Specification
Field of the Invention
This present invention generally relates to muscarinic receptor antagonists, which are
suitable, among other uses, for the treatment of various diseases of the respiratory, urinary and
gastrointestinal systems mediated through muscarinic receptors. The invention also relates to the
process for the preparation of disclosed compounds, pharmaceutical compositions containing the
disclosed compounds, and the methods for treating diseases mediated through muscarinic receptors.
Background of the Invention
Muscarinic receptors as members of the G Protein Coupled Receptors (GPCRs) are
composed of a family of 5 receptor sub-types (Mi, M2, M3, M4 and M5) and are activated by the
neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and
tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission.
The regional distribution of these receptor sub-types in the brain and other organs has been
documented (for example, the M] subtype is located primarily in neuronal tissues such as cereberal
cortex and autonomic ganglia, the Ma subtype is present mainly in the heart where it mediates
cholinergically induced bradycardia, and the Mj subtype is located predominantly on smooth
muscle and salivary glands (Nature, 323, p.411 (1986); Science, 237, p.527 (1987)).
A review in Current Opinions in Chemical Biology, 3, p. 426 (1999), as well as in Trends in
Pharmacological Sciences, 22, p. 409 (2001) by Eglen et. al., describes the biological potentials of
modulating muscarinic receptor subtypes by ligands in different disease conditions, such as
Alzheimer's Disease, pain, urinary disease condition, chronic obstructive pulmonary disease, and
the like.
A review in J. Med. Chem., 43, p. 4333 (2000), by Felder et. al. describes therapeutic
opportunities for muscarinic receptors in the central nervous system and elaborates on muscarinic
receptor structure and function, pharmacology and their therapeutic uses.
The pharmacological and medical aspects of the muscarinic class of acetylcholine agonists
and antagonists are presented in a review in Molecules, 6, p. 142 (2001).
Birdsall et al. in Trends in Pharmacological Sciences, 22, p. 215 (2001) have also
summarized the recent developments on the role of different muscarinic receptor subtypes using
different muscarinic receptor of knock out mice.
Muscarinic agonists such as muscarine and pilocarpine and antagonists such as atropine
have been known for over a century, but little progress has been made in the discovery of receptor
subtype-selective compounds, making it difficult to assign specific functions to the individual
receptors. Although classical muscarinic antagonists such as atropine are potent bronchodilators,
their clinical utility is limited due to high incidence of both peripheral and central adverse effects
such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc.. Subsequent
development of the quarterly derivatives of atropine such as ipratropium bromide are better
tolerated than parenterally administered options, but most of these are not ideal anti-cholinergic
bronchodilators, due to lack of selectivity for muscarinic receptor sub-types, resulting in doselimiting
side-effects such as thirst, nausea, mydriasis and those associated with the heart such as
tachycardia mediated by the Ma receptor.
Annual Review of Pharmacological ToxicoL, 41, p. 691 (2001), describes the
pharmacology of the lower urinary tract infections. Although anti-muscarinic agents such as
oxybutynin and tolterodine that act non-selectively on muscarinic receptors have been used for
many years to treat bladder hyperactivity, the clinical effectiveness of these agents has been limited
due to the side effects such as dry mouth, blurred vision and constipation. Tolterodine is
considered to be generally better tolerated than oxybutynin. (Steers et. al., in Curr. Opin. Invest.
Drugs, 2, 268; Chappie et. al., in Urology, 55, 33; Steers et al., Adult and Pediatric Urology, ed.
Gillenwatteret al., pp 1220-1325, St. Louis, MO; Mosby. 3rd edition (1996)).
There remains a need for development of new highly selective muscarinic antagonists
which can interact with distinct subtypes, thus avoiding the occurrence of adverse effects.
WO 04/005252 discloses azabicyclo derivatives described as muscarinic receptor
antagonists. WO 04/004629, WO 04/052857, WO 04/067510, WO 04/014853, WO 04/014363
discloses 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives described as useful muscarinic
receptor antagonists. WO 04/056811 discloses flaxavate derivatives as muscarinic receptor
antagonists. WO 04/056810 discloses xanthene derivatives as muscarinic receptor antagonists.
WO 04/056767 discloses l-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists.
WO 04/089363, WO 04/089898, WO 04/069835, WO 04/089900 and WO 04/089364 discloses
substituted azabicyclohexane derivatives as muscarinic receptor antagonists.
Compounds having antagonistic activity against muscarinic receptors have been described
in Japanese patent application Laid Open Number 92921/1994 and 135958/1994; WO 93/16048;
U.S. Patent No. 3,176,019; GB 940,540; EP 0325 571; WO 98/29402; EP 0801067; EP 0388054;
WO 9109013; U.S. Patent No. 5,281,601. Also, U.S. Patent Nos. 6,174,900, 6,130,232 and
5,948,792; WO 97/45414 are related to 1,4-disubstituted piperidine derivatives; WO 98/05641
describes fluorinated, 1,4-disubstitued piperidine derivatives; WO 93/16018 and WO96/33973 are
other references of interest. US Patent No. 5,397,800 discloses l-azabicyclo[2.2.1]heptanes. US
Patent No.5, 001,160 describes l-aryl-l-hydroxy-l-substituted-3-(4-substituted-l-piperazinyl)-2-
propanones. WO 01/42213 describes 2-biphenyl-4-piperidinyl ureas. WO 01/42212 describes
carbamate derivatives. WO 01/90081 describes amino alkyl lactam. WO 02/53564 describes novel
quinuclidine derivatives. WO 02/00652 describes carbamates derived from arylalkyl amines. WO
02/06241 describes l,2,3,5-tetrahydrobenzo(c)azepin-4-one derivatives. U.S. application No.
20030105071 describes thiazole and other heterocyclic ligands for mammalian dopamine,
muscarinic and serotonic receptors and transporters, and method of use thereof.
J. Med. Chem., 44, p. 984 (2002), describes cyclohexylmethylpiperidinyltriphenylpropioamide
derivatives as selective Ma antagonist discriminating against the other
receptor subtypes. J. Med. Chem., 36, p. 610 (1993), describes the synthesis and antimuscarinic
activity of some l-cycloalkyl-l-hydroxy-l-phenyl-3-(4-substituted piperazinyl)-2-propanones and
related compounds. J. Med. Chem., 34> P-3065 (1991), describes analogues of oxybutynin,
synthesis and antimuscarinic activity of some substituted 7-amino-l-hydroxy-5-heptyn-2-ones and
related compounds.
Summary of the Invention
In one aspect, there are provided muscarinic receptor antagonists, which can be useful as
safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the
respiratory, urinary and gastrointestinal systems. Also provided are processes for synthesizing such
compounds.
