal standard laboratory chow and maintained under standard environmental
conditions (room temperature of 22 ± 2 °C; 50 ± 10 % relative humidity;12 hrs lightdark
cycle.). All experimental procedures mentioned below were approved by the
institutional animal ethics committee and were performed in accordance with standard
guidelines of Committee for the purpose of control and supervision of experiments on
animals (CPCSEA), Govt of India for the experiment on animals.
HPLC Sample preparation and standard curve:
HPLC: Waters Alliance analytical HPLC equipped with 2996 PDA detector and
Empower software were used to analyze the samples.
HPLC Column: Waters X-Terra RP-18 reversed phase column, 150 X 3.9 mm, 5 
HPLC Method:
Flow: 1 ml/min,
detector set at 2 10 nm and at Maxplot (210-400 nm range).
Solvent A: Acetonitrile;
Solvent B: 0.1% TFA in water.
Injection volume : 20 
Elution method: A linear gradient as specified below:
Blood samples were collected from the rats and the plasma was separated by
centrifugation at 1000xg for 5 min at 4°C. A stock solution of naproxen was prepared
by dissolving it in acetonitrile and working solutions of various concentrations (0.625,
1.25, 2.5, 5, 10, 20 g/ml) were prepared by spiking the blood plasma with the
naproxen stock solution. Each plasma sample (50 ) was then transferred to a
microcentrifuge tube containing acetonitrile (200 ) , mixed by vortex and centrifuged
for 5 min (1000xg) at 4°C. The supernatant layer (150 ) obtained after centrifugation
was then transferred to HPLC vials. The sample solution (25 ) was then injected in
to HPLC for analysis. A linear calibration curve between the naproxen concentration
in plasma (0.625, 1.25, 2.5, 5, 10, 20 g/ml) and the peak area ratio was obtained.
The rats were divided in to six groups of three each. Naproxen (10 mg/kg) was
administered orally to one group of rats and the representative compounds of formula
(I) i.e. the nitric oxide releasing prodrugs of naproxen (I-CD1 -L1-R1 , I-CD1 -L2-R1 , ICD1-
L3-R1 , I-CD1-L4-R1 , I-CD1-L1 6-R1 , I-CD1-L17-R1 and I-CD1-L18-R1 ) (at a
dose containing 10 mg/kg of naproxen) were administered orally to the remaining
groups. Blood was collected from orbital plexus of the rats according to a specific
schedule (0.25, 0.5, 1, 2, 4, 6 and 8 h after dosing) and the plasma was separated
from each sample by centrifugation for 5 min ( 1000xg) at 4 °C. Each collected plasma
sample (50 ) corresponding to naproxen and the aforementioned nitric oxide
releasing prodrugs of naproxen was then transferred to a microcentrifuge tube
containing acetonitrile (200 ) , mixed by vortex and centrifuged for 5 min (1000xg) at
4°C. The supernatant layer ( 150 ) obtained after centrifugation was then transferred
to HPLC vials. A (25 ) volume of each sample solution was injected in to HPLC for
analysis. The peak area values obtained for each of the plasma samples was
compared with the naproxen standard curve to determine the plasma concentration of
naproxen in rats after oral administration of naproxen and each of the nitric oxide
releasing prodrugs of naproxen. The plasma concentration of naproxen in rats after
oral administration of naproxen and each of the nitric oxide releasing prodrugs of
naproxen versus time intervals was plotted and the area under the curve was
determined by trapezoidal rule (Gibaldi, M. and Perrier, D., Pharmacokinetics, Second
edition, 15:445-447) for each of the samples corresponding to naproxen and nitric
oxide releasing prodrugs of naproxen. The AUC values for the nitric oxide releasing
prodrugs of naproxen presented in Table 1 indicate that said prodrugs release a
substantial amount of naproxen parent drug in the rat plasma.
Table 1
Pharmacokinetic study data
All the compounds were administered per oral at 10mg/kg equivalent dose of naproxen.
Example 44
Estimation of nitrate / nitrite release from the compounds of the invention in
plasma:
Male Sprague-Dawley rats (180-220 g) were acclimatized for a week and fasted 12-
14 hours prior to the commencement of the experiment. The representative
compounds of formula (I) i.e. the nitric oxide releasing prodrugs of naproxen (I-CD1-
L 1-R1 , I-CD1-L2-R1 , I-CD1-L4-R1 , and I-CD1-L18-R1) (at a dose of 10 mg/kg of
naproxen) were administered orally to the rats. The blood sample was collected from
the rats administered with each of the aforementioned nitric oxide releasing prodrugs
of naproxen according to a specific schedule (0.5, 1, 2, 4, 6 and 8 hours) and the
plasma was separated by centrifugation ( 1000xg) for 5 min at 4°C. The release
profile of the nitrate/nitrite in the blood plasma which is an indirect measure of the
nitric oxide released in the blood plasma was measured using Griess method by
employing colorimetric nitrate/nitrite assay kit from Fluka.
The blood plasma samples were filtered using Millipore ultra-filtration 96-well plate to
remove the plasma proteins having particle size of > 10 kDa. The assay was
performed in a 96-well plate according to standard procedure described in the kit. The
method comprised adding to the well, standard (sodium nitrate) (80 ) of various
concentrations (0, 20, 40, 60, 80 and 100 ) followed by the reagents, nitrate
reductase (10 ) and enzyme co-factor ( 10 ) . The plasma sample (80 ) obtained
from the blood sample collected at various time intervals from the rats (0.5, 1, 2, 4, 6
and 8 hours) were added to separate wells, followed by the reagents, nitrate
reductase ( 10 ) and enzyme co-factor ( 10 ) . The plate was incubated for 2 h at
room temperature on orbital shaker (350-400 rpm). Griess reagent A (50 ) was
added to each well followed by incubation for 5 min and subsequently, Griess reagent
B (50 ) was added to each well followed by incubation for 10 min. The absorbance
of assay plate was measured by using a 96-well plate reader (Bio-Tek instruments) at
540 nm. This procedure was carried out for each of the aforementioned nitric oxide
releasing prodrugs of naproxen separately. A standard curve between the sodium
nitrate concentration () (0, 20, 40, 60, 80 and 100 ) on X-axis versus
absorbance values on Y-axis was plotted. The absorbance values of each of the
plasma samples collected at different time intervals corresponding to the
aforementioned nitric oxide releasing prodrugs of naproxen from the rats was
compared with the standard curve to determine the plasma nitrate concentration in
mice after oral administration of the aforementioned nitric oxide releasing prodrugs of
naproxen. The plasma nitrate concentration in rats after oral administration of the the
aforementioned nitric oxide releasing prodrugs of naproxen versus time intervals was
plotted and the area under the curve was determined for each of the samples
corresponding to the aforementioned nitric oxide releasing prodrugs of naproxen as
presented in the following Table 2. The results indicate that significant amounts of
nitric oxide is released in the blood plasma by administering the aforementioned nitric
oxide releasing prodrugs of naproxen.
Table 2
Estimation of nitrate / nitrite release from the compounds of the invention in
plasma
All the compounds were administered per oral at 10mg/kg equivalent dose of naproxen.
Example 45
Determination of the anti-inflammatory activity of the compounds of the
invention
The anti-inflammatory activity of naproxen and the nitric oxide releasing prodrug of
naproxen, I-CD1-L2-R1 was assessed in carrageenan-induced rat paw edema model
according to the procedure described in Takeuchi et al., J. Pharmacol. Exp. Ther.
1998, 286 (1), 115-1 2 1) . Male Sprague-Dawley rats were divided into three groups of
ten each. Naproxen (5 mg/kg) and the nitric oxide releasing prodrug of naproxen, ICD1-
L2-R1 (at a dose containing 5 mg/kg of naproxen), were dissolved in PEG 400
and administered orally to overnight fasted rats of different groups. One hour later,
carrageenan (100 , 1% w/v) was injected in to their paws. The control group
received PEG 400 ( 1 ml/kg). The paw volume of the group of rats administered with
naproxen and those administered with naproxen prodrug were measured before
carrageenan injection and also at a time period of 3 and 5 hours after the
carrageenan was injected. The (%) inhibition of paw edema in rats administered with
naproxen and the nitric oxide releasing prodrug of naproxen, I-CD1 -L2-R1 after 3 and
5 hours respectively were calculated as compared to the control group and presented
in Table 3. The results indicate that the nitric oxide releasing prodrug of naproxen, ICD1-
L2-R1 exhibited anti-inflammatory activity comparable to that of naproxen in the
carrageenan-induced rat paw edema model.
Ulcerogenic activity
The ulcerogenic potential of the nitric oxide releasing prodrug of naproxen, ICD1-
L2-R1 in rats was assessed. Naproxen ( 100 mg/kg) and the nitric oxide
releasing prodrug of naproxen, I-CD1 -L2-R1 (at a dose containing 100 mg/kg of
naproxen) was administered to overnight fasted rats of different groups. The animals
were sacrificed after 5 h of drug administration. The stomachs of the animals treated
were separated, perfused with 2 % formalin ( 10 ml), and then a large curvature was
excised. The severity of the mucosal damage was assessed on the basis of the size
of the observed ulcer lesions in the images captured using a stereomicroscope
attached to a digital camera (Stemi 2000, Zeiss, Germany). The Image Pro Plus
software (version 5.1) was used to quantify the hemorrhagic/ulcer lesions in pixels
and converted into mm2. The total area of lesions were calculated for each treatment
group and the measure of gastric ulcers (Mean± SEM) (mm2) presented in Table 3.
The results indicate that none of the animals treated with the nitric oxide releasing
prodrug of naproxen, I-CD1-L2-R1 showed any signs of development of ulcers.
However, severe haemorrhagic lesions were found in rats administered with
naproxen.
