The present invention relates to certain sulfone acetic acid derivatives as MMP
inhibitor and processes for its syntheses. The invention also relates to pharmacological
compositions containing the compounds of the present invention and methods of treating
asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis,
pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome,
perodontitis, multiple scleorisis, gingivitis, atherosclerosis, dry eye, and neointimal
proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease,
tumor metastasis, and other inflammatory disorders characterized by over expression and
over activation of a matrix metalloproteinase using the compounds.
Background of the Invention
Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases
(enzymes) found in most mammals. The superfamily is composed of at least 26 members
of zinc-containing enzymes produced by many cell types; sharing structural and functional
features. Based on structural and functional considerations proteinases have been
classified into different families and subfamilies (Vartak et a , J. Drug Targeting, 15, p.
1-20 (2007), and Hopper, FEBS, 354, p. 1-6 (1994), such as collagenases (MMP-1, -8 and
-13), gelatinases (MMP-2, and -9), metalloelastases (MMP-12), the MT-MMPs (MMP-14,
-15, -16, -17, -24 and -25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10 and
- 11) and sheddases such as TNF-converting enzymes (TACE, and ACE).
Metalloproteinases are believed to be important in physiological disease processes
that involve remodeling such as embryonic development, bone formation and uterine
remodeling during menstruation. One major biological function of MMPs is to catalyze
the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze
various components of tissue or matrix. Apart from their role in degrading connective
tissue, MMPs are involved in the activation of zymogen (pro) forms of other MMPs
thereby inducing MMP activation. They are also involved in the biosynthesis of TNFalpha
which is implicated in many pathological conditions.
MMP-9 (gelatianse B) has been implicated in pathogenesis of COPD, MS and
other inflammatory disorders. MMP-9 is secreted as proenzyme and upon activation,
exhibits distinct roles in the progression of both disease states. For example, leukocyte
mediated activation of MMP-9 exhibits during the inflammatory response associated with
COPD, marks the onset of processes linked to airway obstruction. MMP-9 is the primary
pro-inflammatory mediator of the inflammation and its expression goes higher in all
inflammatory diseases, like COPD, MS, arthritis, psoriasis, etc. Other MMPs are also
involved in some vital and regulatory functions of the cell, so an MMP-9 selective
inhibitor would only target the inflammation component of the disease and would be free
of undesirable toxicity.
Over-expression or over-activation of an MMP, or an imbalance between an MMP
and a natural {i.e., endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has
been linked to a pathogenesis of diseases characterized by the breakdown of connective
tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in treatment of
various inflammatory, autoimmune and allergic diseases such as, inflammation of the
joint, inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound
healing disorders, etc.
The design and therapeutic application of MMP inhibitors has revealed that the
requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a
functional group {e.g., carboxylic acid, hydroxamic acid or sulphydryl) capable of
chelating to the active site Zn + ion (Whittaker et al, Chem. Rev., 99; p. 2735-76 (1999).
WO 03/82841 discloses new 5-substituted l,l-dioxo-l,2,5-thiazolidine-3-one
derivatives as protein tyrosine phosphatase inhibitors used for treating, e.g., diabetes,
metabolic disorders, obesity and ischemic disease. EP 0 507 238 discloses R- and Scarboxylic
acids in the treatment of diabetes, especially diabetes mellitus. EP 0 279 162
discloses new 2-substituted thio-alkanoic acid derivatives useful for treating diabetes,
atherosclerosis, and diseases of lipid metabolism.
Research has been carried out into the identification of inhibitors that are selective,
e.g. , for a few of the MMP subtypes. An MMP inhibitor of improved selectivity would
avoid potential side effects associated with inhibition of MMPs that are not involved in the
pathogenesis of the disease being treated.
Further, use of more selective MMP inhibitors would require administration of a
lower amount of the inhibitor for treatment of disease than would otherwise be required
and, after administration, partitioned in vivo among multiple MMPs. Still further, the
administration of a lower amount of compound would improve the margin of safety
between the dose of the inhibitor required for therapeutic activity and the dose of the
inhibitor at which toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules, i.e., chiral and will
therefore have several stereoisomers depending upon the number of chiral centers present.
The importance of evaluating new chemical entities having chiral centers as single isomers
is to understand their effect on pharmacological and toxicological aspects. There are often
pharmacodynamic, pharmacokinetic and/or toxicological differences between
enantiomers/diastereomers. Even if natural physiological mediators are achiral, based on
their target environment, their receptors/enzymes may demonstrate a preference for only
one optically pure enantiomer of agonists, antagonists or inhibitors. From a
pharmacokinetics point of view, chirality can have an influence on drug absorption,
distribution, metabolism and elimination. Pure single isomers may also offer advantages
in terms of these pharmacokinetic parameters thus enabling better developability of such
molecules as drug candidates. It is also known that chirality has a significant effect of the
physicochemical properties and crystallinity of a chiral molecule which in turn have
profound effects on the pharmacokinetics and developability of the molecule. Besides
those mentioned above, regulatory principles guide one to preferably develop single
isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and
toxicological problems that may arise due to interactions of an unwanted isomer with
undesirable molecular targets.
In this context, synthetic strategies to produce pure single isomers offer advantages
over analytical techniques of separation of isomer not only in terms of cost and efficiency
but larger amounts of compound can be prepared for elaborate pharmaceutical testing.
Thus, compounds of present invention, which are single chiral isomers, have improved
potency, improved pharmacokinetics and/or improved physicochemical properties as
compared to racemic compounds.
The present invention is directed to overcoming problems encountered in the art.
Summary of the Invention
The present invention provides sulfone acetic acid derivatives as matrix
metaIloproteinase-9 inhibitors which are effective therapeutic or prophylactic agents for
the treatment of various inflammatory and allergic diseases. Also provides are processes
for synthesizing such compounds.
The compounds of the present invention are useful for the treatment of
inflammatory and autoimmune diseases.
Pharmaceutical compositions containing such compounds are provided together
with the pharmaceutically acceptable carriers or diluents, which can be used for the
treatment or prevention of inflammatory and autoimmune diseases. These pharmaceutical
compositions may be administered or co-administered by a wide variety of routes
including, for example, oral, topical, rectal, intranasal or by parenteral route. The
composition may also be administered or co-administered in slow release dosage forms.
Although, the specific enantiomers have been shown by way of examples,
racemates, diastereomers, and pharmaceutically acceptable salts are also provided.
Pharmaceutical compositions comprising such compounds, their racemates, enantiomers,
diastereomers, and pharmaceutically acceptable salts are also included.
The therapeutically effective amount of one or more compounds of the present
invention ca be used in combination with one or more other therapeutic agents, for
example, protein synthesis inhibitors, amino glycosides, cell wal synthesis inhibitor
(glycopeptides, beta-lactams, etc.), R A, and DNA synthesis inhibitors or fatty acid
synthesis inhibitors.
Other objects will be set forth in accompanying description and in the part will be
apparent from the description or may be by the practice of the invention.
Detailed Description of the Invention
In accordance with one aspect there is provided a compounds having structure of
Formula I:
COOH
Formula I
including racemates, enantiomers and diastereomers, thereof or a pharmaceutically
acceptable salts thereof.