In another aspect, pharmaceutical compositions containing such compounds are provided
together with acceptable carriers, excipients or diluents which can be useful for the treatment of
various diseases of the respiratory, urinary and gastrointestinal systems.
The enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts
and pharmaceutically acceptable solvates of these compounds as well as metabolites having the
same type of activity are also provided, as well as pharmaceutical compositions comprising the
compounds, their metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or
pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable
carrier and optionally included excipients.
Other aspects will be set forth in the description which follows, and in part will be apparent
from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having the structure of
Formula I:
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters,
enantiomers, diastereomers, N-oxides, polymorphs, metabolites, wherein
represents an optional double bond;
X can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl alkyl, or
heteroarylalkyl.
RI can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy; -(CH2)o-2-
heterocyclylalkyl, or -(CH2)o-2-heteroarylalkyl.
R2 can be -(CH2)o-2-heteroaryl, -(CH2)o-2-heterocyclyl, or -(CH2)o-2-aryl, or RI and R2 may together
combine to form a (un)saturated monocyclic or bicyclic ring system containing 0-4 heteroatoms (O,
N or S) wherein the ring can be optionally substituted with one or more of alkyl; alkenyl; alkynyl;
cycloalkyl; alkaryl; alkoxy; aryloxy; halogen (F, Cl, Br, I); heterocyclyl; heteroaryl;
heterocyclylalkyl; heteroarylalkyl; carboxy; nitro; cyano; -C(=O)NRxRy (wherein Rx and Ry can be
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, aryloxy, -(CH2)o-2-heteroaryl, or -
(CH2)o-2-heterocyclyl); -NRxRy (wherein Rx and Ry are as defined above), or -O-C(=O)NRxRy
(wherein Rx and Ry are as defined above).
G can be -OR (wherein R represents hydrogen or unsubstituted lower (Ci-Ce) alkyl); -NOR
(wherein R is the same as defined above); -NHYR' (wherein R' is hydrogen, alkyl or aryl and Y is
-C(=0), -SO or -SO2); or oxygen (provided that RI and R2 together does not form a pyrrolidine, 4-
hydroxy piperidine, 4-pyrrolidinyl piperidine, piperazine or azabicyclo [3.1.0] hexane ring).
The following definitions apply to terms as used herein.
The term "alkyl," unless otherwise specified, refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is
exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, nhexyl,
n-decyl, tetradecyl, and the like. Alkyl may further be substituted with one or more
substituents such as alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl,
arylthio, thiol, alkylthio, aryloxy, aminosulfonyl, aminocarbonylamino, -NRxRy, -C(=O)NRxRy, -0-
C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), nitro, -S(O)nR3 wherein Ra is
alkyl, aryl or heteroaryl. Unless otherwise constrained by the definition, all substituents may be
further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, -C(=0)NRxRy, -OC(=
O)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CFs,
cyano, and -S(O)nR3, where Ra is the same as defined earlier and n is 0, 1 or 2. Alkyl groups may
also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa-,
where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl. Unless
otherwise constrained by the definition, all substituents may be further substituted by 1-3
substituents chosen from alkyl, carboxy, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and
Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CFs, cyano, and -S(O)nR3 where n
and RS are the same as defined earlier.
The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis
or trans geometry. Particular alkenyl groups include ethenyl or vinyl, 1-propylene or allyl, isopropylene,
bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to the
heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl may further be substituted
with one or more substituents such as alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and Ry are the same as
defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
arylthio, thiol, alkylthio, aryl, alkaryl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl,
heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, S(O)nR3 (wherein R3 is
the same as defined earlier). Unless otherwise constrained by the definition, all substituents may
optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy,
halogen, -CF3, cyano, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and Ry are the same as
defined earlier) and -S(O)nR3, where R3 and n are the same as defined earlier.
The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated
hydrocarbon, preferably having from 2 to 20 carbon atoms. Particular alkynyl groups include, for
example, ethynyl, propargyl or propynyl, and the like. In the event that alkynyl is attached to the
heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl may further be substituted
with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy,
cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen,
hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, alkaryl, aryloxy, aminosulfonyl,
aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NRxRy,-
C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), -S(O)nR3
wherein R3 is the same as defined earlier. Unless otherwise constrained by the definition, all
substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy,
carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx
and Ry are the same as defined earlier), cyano, and -S(O)nR3, where R3 and n are the same as
defined earlier.
The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a
single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example,
single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or
multiple ring structures such as adamantanyl, and bicyclo [2.2.1]heptane, or cyclic alkyl groups to
which is fused an aryl group, (for example, indane, and the like. Spiro groups are also envisioned.
Cycloalkyl groups may further be substituted with one or more substituents such as alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido,
cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl,
alkaryl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy
(wherein Rx and Ry are the same as defined earlier), nitro, heterocyclyl, heteroaryl,
heterocyclylalkyl, heteroarylalkyl, S(O)nR3 wherein R3 is same as defined earlier. Unless otherwise
constrained by the definition, all substituents may optionally be further substituted by 1-3
substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=O)NRxRy, OC(=
O)NRxRy (wherein Rx and Ry are the same as defined earlier), cyano and -S(O)nR3, where R3
and n are the same as defined earlier.
The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.
The term "alkaryl" refers to aryl linked through alkyl (wherein alkyl is the same as defined above)
portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is as defined below.
The term "aryl" herein refers to a carbocyclic aromatic group, (for example, phenyl,
biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from
the group consisting of halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy,
acyl, aryloxy, cyano, nitro, -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and Ry are the
same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or
amino carbonylamino. The aryl group may optionally be fused with heterocyclyl, cycloalkyl or
heteroaryl ring system.
The term "carboxy" as defined herein refers to -C(=:O)O-R4 wherein R* is selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl.
The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure
containing 5 to 7 ring atoms, or a bicyclic aromatic group having 8 to 12 ring atoms, with one or
more heteroatom(s) (N, O or S) optionally substituted with 1 to 3 substituent(s) such as halogen (F,
Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, alkaryl, cyano,
nitro, aminocarbonylamino, -NRxRy, -C(=O)NRxRy and -O-C(=O)NRxRy (wherein Rx and Ry are
the same as defined earlier). Examples of heteroaryl groups include pyridinyl, pyridazinyl,
pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl,
indolyl, benzothiazolyl, benzoxazolyl, and the like.