Table 3
Data : Anti-inflammatory and ulcerogenic activity of naproxen and I-CD1-L2-R1
Mean ± SEM, n = 8
Example 46
AMES Genotoxicity Assay:
AMES test or bacterial reverse mutation test uses five mutant strains (i.e., TA98,
TA100, TA1535, TA1537, TA102) of Salmonella typhimurium to test the mutagenicity
of chemical substances (Kristien Mortelmans and Errol Zeiger, The Ames
Sa/mone//a/microsome mutagenicity assay, Mutation Research 2000, 455, 29-60 and
the relevant reference cited therein). These mutants are called his mutants because
of their dependence on an external source of histidine to grow. The test also uses one
trp mutant strain WP2 uvrA (which needs external supply of tryptophan for its growth)
of Escherichia coli (Kristein Mortelmans and Edward S. Riccio, The bacterial
tryptophan reverse mutation assay with Escherichia coli WP2, Mutation Research
2000, 455, 61-69 and the relevant references cited therein). If the bacteria are
incubated in the presence of a mutagen, a reverse mutation is induced, and the
bacteria will grow. However, if the chemical substance is not mutagenic, there will be
no reversion and thus no growth. The result is thus obtained in the absence of
metabolic activation. Because many chemicals that are poor mutagens become
potent mutagens after they have passed through the liver, homogenate of rat liver,
called the S9 extract, are added to the bacteria before incubation. The bacteria/S9
mixture is then plated on a medium containing no histidine (use of tryptophandeficient
medium in case of E. coli strain), and the test chemical is placed in the
center of the plate. The result is thus obtained in the presence of metabolic activation.
A second plate that contains a non-mutagenic solvent as a negative control and a
third plate that contains a known mutagen as a positive control are also run
simultaneously. All the 3 types of plates (each type of plate, in fact, run
simultaneously in triplicate for obtaining statistically significant data) are incubated for
48 hours at 37 °C. The above procedure is called the plate incorporation method. The
presence of numerous colonies of revertants in the test disk indicates a positive
result: that is, the chemical substance is a mutagen (i.e., mutagenic if the increase in
revertants is >2 fold for TA98, TA100, TA102 and WP2/uvrA or >3 fold for TA1535
and TA1537). Also, a positive result would be considered reliable when there is a
dose-dependent increase in revertants at any two consecutive non-toxic
concentrations which can be in the range of 10-5000 g/plate. The presence of only a
few spontaneous revertant colonies indicates a negative result. If a negative or
equivocal result is obtained, the pre-incubation method is performed in which the cells
are exposed to the test compounds for 30 min before plating. Also, before Ames test
is initiated, a toxicity test on the chemical substance is performed using TA1 00 strain
in the concentration range of 10-5000 g/plate. The above Ames mutagenicity test is
initiated only when the test substance is non-toxic to TA1 00 in the concentration
range of 10-5000 g/plate. When the test substance is found to be toxic at higher
concentration range then the genotoxicity of that material is tested only in the no n
toxic lower concentration range.
When the nitric oxide releasing prodrugs of naproxen, (I-CD1 -L1-R1 , I-CD1-L2-R1 , ICD1-
L4-R1 , I-CD1 -L1 6-R1 and I-CD1 -L1 8-R1 ) were subjected to AMES test in AMES
mutagenicity assay, said prodrugs were found to be non-toxic to TA100 and nonmutagenic
in all the aforementioned six bacterial strains in the concentration range of
10-5000 g/plate. The corresponding data is presented in the following Table 4.
Table 4
Genotoxicity data
All the compounds were administered per oral at 10mg/kg equivalent dose of naproxen.
2Salmonella strains TA 100, TA98, TA 1535, TA 1537 and TA 102 and Escherichia coli strain WP2 uvrA
were used; ND = Not Determined.
Example 47
ln-vitro aspirin release study of NO-aspirin prodrugs
The test compounds were dissolved in acetonitrile to get a concentration of 200 mM
which was used as stock solution. Blood samples were obtained from rats or humans in
heparinized centrifuge tubes. Plasma was separated by centrifugation of blood samples
at 8000 rpm at 4 °C. The plasma samples collected were stored at -20 ° till use.
Plasma samples were incubated at 37 ° in an incubator-shaker. The reaction mixture
(2000 ) consisted of the compound stock solution (10 ) spiked into the plasma
sample ( 1990 _) to obtain a final compound concentration of 2 mM. Aspirin at
concentration of 2 mM was used as standard control. At different time points after
addition of compound viz., 2, 5, 10, 20, 40 and 60 min, 60 of sample was removed
from the reaction mixture. The samples were added to 200 of acetonitrile and
vortexed for 1 min followed by centrifuging at 12,000 rpm for 15 min. The supernatant
obtained was subjected to HPLC analysis to determine the amount of aspirin and
salicylate in the samples. The HPLC analysis gave the amount () of aspirin and
salicylate present in the samples at their respective time-points. The percent release of
aspirin was calculated based on the initial concentration (2 mM) of the compound in the
reaction mixture versus the amount of aspirin released at different time-points.
Table 5
ln-vitro aspirin release data of NO-aspirin prodrugs
Compound Plasma sample % Release (max) Time
I-CD2-L15-R1-A Rat 16.24 10 min
I-CD2-L15-R1-A Human 20.84 10 min
I-CD2-L15-R1-B Rat 10.28 10 min
I-CD2-L15-R1-B Human 12.53 20 min
Claims:
1. A compound of formula (I), all its stereoisomeric forms or a pharmaceu
acceptable salt thereof;
wherein,
D independently represents a drug comprising of one or more of the functional groups
selected from a carboxylic acid, an amino, a hydroxyl or a sulfhydryl group that are
capable of forming a covalent bio-cleavable linkage with a bio-cleavable linker
represented by the formula (IA):
(IA)
wherein,
X1 is a bond, O, S, or NR3;
X2 is a bond, O or NR3;
R3 is a bond or H;
Y is C=0 or a spacer group selected from:
wherein:
R4 is a bond, H, alkyl or a metal ion;
R5 is H, C-1-6 alkyl or phenyl;
R6 is H or a group selected from:
-CH 3, -CH(CH 3)2, -CH 2CH(CH 3)2, -CH(CH 3)CH 2CH3, -CH 2C0 2H, -CH 2CH2C0 2H, -
CH2OH, -CH(CH 3)OH, -CH 2SH, -CH 2CH2SCH3, -CH 2CH2CH2CH2NH2, -C6H5, -
CH2C6H5 -CH 2C6H4-p-OH, -CH 2CH2CH2NHC(=NH)NH 2, -CH 2C(=0)NH 2, -
CH2CH2C(=0)NH 2, -CH 2-indol-3-yl or -CH 2-imidazole;
X3 is O, S, SO, S0 2 or NR3 ;
R7 is H or a group selected from: acetyl, benzoyl, alkyloxycarbonyl,
benzyloxycarbonyl, 9-fluorenylmethyloxy carbonyl or its pharmaceutically
acceptable ammonium salts;
R8 is H or Ci-6 alkyl;
c is an integer from 0 to 2 ;
d is an integer from 1 to 5 ;
e is an integer from 1 to 4 ;
Z 1 represents (CH 2)a ; where a is an integer from 0 to 3;
Z2 represents (CH 2)b ; where b is an integer from 0 to 3;
A is selected from a bond, S , SO, S0 2, S-S, CH=CH, 1,2-phenylene, 1,3-phenylene,
1,4-phenylene, 2,3-pyridine, 3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkylene, CR R10 , C6-C 0-
arylene, a 5- or 6-membered heteroarylene or a 5- or 6-membered heterocyclylene
wherein, said arylene, heteroarylene and heterocyclylene may be unsubstituted or
substituted by one or more substituent(s) independently selected from the group
consisting of C _6 alkyl, C alkoxy, hydroxyl, trifluoromethyl, cyano, amino and halogen;
R and R10 are independently selected from: H or C -6 alkyl; or R and R10 taken
together with the carbon atom to which they are attached form a cycloalkyi or a
heterocyclic ring;
R1 is H; and R2 is alkyl, cycloalkyi, aryl or aralkyl; or
R2 is H; and R1 independently is alkyl, cycloalkyi, aryl or aralkyl;
with the provisos that:
c) when A represents S, then a and b independently represent 3; or
d) when A represents D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then
a and b independently represent 0.
2. The compound according to claim 1, wherein,
D is a drug containing a carboxylic acid group that is capable of forming a bio-cleavable
covalent linkage with the linker of formula (IA);
X2 is O;
R1 is H and R2 is Ci-6 alkyl; or
R2 is H and R1 is C1-6 alkyl;
X1 is a bond;
Y is C=0 or a spacer group selected from:
where R4 is a bond, H, alkyl or a metal ion; R5 is H, C -6 alkyl or phenyl;
A is selected from a bond, S, SO, S0 2, S-S, CH=CH , 1,2-phenylene, 1,3-phenylene,
1,4-phenylene, 2,3-pyridine, 3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkylene and CR R10, where
R and R10 independently represent H or C -6 alkyl; with the provisos that:
e) when A is S, then a and b is 3; or
f) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0.
3. The compound according to claim 1 or claim 2, wherein D, the drug containing a
carboxylic acid group, is selected from anti-inflammatory and analgesic agents,
cardiovascular agents, anti-allergic agents, anti-cancer agents, anti-depressants, ant i
convulsant agents, anti-bacterial agents, anti-fungal agents, anti-viral agents, ant i
malarial agents, anti-diabetic agents, anti-ulcer agents, anti-oxidants or vitamins.
4. The compound according to claim 3, wherein the anti-inflammatory and analgesic
agent is selected from opioids, steroids (glucocorticoids) or non-steroidal ant i
inflammatory drugs (NSAIDs).
5. The compound according to claim 4, wherein the anti-inflammatory and analgesic
drug is selected from aceclofenac, acemetacin, acetamidocaproic acid,
acetylsalicylsalicylic acid, actarit, alclofenac, 3-alminoprofen, amfenac, 3-amino-4-
hydroxybutyric acid, aspirin (acetylsalycilic acid), balsalazide, bendazac, benoxaprofen,
bromprofen, bromfenac, 5-bromosalicylic acid acetate, bucloxic acid, bumadizone,
butibufen, carprofen, cinchophen, cinmetacin, clidanac, clometacin, clonixin, clopirac,
diacerein, diclofenac, diflunisal, dipyrocetyl, enfenamic acid, enoxolone, etodolac,
felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentiazac, flufenamic acid,
flunoxaprofen, fluocortolone-21-acid, flurbiprofen, fosfosal, gentisic acid, ibufenac,
ibuprofen, indomethacin, indoprofen, isofezolac, isoxepac, ketoprofen, ketorolac,
lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, mesalamine, metiazinic
acid, mofezolac, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, pirazolac,
pirprofen, pranoprofen, protizinic acid, salicysulfuric acid, salicylamide o-acetic acid,
salsalate, sulfasalazine, sulindac, suprofen, suxibuzone, tiaprofenic acid, tolfenamic
acid, tolmetin, tropesin, ximoprofen, zaltoprofen or zomepirac.