Wherein,
X can be S, SO or S0 ;
L can be selected from bond, -0-, -S-, -SO, -SO2, -CH , -NR4, -NHCO(CH )„-,
-(CH ) CONH-, -NHCONH-, -S0 NH-, -NHSO2-, -NHCO(O)-, -0-(CH 2)„,
-(CH )„-0-, -OC(0)NH-, -C(S)NH-, -NHC(S), -NHC(S)NH-, -COO- wherein n
can be zero or an integer between 1 and 2;
can be -OCONHR 3, OCSNHR 3, OC¾R 3;
When R is OCONHR 3 or OCSNHR 3 then R can be hydrogen, Ci-Cealkyl,
hydroxy!, C alkoxy, cyano, nitro, halogen, halogeno Ci-C al l, C -C aryl,
C -C cycloalkyl, C5-C12 heteroaryl wherein C -C aryl, C3-C cycloalkyl, C5-C12
heteroaryl is optionally substituted with one or more times with R5;
When R is OCH R3, then R can be C6-Ci aryl, C3-C cycloalkyl, -C12
heteroaryl;
R3 is alkyl, alkenyl, alkynyl, Ce-C^ary], C3-C8 cycloalkyl, C5-C12 heteroaryl, C3-
C12 heterocyclyl which may optionally be substituted one or more times with R5;
R 4 can be H, Ci-ealkyl, Ci-4alkylaryl;
R5 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-
Ci-C alkyl, halogeno-Ci-C& aikoxy, azido, thiol, alkylthiol, -(CH2)n- , -C(=0
Rf, -COORf, -NRfRq, -(CH ) - OC
f , , (CH2)„ NHC^NR R,,, -(CH ) -0-C(=0> R , -iCH )„-NH-C(=0>
Rf or -(CH ) S(=0) -NRrRq {whereinRf and R , are independently selected from
hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl,
alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2};
In one aspect the invention encompasses compounds that include, for example,
4-{[(4-Chlorophenyl)carbamoyl]oxy} -2-[(4-chlorophenyl)sulfanyl]butanoic acid
(Compound no. 1);
2-[(4-Chlorophenyl)sulfanyl]-4- {[(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 2);
4-{[(4-Chlorophenyl)carbamoyl]oxy} -2-[(4-chlorophenyl)sulfony1]butanoic acid
(Compound no. 3);
2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 4);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(4-fluorophenyl
carbamoyl]oxy}butanoic acid (Compound no. 5);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[2-fluoro-5-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
2-[(4-{[(4-Chlorophenyl)carbonyl] amino}phenyl)sulfanyl] -4-{[(3 ,5-
dimethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 7);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(5-fluoro-2-methyl
phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
2-[(4-{[(4-Chlorophenyl)carbonyl] amino}phenyl)sulfanyl] -4-{[(2-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 9);
4-{ [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4- {[(4-chlorophenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3-
ethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 11);
4-{[(3-Chlorophenyl)carbamoyl]oxy} -2-[(4-{[(4-
chlorophenyl)carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 12);
4-{[(4-Chlorophenyl)carbamothioyl]oxy} -2-[(4-{[(4-chlorophenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 13);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3-cyanophenyl)
carbamothioyl]oxy}butanoic acid (Compound no. 14);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{ [(4-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 15);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[2-fluoro-5-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 16);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(5-fluoro-2-methyl
phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4-{[(4-
chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 19);
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 20);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(3-cyanophenyl)
carbamothioyl]oxy}butanoic acid (Compound no. 21);
4-(Benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 22;)
4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 23);
4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 24);
4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 25);
4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino}phenyl)
sulfonyl]butanoic acid (Compound no. 26);
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 27)
4-(Benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid (Compound no. 28);
4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 29);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 30);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 31);
4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 32);
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 33);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 34);
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 35);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(2-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 36);
4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 37);
4-[(fert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 38);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 39);
4-{[(2-Fluorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 40);
4-{[(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 41);
4-{[(3,4-Dichlorophenyl)carbamoy] ]oxy}-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 42);
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbony1]amino}phenyl)sulfanyl]butanoic acid (Compound no. 44);
4-{[(4-Chlorophenyl)carbamoyl]oxy) -2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 45);
4-{[(4-Ethylphenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 46);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)
carbonyl]aminophenyl)}sulfonyl]butanoic acid (Compound no. 48);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49);
4-[(tert-Butylcarbamoy l)oxy]-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 50);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 51);
4-{[(2-Fluorophenyl)carbamoyl] oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 52);
4-{[(3-Fluorophenyl)carbamoyl] oxy}-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 53);
4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy} -2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 54);
4-{[(3,4-Dichlorophenyl)carbamoyl ]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55);
4-{ [(3,4-Dichlorophenyl)carbamoyl]oxy} -2-[(4-{ [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy }-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
4-{ [(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 58);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 59);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-
ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 60);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(propan-2-yl)phenyl]
carbamoyl}oxy)butanoic acid (Compound no. 61);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methoxyphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 62);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 64);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 65);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,4-
difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 67);
2-({4-[(4-Chlorophenyl)carbamoy]]phenyl}sulfanyl)-4-{ [(4-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 68);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,6-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 69);
4-[(t rt-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl}sulfanyl)butanoic acid (Compound no. 70);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3,4-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 71);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-
[(pentylcarbamoyl)oxy]butanoic acid (Compound no. 72);
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 73);
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 74);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 75);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4-
ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 76);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 77);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4- {[(4-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 78);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-( {[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4-
difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4- {[(4-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 81);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-{ [(2,6-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 82);
4-[( r t-Butylcarbamoyl)oxy]-2-( {4-[(4-chlorophenyl)carbamoyl]
phenyl}sulfonyl)butanoic acid (Compound no. 83);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(3,4-dichlorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 84);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-
[(pentylcarbamoyl)oxy]butanoic acid (Compound no. 85);
4-{[(3-Chlorophenyl)carbamoyl]oxy} -2-({4-[(4-chlorophenyl)carbamoyl]
phenyl} sulfonyl)butanoic acid (Compound no. 86);
4-[(Butylcarbamoyl)oxy] -2-( {4-[(4-
chlorophenyl)carbamoyl]phenyl}sulfonyl)butanoic acid (Compound no. 87);
2-[(4-{[(2-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 89);
2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 90);
2-( {4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({ [4-
(trifluoromethyl)phenyl carbamoyl}]oxy)butanoic acid (Compound no. 91);
2-[(4-{[(2-Methylphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 92);
2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 93);
2-[(4-{[(2,3-Difluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 94);
2-[(4-{[(3,4-Dichlorophenyl)carbony1] amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 95);
2-[(4-{[(4-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 96);
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 97);
2-[(4-{[(2,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98).
In another aspect, provided herein, are pharmaceutical compositions comprising
therapeutically effective amounts of one or more compounds described herein together
with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided herein are methods for treating or preventing various
inflammatory and allergic diseases comprising administering to a mammal in need thereof
therapeutically effective amount of one or more compounds of Formula 1 described
herein.
In yet another aspect, the present invention relates to the therapeutically effective
amount of compounds of Formula I in combination with one or more of other therapeutic
agents used in treating various inflammatory and allergic diseases. Examples of such
therapeutic agents includes but are not limited to:
a) anti-inflammatory agents, experimental or commercial (i) such as
nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids,
fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin
inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5-
lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors,
(iv) MMP inhibitors, and (v) interleukin-I inhibitors;
b) antihypertensive agents, (i) ACE inhibitors, e.g., enalapril, lisinopril,
valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists
and agonists, e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan,
(iii) b-blockers, and (iv) calcium channel blockers.
c) immunosuppressive agents such as cyclosporine, azathioprine and
methotrexate, and anti inflammatory corticosteroids.
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 can
be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term "alkenyl" unless otherwise specified, refers to a monoradical of a
branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms
with cis, trans or geminal geometry.
The term "aikynyl" unless otherwise specified, refers to a monoradical of an
unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
The term "cycloalkyl" unless otherwise specified, refers to cyclic alkyl groups of
from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which
may optionally contain one or more olefinic bonds, unless otherwise constrained by the
definition. Such cycloalkyl groups can include, for example, single ring structures,
including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyi, and the like or multiple ring
structures, including 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 and fused ring
structures can also be included.
The term "aryl" unless otherwise specified, refers to aromatic system having 6 to
14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are
carbocyclic aromatic groups. For example, aryl groups include, but are not limited to,
phenyl, biphenyl, anthryl or naphthyl ring and the like, optionally substituted with 1 to 3
substituents selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, aikynyl,
cycloalkyl, alkoxy, acyl, aryloxy, CF , cyano, nitro, COOR , NHC (=0)R L, -NR R„,
-C(=0)NRxR», -NHC(=0)NRxR , -0-C(=0)NR¾R„, -SOmR , carboxy, heterocyclyl,
heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino, mercapto,
haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl,
-CONHR,, -OCOR,, -COR , -NHS R or -SOaNHR. (wherein R , R ,m and are the
same as defined earlier). Aryl groups optionally may be fused with a cycloalkyl group,
wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
The term "aralkyl" unless otherwise specified, refers to alkyl-aryl linked through
an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6
carbon atoms and aryl is as defined above. Examples of aralkyl groups include benzyl,
ethylphenyl, propylphenyl, naphthylmethyl, and the like.
The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined
above.
The term "heteroaryl" unless otherwise specified, refers to an aromatic ring
structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from
8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
Unless otherwise constrained by the definition, the substituents are attached to a ring atom,
i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl,
imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl,
benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl,
isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl,
benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl,
benzothiazolyl or benzoxazolyl, and the like.
The term "heterocyclyl" unless otherwise specified, refers to a non-aromatic
monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms
in a ring are replaced by heteroatoms selected from O, S or N, and optionally are
benzofused or fused heteroaryl having 5-6 ring members. Examples of heterocyclyl
groups include benzotriazinone, isoindoledione, pyrimidinedione, azaspiro[
4.5]decanedione, benzo-oxazinedione, imidazolidinedione, phthalazinone,
oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl,
benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl,
dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl,
dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl,
3H-imidazo[4,5-6]pyridine, isoquinolinyl, lH-pyrrolo[2,3-6]pyridine or piperazinyl, and
the like.
The term "cycloalkylalkyl" refers to cycloalkyl group linked through alkyl
portion, wherein the alkyl having 1 to 6 carbon atoms and cycloalkyl are the same as
defined earlier.
The term "heteroarylalkyl" refers to heteroaryl group linked through alkyl portion,
wherein the alkyl having 1 to 6 carbon atoms and heteroaryl are the same as defined
earlier.
The term "heterocyclylalkyl" refers to heterocyclyl group linked through alkyl
portion, wherein the alkyl having 1 to 6 carbon atoms and heterocyclyl are the same as
defined earlier.
The term "amino" refers to —NH2
The term "halogen or Halo" refers to fluorine, chlorine, bromine or iodine;
The term "leaving group" refers to groups that exhibit or potentially exhibit the
properties of being labile under the synthetic conditions and also, of being readily
separated from synthetic products under defined conditions. Examples of leaving groups
include, but are not limited to, halogen (e.g., F, CI, Br, I), triflates, tosylate, mesylates,
alkoxy, thioalkoxy, or hydroxy radicals, and the like.
The term "protecting groups" refers to moieties that prevent chemical reaction at a
location of a molecule intended to be left unaffected during chemical modification of such
molecule. Unless otherwise specified, protecting groups may be used on groups, such as
hydroxy, amino, or carboxy. Examples of protecting 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., which is incorporated herein by reference. The species of the carboxylic
protecting groups, amino protecting groups or hydroxy protecting groups employed are
not critical, as long as the derivatised moieties/moiety is/are stable to conditions of
subsequent reactions and can be removed without disrupting the remainder of the
molecule.