The term 'heterocyclyl" unless and otherwise specified refers to a non-aromatic monocyclic
or bicyclic cycloalkyl group having 5 to 10 atoms in which 1 to 3 carbon atoms in a ring are
replaced by heteroatoms (O, S or N), and are optionally benzofused or fused heteroaryl of 5-6 ring
members and the heterocyclyl group can be optionally substituted with substituents for example
halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl,
cyano, nitro, oxo, carboxy, aminocarbonylamino, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and
Ry are the same as defined earlier). Examples of heterocyclyl groups include tetrahydrofuranyl,
dihydrofuranyl, dihydropyridinyl, piperidinyl, piperazinyl, dihydrobenzofuryl, azabicyclohexyl,
dihydroindolyl, and the like.
"Heteroarylalkyl" refers to heteroaryl (wherein heteroaryl is same as defined earlier) linked
through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion
contains from l-6carbon atoms.
"Heterocyclylalkyl" refers to heterocyclyl (wherein heterocyclyl is same as defined earlier)
linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion
contains from 1-6 carbon atoms.
"Acyl" refers to -C(=0)R" wherein R" is selected from the group hydrogen, alkyl,
cycloalkyl, aryl, alkaryl, hydroxy, alkoxy, heteroaryl, heterocyclyl, heteroarylalkyl or
heterocyclylalkyl.
The term "protecting groups" is used herein to refer to known moieties which have the
desirable property of preventing specific chemical reaction at a site on the molecule undergoing
chemical modification intended to be left unaffected by the particular chemical modification. Also
the protecting group, unless otherwise specified, may be used with groups such as hydroxy, amino,
carboxy and example of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective
Groups in Organic Synthesis", 2nd ED, John Wiley and Sons, New York, N.Y. The species of the,
for example, carboxylic protecting groups, amino protecting groups or hydroxy protecting groups
employed is not critical so long as the derivatised moiety/moieties is/are stable to conditions of
subsequent reactions and can be removed at the appropriate point without disrupting the remainder
of the molecule.
In accordance with a second aspect, there is provided a method for treatment or prophylaxis
of an animal or a human suffering from a disease or disorder of the respiratory, urinary and
gastrointestinal systems, wherein the disease or disorder is mediated through muscarinic receptors.
The method includes administration of at least one compound having the structure of Formula I.
In accordance with a third aspect, there is provided a method for treatment or prophylaxis of
an animal or a human suffering from a disease or disorder associated with muscarinic receptors,
comprising administering to a patient in need thereof, an effective amount of a muscarinic receptor
antagonist compound as described above.
In accordance with a fourth aspect, there is provided a method for treatment or prophylaxis
of an animal or a human suffering from a disease or disorder of the respiratory system such as
bronchial asthma, chronic obstructive pulmonary disorders (COPD), pulmonary fibrosis, and the
like; urinary system which induce such urinary disorders as urinary incontinence, lower urinary
tract symptoms (LUTS), etc.; and gastrointestinal system such as irritable bowel syndrome, obesity,
diabetes and gastrointestinal hyperkinesis with compounds as described above, wherein the disease
or disorder is associated with muscarinic receptors.
In accordance with a fifth aspect, there are provided processes for preparing the compounds
as described above.
The compounds described herein exhibit significant potency in terms of their activity, as
determined by in vitro receptor binding and functional assays and in vivo experiments using
anaesthetized rabbits. The compounds that were found active in vitro were tested in vivo. Some of
the compounds are potent muscarinic receptor antagonists with high affinity towards MS receptors.
Therefore, pharmaceutical compositions for the possible treatment for the disease or disorders
associated with muscarinic receptors are provided. In addition, the compounds can be administered
orally or parenterally.
Detailed Description of the Invention
The compounds of the present invention may be prepared by techniques well known in the
art and familiar to the average synthetic organic chemist. In addition, the compounds of the present
invention may be prepared, for example, by generally following the reaction scheme(s) as depicted
below.
(Figure Removed)
The compound of Formula Vlllb, X, IXa, XI and XIa may be prepared, for example, by the
reaction sequence as shown in Scheme I. The preparation comprises reacting a compound of
Formula II (wherein X is the same as defined earlier) with a compound of Formula T2 (wherein T2
is lithium acetylide, cerium acetylide, sodium acetylide, potassium acetylide or lithium acetylide in
complex with diethylamine), to give a compound of Formula III, which is further reacted with
mercuric acetate to give a compound of Formula IV, which is hydrolysed to give a compound of
Formula V, which is halogenated to give a compound of Formula VI (wherein hal is F, Cl, Br or I),
which is reacted with a compound of Formula VII to give a compound of Formula VIII (wherein RI
and R2 are the same as defined earlier).
Path a: The compound of Formula VIII can be reacted with a compound of Formula -NH2OR to
give compound of Formula X (wherein R is the same as defined earlier)
Path b: The compound of Formula VIII can be reduced to give a compound of Formula IX (when
R2 is (CHl>"" N _ /NP wherein P represents a protecting group such as alkaryl or acyl) Path bl: The
compound of Formula IX undergoes N-derivatization (when Rl and R2 together joins to form
piperazine) to give a compound of Formula IXa.
Path b2: The compound of Formula IX undergoes deprotection to give a compound of Formula XI
(wherein W is "' or, which undergoes reductive amination (when W is
to give a compound of Formula XIa.
Path c: The compound of Formula VIII can undergo reductive amination reaction to give a
compound of Formula Villa.
_ . ,
Path d: The compound of Formula VIII (when R2 is ^^ ) can undergo deprotection to give a
compound of Formula VHIb.
The compound of Formula II can be reacted with a compound of Formula T2 in an organic solvent
(for example, tetrahydrofuran, diethyl ether or 1 ,4-dioxane) to give a compound of Formula III
which can be reacted with mercuric acetate in the presence of a corresponding anhydride (for
example, acetic anhydride) in an organic solvent (for example, acetic acid, propionic acid or formic
acid) to give a compound of Formula IV which can be hydrolyzed in the presence of an inorganic
base (for example, potassium hydroxide, sodium hydroxide or lithium hydroxide) in an organic
solvent (for example, methanol, ethanol, propanol or isopropanol) to give a compound of Formula
V which can be halogenated in the presence of a halogenating agent (for example, pyridine
hydrobromide perbromide, 2-pyrrolidone hydrobromide perbromide, N-bromosuccinimide, Nchlorosuccinimide
or N-iodosuccinimide) in an organic solvent (for example, tetrahydrofuran,
diethyl ether or 1,4-dioxane) to give a compound of Formula VI which can be reacted with a
compound of Formula VII in the presence of an organic base (for example, triethylamine,
pyridine, diisopropylamine or N-methylmorpholine in an organic solvent (for example,
dichloromethane, dichloroethane, chloroform or carbon tetrachloride) to give a compound of
Formula VIII which can be reacted with a compound of Formula -NH2OR (path a) in the presence
of an organic base (for example, pyridine, triethylamine or trimethylamine) in an organic solvent
(for example, ethanol, methanol, propanol or isopropanol) to give a compound of Formula X. The
reduction of the compound of Formula VIII (path b) can be carried out in the presence of a
reducing agent (for example, sodium borohydride, sodium cyanoborohydride or lithium aluminium
hydride) in an organic solvent (for example, methanol, ethanol, propanol or isopropanol) to give a
compound of Formula IX.