6. The compound according to claim 3, wherein the cardiovascular agent is an ant i
hypertensive agent selected from: angiotensin converting enzyme (ACE) inhibitors,
beta-blockers, sartans (angiotensin I I blockers), anti-thrombotic and vasoactive agents,
anti-hyperlipidemic drugs (including HMG-CoA-reductase inhibitors i.e., statins),
fibrates, anti-anginal agents, anti-arrhythmic agents, anti-hypotensive agents, calcium
channel blockers, cardiotonic agents, cardioprotective agents, diuretics or vasodilators.
7. The compound according to claim 6, wherein the cardiovascular agent is selected
from acifran, acipimox, acetylsalicylic acid, alacepril, gama-aminobutyric acid,
angiotensin, argatroban, atorvastatin, benazepril, benfurodil hemisuccinate, beraprost,
bezafibrate, bumetanide, candesartan, capobenic acid, captopril, carmoxirole,
ceronapril, cerivastatin, chromocarb, cilazapril, ciprofibrate, clinofibrate, clofibric acid,
dalteparin, daltroban, delapril, dextrothyroxine, eicosapentaenoic acid, eledoisin,
enalapril, enalaprilat, enoxaparin, eprosartan, ethacrynic acid, fluvastatin, fosinopril,
furosemide, gemfibrozil, iloprost, imidapril, indobufen, isbogrel, heparin, lamifiban,
limaprost, lisinopril, lotrafiban, meglutol, melagatran, mercamphamide, mercaptomerin
sodium, mercumallylic acid, mersalyl, methyldopa, moexipril, moveltipril, nadroparin,
omapatrilat, ozagrel, oxiniacic acid, perindopril, piretanide, pitavastatin, pravastatin
sodium, prostaglandin Ei quinapril, ramipril, ramiprilate, reviparin sodium salt, ridogrel,
sampatrilat, saralasin, satigrel, spirapril, taprostene, telmisartan, temocapril, thyropropic
acid, ticrynafen, tinzaparin, tirofiban, trandolapril, triflusal, valsartan, xanthinol niacinate
or xenbucin.
8. The compound according to claim 3, wherein the anti-allergic agent is selected from
steroidal bronchodilators, mast cell stabilizers or anti-histamines.
9. The compound according to claim 8, wherein the anti-allergic agent is selected from
acrivastine, amlexanox, bepotastine, cetirizine, fexofenadine, levocetirizine,
lodoxamide, montelukast sodium, nedocromil, olopatadine, pentigetide or tranilast.
10. The compound according to claim 3, wherein the anti-cancer agent is selected from:
acitretin (etretin), aminolevulinic acid, amsilarotene, butyric acid, eflornithine
hydrochloride, melphalan, methotrexate, minodronate (minodronic acid), retinoic acids
(including 13-cis retinoic and all trans-retinoic acids), sulindac, tamibarotene or valproic
acid.
11. The compound according to claim 3, wherein the antidepressant is selected from
anti-maniacs and anti-psychotics.
12. The compound according to claim 11, wherein the antidepressant is selected from
amineptine, gabapentin, 5-hydroxytryptophan (oxitriptan), pregabalin, tianeptine,
valproic acid or vigabatrin.
13. The compound according to claim 3, wherein the anticonvulsant is selected from
carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, licarbazepine,
oxcarbazepine, pregabalin, topiramate, valpromide, vigabatrin, or zonisamide.
14. The compound according to claim 3, wherein the anti-bacterial is selected from:
acediasulfone, amdinocillin, p-aminosalicylic acid, amoxicillin, amphomycin, ampicillin,
apalcillin, apicycline, aspoxicillin, azidocillin, azlocillin, aztreonam, bacitracin,
balofloxacin, benzoylpas, benzylpenicillin, betamipron, biapenem, carbenicillin,
carindacillin, carumonam, cefaclor, cefadroxil, cefalexin, cefamandole, cefatiam,
cefatrizine, cefazedone, cefazolin, cefbuperazone, cefclidin, cefdinir, cefditoren,
cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime,
cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam,
cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefroxadine, cefsulodin,
ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefprozil,
cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine,
cephalosporin C, cephalothin, cephapirin sodium, cephradine, cilastatin, cinoxacin,
ciproflaxacin, clavulinic acid, clavulanate, clinafloxacin, clometocillin, cyclacillin,
dicloxacillin, difloxacin, enoxacin, epicillin, ertapenem, fenbenicillin, fleroxacin, flomoxef,
floxacillin, flumequine, fosfomycin, fropenem, fusidic acid, garenoxacin, gatifloxacin,
gemifloxacin, grepafloxacin, hetacillin, hydnocarpic acid, imipenem, lomefloxacin,
loracarbef, lymecycline, merbromin, meropenem, metampicillin, methicillin, mezlocillin,
miloxacin, moxalactam, moxifloxacin, nadifloxacin, nafcillin, nalidixic acid, negamycin,
noprysulfamide, norfloxacin, ofloxacin, opiniazide, oxacillin, oxolinic acid, panipenem,
pazufloxacin, pefloxacin, penicillin(s), penimepicycline, phenethicillin,
phthalylsulfacetamide, phthalylsulfathiazole, pipemidic acid, piperacillin, piromidic acid,
propicillin, prulifloxacin, quinacillin, ritipenem, rosoxacin, rufloxacin,
salazosulfadimidine, salbactam, sitafloxacin, sparfloxacin, succinylsulfathiazole,
succisulfone, sulbenicillin, sulfachrysoidine, sulfaloxic acid, 4-sulfanilamidosalicylic acid,
sulfanilic acid, tazobactam, teicoplanin, temocillin, ticarcillin, tigemonam, tosufloxacin,
trovafloxacin, tyrocidine or vancomycin.
15. The compound according to claim 3, wherein the antifungal agent is selected from:
amphotericin B, azaserine, benzoic acid, candicidin, lucensomycin, natamycin, nystatin,
propionic acid, salicylic acid or undecylenic acid (10-undecenoic acid).
16. The compound according to claim 3, wherein the antiviral agent is selected from
foscarnet sodium or zanamivir.
17. The compound according to claim 3, wherein the anti-malarial agent is artesumate.
18. The compound according to claim 3, wherein the antidiabetic agent is selected from
mitiglinide, nateglinide or repaglinide.
19. The compound according to claim 3, wherein, the anti-ulcer agent is selected from:
acetoxolone, arbaprostil, carbenoxolone, cetraxate, ecabet, S-methylmethionine,
proglumide, rebamipide, rosaprostol, rotraxate, sofalcone or trimoprostil.
20. The compound according to claim 3, wherein the anti-oxidant is selected from: o -
lipoic acid, L-Carnitine, N-acetyl L-cysteine, N-acetyl carnosine, raxofelast, tetomilast or
SCMC-Lys (S-carboxymethyl-L-cysteine Lysine salt. H20).
2 1 . The compound according to claim 3, wherein the vitamin is selected from: biotin
(vitamin H or coenzyme R), folic acid (vitamin M), menadoxime, nicotinic acid (niacin),
pantothenic acid or vitamin B5 (a member of the B complex vitamins).
22. The compound according to claim 1, wherein,
D is a drug containing an amino group that is capable of forming a bio-cleavable
covalent linkage with the linker of formula (IA);
X2 is O;
R1 is H and R2 is C1-6 alkyl; or
R2 is H and R1 is Ci -6 alkyl;
X1 is NR3, where R3 is H or a bond;
Y is C=0 or a spacer group:
o
wherein, R4 represents a bond , H or a metal ion;
A is selected from a bond, S, SO, S0 2, S-S, CH=CH, 1,2-phenylene, 1,3-phenylene,
1,4-phenylene, 2,3-pyridine, 3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkylene or CR R10 , where R
and R10 independently represent H or C _6 alkyl with the provisos that:
g) when A is S, then a and b is 3; or
h) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0.
23. The compound according to claim 1 or claim 22 wherein D, the drug containing an
amino group is selected from: anti-inflammatory and analgesic agents, cardiovascular
agents, anti-allergic agents, anti-cancer agents, anti-depressants, anti-convulsant
agents, anti-bacterial agents, anti-fungal agents, anti-viral agents, anti-malarial agents,
anti-diabetic agents, anti-ulcer agents, anti-oxidants or vitamins.
24. The compound according to claim 23, wherein, the anti-inflammatory and analgesic
drug is selected from: opioids, steroids (glucocorticoids) or non-steroidal ant i
inflammatory drugs (NSAIDs).
25. The compound according to claim 24, wherein the anti-inflammatory and analgesic
drug is selected from: aceclofenac, acetaminophen, acetaminosalol, actarit,
alminoprofen, amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid,
ampiroxicam, aminopropylon, anileridine, antrafenine, benorylate, benzpiperylon, pbromoacetanilide,
bromfenac, bucetin, bucolome, bufexamac, bumadizone, butacetin,
capsaicine, carprofen, carsalam, celecoxib, clonixin, dezocine, diclofenac, difenamizole,
difenpiramide, enfenamic acid, etersalate, ethenzamide, ethoxazene, etodolac,
etofenamate, fepradinol, flipirtine, floctafenine, flufenamic acid, glafenine, ibuproxam,
isoladol, isonixin, isoxicam, p-lactophenetide, lornoxicam, meclofenamic acid,
mefenamic acid, meloxicam, mesalamine, mofebutazone, nifenazone, niflumic acid,
nimesulide, norlevorphanol, normorphine, oxametacine, paranyline, parecoxib,
parsalmide, phenacetin, phenazopyridine, phenocoll, phenopyrazone, phenylramidol,
piketoprofen, piminodine, piperylone, piroxicam, piritramide, propacetamol,
ramifenazone, salverine, salacetamide, salicylamide, salicylamide o-acetic acid,
sulfasalazine, talniflumate, tenidap, terofenamate, tinoridine, tenoxicam, tolfenamic acid
and valdecoxib.
26. The compound according to claim 23, wherein the cardiovascular agent is an ant i
hypertensive agent selected from: angiotensin converting enzyme (ACE) inhibitors,
beta-blockers, sartans (angiotensin I I blockers), anti-thrombotic and vasoactive agents,
anti-hyperlipidemic drugs (including HMG-CoA-reductase inhibitors i.e., statins),
fibrates, anti-anginal agents, anti-arrhythmic agents, anti-hypotensive agents, calcium
channel blockers, cardiotonic agents, cardioprotective agents, diuretics or vasodilators.