The compounds of this invention can contain one asymmetric carbon atom and
thus may occur as racemic mixtures, enantiomers and diasteromers. These compounds
can also exist as conformers/rotamers. All such isomeric forms of these compounds are
included in the present invention. Each stereogenic carbon atom may be of the R T S
configuration. Although the specific compounds exemplified in this application may be
depicted in a particular sterochemical configuration, compounds having either the opposite
stereochemistry at any given chiral center or mixture thereof are envisioned as part of the
invention.
The term "pharmaceutically acceptable salts" forming part of this invention
includes the salts of carboxylic acids moiety, which can be prepared by reacting the
compound with appropriate base to provide corresponding base addition salts. Examples
of such base are alkali metal hydroxide including potassium hydroxide, sodium hydroxide,
and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and
calcium hydroxide. Further, the salts of organic bases such as lysine, arginine, guanidine,
ethanolamine, choline and the like, inorganic bases, e.g., ammonium or substituted
ammonium salts are also included. Wherever appropriate, compounds with
pharmaceutically acceptable organic and inorganic acids, e.g., hydro halides, such as
hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding
salts, such as sulphate, nitrate, phosphate etc. and alkyl and mono-arylsulphonates, such as
ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids
and their corresponding salts, such as acetate, tartaratae, maleate, succinate, citrate, etc.
In another aspect, the compounds disclosed herein may be prepared by following
reaction sequences as depicted in Schemes I, and II.
Scheme I
Formula 16
Formula I when L is
-NHCO and R1 is OC(Z)NHR»
The compound of Formula 8 (Path A), Formula 9 (Path A), Formula 1 (Path B),
Formula 16 (Path B), Formula 19 (Path C) and Formula 20 (Path C) can be prepared
according to Scheme I. Thus, reacting a compound of Formula 2 (wherein Y is N0 , Hal
and COOH) with alpha bromo lactone gives a compound of Formula 3. The compound of
Formula 3 can react in three ways to give a compound of Formula 8, Formula 9, Formula
15, Formula 16, Formula 19 and Formula 20.
Path A (when Y is COOBT): The reaction of a compound of Formula 3 with a compound
of Formula 3' (where R2 is same as defined earlier) to give a compound of Formula 4
which upon reaction with a compound of Formula 4' (wherein R' is alkyl, allyl, benzyl, tbutyl,
silyl and Hal is F, CI, Br, I) gives a compound of Formula 5. The reaction of a
compound of Formula 5 with a compound of Formula 6 (where R3 is same as defined
earlier and Z is O or S) gives a compound of Formula 7. The hydrolysis of a compound of
Formula 7 gives a compound of Formula 8 which upon oxidation gives a compound of
Formula 9.
Path B (when Y is N0 2): The reduction of a compound of Formula 3 gives a compound
of Formula 10 which upon reaction with a compound of Formula 11 (wherein R2 is same
as defined earlier and U is a leaving group such as halide, alkyloxy, aryloxy) gives a
compound of Formula 12. The compound of Formula 12 upon reaction with a compound
of Formula 4' (wherein R' and Hal are same as defined earlier) gives a compound of
Formula 13. The reaction of a compound of Formula 13 with a compound of Formula 6
(wherein R3 and Z are same as defined earlier) gives a compound of Formula 14. The
hydrolysis of a compound of Formula 14 gives a compound of Formula 15 which upon
oxidation gives a compound of Formula 16.
Path C (when Y is halogen): The reaction of a compound of Formula 3 with a compound
of Formula 4' (wherein R' and Hal is same as defined earlier) gives a compound of
Formula 17 which upon reaction with a compound of Formula 6 (wherein R3 and Z are
same as defined as earlier) gives a compound of Formula 18. The hydrolysis of a
compound of Formula 18 gives a compound of Formula 19 which upon oxidation gives a
compound of Formula 20.
The reaction of a compound of Formula 2 with alpha bromo lactone to give a
compound of Formula 3 can be carried out in the presence of organic base, for example,
triethylamine, pyridine, N iV-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, Nethyldiisopropylamine
or N-methylmorpholine in a solvent selected from,
dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s) thereof.
The reaction of a compound of Formula 3 (Path A) with a compound of Formula 3'
to give a compound of Formula 4 can be carried out using base selected from
triethylamine, pyridine, N N-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, Nethyldiisopropylamine
or N-methylmorpholine, in the presence of a additives, for example,
hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo- 1,2,3-benzotriazine, 2-
hydroxypyridine, N-hydroxysuccinimide or l-hydroxy-7-azabenzotriazole, with a suitable
condensing agent, for example, dicyclohexyl carbodiimide, l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride, chlorotripyrrolidinophosphonium hexafluorophosphate
or (benzotriazol- 1-yloxy)ira-(dimethylamino)phosphonium hexafluorophosphate.
The reaction of a compound of Formula 4 with a compound of Formula 4' to give
a compound of Formula 5 can be carried out in the presence of 18-crown-6 using one or
more inorganic base selected from sodium bicarbonate, sodium hydroxide, potassium
hydroxide, lithium hydroxide in the presence of a solvent, selected from, N, N -
dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile,
water, or mixture thereof.
The reaction of a compound of Formula 5 with a compound of Formula 6 to give a
compound of Formula 7 can be carried out in the presence of organic base selected from,
for example, triethylamine, pyridine, N iV-dimethylaminopyridine, 2,6-lutidine, 1-
methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected
from tetrahydrofuran, dimethylsulfoxide, acetonitrile, N, N -dimethylformamide, or
mixture(s) thereof.
The hydrolysis of a compound of Formula 7 to give a compound of Formula 8 can
be carried out in the presence of inorganic base selected from, for example, lithium
hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide in solvents for
example, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol, dimethylsulfoxide, or
mixture(s) thereof.
The oxidation of a compound of Formula 8 to give a compound of Formula 9 can
be carried out with oxidizing agents, for example, meta-chloroperbenzoic acid or oxone in
a solvent, selected from, chloroform, dichloromethane, methanol, water, carbon
tetrachloride, or mixture(s) thereof.
The reduction of a compound of Formula 3 (Path B) to give a compound of
Formula 10 can be carried out using reducing agent selected from, for example, Pd/C,
lithium aluminum hydride, Raney Nickel in the presence of hydrazine hydrate, zinc, tin or
iron in the presence of hydrochloric acid in a solvent selected from tetrahydrofuran,
methanol, ethanol, dichloromethane, or mixture(s) thereof.
The reaction of a compound of Formula 10 with a compound of Formula 11 to give
a compound of Formula 1 can be carried out in the presence of organic base, for
example, triethylamine, pyridine, 2,6-lutidine, 1-
methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected
from, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s)
thereof.
The ring opening of a compound of Formula 12 with a compound of Formula 4' to
give a compound of Formula 13 can be carried out under similar conditions as described
for the reaction of a compound of Formula 4 with a compound of Formula 4' to give a
compound of Formula 5.
The reaction of a compound of Formula 13 with a compound of Formula 6 to give
a compound of Formula 14 can be carried out under similar conditions as described for the
reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound
of Formula 7.
The hydrolysis of a compound of Formula 14 to give a compound of Formula 15
can be carried out under similar conditions as described for the reaction of a compound of
Formula 7 to give a compound of Formula 8.
The oxidation of a compound of Formula 15 to give a compound of Formula 16
can be carried out under similar conditions as described for the compound of Formula 8 to
give a compound of Formula 9.
The reaction of a compound of Formula 3 (Path C) with a compound of Formula 4'
to give a compound of Formula 17 can be carried out under similar conditions as described
for the reaction of compound of Formula 4 with a compound of Formula 4' to give a
compound of Formula 5.
The reaction of a compound of Formula 17 with a compound of Formula 6 to give
a compound of Formula 18 can be carried out under similar conditions as described for the
reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound
of Formula 7.
The hydrolysis of a compound of Formula 18 to give a compound of Formula 19
can be carried out under similar conditions as described for the hydrolysis of a compound
of Formula 7 to give a compound of Formula 8.
The oxidation of a compound of Formula 19 to give a compound of Formula 20
can be carried out under similar conditions as described for the compound of Formula 8 to
give a compound of Formula 9.
Scheme P
Formula 29 Formula 28 Formula 27
The compound of Formula 27 (Path D) and Formula 30 (Path E) can be prepared
according to Scheme II. Thus, reaction of a compound of Formula 2 1 with a compound of
Formula 22 (wherein R' and Hal are same as defined earlier) gives a compound of
Formula 23 which upon oxidation gives a compound of Formula 24. The reaction of a
compound of Formula 24 with a compound of Formula 25 (Bn is benzyl group and Hal is
same as defined earlier) forms a compound of Formula 26. The compound of Formula 26
can be reacted in two ways to give a compound of Formula 27 and Formula 30.
Path D: The hydrolysis of a compound of Formula 26 gives a compound of Formula 27.
Path E: The reduction of a compound of Formula 26 gives a compound of Formula 28
which upon reaction with a compound of Formula 11 (wherein R2 and U are same as
defined earlier) gives a compound of Formula 29. The compound of Formula 29 upon
hydrolysis gives a compound of Formula 30.
The reaction of a compound of Formula 2 1 with a compound of Formula 22 to give
a compound of Formula 23 can be carried out in the presence of organic base selected
from, for example, triethylamine, pyridine, N N'-dimethylaminopyridine, 2,6-lutidine, 1-
methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected
from dichlormethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran,
dimethylsulfoxide, acetonitrile, N, N'-dimethylformamide, or mixture(s) thereof.