The compound of Formula IX undergoes N-derivatization (path bl) to give a compound of
Formula IXa in an organic solvent (for example, acetonitrile, dichloromethane, chloroform or
carbon tetrachloride) in the presence of a base (for example, potassium carbonate, sodium
carbonate or sodium bicarbonate). The compound of Formula IX undergoes (path b2) undergo
deprotection in the presence of a deprotecting agent (for example, palladium on carbon in presence
of hydrogen gas or palladium on carbon in ammonium formate solution) in an organic solvent (for
example, methanol, ethanol, propanol or isopropyl alcohol) to a give a compound of Formula XI,
which undergoes reductive amination to give a compound of Formula XIa with formaldehyde in an
organic solvent (for example, acetonitrile or dichloromethane) with formaldehyde in the presence
of reducing agent (for example, sodium cyanoborohydride or sodium triacetoxy borohydride).. The
reductive amination of a compound of Formula VIII (path c) with formaldehyde to give a
compound of Formula VIII can be carried out in an organic solvent (for example, acetonitrile or
dichloromethane) with formaldehyde in the presence of reducing agent (for example, sodium
cyanoborohydride or sodium triacetoxy borohydride). The compound of Formula VIII (when R.2 is
~^ ) (path d) can undergo deprotection to give a compound of Formula Vlllb in the presence of
a deprotecting agent (for example, palladium on carbon in presence of hydrogen gas or palladium
on carbon in ammonium formate solution) in an organic solvent (for example, methanol, ethanol,
propanol or isopropyl alcohol).
Particular compounds generally prepared in this manner are shown here:
3-(3-Azabicyclo[3.1.0]hex-6-ylamino)-l-cyclopentyl-l-phenyl-propane-l,2-diol (Compound No. 3)
3-(3-Azabicyclo[3.1.0]hex-6-ylamino)-l,l-diphenyl-propane-l,2-diol (Compound No. 5)
3-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl)-methyl-amino]-1 -cyclopentyl-1 -phenyl-propane-
1,2-diol (Compound No. 6)
3 - [(3 -benzyl-3 -aza-bicyclo [3.1.0] hex-6-ylmethyl)-methyl-amino] -1 -cyclopentyl-1 -hydroxy-1 -
phenyl-propan-2-one-oxime (Compound No. 8)
3-[(3-Azabicyclo[3.1.0]hex-6-ylmethyl)-methyl-amino]-l -cyclopentyl- l-phenyl-propane-l,2-diol
(Compound No. 9)
1-Cyclopentyl-l-phenyl-3-(piperazin-l-yl)-propane-l,2-diol (Compound No. 10)
l-Cyclopentyl-3-(4-methyl-piperazin-l-yl)-l-phenyl-propane-l,2-diol (Compound No. 11)
3-(4-Benzyl-piperazin-l-yl)-l-cyclopentyl-l-phenyl-propane-l,2-diol (CompoundNo. 12)
1-Cyclopentyl-l-phenyl-3-(piperidin-l-yl)-propane-l,2-diol (Compound No. 13)
l-Cyclopentyl-l-hydroxy-l-phenyl-3-(piperidin-l-yl)-propan-2-one (Compound No. 14)
l-Cyclopentyl-l-hydroxy-3-(morpholin-4-yl)-l-phenyl-propane-2-one (Compound No. 15)
l-Cyclopentyl-3-(morpholin-4-yl)-l-phenyl-propane-l,2-diol (Compound No. 16)
3-(l-Benzyl-piperidin-4-ylamino)-1 -cyclopentyl-1 -hydroxy-1 -phenyl-propan-2-one (Compound
No. 17)
3-(1 -Benzyl-piperidin-4-ylamino). 1 -cyclopentyl-l-phenyl-l,2-diol (Compound No. 18)
3-[(l-Benzyl-piperidin-4-yl)-methyl-amino]-l-cyclopentyl-l-hydroxy-l-phenyl-propan-2-one
(Compound No. 19)
3-( 1 -Benzyl-piperidin-4-ylamino)-1 -cyclopentyl-1 -hydroxy-1 -phenyl-propan-2-one oxime
(Compound No. 20)
l-Cyclopentyl-3-(3,5-dimethyl-piperazin-l-yl)-l-hydroxy-1-phenyl-propan-2-one (Comp No. 21)
l-Cyclopentyl-3-(3,5-dimethyl-piperazin-l-yl)-l-phenyl-propane-l,2-diol (CompoundNo. 22)
1 -Cyclopentyl-1 -hydroxy-3-[methyl-(l -methyl-piperidin-4-yl)-amino] -1-phenyl-propan-2-one
(Compound No. 23)
1 -Cyclopentyl-3-[methyl-(l -methyl-piperidin-4-yl)-amino]-1 -phenyl-propane-1,2-diol (Compound
No. 24)
3-[(3-Benzyl-3-aza-bicyclo[3.1.0]hex-6-yl)-methyl-amino]-l-cyclopentyl-l-hydroxy-1-phenylpropan-
2-one (Compound No. 25)
3-[(3-Benzyl-3-aza-bicyclo[3.1.0]hex-6-yl)-methyl-amino]-l -cyclopentyl-1 -phenyl-propane-1,2-
diol (Compound No. 26)
3-[(3-Aza-bicyclo[3.1.0]hex-6-yl)-methyl-amino]-l-cyclopentyl-l-hydroxy-1-phenyl-propan-2-one
(Compound No. 27)
3-( 1 -Benzyl-piperidin-4-ylamino)-1 -cyclopentyl-1 -hydroxy-1 -phenyl-propan-2-one (Compound
No. 28)
3-(l-Benzyl-pyrrolidin-3-ylamino)-l-cyclopentyl-l-propan-l,2-diol (Compound No. 29)
l,l-Diphenyl-3-piperazin-l-yl-propane-l,2-diol (Compound No. 30)
3-(4-Methyl-piperazin-l-yl)-l,l-diphenyl-propane-l,2-diol (Compound No. 31)
1 -Hydroxy-3 - [methyl-( 1 -methyl-piperidin-4-yl)-amino)-1,1 -diphenyl-propan-2-one (Compound
No. 32)
3-[Methyl-(l-methyl-piperidin-4-yl)-amino]-l,l-diphenyl-propane-1,2-diol (Compound No. 33)
3-( 1 -Benzyl-pyrrolidin-3-ylamino)-1 -cyclopentyl-1 -hydroxy-1 -phenyl-propan-2-one (Compound
No. 34)