27. The compound according to claim 26, wherein the cardiovascular agent is selected
from: acadesine, acebutolol, acecainide, adenosine, alacepril, alfuzosin, alprenolol,
althiazide, amanozine, ambuside, amezinium methyl sulfate, amiloride, gamaaminobutyric
acid, aminometradine, 2-amino-4-picoline, amisometradine, amiodipine,
amosulalol, amrinone, angiotensin, aranidipine, argatroban, arotinolol, atenolol,
azosemide, bamethan, barnidipine, benazepril, bendazol, bendroflumethiazide,
benfluorex, benidipine, benzalbutyramide, benzylhydrochlorothiazide, benzthiazide,
betahistine, bethanidine, betaxolol, bevantolol, bidisomide, bisoprolol, bopindolol,
bosentan, bradykinin, bucindolol, bucladesine, bucumolol, budralazine, bufeniode,
bufetolol, bufuralol, bumetanide, bunazosin, bunitrolol, bupranolol, butalamine,
butazolamide, buthiazide, butidrine, butofilolol, cadralazine, candesartan, capobenic
acid, carazolol, cariporide, carmoxirole, caronapril, carteolol, carvedilol, celiprolol,
cetamolol, chloraminophenamide, chlorazanil, chlormerodrin, chlorothiazide,
chlorthalidone, ciclosidomine, cifenline, cilazapril, cilnidipine, cilostazol, clofenamide,
clonidine, clopamide, cloranolol, clorexolone, cyclopenthiazide, cyclothiazide,
debrisoquin, delapril, denopamine, diazoxide, dihydralazine, dilevalol, dimetofrine,
disopyramide, disulfamide, dobutamine, docarpamine, dofetilide, dopamine,
dopexamine, doxazosin, droprenilamine, edeserpidine, efonidipine, eledoisin,
elgodipine, enalapril, enalaprilat, encainide, endralazine, enoxaparin, enoximone,
epanolol, erythrophleine, esmolol, ethiazide, ethoxzolamide, etifelmin, etilefrin,
etiroxate, fasudil, felodipine, fendiline, fenoldopam, fenquizone, flecainide, furosemide,
gepefrine, guanabenz, guanacline, guanazodine, guanethidine, guanochlor, guanadrel,
guanfacine, guanoxabenz, guanoxan, heptaminol, hydracarbazine, hydralazine,
hydrochlorothiazide, hydroflumethiazide, ibopamine, imidapril, imolamine, indapamide,
indecainide, indenolol, indoramin, irbesartan, isoxsuprine, isradipine, itramin tosylate,
kallidin, ketanserin, labetalol, lacidipine, lamifiban, landiolol, lercanidipine,
levosimendan, lidoflazine, lisinopril, lofexidine, loprinone, losartan, lotrafiban,
manidipine, mebutamate, mecamylamine, mefruside, melagatran, meobentine,
mephentermine, mepindolol, metaraminol, methazolamide, methoxamine,
methyclothiazide, methyldopa, methyl 4-pridyl ketone thiosemicarbazone, meticrane,
metipranolol, metolazone, metoprolol, mexiletine, mibefradil, midodrine, milrinone,
minoxidil, moexipril, molsidomine, monatepil, moprolol, moricizine, moveltipril,
moxonidine, muzolimine, nadolol, nadoxolol, nebivolol, nicardipine, nicorandil,
nifedipine, nifenalol, nilvadipine, nimodipine, nipradilol, nisoldipine, nitrendipine,
norepinephrine, nylidrin, olmesartan, oxprenolol, oxyfedrine, pamabrom, paraflutizide,
penbutolol, pentisomide, perhexiline, perindopril, pheniprazine, phentolamine,
pholedrine, picotamide, pildralazine, pilsicainide, pimefylline, pimobendan, pinacidil,
pindolol, piretanide, plafibride, polythiazide, practolol, prazosin, prenalterol,
prenylamine, procainamide, pronethalol, propafenone, propranolol, quinapril,
quinethazone, ramipril, ranolazine, raubasine, rescimetol, rescinnamine, reserpiline,
reserpine, rilmenidine, roxifiban, sampatrilat, saralasin, sematilide, sotalol, spirapril,
sulfinalol, sulmazole, suloctidil, synephrine, syrosingopine, talinolol, tasosartan,
teclothiazide, temocapril, terazosin, terodiline, tertatolol, theobromine, tiamenidine,
tilisolol, timolol, tinofedrine, tirofiban, tocainide, todralazine, tolazoline,toliprolol,
tolonidine, torsemide, trandolapril, triamterene, trichlormethiazide, trimazosin,
trimetazidine, tripamide, urapidil, valsartan, vesnarinone, viquidil, xamoterol,
xemilofiban, xibenolol, ximelagatran or xipamide.
28. The compound according to claim 23, wherein the anti-allergic agent is selected
from steroidal bronchodilators, mast cell stabilizers or anti-histamines.
29. The compound according to claim 28, wherein the anti-allergic agent is selected
from: amlexanox, antazoline, astemizole, bambuterol, cetoxime, clobenzepam,
desloratadine, epinastine, mizolastine, oxatomide, pemirolast, pentigetide, pifatidine
(roxatidine acetate hydrochloride), repirinast, salbutamol, salmeterol, suplatast,
tazanolast, tranilast, tritoqualine or traxanox.
30. The compound according to claim 23, wherein, the anti-cancer agent is selected
from: 9-aminocamptothecin, aminolevulinic acid, 3-aminopyridine-2-carboxaldehyde
thiosemicarbazone (3-ap),3-aminopyridine-4-methyl-2-carboxaldehyde thiosemicarbazone
(3-amp/triapine/ocx-1 91/ocx-0191), amsacrine, ancitabine, anthramycin,
azacitidine, bicalutamide, bisantrene, bleomycins, bropirimine, buserelin, carboplatin,
carboquone, carmofur, carmustine, carubicin, chlorozotocin, cisplatin, cladribine,
cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine,
defosfamide, demecolcine, diaziquone, 6-diazo-5-oxo-l-norleucine (don), docetaxel,
doxorubicin, ecteinascidins, edatrexate, efaproxiral, eflornithine, eniluracil, epirubicin,
erlotinib, fluorouracil, gefitinib, gemcitabine, goserelin, histamine, hydroxyurea,
idarubicin, ifosfamide, imatinib, improsulfan, lanreotide, leuprolide, liarozole, lobaplatin,
lomustine, lonafarnib, mannomustine, marimastat, melphalan, 6-mercaptopurine,
methotrexate, methyl aminolevulinate, miboplatin, mitoguazone, mitoxantrone,
nilutamide, nimustine, nolatrexed, oxaliplatin, pemetrexed, pentostatin, peplomycin,
perfosfamide, phenamet, pirarubicin, piritrexim, prinomastat, procarbazine, puromycin,
raltitrexed, tariquidar, temozolomide, thiamiprine, thioguanine, tiazofurin, tipifarnib,
tirapazamine, troxacitabine, trimetrexate, uracil mustard (uramustine), vindesine or
zorubicin.
3 1 . The compound according to claim 23, wherein, the antidepressant is selected from
an anti-maniac or anti-psychotic agent.
32. The compound according to claim 3 1, wherein, the antidepressant is selected from:
S-adenosylmethionine, amineptine, amisulpride, amoxapine, aripiprazole, benperidol,
caroxazone, carpipramine, clocapramine, clomacran, clospirazine, clozapine,
demexiptiline, desipramine, droperidol, duloxetine, fencamine, fluoxetine, fluspirilene,
fluvoxamine, 5-hydroxytryptophan (oxitriptan), indalpine, indeloxazine hydrochloride,
iproclozide, iproniazid, isocarboxazid, levophacetoperane, maprotiline, metapramine,
milnacipran, minaprine, moclobemide, molindone, mosapramine, nemonapride,
nialamide, nomifensine, nortriptyline, octamoxin, olanzapine, oxypertine, paroxetine,
pimozide, pipamperone, protriptyline, reboxetine, remoxipride, rolipram, roxindole,
sertindole, sertraline, spiperone, sulpiride, sultopride, tianeptine, timiperone, tofenacin,
tranylcypromine, viloxazine, benmoxine, rolicyprine or ziprasidone.
33. The compound according to claim 23, wherein the anticonvulsant is selected from:
acetylpheneturide, albutoin, 4-amino-3-hydroxybutyric acid, atrolactamide, n-benzyl-3-
chloropropionamide, buramate, carbamazepine, cinromide, clonazepam, decimemide,
dimethadione, doxenitoin, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin,
lamotrigine, levetiracetam, licarbazepine, mephenytoin, mephobarbital, metharbital,
methetoin, 5-methyl-5-(3-phenanthryl)hydantoin, 3-methyl-5-phenylhydantoin,
nitrazepam, oxcarbazepine, oxicarbamazepine, phenacemide, phenetharbital,
pheneturide, phenobarbital, phenylmethylbarbituric acid, phenytoin, phethenylate
sodium, pregabalin, primidone, progabide, remacemide, rufinamide, suclofenide,
sulthiame, talampanel, tetrantoin, topiramate, valpromide, vigabatrin or zonisamide.