The oxidation of a compound of Formula 23 to form a compound of Formula 24
can be carried out under similar conditions as described for the compound of Formula 8 to
give a compound of Formula 9.
The reaction of a compound of Formula 24 with a compound of Formula 25 to give
a compound of Formula 26 can be carried out using tetrabutylammonium iodide in the
presence of inorganic base selected from lithium carbonate, sodium carbonate, potassium
carbonate, barium carbonate using a solvent selected from, N N -dimethylformamide,
acetonitrile, tetrahydrofuran, dimethylsulfoxide, or mixture(s) thereof.
The hydrolysis of a compound of Formula 26 (Path D) to give a compound of
Formula 27 can be carried out under similar conditions as described for the compound of
Formula 7 to give a compound of Formula 8.
The reduction of a compound of Formula 26 (Path E) to give a compound of
Formula 28 can be carried out using reducing agent selected from, for example, lithium
aluminum hydride, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or
iron in the presence or in the absence of hydrochloric acid.
The reaction of a compound of Formula 28 with a compound of Formula 11 to give
a compound of Formula 29 can be carried out under similar conditions as described for the
reaction of a compound of Formula 10 with a compound of Formula 11 to give a
compound of Formula 12.
The hydrolysis of a compound of Formula 29 to give a compound of Formula 30
can be carried out under similar conditions as described for the compound of Formula 7 to
give a compound of Formula 8.
In the above schemes, where specific reagents, for example, bases, acids, solvents,
condensing agents, hydrolyzing agents, catalysts, etc., as mentioned, is to be understood
that other reagents, e.g., other acids, bases, solvents, condensing agents, reducing agent,
deprotecting agent, hydrolyzing agents, catalysts, etc., known to one of ordinary skill in
the art may be used. Similarly, reaction temperatures and durations may be adjusted
according to the desired needs without undue experimentation and well within the abilities
of one of ordinary skill in the art.
The compounds described herein may be administered to an animal for treatment
orally, topically, rectally, intemasally or by parenteral route. Pharmaceutical compositions
disclosed herein comprise pharmaceutically effective amounts of compounds described
herein formulated together with one or more pharmaceutically acceptable carriers,
excipients or diluents.
Solid form preparations for oral administration include capsules, tablets, pills, powder,
granules, lozenges, troches, cachets and suppositories. For solid form preparations, active
compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or
carrier. Tablets and capsules for oral administration may contain conventional excipients,
such as binding agents and/or dissolution enhancers, for example, polyvinyl pyrrolidine,
cellulose, mucilage of starch, gelatin, sorbitol, syrup, acacia or tragacanth; fillers or
bulking agents, for example, microcrystalline cellulose, sugar, maize-starch, calcium
phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethyleneglycol,
magnesium stearate or stearic acid; disintegrating agents and binder, for example,
croscarmellose sodium, pregelatinized starch, sodium starch gylcollate or potato starch;
glidants, for example, colloidal silicon dioxide or talc; antiadherants, for example,
magnesium stearate or sodium luaryl sulfate; and coating materials.
Capsules, tablets or pills may also comprise buffering agents.
Tablets, capsules, pills or granules can be prepared using one or more coatings or
shells to modulate the release of active ingredients, for example, enteric coatings or other
coatings known to one of ordinary skill in the art.
General Example
A formulation of a tablet could typically contain from 0.01 mg to 500 mg of active
compound whilst tablet fill weight may range from 50 mg to 1000 mg. An example is
illustrated below.
Ingredients Amount % w/w
Active Compound 0.01 to 20 mg
Microcrystalline Cellulose about 50% to about 90%
Croscarmellose Sodium about 1% to about 10%
Pregelatinized Starch about 1% to about 15%
Polyvinyl Pyrrolidone (K-30) about 5% to about 12%
Talc about 0.1% to about 2%
Magnesium Stearate about 0.1% to about 2%
Colloidal Silicon Dioxide about 0.1% to about 2%
Liquid form preparations for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form
preparations, active compounds can be mixed with water or one or more non-toxic
solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn,
germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan, or mixtures
thereof. Oral compositions can also include one or more adjuvants, for example, wetting
agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents,
perfuming agents, or mixtures thereof.
Injectable preparations, for example, sterile injections, and aqueous suspensions
may be formulated according to methods known to one of ordinary skill in the art, and in
particular, using one or more suitable dispersing or wetting and suspending agents.
Acceptable vehicles and solvents that may be employed include one or more of water,
Ringer's solution, isotonic sodium chloride, or mixtures thereof.
Suppositories for rectal administration of the compound of this invention can be
prepared by mixing the drug with suitable nonirritating excipients such as coca butter and
polyethylene glycols, which are solid at ordinary temperatures but liquid at body
temperature and which therefore melt in the rectum and release the drug.
Dosage forms for topical or transdermal administration of a compound of the
present invention include ointments, pastes, creams, lotions, gels, powders, solutions,
sprays, inhalants or patches. Active compounds can be admixed under sterile condition
with one or more pharmaceutically acceptable carriers and optionally any preservatives or
buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders
and solutions are also encompassed within the scope of this invention.
Pharmaceutical preparations may be in unit dosage form. In unit dosage form, the
preparations can be subdivided into unit doses containing appropriate quantities of active
components. Unit dosage forms can be packaged preparations containing discrete
capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams
or any combination and number of such packaged forms.
The following examples are set forth to demonstrate general synthetic procedures
for the preparation of representative compounds of the present invention. The examples
are provided to illustrate particular aspect of the disclosure and do not limit the scope of
the present invention.
Experimental
Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc.,
were dried using various drying reagents according to procedure as described in the
literature.
Example 1: Synthesis of 2-(i4-[(4-chlorophenvncarbamoyl1phenyl}sulfanyl)-4-ir(4-
fluoro phenyl)carbamoyl1oxy}butanoic acid (Compound no. 68) (Scheme Path A,
Formula 8)
Step a: Preparation of 4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]benzoic acid
To an ice cooled solution of 4-mercaptobenzoicacid (0.5 g, 0.003 moles) in
dichloromethane (5 mL) under argon atmosphere were added triethylamine (0.909 g,
0.009 moles) and a solution of bromo lactone (0.53 g, 0.003 moles) in dichloromethane (5
mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes. After
completion, reaction mixture was diluted by adding water and extracting in
dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate
and concentrated to get crude product which was purified by silica gel column using 70%
ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.800 g
LCMS: 239.16 (M+l)
Step b: Preparation of N-(4-chlorophenyl)-4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]
benzamide
To the solution of compound obtained from Step a (15.0 g, 0.0630 moles) in
dichloromethane (150 mL) were added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide)
(EDCI, 18.0 g, 0.0942 moles), hydroxybenzotriazole (HOBT 10.2 g, 0.0689 moles), 4-
dimethylaminopyridine (DMAP 1.5 g, 0.0122 moles) and stirred for about 30 minutes
under argon atmosphere. After 30 minutes, 4-chloroaniline (8.0 g, 0.0630 moles) was
added and again stirred for about 12 hours at room temperature. After completion,
reaction mixture was diluted by adding water and extracting in dichloromethane. The
combined organic layer was dried over anhydrous sodium sulphate and concentrated to get
crude compound which was purified by column chromatography using 40% ethyl acetate
in hexane as eluent to get desired compound.
Yield: 13.0 g
LCMS: 348.05 (M+l)
Step c : Preparation of methyl 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-
hydroxybutanoate
To a solution of compound obtained from Step b (13.0 g, 0.037 mole) in N,Ndimethylformamide
(52 mL) and water (13 mL) was added sodium hydroxide (1.70 g,
0.044 moles). The reaction mixture was allowed to stir for about 30 minutes at room
temperature. After 30 minutes, sodium bicarbonate (3.7 g, 0.044 moles), 18 crown 6
(0.970 g, 0.0037 moles) and methyl iodide (7.80 g, 0.055 moles) were added and stirred
for overnight. After completion, reaction mixture was diluted by adding water and
extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium
sulphate and concentrated to get crude product which was purified by silica gel column
using 30% ethyl acetate in hexane as eluent to get desired compound.
Yield: 8.0 g
Step d: Preparation of methyl 2-({4-[(4-chlorophenyl)carbamoyl] phenyl}sulfanyl)-4-
{[(4-fluorophenyl)carbamoyl]oxy}butanoate
To a solution of compound obtained from Step c (0.500 g, 0.0013 moles) in
tetrahydrofuran (5 mL) under argon atmosphere were added triethylamine (0.393 g,
0.0038 moles) and 4-fluoro-isocyanate (0.213 g, 0016moles) and stirred for about 2 hours
at room temperature. After completion, reaction mixture was diluted by adding water and
extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium
sulphate and concentrated to get crude product which was purified by silica gel column
using 30% ethyl acetate in hexane as eluent to afford desired compound.
Yield: 0.3 g
Step e: Preparation of 2-({4-[(4-chlorophenyl)carbamoyI]phenyl}sulfanyl)-4-{[(4-
fluorophenyl)car ba oy1] ox }butanoic acid
To a solution of compound obtained from Step d (0.300 g, 0.0005 moles) in
tetrahydrofuran (5ml)/methanol (5ml) was added a solution of lithium hydroxide (0.036 g,
0.0006 moles) in water ( 1 mL) and stirred for about one hour at room temperature. After
completion, reaction mixture was acidify by adding sodium bisulphite solution and
extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium
sulphate and concentrated to get a compound which was purified by preparative TLC
eluted using 10% methanol in dichloromethane.