3 - [(1 -Benzyl -pyrrolidin-3 -yl)-methyl-amino] -1 -cyclopentyl-1 -hydroxy-1 -phenyl-propan-2-one
(Compound No. 35)
3-[4-(4-Chloro-benzyl)-piperazin-l-yl]-l-cyclopentyl-l-phenyl-propane-l,2-diol (Comp No. 36)
1-Cyclopentyl-l-hydroxy-3-(3-methyl-piperazin-l-yl)-l-phenyl-propan-2-one (Compound No. 39)
l-Cyclopentyl-3-(3-methyl-piperazin-l-yl)-l-phenyl-propane-1,2-diol (Compound No. 40)
l-Cyclopentyl-3-[l,4]diazepan-1-yl-l-hydroxy-l-phenyl-propan-2-one (CompoundNo. 41)
l-Cyclopentyl-3-[l,4]diazepan-l-yl-l-phenyl-propane-l,2-diol (Compound No. 42)
3-[l,4']Bipiperidinyl-r-yl-l-cyclopentyl-l-hydroxy-l-phenyl-propan-2-one (Compound No. 43)
3-[l,4']Bipiperidinyl-l'-yl-l-cyclopentyl-l-phenyl-propane-l,2-diol (Compound No. 44)
(2R)-1 -Cyclopentyl-3 - {[2-(dimethylamino)ethyl] amino} -1 -hydroxy-1 -phenylacetone
(Compound No. 45)
l-Cyclopentyl-3-[r-(3-cyclopentyl-2,3-dihydroxy-3-phenyl-propyl)-[4,4']bipiperidinyl-l-yl]-lphenyl-
propane-l,2-diol (CompoundNo. 46)
3-(l-Benzyl-pyrrolidin-3-ylamino)-l,l-diphenyl-propane-l,2-diol (Compound No. 47)
3-[4-(2-Benzo[l,3]dioxol-5-yl-ethyl)-[l,4]diazepan-l-yl]-l-cyclopentyl-l-phenyl-propane-l,2-diol
(Compound No. 51)
l-Cyclopentyl-3-dimethylamino-l -hydroxy-l-phenyl-propan-2-one (Compound No. 53)
l-Cyclopentyl-3-dimethylamino-l-phenyl-propane-l,2-diol (CompoundNo. 54)
3-[l,4]Diazepan-l-yl-l-hydroxy-l,l-diphenyl-propan-2-one (CompoundNo. 55)
3-[l,4]Diazepan-l-yl-l,l-diphenyl-propane-l,2-diol (CompoundNo. 56)
3-[4-(2-Benzo[l,3]dioxol-5-yl-ethyl)-[l,4]diazepan-l-yl]-l-hydroxy-l,l-diphenyl-propan-2-one
(Compound No. 57)
3-[4-(2-Benzo[l,3]dioxol-5-yl-ethyl)-[l,4]diazepan-l-yl]-l,l-diphenyl-propane-l,2-diol
(Compound No. 58)
1 -Cyclopentyl-3-(4-hydroxy-piperidin-l-yl)-l-phenyl-propane-l,2-diol (CompoundNo. 59)
l-Cyclopentyl-3-(2-dimethylamino-ethylamino)-l-phenyl-propane-l,2-diol (Compound No. 60)
l-Cyclopentyl-l-hydroxy-3-(4-methyl-[l,4]diazepan-l-yl)-l-phenyl-propan-2-one (Comp No. 61)
l-Cyclopentyl-3-(4-methyl-[l,4]diazepan-l-yl)-l-phenyl-propane-l,2-diol (Compound No. 62)
l-[l,4]Diazepan-l-yl-3-hydroxy-4-methyl-3-phenyl-pentan-2-one (Compound No. 63)
l-[l,4]Diazepan-l-yl-4-methyl-3-phenyl-pentane-2,3-diol (CompoundNo. 64)
l-Cyclopentyl-l-hydroxy-3-imidazol-l-yl-l-phenyl-propan-2-one (Compound No. 65)
1-Cyclopentyl-3-imidazol-1-yl-l-phenyl-propane-1,2-diol (Compound No. 66)
l-Cyclopentyl-l-hydroxy-3-(2-methyl-imidazol-1-yl)-l-phenyl-propan-2-one (Compound No. 67)
l-Cyclopentyl-3-(2-methyl-imidazol-l-yl)-l-phenyl-propane-1,2-diol (Compound No. 68)
l-Cyclopentyl-l-hydroxy-3-(2-isopropyl-imidazol-l-yl)-l-phenyl-propan-2-one (CompNo. 69)
1 -Cyclopentyl-3-(2-isopropyl-imidazol-l-yl)-l-phenyl-propane- 1,2-diol (Compound No. 70)
l-Cyclopentyl-l-hydroxy-3-(2-methyl-4,5-dihydro-imidazol-l-yl)-l-phenyl-propan-2-one
(Compound No. 71)
1-Cyclopentyl-l-hydroxy-l-phenyl-3-pyrrolidin-l-yl-propan-2-one (Compound No. 72)
l-Cyclopentyl-l-phenyl-3-pyrrolidin-l-yl-propane-1,2-diol (Compound No. 73)
3-Azepan-l-yl-l-cyclopentyl-l-hydroxy-l-phenyl-propan-2-one (Compound No. 74)
3-Azepan-l-yl-l-cyclopentyl-l-phenyl-propane- 1,2-diol (Compound No. 75)
l-Cyclopentyl-l-hydroxy-3-(3-hydroxy-piperidin-l-yl)-l-phenyl-propan-2-one (Comp No. 76)
l-Cyclopentyl-3-(3-hydroxy-piperidin-l-yl)-l-phenyl-propane-l,2-diol (Compound No. 77)
3-(4-Benzyl-piperidin-l-yl)-l-cyclopentyl-l-hydroxy-l-phenyl-propan-2-one (Compound No. 78)
1 -Cyclopentyl-3-(2-dimethylamino-ethylamino)-l-phenyl-propane- 1,2-diol (Compound No. 80)
(2R)-l-Cyclopentyl-l-hydroxy-3-(2-methyl-imidazol-l-yl)-l-phenyl-propan-2-one (Comp No. 81)
5-(3-Cyclopentyl-3-hydroxy-2-oxo-3-phenyl-propyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic
acid tert-butyl ester (Compound No. 82)
Methanesulfonic acid 3-(3-cyclopentyl-3-hydroxy-2-oxo-3-phenyl-propyl)-3-aza-bicyclo[3.2.1]oct-
8-yl ester (Compound No. 83)
Methanesulfonic acid 3-(3-cyclopentyl-3-hydroxy-2-oxo-3-phenyl-propyl)-3-aza-bicyclo[3.2.1]oct-
8-yl ester (Compound No. 84)
(2R)-l-Cyclopentyl-l-hydroxy-3-(2-methyl-4,5-dihydro-imidazol-l-yl)-l-phenyl-propan-2-one
(Compound No. 85)
(Figure Removed)
The compounds of Formula XI may also be prepared, (for example, by the reaction
sequence as shown in Scheme II. The preparation comprises hydrogenating a compound of
Formula III (where X is the same as defined earlier except alkyne) to give a compound of Formula
XII, which can be oxidized to give a compound of Formula XIII, which can be reacted with a
compound of Formula VII to give a compound of Formula IX (wherein RI and RI are the same as
undefined
earlier), which can be deprotected (when R2 is N—/ wherein P is the same as defined
earlier) to give a compound of Formula XI.