34. The compound according to claim 23, wherein the anti-bacterial is selected from:
acedapsone, acediasulfone, acetosulfone sodium, ambazone, amikacin, paminosalicylic
acid, p-aminosalicylic acid hydrazide, amoxicillin, amphomycin,
ampicillin, apalcillin, apicycline, arbekacin, aspoxicillin, azidamfenicol, azidocillin,
azlocillin, aztreonam, bacampicillin, bacitracin, balofloxacin, bambermycins,
benzoylpas, benzylsulfamide, betamipron, brodimoprim, 5-bromosalicylhydroxamic
acid, butirosin, capreomycin, carbenicillin, carindacillin, carumonam, cefaclor,
cefadroxil, cefamandole, cefatiam, cefatrizine, cefazedone, cefazolin, cefbuperazone,
cefdinir, cefcapene pivoxil, cefclidin, cefditoren, cefepime, cefetamet, cefixime,
cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide,
cefoselis, cefotaxime, cefotetan, cefotiam, cefoxitin, cefozopran, cefpimizole,
cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin,
ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,
cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine,
cephalosporin c, cephalothin, cephapirin sodium, cephradine, chloramine-B,
chloramine-T, chloramphenicol, chlortetracycline, cilastatin, ciproflaxacin, clinafloxacin,
clindamycin, clometocillin, clomocycline, cloxacillin, colistin, cyacetacide, cyclacillin,
cycloserine, dalfopristin, dapsone, demeclocycline, deoxydihydrostreptomycin,
dibekacin, dicloxacillin, dihydrostreptomycin, dirithromycin, doxycycline, enoxacin,
enviomycin, epicillin, ertapenem, ethambutol, ethionamide, fenbenicillin, flomoxef,
floxacillin, N2- forimicins, formylsulfisomidine, furazolium chloride, furonazide,
garenoxacin, gatifloxacin, gemifloxacin, gentamycin, glyconiazide, n4-beta-dglucosylsulfanilamide,
gramicidin(s), grepafloxacin, guamecycline, hetacillin, imipenem,
isepamicin, isoniazid, kanamycin(s), lenampicillin, lincomycin, linezolide, lomefloxacin,
loracarbef, lymecycline, mafenide, meclocycline, meropenem, metampicillin,
methacycline, methicillin, 4'-(methylsulfamoyl)sulfanilanilide, mezlocillin, micronomicin,
mikamycin, minocycline, morphazinamide, moxalactam, moxifloxacin, nafcillin,
negamycin, neomycin, netilmicin, nifuradene, nitrofurantoin, noprysulfamide,
norfloxacin, novobiocin, opiniazide, oxacillin, oxytetracycline, panipenem,
paromomycin, pazufloxacin, penamecillin, penethamate hydriodide, penicillin(s),
penimepicycline, pexiganan, phenethicillin, phenyl aminosalicylate,
phthalylsulfacetamide, phthalylsulfathiazole, picloxydine, pipacycline, pipemidic acid,
piperacillin, pivampicillin, pivcefalexin, polymyxin, porfiromycin, primycin, pristinamycin,
protionamide, pyrazinamide, quinacillin, quinupristin, ramoplanin, ribostamycin,
rifabutin, rifalazil, rifamide, rifamycin sv, rifampin, rifapentine, rifaximin, ristocetin,
ritipenem, rolitetracycline, salazosulfadimidine, salinazid, sancycline, sisomicin,
sitafloxacin, solasulfone, sparfloxacin, spectinomycin, streptolydigin, streptomycin,
streptonicozid, subathizone, 4,4'- succinylsulfathiazole, succisulfone, sulbenicillin,
sulfachrysoidine, sulfanilic acid, 2-p-sulfanilylanilinoethanol, sulfinyldianiline, sulfoxone
sodium, 4'-sulfanilylsulfanilamide, sulfoniazide, sulfabenzamide, sulfacetamide,
sulfachlorpyridazine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine,
sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfaloxic acid,
sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,
sulfamethoxazole, sulfamethoxypyridazine, sulfamethylthiazole, sulfametrole,
sulfamidochrysoidine, sulfamoxole, sulfanilamide, 4-sulfanilamidosalicylic acid, psulfanilylbenzylamine,
sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfaperine,
sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfasomizole, sulfasymazine,
sulfathiazole, sulfathiourea, sulfisomidine, sulfisoxazole, sultamicillin, sulfanamide,
talampicillin, taurolidine, teicoplanin, temocillin, tetroxoprim, thiamphenicol,
thiazosulfone, thiacetazone, thiostrepton, ticarcillin, tigemonam, tiocarlide, tobramycin,
tosufloxacin, trimethoprim, trospectomycin, trovafloxacin, tuberactinomycin, tyrocidine,
vancomycin, viomycin or virginiamycin.
35. The compound according to claim 23, wherein the antifungal agent is selected from:
acrisorcin (9-aminoacrindine compound with 4-hexylresorcinol ( 1 :1)), amphotericin B,
anidulafungin, azaserine, bromosalicylchloranilide, buclosamide, candicidin,
caspofungin, chlordantoin, exalamide, flucytosine, loflucarban, lucensomycin, magenta
I, mepartricin, micafungin, natamycin, nystatin, perimycin, pyrrolnitrin, salicylanilide or
tubercidin.
36. The compound according to claim 23, wherein, the antiviral agent is selected from
abacavir, acyclovir, adefovir, amantadine, amidinomycin, amprenavir, atazanavir,
atevirdine, capravirine, cidofovir, delavirdine, didanosine, dideoxyadenosine, efavirenz,
emtricitabine, entecavir, famciclovir, ganciclovir, imiquimod, indinavir, lamivudine,
lopinavir, mantadine, methisazone, 5-(methylamino)-2-deoxyuridine (madu),
moroxydine, nelfinavir, nevirapine, oseltamivir, penciclovir, resiquimod, ribavirin,
rimantadine, ritonavir, saquinavir, stallimycin, tenofovir, tipranavir, trimetazidine,
tromantadine, valacyclovir, valganciclovir, vidarabine, zalcitabine or zanamivir.
37. The compound according to claim 23, wherein, the antimalarial agent is selected
from amodiaquine, chlorguanide, chloroquine, chlorproguanil, cycloguanil,
hydroxychloroquine, mefloquine, 3-methylarsacetin, pamaquine, plasmocid,
primaquine, pyronaridine, quinocide or tafenoquine.
38. The compound according to claim 23, wherein, the antidiabetic agent is selected
from acetohexamide, buformin, carbutamide, chlorpropamide, fidarestat, glibornuride,
gliclazide, glimepiride, glipizide, gliquidone, glisoxepid, glyburide, glybuthiazol(e),
glybuzole, glyhexamide, glymidine, glypinamide, metformin, phenformin, pioglitazone,
repaglinide, rosiglitazone, tolazamide, tolbutamide, tolcyclamide, troglitazone or
voglibose.
39. The compound according to claim 23, wherein, the anti-ulcer agent is selected from:
aldioxa, benexate HCI, carbenoxolone, cetraxate, cimetidine, ebrotidine, ecabapide,
esaprazole, esomeprazole, famotidine, irsogladine, lafutidine, lansoprazole,
leminoprazole, S-methylmethionine, nizatidine, omeprazole, pantoprazole, pirenzepine,
polaprezinc, rabeprazole, ranitidine, rebamipide, rotraxate, roxatidine, telenzepine or
troxipide.
40. The compound according to claim 23, wherein the anti-oxidant is selected from:
BTX-51072 (4,4-dimethyl-3,4-dihydro-2H-1 ,2-benzoselenazine), carnosine, melatonin,
(+)-R-pramipexole, SCMC-Lys (S-carboxymethyl-L-cysteine Lysine salt H20), stobadine
or zeatin.
4 1. The compound according to claim 23, wherein the vitamin is selected from:
acetiamine (diacethiamine or D.A.T.), benfotiamine (s-benzoylthiamine monophosphate
or BTMP), biotin (vitamin H or coenzyme R), bisbentiamine (O-benzoylthiamine
disulfide), cetotiamine (0,S-dicarbethoxythiamine or DCET), cobamamide (vitamin B2
coenzyme), cyanocobalamin (vitamin B 2) , folic acid (vitamin M), fursultiamine
(thiamine tetrahydrofurfuryl disulfide), hydroxocobalamin (vitamin B 2a) , nicotinamide,
octotiamine, prosultiamine, thiamine (vitamin B or vitamin K5.
42. The compound according to claim 1, wherein,
D is a drug containing hydroxyl group that is capable of forming a bio-cleavable
covalent linkage with the linker of formula (IA);
X2 is O or bond;
R1 is H and R2 is C -6 alkyl; or R2 is H and R1 represents C -6 alkyl;
X1 is O;
Y is C=0;
A is selected from: a bond, S, SO, S0 2, S-S, CH=CH, 1,2-phenylene, 1,3-phenylene,
1,4-phenylene, 2,3-pyridine, 3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkylene and CR R10 ;
R and R10 independently represent H or C _6 alkyl;
with the provisos that:
i) when A is S, then a and b is 3; or
j) when A is D-isosorbide skeleton or 1,4-anhydroerythritol skeleton, then a and b
is 0.
43. The compound according to claim 1 or claim 42, wherein D the drug containing a
hydroxyl group is selected from: anti-inflammatory and analgesic agents, cardiovascular
agents, anti-allergic agents, anti-cancer agents, anti-depressants, anti-convulsant
agents, anti-bacterial agents, anti-fungal agents, anti-viral agents, anti-malarial agents,
anti-diabetic agents, anti-ulcer agents, anti-oxidants or vitamins.
44. The compound according to claim 43, wherein the anti-inflammatory and analgesic
drug is selected from: opioids, steroids (glucocorticoids) or non-steroidal antiinflammatory
drugs (NSAIDs).
45. The compound according to claim 44, wherein the anti-inflammatory and analgesic
drug is selected from: acetaminophen, acetaminosalol, 21-acetoxypregnenolone,
alclometasone, alfa-aluminum bis(acetylsalicylate), algestone, amcinonide, 3-amino-4-
hydroxybutyric acid, balsalazide, beclomethasone, benzylmorphine, betamethasone,
bisabolol, bucetin, budesonide, bufexamac, buprenorphine, butorphanol, capsaicine,
chlorobutanol, chloroprednisone, ciclesonide, ciramadol, clobetasol, clobetasone,
clocortolone, cloprednol, corticosterone, cortisone, codeine, deflazacort, diflorasone,
desomorphine, desonide, desoximetasone, dexamethasone, dezocine, diflorasone,
diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydromorphine,
dihydroxyaluminum acetylsalicylate, dimepheptanol, ditazol, enoxolone, eptazocine,
ethylmorphine, etofenamate, eugenol, fendosal, fepradinol, floctafenine, fluazacort,
fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fludrocortisone,
flumethasone, fluperolone acetate, fluprednidene acetate, fluprednisolone,
fluorometholone, flurandrenolide, fluticasone, formocortal, gentisic acid, glafenine,
glucametacin, halcinonide, halobetasol propionate, halometasone, halopredone
acetate, hydrocortamate, hydrocortisone, hydromorphone, hydroxypethidine,
ibuproxam, isoladol, isoxicam, ketobemidone, p-lactophenetide, levorphanol,
lornoxicam, loteprednol etabonate, mazipredone, medrysone, meloxicam,
meprednisone, meptazinol, mesalamine, metazocine, methylprednisolone, metopon,
mometasone furoate, morphine, nalbuphine, norlevorphanol, normorphine, olsalazine,
oxaceprol, oxametacine, oxycodone, oxymorphone, oxyphenbutazone, paramethasone,
pentazocine, perisoxal, piroxicam, phenazocine, phenoperidine, phenylramidol,
phenylsalicylate, prednicarbate, prednisolone, prednisolone 21-diethylaminoacetate,
prednisone, prednival, prednylidene, rimexolone, salacetamide, salicin, salicylamide,
salsalate, sulfasalazine, tenoxicam, tixocortol, tramadol, triamcinolone acetonide,
viminol or ximoprofen,
46. The compound according to claim 43, wherein the cardiovascular agent is an antihypertensive
agent selected from: angiotensin converting enzyme (ACE) inhibitors,
beta-blockers, sartans (angiotensin I I blockers), anti-thrombotic and vasoactive agents,
anti-hyperlipidemic drugs (including HMG-CoA-reductase inhibitors i.e., statins),
fibrates, anti-anginal agents, anti-arrhythmic agents, anti-hypotensive agents, calcium
channel blockers, cardiotonic agents, cardioprotective agents, diuretics orvasodilators.