Yield: 0.050 g
LCMS: 501.15 (M-l)
H NMR (400 MHz, DMSO- )- :10.28 - 10.35 (1H, s), 9.67 (1H, s), 7.76 - 7.78 (4H, m),
7.53 - 7.55 (2H, m), 7.32 - 7.44 (3H, m), 7.07 - 7.20 (3H, m), 4.18 - 4.21 (2H, m), 3.98 -
4.02 (1H, m), 1.90 -2.23 (2H, m).
The following compounds can be prepared by following the above synthetic route.
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 59);
LCMS: 501.17 (M-l)
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- {[(4-
ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 60);
LCMS: 5 11.22 (M-2)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(propan-2-yl)phenyl]
carbamoyl }oxy)butanoic acid (Compound no. 61);
LCMS: 525.19 (M-2)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methoxyphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 62);
LCMS: 513.18 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
LCMS: 497.18 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3-fluoro phenyl)
carbamoyl]oxy}butanoic acid (Compound no. 64);
LCMS: 501.16 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 65);
LCMS: 417.17 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);
LCMS: 551.09 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,4-difluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 67);
LCMS: 519.15 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- {[(2,6-
dichlorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 69);
LCMS: 553.06 (M)
4-[(rert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl
butanoic acid (Compound no. 70);
LCMS: 463.20 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3,4-
dichlorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 71);
LCMS: 553.03 (M)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-
[(pentylcarbamoyl)oxy]butanoic acid (Compound no. 72);
LCMS: 477.19 (M-l)
4-{[(3-Chlorophenyl)carbamoy1 ]oxy}-2-( {4-[(4-chlorophenyl)carbamoy l]phenyl }
sulfanyl)butanoic acid (Compound no. 73);
LCMS: 519.10 (M)
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-
chlorophenyl)carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 74);
LCMS: 463.17 (M-l)
Example 2: Synthesis of 2-( 4- (4-chlorophenyl)carbamoyl1phenyl?sulfonyl)-4-{[(4-
fluorophenvDcarbamoylloxylbutanoic acid (Compound no. 81) (Scheme I, Path A,
Formula 9)
To an ice-cooled solution of 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)-
4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid (0.050 g, 0.00009 moles) in chloroform
(5 mL) was added metachloroperbenzoic acid (0.065 g, 0.00037 moles) and stirred for 1
hour at room temperature. The reaction mixture was quenched by adding sodium
metabisulphite solution and then extracted in dichloromethane. The combined organic
layer was dried over anhydrous sodium sulphate and concentrated to get crude product
which was purified by preparative TLC eluted in 12% methanol in dichloromethane.
Yield: 0.030 g
LCMS: 533.18 (M-l)
H NMR (400 MHz, DMSO- ) -d: 10.63 - 10.71 (1H, s), 9.10 (1H, s), 8.10 - 8.12 (2H, d,
J = 8.0 Hz), 7.96 -7.98 (2H, d, J = 8.0 Hz), 7.83 - 7.86 (2H, m), 7.41 - 7.44 (4H, m), 7.10 -
7.21 (2H, m), 4.17 (2H, m), 3.86 (1H, m), 2.1 1 (2H, m).
The following compounds can be prepared by following the above synthetic route.
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- {[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 75);
LCMS: 533.21 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4-
ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 76);
LCMS: 543.24 (M-2)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 77);
LCMS: 529.22 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 78);
LCMS: 529.20 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-( {[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79);
LCMS: 583.21 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4-
difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80);
LCMS: 551.19 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- {[(2,6-dichlorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 82);
LCMS: 541.11 (M-44)
4-[(t rt-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl}
sulfonyl)butanoic acid (Compound no. 83);
LCMS: 451.19 (M-45)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(3,4-dichlorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 84);
LCMS: 585.09 (M)
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-
[(pentylcarbamoyl)oxy]butanoic acid (Compound no. 85);
LCMS: 509.24 (M-l)
4-{[(3-Chlorophenyl)carbamoyl]oxy }-2-( {4-[(4-chlorophenyl)carbamoyl]phenyl }
sulfonyl butanoic acid (Compound no. 86);
LCMS: 551.11 (M)
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl}
sulfonyl)butanoic acid (Compound no. 87);
LCMS: 495.24
Example 3: Synthesis of 2-[(4-{[(4-chlorophenyl )carbonyl1amino|phenyl)sulfanyll -4-
{[(4-fluoro phenyl)carbamoyl]oxyl butanoic acid (Compound no. 5) (Scheme I, Path B
Formula 15)
Step a: Preparation of 3-[(4-nitrophenyl)sulfanyl]dihydrofuran-2(3 H)-one
To an ice-cooled solution ofp-nitro thiophenol (10.0 g, 0.0645 moles) in
dichloromethane (75 mL) under argon atmosphere were added triethylamine (19.4 g,
0.1935 moles) and a solution of bromo-lactone (11.1 g, 0.067 moles) in dichloromethane
(75 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes at room
temperature. After completion, reaction mixture was diluted with water and extracted in
dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate
and concentrated to get a crude product. The crude product so obtained was purified by
silica gel column using 30% ethyl acetate in hexane as eluent to get title compound.
Yield: 11 g
Step b: Preparation of 3-[(4-aminophenyl)sulfanyl]dihydrofuran-2(3H)-one
To the solution of compound obtained from Step (10.0 g, 0.04184 moles) in
tetrahydrofuran/methanol (100 mL: 100 mL) was added Pd/C (4 g) under vacuum and
hydrogen pressure was applied using balloon. The reaction mixture was allowed to stir for
about 2 hours at room temperature. After completion, reaction mixture was filtered
through celite and concentrated to get desired compound.
Yield: 5.0 g
LCMS: 210 (M+1)
Step c : Preparation of 4-chloro-N-{4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]phenyl}
benzamide
To a solution of compound obtained from Step b (4.86 g, 0.0232 moles) in
dichloromethane ( 100 mL) under argon atmosphere was added triethylamine (7.04 g,
0.0697 moles) and cooled to 0°C and then 4-chlorobenzoyl chloride (4.27 g, 0.024 moles)
was added slowly drop wise. The reaction mixture was allowed to stir for 10 minutes at
room temperature. After completion, reaction mixture was diluted with water and
extracting in dichloromethane. The organic layer was washed with sodium bicarbonate
and separated. The organic layer was dried over anhydrous sodium sulphate and
concentrated to obtain a crude product. The crude product obtained was purified by silica
gel column using 10% ethyl acetate in hexane as eluent.
Yield: 4.0 g
LCMS: 348 (M+l)
Step d: Preparation of methyl 2-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl)
sulfanyl]-4-hydroxybutanoate
To a solution of compound obtained from Step c (8.2 g, 0.0236 moles) in N, -
dimethylformamide (32 mL) and water (8 mL) was added sodium hydroxide (1.12 g,
0.0283 moles). The reaction mixture was allowed to stir for about 30 minutes at room
temperature. After 30 minutes, sodium bicarbonate (2.3 g, 0.0283 moles), 18 crown 6
(0.620 g, 0.0023 moles) and methyl iodide (5.02 g, 0.0354 moles) were added to reaction
mixture and stirred for overnight at room temperature. After completion, reaction mixture
was diluted by adding water and extracting in ethyl acetate. The organic layer was dried
over anhydrous sodium sulphate and concentrated to get a crude product which was
purified by silica gel column using 8% ethyl acetate in hexane as eluent.
Yield: 8.0 g
Step e : Preparation of methyl 4-{[(4-chlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-
chlorophenyl)carbony 1]amino}phenyl)sulfany1] butanoate
To a solution of compound obtained from Step d (0.500 g, 0.0013 1 moles) in
tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.266 g,
0.0026 moles) and l-chloro-4-isocyanatobenzene (0.211 g, 0.0015 moles) and stirred for
about 2 hours at room temperature. After completion, reaction mixture was diluted by
adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous
sodium sulphate and concentrated to get crude product which was purified by silica gel
column using 15% ethyl acetate in hexane as eluent.
Yield: 0.4 g
Step f : Preparation of 4-{[(4-chlorophenyl)carbamoyl]oxy }-2-[(4-{[(4-chlorophenyl)
carbonyl]amino}phenyl)sulfanyl] butanoic acid
To a solution of compound obtained from Step e (0.300 g, 0.0005 moles) in
tetrahydrofuran /methanol (5 mL:5 mL) was added a solution of lithium hydroxide (0.034
g, 0.0008 moles) in water and stirred at room temperature for about one hour. After
completion, reaction mixture was acidify with sodium bisulphite solution and then
extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium
sulphate and concentrated to get crude product which was purified by preparative TLC
using 10% methanol/dichloromethane as eluent.