Hydrogenation of a compound of Formula III can be carried out in the presence of a
reducing agent (for example, palladium on calcium carbonate or sodium in liquid ammonia
solution) in a hydrocarbon (for example, toluene, heptane, xylene or benzene) to give a compound
of Formula XII which can be oxidized in the presence of an oxidising agent (for example, mchloroperbenzoic
acid, perbenzoic acid or peracetic acid) in an organic solvent (for example,
dichloromethane, dichloroethane, carbon tetrachloride or chloroform) to give a compound of
Formula XIII which can be reacted with a compound of Formula VII in the presence of an organic
base (for example, triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine) in an
organic solvent (for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform)
to give a compound of Formula IX which can be deprotected in the presence of a deprotecting
agent (for example, palladium on carbon in hydrogen gas or palladium on carbon in ammonium
formate solution in an organic solvent (for example, methanol, ethyl acetate, ethanol or
isopropanol) to give compound of Formula XI.
Particular exemplary compounds prepared according to the procedure described are shown
here:
(R or S) 3-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino)-l-cyclopentyl-l-phenyl-propane-l,2-diol
(Compound No. 1)
(R or S) 3-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino)-l,l-diphenyl-propane-l,2-diol
(Compound No. 2)
(Ror S) 3-[(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylmethyl-amino)]-l-cyclopentyl-l-phenyl-propane-
1,2-diol (Compound No. 4)
(R or S) 3-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino)-l-cyclopentyl-l-phenyl-propane-l,2-diol
(Compound No. 7)
The compounds of Formula XI may be prepared, for example, by the reaction sequence as
shown in Scheme III. The preparation comprises reacting a compound of Formula II (wherein X is
the same as defined earlier) with vinyl magnesium bromide to give a compound of Formula XII,
which can be oxidized to give a compound of Formula XIII, which can be reacted with a compound
of Formula VII to give a compound of Formula IX (wherein RI and R2 are the same as defined
earlier), which can be deprotected (when RI is
give a compound of Formula XI.
wherein P is the same as defined earlier) to
(Figure Removed)
The reaction of a compound of Formula II with vinyl magnesium bromide can be carried
out in an organic solvent (for example, tetrahydrofuran, diethyl ether or dioxane) to give a
compound of Formula XII which can undergo oxidation in the presence of an oxidizing agent (for
example, m-chloroperbenzoic acid, perbenzoic acid or peracetic acid) in an organic solvent (for
example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform) to give a compound
of Formula XIII which on reaction with a compound of Formula VII in the presence of an organic
base (for example, triethylamine, pyridine, N-methylmorpholine or di-isopropyl ethylamine in an
organic solvent (for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform)
can give a compound of Formula IX which can undergo deprotection in the presence of a
deprotecting agent (for example, palladium on carbon or palladium on carbon) in ammonium
formate solution in an organic solvent (for example, methanol, ethyl acetate, ethanol or
isopropanol) to give a compound of Formula XI.
The compounds of Formula XVIII may be prepared, for example, by the reaction sequence
as shown in Scheme IV. The preparation comprises reacting a compound of Formula IX (wherein
X is the same as defined earlier) with a compound of Formula Rs-hal (wherein RS is mesyl, tosyl or
4-nitrobenzenesulphonyl group and hal is the same as defined earlier) to give of Formula XIV,
which can be treated with sodium azide to give a compound of Formula XV, which can be further
reduced to give a compound of Formula XVI, which is reacted with a compound of Formula XVII
to give a compound of Formula XVIII (wherein R' and Y the same as defined earlier).
The compound of Formula IX can be reacted with a compound of Formula Rs-hal in the
presence of an organic base (for example, triethyl amine or trimethyl amine) in an organic solvent
(for example, dichloromethane, chloroform or carbon tetrachloride) to give a compound of Formula
XIV which can be reacted with sodium azide in an organic solvent (for example,
dimethylformamide or dimethylsulphoxide) to give a compound of Formula XV which can be
reduced with a suitable reducing agent (for example, triphenylphosphine or lithium aluminum
hydride) in an organic solvent (for example, tetrahydrofuran or 1,4-dioxane) to give a compound of
Formula XVI which can be reacted with a compound of Formula XVII in the presence of an
organic base (for example, triethylamine or pyridine) in an organic solvent (for example,
dichloromethane, carbon tetrachloride or ethyl acetate) to give a compound of Formula XVIII.
Scheme V
X
FormulaXX FormuteXXI
The compounds of Formulae XX and XXI may be prepared, for example, by the reaction
sequence as shown in Scheme V. The preparation comprises N-derivatizing a compound of
Formula XIX to give a compound of Formula XX, which undergoes reduction to give a compound
of Formula XXI.
The N-derivatization of a compound of Formula XIX to give a compound of Formula XX
can be carried out in an organic solvent (for example, acetonitrile, dichloromethane, chloroform or
carbon tetrachloride) in the presence of a base (for example, potassium carbonate, sodium
carbonate or sodium bicarbonate).
The reduction of a compound of Formula XX to give a compound of Formula XXI can be
carried out in the presence of a reducing agent (for example, sodium borohydride, sodium
cyanoborohydride or lithium aluminium hydride) in an organic solvent (for example, methanol,
ethanol, propanol or isopropanol).