47. The compound according to claim 46, wherein the cardiovascular agent is selected
from: acadesine, acebutolol, ajmaline, alprenolol, ambuside, amosulalol, angiotensin,
arotinolol, atenolol, atorvastatin, bamethan, benzarone, benziodarone, beraprost,
betaxolol, bevantolol, bisoprolol, bosentan, bradykinin, brovincamine, bucindolol,
bucumolol, bufeniode, buflomedil, bufuralol, bunitrolol, bupranolol, butofilolol,
cadralazine, calcifediol, calcitriol, canrenone (hydroxyl of its ketoxime), carazolol, Icarnitine
(levocarnitine), carteolol, carvedilol, celiprolol, cerivastatin, cetamolol,
chlorthalidone, chromocarb, cicletanine, clobenfurol, clobenoside, convallatoxin,
cyclandelate, denopamine, deslanoside, digitalin, dihydrotachysterol, dilevalol,
dimetofrine, diosmin, dobesilate calcium, dobutamine, dopamine, dopexamine, efloxate,
eledoisin, enoximone, epanolol, erythrophleine, escin, etafenone , ethacrynic acid,
etilefrin, ezetimibe, fenofibrate, fenoldopam, fluvastatin, furazabol, gepefrine, gitoxin,
guanoxabenz, heptaminol, ibudilast, ifenprodil, iloprost, indenolol, ipriflavone,
isosorbide, isoxsuprine, kallidin, khellin, labetalol, lanatosides, leucocyanidin,
levcromakalim, limaprost, losartan, lovastatin, meglutol, mannitol, mepindolol,
metaraminol, methoxamine, methyldopa, metipranolol, metoprolol, mevastatin,
midodrine, moprolol, nadolol, naftopidil, nebivolol, neriifolin, nicomol, nicotinyl alcohol,
nifenalol, nipradilol, norepinephrine, nylidrin, oleandrin, olmesartan, oxprenolol,
oxyfedrine, penbutolol, pentrinitrol, perhexiline, phenactropinium chloride,
phentolamine, pholedrine, pildralazine, pindolol, pirifibrate, pitavastatin, pravastatin
sodium, prenalterol, probucol, pronethalol, propranolol, proscillaridin, prostaglandin ei ,
protheobromine, protoveratrines, ouabain, quercetin, ranolazine, rescimetol,
resibufogenin, rutin sampatrilat, scillaren, scillarenin, simvastatin, sotalol,
spironolactone, sulfinalol, suloctidil, synephrine, talinolol, tertatolol, thyropropic acid,
ticrynafen, timolol, tinofedrine, toliprolol, tricromyl, trimazosin, troxerutin, ubiquinones,
vincamine, viquidil, xamoterol, xanthinol niacinate or xipamide.
48. The compound according to claim 43, wherein the anti-allergic agent is selected
from steroidal bronchodilators, mast cell stabilizers or anti-histamines.
49. The compound according to claim 48, wherein the anti-allergic agent is selected
from: amlexanox, bambuterol, beclomethasone, cetoxime, ciclesonide, ebastine,
fexofenadine, flunisolide, fluticasone and its approved esters, nhydroxyethylpromethazine
chloride, hydroxyzine, ibudilast, methyl prednisolone,
montelukast sodium, pentigetide, repirinast, roxatidine, salbutamol, salmeterol,
suplatast, terfenadine or tranilast.
50. The compound according to claim 43, wherein the anti-cancer agent is selected
from: aclacinomycins, ancitabine, anthramycin, arzoxifene, azacitidine, bicalutamide,
bleomycins, bropirimine, broxuridine, buserelin, calusterone, capecitabine, carubicin,
CC-1 065 (NSC 298223), chlorozotocin, chromomycins, cladribine, cytarabine,
daunorubicin, decitabine, defosfamide, diethylstilbestrol, docetaxel, doxifluridine,
doxorubicin, droloxifene, dromostanolone, ecteinascidins, enocitabine, epirubicin,
epitiostanol, estramustine, etanidazole, etoposide, fenretinide, flavopiridol, formestane,
fosfestrol, fulvestrant, gemcitabine, hydroxyurea, idarubicin, irinotecan, leuprolide,
marimastat, melengestrol, menogaril, 6-mercaptopurine, miltefosine, minodronate
(minodronic acid), mitobronitol, mitolactol, mopidamol, nitracrine, nogalamycin,
nordihydroguaiaretic acid (masoprocol), olivomycins, paclitaxel and other known
paclitaxel analogs, pentostatin, peplomycin, perfosfamide, pirarubicin, podophyllotoxin,
prinomastat, puromycin, ranimustine, resveratrol, roquinimex, rubitecan, seocalcitol,
streptonigrin, streptozocin, temoporfin, teniposide, tenuazonic acid, tiazofurin,
topotecan, troxacitabine, valrubicin, vinblastine, vincristine, vindesine, vinorelbine,
zorubicin or zosuquidar.
5 1 . The compound according to claim 43, wherein the antidepressant is selected from
anti-maniacs or anti-psychotics.
52. The compound according to claim 5 1, wherein, the antidepressant is selected from:
acetophenazine, S-adenosylmethionine, befloxatone, bromperidol, bupropion,
butaperazine, carphenazine, clopenthixol (c/s-isomer), clospirazine, dixyrazine,
fenpentadiol, fluanisone, flupentixol (c/s-form), fluphenazine, fluspirilene, haloperidol, 5-
hydroxytryptophan (oxitriptan), hypericin, melperone, moperone, mosapramine,
opipramol, penfluridol, pericyazine, perimethazine, perphenazine, pipamperone,
piperacetazine, pipotiazine, pyrisuccideanol, quetiapine, roxindole, spiperone,
sultopride, timiperone, toloxatone, tramadol, trifluperidol or venlafaxine.
53. The compound according to claim 43, wherein the anticonvulsant is selected from
4-amino-3-hydroxybutyric acid, atrolactamide, buramate or ganaxolone.
54. The compound according to claim 43, wherein the anti-bacterial is selected from:
amikacin, p-aminosalicylic acid, p-aminosalicylic acid hydrazide, amoxicillin, apalcillin,
apicycline, arbekacin, aspoxicillin, azidamfenicol, azithromycin, bambermycins,
benzoylpas, biapenem, 5-bromosalicylhydroxamic acid, butirosin, cefadroxil,
cefamandole, cefatrizine, cefbuperazone, cefdinir, cefminox, cefonicid, cefoperazone,
cefoselis, cefpiramide, cefprozil, chloramphenicol, chloroxylenol, chlorquinadol,
chlortetracycline, clofoctol, clomocycline, cloxacillin, cloxyquin, clarithromycin,
clindamycin, colistin, dalfopristin, demeclocycline, deoxydihydrostreptomycin,
diathymosulfone, dibekacin, dihydrostreptomycin, dirithromycin, doxycycline,
enviomycin, ertapenem, erythromycin and its ester derivatives, ethambutol, flomoxef,
forimicins, fropenem, fusidic acid, gentamycin, glyconiazide, glucosulfone sodium, n4-
beta-d-glucosylsulfanilamide, gramicidin(s), guamecycline, imipenem, isepamicin,
josamycin, kanamycin(s), leucomycins, lincomycin, lymecycline, meclocycline,
merbromin, meropenem, methacycline, micronomicin, midecamycins, mikamycin,
minocycline, miokamycin, moxalactam, nadifloxacin, neomycin, netilmicin, nifurpirinol,
nifurtoinol, nitroxoline, novobiocin, oleandomycin, oxytetracycline, panipenem,
paromomycin, phenyl aminosalicylate, pipacycline, polymyxin, primycin, pristinamycin,
quinupristin, ramoplanin, ribostamycin, rifabutin, rifalazil, rifamide, refampicin, rifamycin
sv, rifampin, rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin, rolitetracycline,
rosaramicin, roxarsone, roxithromycin, salazosulfadimidine, salinazid, sancycline,
sisomicin, spectinomycin, spiramycin, streptolydigin, streptomycin, streptonicozid,
sulfaloxic acid, 4-sulfanilamidosalicylic acid, 2-p-sulfanilylanilinoethanol, teicoplanin,
telithromycin, thiamphenicol, thiostrepton, tobramycin, trospectomycin,
tuberactinomycin, tyrocidine, vancomycin, viomycin, virginiamycin, xanthocillin or
xibornol.
55. The compound according to claim 43, wherein the antifungal agent is selected from:
acrisorcin (9-aminoacrindine compound with 4-hexylresorcinol ( 1 :1)), amphotericin B,
anidulafungin, bromosalicylchloranilide, buclosamide, candicidin, caspofungin,
chlorphenesin, ciclopirox, dermostatin, griseofulvin, filipin, fluconazole, fungichromin,
mepartricin, micafungin, natamycin, nystatin, lucensomycin, pecilocin, perimycin,
posaconazole, ravuconazole, rubijervine, salicylanilide, siccanin, 2,4,6-tribromo-mcresol,
tubercidin, viridian or voriconazole.
56. The compound according to claim 43, wherein the anti-viral agent is selected from
abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, didanosine,
dideoxyadenosine, edoxudine, emtricitabine, entecavir, floxuridine, ganciclovir,
idoxuridine, indinavir, kethoxal, lamivudine, lopinavir, 5-(methylamino)-2-deoxyuridine
(madu), nelfinavir, nevirapine, penciclovir, podophyllotoxin, resiquimod, ribavirin,
ritonavir, saquinavir, sorivudine, stavudine, tenofovir, tipranavir, trifluridine,
tromantadine, valganciclovir, vidarabine, zalcitabine, zanamivir or zidovudine.
57. The compound according to claim 43, wherein the anti-malarial agent is selected
from: amodiaquine, arteflene, artemisinin alcohol, bebeerines, cinchonidine, cinchonine,
dihydroartemisinin, fosmidomycin, gentiopicrin, halofantrine, hydroxychloroquine,
lumefantrine, mefloquine, pyronaridine, quinine or yingzhaosu A.