Yield: 0.080 g
LCMS: 503 (M+l), 520 (M+18)
H NMR (400 MHz, DMSO- ¾ d 10.4 (1H, s), 9.66 (1H, s), 7.95 - 7.97 (2H, d, J = 8.4
Hz), 7.73 - 7.76 (2H, d, J = 8.4 Hz), 7.59 - 7.61 (2H, d, J = 8.4 Hz), 7.43 - 7.49 (4H, d, J =
8.4 Hz), 7.06 - 7.15 (2H, d, J = 4.0 Hz), 5.7 (1H, s), 4.12 - 4.23 (2H, m), 3.72 - 3.76 (1H,
m), 2.07 - 2.12 (1H, m), 1.89 -1.96 (1H, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[2-fluoro-5-
(trifluoro methyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
LCMS: 571.11 (M+l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3,5-
dimethoxyphenylcarbamoyl]oxy}butanoic acid (Compound no. 7);
LCMS: 545.11 (M)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(5-fluoro-2-methyl
phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
LCMS: 517.17 (M+l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 9);
LCMS: 503.11 (M+l)
4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4- {[(4-chlorophenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
LCMS: 549.03 (M)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3-ethoxyphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 11);
LCMS: 529.15 (M), 546.19 (M+l 7)
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]amino}
phenyl)sulfanyl]butanoic acid (Compound no. 12);
LCMS: 519.07 (M), 536.11 (M+l 7)
4-{[(4-Chlorophenyl)carbamothioyl]oxy} -2-[(4- {[(4-chlorophenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 13);
LCMS: 535.03 (M)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3-
cyanophenyl)carbamothioyl]oxy}butanoic acid (Compound no. 14);
LCMS: 527.12 (M+l)
4-{[(2-Fluorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methylphenyl)carbonyl]amino}
phenyl)sulfanyl]butanoic acid (Compound no. 29) ;
LCMS: 483.14 (M+l)
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl]amino}
phenyl)sulfanyl]butanoic acid (Compound no. 30);
LCMS: 483.21 (M+l)
4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}
phenyl)sulfanyl]butanoic acid (Compound no. 32);
LCMS: 513.22 (M-l)
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4- {[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 33);
LCMS: 507.28 (M-l)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 34);
LCMS: 547.20 (M-l)
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 35);
LCMS: 547.3 (M-2)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(2-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 36);
LCMS: 493.22 (M-l)
4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 37);
LCMS: 509.26 (M-l)
4-[( rt-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}phenyl)
sulfanyl]butanoic acid (Compound no. 38);
LCMS: 459.24 (M-l)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 39);
LCMS: 515.20 (M-l)
4-{ [(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)carbonyl]amino}
phenyl)sulfanyl]butanoic acid (Compound no. 40);
LCMS: 497.25 (M-l)
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}
phenyl)sulfanyl]butanoic acid (Compound no. 41);
LCMS: 497.25 (M-l)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 42);
LCMS: 547.14 (M-2)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
LCMS: 535.09 (M+2)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 44);
LCMS: 501.15 (M+l)
2-[(4-{[(2-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88);
LCMS: 535.27 (M-l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 89);
LCMS: 551.27 (M-l)
2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 90);
LCMS: 577.29 (M-l)
2-( {4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 91);
LCMS: 483.19 (M+l)
2-[(4-{[(2-Methylphenyl)carbonyl]amino} phenyl)sulfanyl] -4-({[4-
(trifluoromethyl)phenyl] carbamoyl} oxy)butanoic acid (Compound no. 92);
LCMS: 531.25 (M-l)
2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 93);
LCMS: 561.27 (M-l)
2-[(4- {[(2,3-Difluorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-( {[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 94);
LCMS: 553.21 (M-l)
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 95);
LCMS: 585.21 (M-2)
2-[(4-{[(4-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 96);
LCMS: 561.28
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 97);
LCMS: 523.33 (M-l)
2-[(4-{[(2,4-Dichlorophenyl)carbonyl] amino}phenyl)sulfanyl] -4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98);
LCMS: 585.19 (M-2), 587.15 (M).
Example 4: Synthesis of 2-[(4-{[(4-chlorophenyl)carbonyllamino}phenyl)sulfonvn-4-
[(4-fluoro phenyl)carbamoyl]oxy}butanoic acid (Compound no. 15) (Scheme I, Path B
Formula 16)
To an ice-cooled solution of 4-{[(4-fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-
chlorophenyl)carbonyl]amino}phenyl)sulfanyl]butanoic acid (0.080 g, 0.00015 moles)
was added meta-chloroperbenzoic acid (0.101 g, 0.00059 moles) and stirred for about one
hour at room temperature. After completion, reaction mixture was quenched by adding
sodium metabisulphite solution and then extracted in dichloromethane. The organic layer
was dried over anhydrous sodium sulphate and concentrated to obtain a crude product
which was purified by preparative TLC using 10% methanol in dichloromethane as eluent.
Yield: 0.020 g
LCMS: 535 (M+l), 557 (M+23)
NMR (400 MHz, DMSO- ¾ - 11.00 (IH, s), 9.67 (1H, s), 7.98 - 8.05 (4H, d, J = 8.4 Hz),
7.78 -7.80 (2H, d, J = 9.2 Hz), 7.57 - 7.60 (2H, d, J = 8.4 Hz), 7.42 - 7.45 (2H, d, J = 8.8
Hz), 7.05 - 7.10 (2H, d, J = 8.8 Hz), 4.17 - 4.19 (IH, m), 3.97 - 4.03 (IH, m), 3.70 - 3.79
(1H, m), 2.07 - 2.11 (2H, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[2-fluoro-5-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 16);
LCMS: 603.22 (M+l), 620.22 (M+18)
2-[(4- {[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4- {[(5-fluoro-2-methyl
phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
LCMS: 548.03 (M)
4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4- {[(4-
chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18);
LCMS: 581.33 (M), 603.08 (M+l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 19);
LCMS: 535.22 (M+l), 552.28 (M+18)
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]amino}
phenyl)sulfonyl]butanoic acid (Compound no. 20);
LCMS: 552.01 (M+l), 573.14 (M+22)
2-[(4- {[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4- {[(3-cyanophenyl)
carbamothioyl]oxy}butanoic acid (Compound no. 21);
LCMS: 564.12 (M+6), 542.24 (M-16)
4-{[(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methylphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 31);
LCMS: 515.09 (M+l)
4-{[(4-Chlorophenyl)carbamoyl] oxy}-2-[(4- {[(4-methoxypheny l)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 45);
LCMS: 547.20 (M+l)
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}
phenyl)sulfonyl]butanoic acid (Compound no. 46);
LCMS: 540.25 (M)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
LCMS: 579.24 (M-l)
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 48);
LCMS: 579.18 (M-20)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49);
LCMS: 525.24 (M-l)
4-[( rt-Butylcarbamoyl)oxy] -2-[(4- {[(4-methoxyphenyl)carbonyl] amino}phenyl)
sulfonyl]butanoic acid (Compound no. 50);
LCMS: 491.29 (M-l)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 51);
LCMS: 547.22 (M-l)
4-{[(2-Fluorophenyl)carbamoyl] oxy}-2-[(4- {[(4-methoxyphenyl)carbonyl ]amino }
phenyl)sulfonyl]butanoic acid (Compound no. 52);
LCMS: 529.22 (M-l)
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}
phenyl)sulfonyl]butanoic acid (Compound no. 53);
LCMS: 529.25 (M-l)
4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 54);
LCMS: 575.23 (M-2), 577.17 (M)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55);
LCMS: 579.14 (M-2), 581.16 (M)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56);
LCMS: 565.06 (M)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
LCMS: 533.10 (M+l)
4-{[(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methylphenyl)carbonyl]amino}
phenyl)sulfonyl]butanoic acid (Compound no. 58);
LCMS: 515.15 (M+l)
Example 5: Synthesis of 4-([(4-chlorophenyl)carbamoylloxy)-2-[(4-chlorophenyl)
sulfanyl]butanoic acid (Compound no. 1) (Scheme L Path C Formula 19)
Step a: Preparation of 3-[(4-chlorophenyl)sulfanyljdihydrofuran-2(3H)-one
To an ice cooled solution of -chloro thiophenol (10.0 g, 0.069 moles) in
dichloromethane (75 mL) under argon atmosphere were added triethylamine (21.0 g,
0.208 moles) and a solution of bromo lactone (12.0 g, 0.072 moles) in dichloromethane
(75 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes at 0°C.
After completion, reaction mixture was diluted by adding water and extracting in
dichloromethane. The organic layer was dried over anhydrous sodium sulphate and
concentrated to get a crude product which was purified by silica gel column using 10%
ethyl acetate in hexane as eluent.
Yield: 13.9 g
Step b: Preparation of methyl 2-[(4-chlorophenyl)sulfanyll-4-hvdroxybutanoate
To a solution of compound obtained from Step (5.0 g, 0.02 19 moles) in N, N -
dimethylformamide (20ml) and water (5ml) was added sodium hydroxide (1.05 g, 0.0263
moles). The reaction mixture was allowed to stir for about 30 minutes at room
temperature. After 30 minutes, sodium bicarbonate (1.74 g, 0.0208 moles), 18 crown 6
(0.45 g, 0.0017 moles) and methyl iodide (3.68 g, 0.0259 moles) were added to reaction
mixture and again stirred for overnight at room temperature. After completion, reaction
mixture was diluted by addition of water and extracting in ethyl acetate. The organic layer
was dried over anhydrous sodium sulphate and concentrated to obtain a crude product
which was purified by silica gel column using 8% ethyl acetate in hexane as eluent to get a
title compound.