Particular exemplary compounds prepared according to the procedure described are shown
here:
3-[4-(2-Benzo[l,3]dioxol-5-yl-ethyl)-piperazin-l-yl]-l-cyclopentyl-l-phenyl-propane-l,2-diol
(Compound No. 37)
3 - [4-(2-Benzo [1,3] dioxol-5 -yl-ethyl)-piperazin-1 -yl] -1 -cyclopentyl-1 -phenyl-propane-1,2-diol
(Compound No. 38)
1 -Cyclopentyl-3-[4-(3-methyl-but-2-enyl)-piperazin-1 -yl]-1 -phenyl-propane-1,2-diol (Compound
No. 48)
3 - [4-(2-Benzo[ 1,3] dioxol-5 -yl-ethyl)- [ 1,4] diazepan-1 -yl] -1 -cyclopentyl-1 -hydroxy-1 -phenylpropan-
2-one (Compound No. 49)
1 -Cyclopentyl-3 - {4- [2-(2,3 -dihydro-benzofuran-5-yl)-ethyl] -[1,4] diazepan-1 -yl} -1 -hydroxy-1 -
phenyl-propan-2-one (Compound No. 50)
1 -Cyclopentyl-3 - {4- [2-(2,3 -dihydro-benzofuran-5 -yl)-ethyl] - [ 1,4] diazepan-1 -y 1} -1 -phenylpropane-
1,2-diol (Compound No. 52)
3 - [4-(2-Benzo [1,3] dioxol-5-yl-ethyl)- [ 1,4]diazepan-1 -yl] -1 -cyclopentyl-1 -phenyl-propane-1,2-diol
(Compound No. 79)
In the above scheme, where specific bases, condensing agents, protecting groups,
deprotecting agents, solvents, catalysts, temperatures, etc. are mentioned, it is to be understood that
other bases, condensing agents, protecting groups, deprotecting agents, solvents, catalysts,
temperatures, etc. known to those skilled in the art may be used. Similarly, the reaction
temperature and duration may be adjusted according to the desired needs.
Suitable salts of the compounds represented by the Formula I were prepared so as to
solubilize the compound in aqueous medium for biological evaluations, as well as to be compatible
with various dosage formulations and also to aid in the bioavailability of the compounds.
Examples of such salts include pharmacologically acceptable salts such as inorganic acid salts (for
example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic acid salts (for
example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate).
When carboxyl groups are included in the Formula I as substituents, they may be present in the
form of an alkaline or alkali metal salt (for example, sodium, potassium, calcium, magnesium, and
the like). These salts may be prepared by various techniques, such as treating the compound with
an equivalent amount of inorganic or organic, acid or base in a suitable solvent.
Because of their valuable pharmacological properties, the compounds described herein may
be administered to an animal for treatment orally, or by a parenteral route. The pharmaceutical
compositions described herein can be produced and administered in dosage units, each unit
containing a certain amount of at least one compound described herein and/or at least one
physiologically acceptable addition salt thereof. The dosage may be varied over extremely wide
limits, as the compounds are effective at low dosage levels and relatively free of toxicity. The
compounds may be administered in the low micromolar concentration, which is therapeutically
effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the
patient.
The compounds described herein can be produced and formulated as their enantiomers,
diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as
metabolites having the same type of activity. Pharmaceutical compositions comprising the
molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates
or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable
carrier and optionally included excipient can also be produced.
The examples mentioned below demonstrate general synthetic procedures, as well as
specific preparations of particular compounds. The examples are provided to illustrate the details
of the invention and do not limit the scope of the present invention.
Examples
Various solvents, such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexanes, and
dichloromethane, were dried using various drying reagents according to procedures described in the
literature. IR spectra were recorded as Nujol mulls or a thin neat film on a Perkin Elmer Paragon
instrument. Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian XL-300 MHz
instrument using tetramethylsilane as an internal standard.
Example 1: Preparation of 1 -cvclopentyl-1 -hydroxy-1 -phenvl propvne
A solution of n-butyl lithium (15%, 54.0 mL, 92.0 mM) in dry tetrahydrofuran (200.0 mL)
was saturated with dry acetylene gas at -78°C. To the reaction mixture thus obtained was added
phenyl cyclopentyl ketone (8.0 g, 46.0 mM) in dry tetrahydrofuran (50.0 mL) dropwise at the same
temperature under stirring. The reaction mixture was brought to 25-30°C under stirring and
saturated ammonium chloride solution (30.0 mL) was added, followed by stirring for 5 minutes.
The organic layer was separated and washed with saturated brine solution (30.0 mL).
Tetrahydrofuran was distilled off under reduced pressure and the residue was purified through
column chromatography using 10% ethyl acetate in hexane solvent mixture as an eluent to get the
title organic compound.
Yield: 87% (8.0 g); IR (DCM): 3422.8, 3299.9, 2110.9 cm'1; [H NMR (CDC13):5 7.65-7.67 (m,
2H), 7.28-7.39 (m, 3H), 2.68 (s, 1H), s, 1H), 2.38-2.43 (m, 1H), 1.57-1.78 (m, 5H), 1.40-1.50 (m,
3H).
Example 2: Preparation of 1 -cyclopentvl-1 -acetoxy-1 -phenvl-2-propanone
To a solution of 1 -cyclopentyl-1 -hydroxy-1-phenyl-2-propyne (3.0 g, 15 mM) in glacial
acetic acid (21.0 mL) was added acetic anhydride (2.1 mL) followed by addition of mercuric
acetate (5.3 g, 16.5 mM) portionwise. The reaction mixture was stirred for 72 hours at 25-30°C
followed by addition of thioacetamide (1.2 g, 16.5 mM). Stirring was continued for three hours at
the same temperature. The reaction mixture was diluted with ether (150.0 mL). The reaction
mixture was filtered through celite pad. The filtrate was washed with water, saturated sodium
bicarbonate solution, dried over anhydrous sodium sulphate and concentrated under reduced
pressure to furnish title organic compound.
Yield: 82% (3.2 g); IR (DCM): 1743.1, 1720.4 cm'1; *H NMR (CDC13):8 7.27-7.38 (m, 5H), 2.94-
3.04 (m, 1H), 2.27 (s, 3H), 1.92 (s, 3H), 1.27-1.70 (m, 8H).
Example 3: Preparation of 1 -cyclopentyl-1 -hydroxy-1 -phenyl-2-propanone
To a solution of 1-cyclopentyl-1-acetoxy-l-phenyl-2-propanone (4.0 g, 15.4 mM) in
methanol (20.0 mL), aqueous potassium hydroxide solution (1.3 g, 23.0 mM, 1.5 mL of water) was
added and the reaction mixture was refluxed for 2 hours. Cooled the reaction mixture to room
temperature and methanol was removed under reduced pressure. The residue thus obtained was
diluted with water (10.0 mL) and extracted with ethyl acetate (3x25.0 mL). The ethyl acetate layer
was washed with water and brine solution. Dried over anhydrous sodium sulphate and
concentrated under reduced pressure to get the title organic compound.