58. The compound according to claim 43, wherein the antidiabetic agent is selected
from acarbose, acetohexamide, miglitol, troglitazone and voglibose.
59. The compound according to claim 43, wherein the anti-ulcer agent is selected from
arbaprostil, enprostil, misoprostol, ornoprostil, gama-oryzanol A, plaunotol, rebamipide,
rioprostil, rosaprostol, spizofurone (i.e., hydroxyl of its oxime derivative), telenzepine,
teprenone (i.e., hydroxyl of its oxime derivative) or trimoprostil.
60. The compound according to claim 43, wherein the anti-oxidant is selected from : Nacetyl
carnosine, ascorbic acid, BN-82451 , L-carnitine (levocarnitine), curcumin,
dexanabinol , edaravone, (-) epigallocatechin gallate, emoxipin, hydroxytyrosol,
idebenone, luteolin, nicanartine, NZ-41 9, oxyresveratrol , probucol (including probucol
prodrugs such as AGI-1 067 and AGI-1 096), quercetin, reductic acid, silybin , SCMCLys,
tempol (4-hydroxy-tempo), alfa-tocopherol (vitamin E) or zeatin.
6 1 . The compound according to claim 43, wherein, the vitamin is selected from :
ascorbic acid, cobamamide (vitamin B2 coenzyme), cyanocobalamin (vitamin B 2) ,
ergosterol (provitamine D), fursultiamine (thiamine tetrahydrofurfuryl disulfide),
hydroxocobalamin (vitamin B12a) , 1 -hydroxycholecalciferol , (1 -hydroxyvitamin D3) ,
inositol (vitamin B complex), menadiol (dihydrovitamin K3) , menaquinones or vitamin K2
(hydroxyl of its ketoxime), methylcobalamin, octotiamine, pantothenic acid (vitamin B5) ,
phylloquinone (hydroxyl of its ketoxime), prosultiamine (dithiopropylthiamine or DTPT or
TPD), pyridoxine hydrochloride (vitamine B6 hydrochloride), pyridoxal 5-phosphate,
riboflavin (vitamin B2 or vitamin G or lactoflavin), riboflavin monophosphate (vitamin B2
phosphate), vitamin A, vitamin D2, vitamin D3, vitamin K5, thiamine (vitamin B^,
thiamine disulfide (vitamin - disulfide) or a-tocopherol (vitamin E supplement).
62. A compound according to claim 1, wherein :
D is a drug containing sulfhydryl group that is capable of forming a bio-cleavable
covalent linkage with the linker of formula (IA) ;
X2 is O;
R1 is H and R2 is C1-6 alkyl or R2 is H and R1 is C1-6 alkyl ;
X1 is S;
Y is C=0;
A is selected from a bond S, SO, S0 2, S-S, CH=CH , 1,2-phenylene, 1,3-phenylene,
1,4-phenylene, 2,3-pyridine, 3,4-pyridine, 2,4-pyridine, 2,5-pyridine, 2,6-pyridine, Disosorbide
skeleton, 1,4-anhydroerythritol skeleton, cycloalkylene or CR R10 ;
R and R10 independently represent H or C -6 alkyl ;
with the provisos that:
k) when A represents S, then a and b independently represent 3; or
I) when A represents D-isosorbide skeleton or 1,4-anhydroerythritol skeleton , then
a and b independently represent 0.
63. The compound according to claim 1 or claim 62, wherein D, the drug containing
sulfhydryl group is selected from cardiovascular agents or glucocorticoids.
64. The compound according to claim 63, wherein, the cardiovascular agent is selected
from captopril or omapatrilat.
65. The compound according to claim 63, wherein, the glucocorticoid is tixocortol.
66. A compound according to claim 1, wherein the biocleavable linker of formula
(IA) is selected from:
IA-L1 4-R1 IA-L1 5-R1
(Mixture of diastereomers) (Mixture of diastereomers)
IA-L1 8-R1 IA-L1 9-R1 or
* Point of attachment to a suitable drug residue.
67. The compound according to claim 1, wherein the compound of formula (I) is
selected from:
O CH3

I-CD1-L14-R1
Mixture of diastereomers)
Mixture of diastereomers)
Mixture of diastereomers)
229
230
HD6-L20-R1
68. A pharmaceutical composition comprising a therapeutically effective amount of the
compound of claim 1, or a pharmaceutically acceptable salt thereof and one or more of
pharmaceutically acceptable carriers, vehicles or diluents.
69. A pharmaceutical composition comprising a therapeutically effective amount of the
compound of claim 67, or a pharmaceutically acceptable salt thereof and one or more
of pharmaceutically acceptable carriers, vehicles or diluents.
70. A method of treating a disease or disorder in a human or mammal where a chronic,
sustained and selective release of the constituent drug or therapeutic agent D or nitric
oxide is beneficial; comprising administering to a mammal or a human in need of the
treatment a therapeutically effective amount of the compound of formula (I) as claimed
in claim 1.
7 1 . A method of treating a disease or disorder in a human or mammal where a chronic,
sustained and selective release of the constituent drug or therapeutic agent D or nitric
oxide is beneficial; comprising administering to said mammal a therapeutically effective
amount of the pharmaceutical composition as claimed in claim 68.
72. The compounds of formula (I) as claimed in any one of the preceeding claims 1 -
65 and 67 for use in the treatment of a disease or disorder where a chronic, sustained
and selective release of the constituent drug or therapeutic agent D or nitric oxide
contained in the compounds of formula (I) is beneficial.
73. The pharmaceutical composition according to claim 68 or 69 for use in the
treatment of a disease or disorder where a chronic, sustained and selective release of
the constituent drug or therapeutic agent D or nitric oxide contained in the compounds
of formula (I) is beneficial.
74. Use of the compounds of formula (I) as claimed in any one of the preceeding claims
1 to 65 and 67 for the treatment of a disease or disorder where a chronic, sustained
and selective release of the constituent drug or therapeutic agent D or nitric oxide
contained in the compounds of formula (I) is beneficial.
75. Use of the pharmaceutical composition as claimed in claim 68 or 69 for the
treatment of a disease or disorder where a chronic, sustained and selective release of
the constituent drug or therapeutic agent D or nitric oxide contained in the compounds
of formula (I) is beneficial.
76. Use of the compounds of formula (I) as claimed in any one of the preceeding claims
1 to 65 and 67 for the manufacture of medicaments for the treatment of a disease or
disorder where a chronic, sustained and selective release of the constituent drug or
therapeutic agent D or nitric oxide contained in the compounds of formula (I) is
beneficial.
77. Use of the pharmaceutical composition as claimed in claim 68 or 69 for the
manufacture of medicaments for the treatment of a disease or disorder where a
chronic, sustained and selective release of the constituent drug or therapeutic agent D
or nitric oxide contained in the compounds of formula (I) is beneficial.
78. A process for the preparation of a compound of formula (I), or a pharmaceutically
acceptable salt thereof,
I
wherein D is a drug containing a carboxylic acid group ; X1, Y, X2, Z1, A, Z2, R1 and R2
are as defined in claim 1;
wherein the process is selected from:
Process 1-1 : A) reacting an aldehyde Sa (R1-C(0)-R 2) with phosgene or its
equivalents in the presence of a base and a solvent to yield chloroformate of
formula X (wherein, R1 and R2 are as defined in claim 1);
O R
crX oArc
i
x
B) reacting a carboxyl-containing drug Da (D-COOH, appropriately protected if the
drug has any additional reactive functional groups) with a linker La (wherein, Z1, A
and Z2 are as defined in claim 1) in the presence of a coupling agent and a base in
a solvent to yield the intermediate alcohol of formula Ia (wherein, Z1, A and Z2 are as
defined in claim 1); or
0
z z2 i i z z2
HO^ ^OH D ^OH
converting the carboxyl-containing drug Da (appropriately protected if the drug has
any additional reactive functional groups) into its carboxyl halide, Da (D-COCI) and
reacting the resulting compound Da with the linker La (wherein, Z1, A and Z2 are as
defined in claim 1) in the presence of a base in a solvent to yield the intermediate
alcohol of formula la; or
reacting the carboxyl-containing drug Da (appropriately protected if the drug has any
additional reactive functional groups) with a base in a solvent to yield the
corresponding carboxylate salt of the drug, Da2 (D-COO M+) and reacting the
resulting Da2 with the linker of formula La ;
LG OR
al
wherein LG is a leaving group (LG) and R is as defined) in the presence of a base in
a solvent to yield the intermediate alcohol of formula la;
C) reacting the intermediate alcohol of formula la (as obtained in Step B above) with
the chloroformate X (obtained in step A above) in the presence of a base and a
solvent to obtain the intermediate of formula lai ;
o O R
R2
D' CI
wherein, Z1, A, Z2, R1 and R2 are as defined in claim 1;
D) optionally subjecting the intermediate of formula lai (as obtained in Step C
above) to nitration using silver nitrate (AgN0 3) in the presence of a solvent to yield
the compound of formula (I), and optionally, converting the compound of formula (I)
to its pharmaceutically acceptable salt;
Process 1-2: subjecting the compound of formula (I) (wherein A = S) (as obtained
in Process 1-1 above) to oxidation with an oxidizing agent in the presence of a
solvent to obtain the corresponding compound of formula (I) (wherein A = SO or
S0 2) , and optionally, converting the compound of formula (I) to its pharmaceutically
acceptable salt;
Process 1-3: A) reacting the chloroformate of formula X (as obtained in Step A of
Process 1-1 above) with the linker of formula La (as defined in Step B of Process 1- 1
above) in the presence of a base and a solvent to yield the linker intermediate of
formula La (wherein, Z1, A, Z2, R1 and R2 are as defined above).
B) subjecting the intermediate of formula La (as obtained in Step A above) to
nitration using silver nitrate in the presence of a solvent to yield the linker
intermediate of formula (wherein, Z1, A, Z2, R1 and R2 are as defined above).