Yield: 3.5 g
Step c: Preparation of methyl 4-{[(4-chlorophenvDcarbamovnoxy}-2-[(4-
chlorophenvDsulfanyllbutanoate
To a solution of compound obtained from Step b (0.425 g, 0.0016 moles) in
tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.323 g,
0.0032 moles) and l-chloro-4-isocyanatobenzene (0.293 g, 0.0019 moles) and stirred for
about 2 hours at room temperature. After completion, reaction mixture was diluted by
adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous
sodium sulphate and concentrated to get crude product which was purified by silica gel
column using 15% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.600 g
Step d: Preparation of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)
sulfanyljbutanoic acid
To a solution of compound obtained from Step c (0.600 g, 0.0014 moles) in
tetrahydrofuran/methanol (5ml:5ml) was added a solution of lithium hydroxide (0.090 g,
0.0021 moles) in water ( 1 mL) and stirred for about one hour at room temperature. After
completion, reaction mixture was acidify with sodium bisulphite solution and then
extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate
and concentrated to get crude product which was purified by preparative TLC using 10%
methanol in dichloromethane as eluent to obtain the desired compound.
Yield: 0.100 g
LCMS: 401.23(M+1)
NMR- (400 MHz, DMSO- ) d: 9.73 (1H, s), 7.45 - 7.53 (6H, d, J = 8.4 Hz), 7.15 - 7.19
(2H, d, J = 8.4 Hz), 4.17 - 4.30 (2H, m), 3.91 - 3.95 (1H, t, J = 7.2 Hz), 2.15 - 2.24 (1H,
m), 1.97 - 2.06 (lH, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-Chlorophenyl)sulfanyl]-4- [(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 2);
LCMS: 384.22 (M++1)
Example 6: Synthesis of 4- f (4-chlorophenvncarbamoylloxy}-2-[(4-
chlorophenyl)sulfonyl]butanoic acid (Compound no. 3) (Scheme Path C Formula 20)
To an ice-cooled solution of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-
chlorophenyl)sulfanyl]butanoic acid (0.100 g, 0.0002 moles) in chloroform (10 mL) was
added meta-chloroperbenzoic acid (0.172 g, 0.001 moles) and stirred at room temperature
for about one hour. After completion, reaction mixture was quenched by sodium
metabisulphite solution and extracted in dichloromethane. The organic layer was dried
over anhydrous sodium sulphate and concentrated to get crude product which was purified
by preparative TLC using 10% methanol in dichloromethane as eluent to get desired
compound.
Yield: 0.090 g
LCMS: 432.12 (M), 434 (M+2), 449.17 (M+18)
NMR-(400 MHz, DMSO-i ) : 9.79 (1H, s), 7.73 - 7.82 (2H, d, J = 8.8 Hz), 7.60 - 7.63
(2H, d, J = 8.8 Hz), 7.44 - 7.46 (2H, d, J = 8.8 Hz), 7.29 - 7.31 (2H, d, J = 8.8 Hz), 4.07 -
4.19 (1H, m), 3.97 - 4.03 (1H, m), 3.75 - 3.76 (1H, m), 2.03 - 2.10 (2H, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 4);
LCMS: 416.13 (M+l)
Example 7: Synthesis of 4-(benzyloxy)-2-[(4-nitrophenvnsulfonyllbutanoic acid
(Compound no. 28 (Scheme II, Path D Formula 27)
Step a: Synthesis of ethyl [(4-nitrophenyI)suIfanyI]acetate
To an ice-cooled solution ofp-nitro thiophenol (5 g, 0.0322 moles) in
dichloromethane (50 mL) under argon atmosphere were added triethylamine (9.7 g,
0.0967 moles) and a solution of ethyl bromoacetate (6.4 g, 0.0387 moles) drop wise. The
reaction mixture was allowed to stir for about 5 hours at room temperature. After
completion, reaction mixture was diluted with water and extracted in dichloromethane.
The organic layer was dried over sodium sulphate and concentrated to get a crude product.
The crude product obtained was purified by silica gel column using 10% ethyl acetate in
hexane as eluent.
Yield: 6.5 g
LCMS: 242 (M+l)
Step b: Preparation of ethyl [(4-nitrophenyl)sulfonyl]acetate
To an ice-cooled solution of compound obtained from Step a (6.5 g, 0.0269 moles)
in chloroform (70 mL) was added meta-chloroperbenzoic acid (18 g, 0.107 moles) and
stirred at room temperature for about one hour. After completion, reaction mixture was
quenched with sodium metabisulphite solution and then extracted in dichloromethane.
The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude
product which was purified by preparative TLC using 10% methanol in dichloromethane
as eluent to obtain a crude product.
Yield: 6.7 g
LCMS: 274 (M+l)
Step c : Preparation of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate
To a solution of compound obtained from Step b (0.500 g, 0.0018 moles) in N, N -
dimethylformamide (5 mL) under argon atmosphere were added potassium carbonate
(0.745 g, 0.0054 moles), tetrabutylammonium iodide (0.067 g, 0.00018 moles) and Obenzyl
ethyl bromide (0.550 g, 0.0027 moles). The reaction mixture was heated to 50° C
and stirred at same temperature for about 4 hours. After completion, reaction mixture was
diluted by adding water and extracting in ethyl acetate. The organic layer was dried over
anhydrous sodium sulphate and concentrated to get a crude product which was purified by
silica gel column using 8% ethyl acetate in hexane as eluent to get title compound.
Yield: 0.450 g
LCMS: 408 (M+l)
Step d: Preparation of 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid
To a solution of compound obtained from Step c (0.100 g, 0.00024 moles) in
tetrahydrofuran/methanol (5 mL:5 mL) was added a solution of lithium hydroxide (0.015
g, 0.00036 moles) in water ( 1 mL). The reaction mixture was allowed to stir at room
temperature for about one hour. After completion, reaction mixture was acidify with
sodium bisulphite solution and then extracted in ethyl acetate. The combined organic
layer was dried over anhydrous sodium sulphate and concentrated to get a crude product
which was purified by preparative TLC using 10% methanol in dichloromethane as eluent
to get title compound.
Yield: 0.040 g
LCMS: 402.12 (M+23)
NMR-(400 MHz, DMSOn_¼) d: 8.35 - 8.46 (2H, d, J = 8.8 Hz), 8.07 - 8.20 (2H, d, J = 8.8
Hz), 7.28 - 7.33 (5H, m, J = 5.6 Hz), 4.41 (2H, s), 3.80 - 3.84 (1¾ m), 3.45 - 3.51 (4H,
m), 2.05 - 2.09 (3H, m), 1.83 (lH, m).
Example 8: Synthesis of 4-fbenzyloxy)-2-[(4-(pf4-methylphenvncarbonyl1amino}
phenyl)sulfonyl]butanoic acid (Compound no. 22) (Scheme II, Path E Formula 30)
Step a: Preparation of ethyl 2-[(4-aminophenyl)sulfonyl]-4-(benzyloxy)butanoate
To a solution of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate (0.500
g, 0.0012 moles) in ethyl acetate (10 mL) was added stannous chloride (0.829 g, 0.0036
moles) and stirred at 80°C for about 2 hours. After completion, reaction mixture was
quenched by adding sodium bicarbonate solution and then extracted in ethyl acetate. The
organic layer was dried over anhydrous sodium sulphate and concentrated under reduced
pressure to get desired compound.
Yield: 0.450 g
LCMS: 378 (M+l)
Step b: Preparation of ethyl 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoate
To a solution of compound obtained from Step a (0.500 g, 0.0013 moles) in
dichloromethane (10 mL) under argon atmosphere was added pyridine (0.3 14 g, 0.0039
moles) and cooled to 0°C. To this cooled solution was added 4-methylbenzoyl chloride
(0.220 g, 0.0014 moles) slowly drop wise. After completion, reaction mixture was
quenched by adding water and extracting in dichloromethane. The organic layer was
washed with sodium bicarbonate, dried over anhydrous sodium sulphate and concentrated
to get crude product which was purified by silica gel column using 10% ethyl acetate in
hexane as eluent to get desired compound.
Yield: 0.400 g
LCMS: 348 (M+l)
Step c: Preparation of 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonylJ
amino}phenyl)sulfonyl] butanoic acid
To a solution of compound obtained from Step b (0.100 g, 0.00020 moles) in
tetrahydrofuran/methanol (5 mL:5ml) was added a solution of lithium hydroxide (0.012 g,
0.00030 moles) in water ( 1 mL) and stirred at room temperature for about one hour. After
completion, reaction mixture was acidify by adding sodium bisulphite solution and then
extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate
and concentrated to get crude product which was purified by preparative TLC using 10%
methanol in dichloromethane as eluent to afford desired compound.
Yield: 0.050 g
LCMS: 467.93 (M), 484.95 (M+17)
H NMR(400 MHZ , DMSO-i¾) d: 10.6 (1H, s), 7.98 - 8.00 (2H, d, J = 8.8 Hz), 7.89 - 7.91
(2H, d, J = 8.0 Hz), 7.76 - 7.78 (2H, d, J = 8.4 Hz), 7.24 - 7.35 (7H, d. J = 8.0 Hz), 4.36
(2H, s), 3.77 (1H, m), 3.46 - 3.49 (1H, m), 2.38 (3H, s), 1.99 - 2.01 (2H, t, J = 6.8 Hz),
1.21-1.22 (3H, t, J =4.0Hz).
The following compounds can be prepared by following the above synthetic route.