Yield: 90% (3.2 g); IR (DCM): 3456.6, 1704.5 cm"1; 'H NMR (CDC13):8 7.52-7.54 (m, 2H), 7.27-
7.38 (m, 3H), 4.61 (s, 1H, OH), 3.02-3.07 (m, 1H), 2.11 (s, 3H), 1.26-1.72 (m, 8H).
Example 4: Preparation of 3 -bromo-1 -cyclopentyl-1 -hydroxy-1 -phenyl-2-propanone
To a solution of 1-cyclopentyl-1-hydroxy-1-phenyl-2-propanone (3.4 g, 15.6 mM) in dry
tetrahydrofuran (150.0 mL), tetrahydrofuran solution of pyridine hydrobromide perbromide (6.0 g,
18.7 mM, 85% pure, 100.0 mL of dry tetrahydrofuran) was added dropwise at room temperature
and the stirring was continued for 36 hour at the same temperature. The solid so separated was
filtered and the filtrate was concentrated under reduced pressure. The residue was purified through
column chromatography using 2% ethyl acetate in hexane as an eluent to get the title organic
compound.
Yield: 64% (3.0 g); IR (DCM): 1721.5 cm'1; 'HNMR (CDC13):5 7.50-7.53 (m, 2H), 7.28-7.40 (m,
3H), 4.05-4.2 (m, 2H), 3.80 (s, 1H, -OH), 3.02-3.08 (m, 1H), 1.28-1.43 (m, 8H).
Example 5: Preparation of 1 -cvclopentyl-1 -hydroxv-1 -phenyl-2-propene
To a solution of 1 -cyclopentyl-1 -hydroxy-1-phenyl-2-propyne (5.0 g, 24.8 mM) in toluene
(50.0 mL), palladium on calcium carbonate (0.5 g) was added and the reaction mixture was
subjected to hydrogenation at room temperature under atmospheric pressure. The reaction mixture
was filtered and the residue thus obtained was purified through column chromatography using 2%
ethyl acetate in hexane as an eluent to get the title organic compound.
IR (DCM): 3479.9 cm"1; *HNMR (CDC13):8 7.19-7.47 (m, 5H), 6.21-6.31 (m, 1H), 5.12-5.31 (m,
2H), 2.47-2.58 (m, 1H), 1.36-1.57 (m, 8H).
Example 6: Preparation of 1 -cvclopentyl-l-hvdroxv-l-phenvl-2,3-epoxy propane
To a solution of l-cyclopentyl-l-hydroxy-l-phenyl-2-propene (0.95 g, 4.7 mM) in dry
dichloromethane (10.0 mL) at 0-5°C, dichloromethane solution of m-chloroperbenzoic acid (2.03 g,
5.9 mM, 15.0 mL dichloromethane) was added dropwise. The reaction mixture was stirred at room
temperature for 12 hour and triethylamine (3.0 mL) was added to the reaction mixture and stirred
for 15 minutes. The reaction mixture was poured onto saturated sodium bicarbonate solution (10.0
mL) and dichloromethane layer was separated, washed with saturated sodium bicarbonate solution
(10.0 mL), water (10.0 mL) and brine solution. Dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The residue was purified by column chromatography using
5% ethyl acetate in hexane to get non-polar epoxide-A (0.28 g) and polar epoxide-B (0.5 g).
Non polar epoxide-A: IR (KBr): 3477.5 cm'1; !H NMR (CDC13):6 7.18-7.46 (m, 5H), 3.36-3.38
(m, 1H), 2.57-2.63 (m, 2H), 1.32-1.67 (m, 9H).
Polar epoxide-B: IR (KBr): 3390.7 cm'1; 'H NMR (CDC13):S 7.24-7.50 (m, 5H), 3.48-3.50 (m,
1H), 2.97-2.99 (m, 1H), 2.83-2.86 (m, 1H), 2.50 (m, 1H), 1.33-1.71 (m, 8H).
Example 7: Preparation of 1.1 -diphenyl-1 -hvdroxv-2-propvne.
The title compound was prepared by using benzophenone in place of phenyl cyclopentyl
ketone following the procedure mentioned for the synthesis of 1-cyclopentyl-1-hydroxy-l-phenyl-
2-propyne.
IR (DCM): 3540.0, 3438.4 cm'1; !H NMR (CDC13):8 7.59-7.62 (m, 4H), 7.27-7.36 (m, 6H), 2.89 (s,
1H), 2.86 (s, 1H).
Example 8: Preparation of 1 .l-diphenvl-l-hvdroxy-2-propene
The title compound was prepared by using corresponding acetylenic compound following
the procedure mentioned for the synthesis of 1-cyclopentyl-l-hydroxy-l-phenyl-2-propene.
Yield: 90%; IR (DCM): 3449.4 cm'1; 'H NMR (CDC13):5 7.24-7.43 (m, 10H), 6.47-6.56 (m, 1H),
5.30-5.35 (m, 2H).
Example 9: Preparation of l.l-diphenvl-l-hvdroxy-2.3-epoxv-propane
The title compound was a prepared starting from the corresponding olefin following the
procedure mentioned for the synthesis of 1-cyclopentyl-l-hydroxy-l-phenyl-2,3-epoxy propane.
Polar epoxide B: Yield: 69%; IR (KBr): 3382.9 cm'1; !H NMR (CDC13):8 7.48-7.50 (m, 2H), 7.24-
7.38 (m, 8H), 3.78-3.80 (m, 1H), 2.97-2.99 (m, 1H), 2.77-2.80 (m, 1H), 2.55 (s, 1H).
Example 10: Preparation of (la. 5a. 6a)-6-methvlamino-methyl-3-benzyl-3-
azabicvclo[3.1 .OJhexane
Step a: Preparation of (la, 5a, 6
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1979-delnp-2007-abstract.pdf |
2011-08-21 |
| 1 |
1979-delnp-2007-form-2.pdf |
2011-08-21 |
| 2 |
1979-delnp-2007-claims.pdf |
2011-08-21 |
| 2 |
1979-delnp-2007-form-1.pdf |
2011-08-21 |
| 3 |
1979-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 3 |
1979-delnp-2007-description(complete).pdf |
2011-08-21 |
| 4 |
1979-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 4 |
1979-delnp-2007-description(complete).pdf |
2011-08-21 |
| 5 |
1979-delnp-2007-claims.pdf |
2011-08-21 |
| 5 |
1979-delnp-2007-form-1.pdf |
2011-08-21 |
| 6 |
1979-delnp-2007-abstract.pdf |
2011-08-21 |
| 6 |
1979-delnp-2007-form-2.pdf |
2011-08-21 |