O R
HO O O O
L
C) the carboxyl-containing drug Da is directly coupled with the linker intermediate of
formula La i (as obtained in Step A above) in the presence of a coupling agent; or the
reactive drug acid halide Da i (as obtained in Step B of Process 1-1) is coupled with
the linker intermediate La i (as obtained in Step A above) in the presence of a base
and in a solvent to yield the compound of formula (la ) , which is subjected to
nitration using silver nitrate in the presence of a solvent to yield the compound of
formula (I), and optionally converting the compound of formula (I) to its
pharmaceutically acceptable salt; or
the carboxyl-containing drug Da is directly coupled with the linker intermediate of
formula (as obtained in step B above) in the presence of a coupling agent or the
reactive drug acid halide Da (as obtained in Step B of Process 1-1) is coupled with
the linker intermediate (as obtained in step B above) in the presence of a base
and in a solvent to yield the compound of formula (I), and optionally converting the
compound of formula (I) to its pharmaceutically acceptable salt;
Process 1-4: A) reacting the linker of formula La (as defined in Step B of Process 1-
1 above) or the linker of formula Lb (wherein, X2 = NH; Z1, A and Z2 are as defined
above) with o -chloroacetyl chloride (ACAC) in the presence of a base and in a
solvent to obtain a chloroacetate of formula La2 or a chloroacetamide of formula Lb i
(wherein, X2, Z1, A and Z2 are as defined above).
A OH
H z Z2
Lb: X2 = NH
/ X A .OH
o
L : X2 = O
Lb : X2 = NH
B) coupling the drug carboxylate salt Da2 (as obtained in Step B of Process 1-1) with
the chloroacetate of formula La2 or the chloroacetamide of formula Lb i (as obtained
in Step A above) in the presence of a base and in a solvent to obtain an
intermediate compound of formula lb (wherein, X2, Z1, A and Z2 are as defined
above).
C) reacting the intermediate lb (as obtained in Step B above) with the chloroformate
X (as obtained in Step A of Process 1-1) in the presence of a base and in a solvent
to obtain the intermediate compound of formula Ibi (wherein, X2, Z1, A, Z2, R1 and
R2 are as defined above);
o
o o R
l
D) subjecting the intermediate compound of formula lbi (as obtained in Step C
above) to nitration using silver nitrate in a solvent to obtain the compound of formula
(I), and optionally converting the compound of formula (I) to its pharmaceutically
acceptable salt; or
Process 1-5: A) reacting a carboxyl-containing drug Da (appropriately protected if
the drug has any additional reactive functional groups) with a linker of formula Lc
(wherein, Z1, A and Z2 are as defined above) in the presence of a coupling agent
and in a solvent to obtain the intermediate of formula lc (wherein, Z1, A and Z2 are as
defined above);
or the drug acid halide Dai (as obtained in Step B of Process 1-1) is reacted with the
intermediate of formula Lc (wherein, Z1, A and Z2 are as defined above) in the
presence of a base and in a solvent to obtain the intermediate compound of formula
B) reducing the intermediate of formula lc (as obtained in Step A above) using a
reducing agent in the presence of a solvent to yield the intermediate compound lci
(wherein, Z1, A and Z2 are as defined above);
C) reacting the intermediate of formula I with the chloroformate X (as obtained in
Step A of Process 1- 1 above) in the presence of a base and in a solvent to obtain
the intermediate compound of formula \c (wherein, Z1, A, Z2, R1 and R2 are as
defined above);
D) subjecting the intermediate compound of formula lC2 (as obtained in Step C
above) to nitration using silver nitrate in the presence of a solvent to yield the
compound of formula (I), and optionally converting the compound of formula (I) to
its pharmaceutically acceptable salt.
79. A process for the preparation of a compound of formula (I), or a pharmaceutically
acceptable salt th
wherein D is a drug containing an amino, a hydroxyl or a sulfhydryl group; X1, Y, X2, Z1,
A, Z2, R1 and R2 are as defined in claim 1;
wherein the process is selected from:
Process 2-1 : A) reacting the linker of formula l
L
with phosgene or its equivalent in the presence of a base and in a solvent to obtain
the corresponding formyl halide of formula Le (wherein, Z1, A, Z2, R1 and R2 are as
defined in claim 1; LG is a leaving group);
B) reacting a drug containing an amino group Db (D-Y-X1H, wherein Y = a bond,
C=0 or S(0) 2; X1 = NR3, wherein R3 is a bond) or a drug containing a hydroxyl or
sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1 = O or S) with phosgene or its
equivalent in the presence of a base and a solvent to obtain the corresponding
reactive formyl halide of the drug of formula Dbi and Dc4 respectively wherein LG is a
leaving group; or reacting an amino-containing drug Db (D-Y-X1H, wherein Y = a
bond, C=0 or S(0) 2; X1 = NR3, wherein R3 is H) with phosgene or its equivalents in
the presence of a base and in a solvent to yield the corresponding isocyanate of
formula Db2 [wherein, Y = bond, C(=0) or S(0) 2, X1 = N];
C) reacting the drug containing an amino group Db (D-Y-X1H, wherein Y = a bond,
C=0 or S(0) 2; X1 = NR3, wherein R3 is a bond or H) or the drug containing a
hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1 = O or S) with the
compound of formula Le) (as obtained in step A above) to obtain the compound of
formula (I), and optionally converting the compound of formula (I) to its
pharmaceutically acceptable salt; or
reacting the carbonyl derivative of formula Db or Dc4 (as obtained in Step B above)
of the drugs Db and Dc respectively with the linker of formula in the presence of a
base and a solvent to obtain the compound of formula (I), and optionally converting
the compound of formula (I) to its pharmaceutically acceptable salt; or reacting the
reactive isocyanate derivative Db2 (as obtained in Step B above) of the drug Db with
the linker of formula in the presence of a base and a solvent to obtain the
compound of formula (I), and optionally converting the compound of formula (I) to its
pharmaceutically acceptable salt;
Process 2-2: A) selectively protecting one hydroxyl group of the linker La (as
defined in Step B of Process 1-1 above) with a suitable protecting group (PG ) to
yield the mono-protected linker of formula La2 (wherein, Z1, A and Z2 are as defined
above).
B) reacting the mono-protected linker of formula La2 (as obtained in step A above)
with phosgene or its equivalents in the presence of a base and in a solvent to obtain
the intermediate of formula La3 (wherein, Z1, A and Z2 are as defined above; LG is a
suitable leaving group, PG is a suitable protecting group).
C) reacting the drug containing an amino group Db (D-Y-X1H, wherein Y = a bond,
C=0 or S(0) 2; X1 = NR3, wherein R3 is a bond or H) or the drug containing a
hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein Y = a bond; X1 = O or S) with the
linker intermediate of formula La3 (as obtained in Step B above) in the presence of a
base and in a solvent to yield an intermediate of formula lf (wherein, X1, Z1, A and Z2
are as defined above, PG is a suitable protecting group).
D) removing the hydroxyl protecting group (PG ) from the intermediate of formula lf
(as obtained in step C above) to yield an intermediate of formula I (wherein, X1, Z1,
A and Z2 are as defined above).
E) reacting the intermediate of formula I (as obtained in step D above) with the
chloroformate of formula X
O R
c r o i
x
in the presence of a base and in a solvent to obtain the intermediate of formula lf2
(wherein, X1, Z1, A, Z2, R1 and R2 are as defined above).
F) subjecting the intermediate lf2 (as obtained in Step E above) to nitration using
silver nitrate in the presence of a solvent to yield the compound of formula (I), and
optionally converting the compound of formula (I) to its pharmaceutically acceptable
salt;
Process 2-3: A) reacting the formyl halide Db i or Dc4 (as obtained in Step B of
Process 2-1 above) with the compound of formula La ;
z z2
HO ^OH
L
wherein Z1, A and Z2 are as defined above, or with the compound of formula Lb ;
x2 OH
H z1 2
Lb
wherein Z1, A and Z2 are as defined above
in the presence of a base in a solvent to obtain the intermediate of formula le
wherein, Y, X1, X2, Z1, A and Z2 are as defined above; or
reacting the isocyanate Db2 (as obtained in Step B of Process 2-1 above) with the
linker La or with linker Lb in the presence of a base in a solvent to obtain the
intermediate of formula le ;
B) reacting the intermediate le (as obtained in step A above) with the chloroformate
X in the presence of a base and in a solvent to yield the intermediate compound of
formula le ;
wherein, Y, X1, X2, Z1, A and Z2 are as defined above,
D) subjecting the intermediate le i (as obtained in Step C above) to nitration using
silver nitrate in the presence of a solvent to obtain the compound of formula (I), and
optionally, converting the compound of formula (I) to its pharmaceutically
acceptable salt;
Process 2-4: A) reacting the formyl halide of formula Db 1 (as obtained in Step B of
Process 2-1 ) with the linker intermediate of formula La i
O R
HO^ A O O CI
Lai
wherein, Z1, A, Z2, R1 and R2 are as defined in claim 1;
in the presence of a base and in a solvent to yield the intermediate of formula lei ;
B) subjecting the intermediate of formula lei (as obtained in Step A above) to
nitration using silver nitrate in the presence of a solvent to obtain the compound of
formula (I), and optionally converting the compound of formula (I) to its
pharmaceutically acceptable salt; or
Process 2-5: A) reacting the drug isocyanate Db2 (as obtained in Step B of Process
2-1) with the linker intermediate of formula Lai in the presence of a base and in a
solvent to yield the intermediate of formula lei ;
B) subjecting the intermediate lei (as obtained in Step A above) to nitration using
silver nitrate in the presence of a solvent to obtain the compound of formula (I), and
optionally converting the compound of formula (I) to its pharmaceutically acceptable
salt.
80. A process for the preparation of a compound of formula (I), or a pharmaceutically
acceptable salt thereof,
I
wherein D is a drug containing a hydroxyl or a sulfhydryl group; X1, Y, X2, Z1, A, Z2, R1
and R2 are as defined in claim 1;
wherein said process comprises the steps of:
A) coupling of a drug containing a hydroxyl or sulfhydryl group Dc (D-Y-X1H, wherein
Y = a bond; X1 = O or S) with the compound of formula Lf ,
H0 2C A . .CHO
\ \ 2
Lf
wherein A = 1,2-, 1,3-, or 1,4-phenylene and Z1 and Z2 = bond in the presence of a
coupling agent, a base and in a solvent to obtain an intermediate lg ;
wherein, X1, Z1, A and Z2 are as defined above;
B) subjecting the intermediate of formula lg in the presence of a reducing agent in a
solvent to obtain the intermediate of formula lg i ,
wherein, X1, Z1, A and Z2 are as defined above;
C) reacting the intermediate lg with the chloroformate of formula X,
x
in the presence of a base and in a solvent to obtain further intermediate of formula
wherein, X1, Z1, A, Z2, R1 and R2 are as defined above,
D) subjecting the intermediate lg2 (as obtained in Step C above) to nitration using
silver nitrate in the presence of a solvent to yield the compound of formula (I), and
optionally converting the compound of formula (I) to its pharmaceutically acceptable
salt.