4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 23);
LCMS: 470.07 (M-l)
4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 24);
LCMS: 486.04 (M-l)
4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 25);
LCMS: 480.14 (M-l)
4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino}phenyl)
sulfonyl]butanoic acid (Compound no. 26);
LCMS: 483.98 (M), 500.97 (M+17)
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 27)
LCMS: 470.07 (M-l)
Assay for Matrix Metallo Proteinases (MMPs)
NCEs/standards were prepared (stock 10 mM) in 100% DMSO and subsequent
dilutions were made in 50% DMSO-50% TCNB (50 mM Tris, 10 mM CaCl2, 150 mM
NaCl, 0.05% Brij-35, pH 7.5). 1 mΐ of the compound and 88 mΐ of TCNB was added to
wells of 96 well plate to achieve the desired final concentration of NCE (final DMSO
concentration should not exceed 0.5%). 1 mΐ of activated, recombinant MMPs was added
to each well (20-100 ng/100 mΐ reaction mixture) except the "negative well". (MMP-1, 9
&14 enzymes require prior activation. For this, supplied enzyme was incubated with
either APMA, final concentration 1mM, for a time period of 1 hour at 37°C). Incubation
was done at room temperature (~ 25°C) for 4 minutes to 5 minutes. Reaction was initiated
with 10 mΐ of 100 mM substrate (ES001: Aliquots were freshly diluted in TCNB; stock: 2
mM) and increase in florescence was monitored at excitation wavelength 320 n followed
by emission at 405 nm for 25-30 cycles. Increase in florescence (RFU) was calculated for
positive, negative and NCE/standard wells. The percent inhibition compared to controls
was calculated and IC50 values determined using Graph-prism software.
Activities for MMP-9 provided IC50 values below 10 nanomolar-10 micromolar.
We claim:
1. A compound of Formula I:
Formula I
luding racemates, enantiomers and diastereomers, thereof or a pharmaceutically
;eptable salts thereof, wherein,
X is S, SO or SC ;
L is selected from bond, -0-, -S-, -SO, -S0 , -CH2, -NR*. -NHCO(CH 2)„-.
-(CH ) CONH-, -NHCONH-, -S0 2NH-, -NHSO2-, -NHCO(0)-, -0 -(CH )n,
-(CH2VO-, -OC(0 )NH-, -C(S)NH-, -NHC(S), -NHC(S)NH-, -COO- wherein n is
zero or an integer between 1 and 2;
R1 is -OCONHR 3, OCSNHR 3, OCH R3;
When R is OCONHR 3 or OCSNHR 3 then R is hydrogen, Ci-C alkyl, hydroxyl,
Ci-Cealkoxy, cyano, nitro, halogen, halogeno Ci-Csalkyl, C -C aryl, C3-
Cgcycloalkyl, C 5-C12 heteroaryl wherein C -Ci2 aryl, Cj-Cgcycloalkyl, C 5-C12
heteroaryl is optionally substituted with one or more times with R5;
When R is OCH2R3, then R2 is C -C aryl, C -Cg cycloalkyl, C -Ci heteroaryl;
R3 is alkyl, alkenyl, alkynyl, C -Ci2 aryl, C -Cg cycloalkyl, Cj-Ci heteroaryl, C -
C|2 heterocyclyl which is optionally substituted one or more times with R5;
R* is H, Ci-ealkyl, C alkylaryl;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce
alkyl, halogeno-Ci-C alkoxy, azido, thiol, alkylthiol, -(CH ) -ORf, -C(=0>R ,
-COORf, -NRjRq, -(CH ) -C(=0 )NRii < , -(CH )„-NHC(=0 )-Rf, -(CH )„- ORf
o -(CH2)nS(=0 )m-NR < {whereinR and R are independently selected from
hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl,
alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2}.
A compound of Formula I, which is:
4-{ [(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfanyl]butanoic acid
(Compound no. 1);
2-[(4-Chlorophenyl)sulfanyl]-4-{ [(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 2);
4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfonyl]butanoic acid
(Compound no. 3);
2-[(4-Chlorophenyl)sulfonyl]-4-{ [(4-fluorophenyl)carbamoy]]oxy}butanoic acid
(Compound no. 4);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(4-fluorophenyl
carbamoyl]oxy}butanoic acid (Compound no. 5);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({ [2-fluoro-5-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3,5-
dimethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 7);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino) phenyl)sulfanyl]-4- {[(5-fluoro-2-methyl
phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
2-[(4-{ [(4-Chlorophenyl)carbony]]amino}phenyl)sulfanyl]-4-{ [(2-fluoro phenyl)
carbamoyl]oxy}butanoic acid (Compound no. 9);
4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{ [(3-
ethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 11);
4-{ [(3-Chlorophenyl)carbamoyl]oxy}-2-[(4- {[(4-chlorophenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 12);
4-{ [(4-Chlorophenyl)carbamothioyl]oxy}-2-[(4-{ [(4-chlorophenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 13);
2-[(4-{[(4-Chlorophenyl)carbony]]amino}phenyl)sulfanyl]-4-{[(3-cyanophenyl)
carbamothioyl]oxy}butanoic acid (Compound no. 14);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{ [(4-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 15);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-({ [2-fluoro-5-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 16);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(5-fluoro-2-methyl
phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
4-{ [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4-{ [(4-
chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 19);
4-{[(3-Chlorophenyl)carbamoyl] oxy}-2-[(4- {[(4-chlorophenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 20);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(3-
cyanophenyl)carbamothioyl]oxy}butanoic acid (Compound no. 21);
4-(Benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 22;)
4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 23);
4-(Benzyloxy)-2-[(4- {[(3-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 24);
4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 25);
4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino}phenyl)
sulfonyl]butanoic acid (Compound no. 26);
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic
acid (Compound no. 27)
4-(Benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid (Compound no. 28);
4-{[(2-Fluorophenyl)carbamoyl] oxy}-2-[(4-{[(4-methylphenyl)carbonyl] amino}
phenyl)sulfanyl]butanoic acid (Compound no. 29);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 30);
4-{[(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methylphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 31);
4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 32);
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 33);
2-[(4-{[(4-Methoxyphenyl)carbonyl] amino}phenyl)sulfanyl] -4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 34);
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 35);
2-[(4- {[(4-Methoxyphenyl)carbonyl] amino}phenyl)sulfanyl] -4-{[(2-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 36);
4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 37);
4-[(/er/-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 38);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 39);
4-{[(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 40);
4-{[(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 41);
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 42);
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy }-2-[(4- {[(4-methylphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
4-{ [(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methylphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 44);
4-{ [(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 45);
4-{[(4-Ethylphenyl)carbamoyl]oxy }-2-[(4- {[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 46);
2-[(4-{ [(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({ [4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
4-{ [(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)
carbonyl]aminophenyl)} sulfonyl]butanoic acid (Compound no. 48);
2-[(4-{ [(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-{ [(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49);
4-[(t rt-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 50);
4-{[(2,4-Difluorophenyl)carbamoyl] oxy}-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 51);
4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}
phenyl)sulfonyl]butanoic acid (Compound no. 52);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 53);
4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 54);
4-{[(3,4-Dichlorophenyl)carbamoyl] oxy}-2-[(4- {[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55);
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy} -2-[(4- {[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
4-{[(2-Fluorophenyl)carbamoyl]oxy} -2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 58);
2-( {4-[(4-Chlorophenyl)carbamoy]]phenyl} sulfanyl)-4- {[(2-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 59);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-ethylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 60);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({ [4-(propan-2-yl)phenyl]
carbamoyl}oxy)butanoic acid (Compound no. 61);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{ [(4-methoxyphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 62);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2-
methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 64);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 65);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,4-difluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 67);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{ [(4-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 68);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,6-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 69);
4-[(te rt-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl} sulfanyl)butanoic acid (Compound no. 70);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3,4-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 71);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-[(pentylcarbamoyl)
oxy]butanoic acid (Compound no. 72);
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-( {4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 73);
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl}sulfanyl)butanoic acid (Compound no. 74);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-fluorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 75);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4-ethylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 76);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 77);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4-methylphenyl)
carbamoyl]oxy}butanoic acid (Compound no. 78);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4-
difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4-
fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 81);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,6-
dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 82);
4-[(fert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl}sulfonyl)butanoic acid (Compound no. 83);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(3,4-dichlorophenyl)
carbamoyl]oxy}butanoic acid (Compound no. 84);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-[(pentylcarbamoyl)
oxy]butanoic acid (Compound no. 85);
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl} sulfonyl)butanoic acid (Compound no. 86);
4-[(Butylcarbamoyl)oxy]-2-( {4-[(4-chlorophenyl)carbamoyl]phenyl}
sulfonyl)butanoic acid (Compound no. 87);
2-[(4-{[(2-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 89);
2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-( {[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 90);
2-({4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({ [4-
(trifluoromethyl)phenylcarbamoyl}]oxy)butanoic acid (Compound no. 91);
2-[(4-{[(2-Methylphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl }oxy)butanoic acid (Compound no. 92);
2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 93);
2-[(4-{[(2,3-Difluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 94);
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 95);
2-[(4-{ [(4-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-( {[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 96);
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-({[4-(trifluoromethyl)
phenyl]carbamoyl}oxy)butanoic acid (Compound no. 97);
2-[(4-{[(2,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-
(trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98).
3. A pharmaceutical composition comprising a therapeutically effective amount of
one or more of compound of Formula I according to claims 1 and 2, together with one or
more pharmaceutically acceptable carrier, excipient or diluents.
4. A compound according to any one of claims 1-2, for use in the treatment or
prophylaxis of an animal or a human suffering from an inflammatory or allergic disease.
5. A compound according to claim 4, wherein the inflammatory disease or allergic
disease is asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis,
psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress
syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal
proliferation associated with restenosis and ischemic heart failure, stroke, renal disease or
tumor metastasis.
6. A pharmaceutical composition according to claim 3, further comprising one or
more of additional active ingredients selected from:
a) anti-inflammatory agents, experimental or commercial, selected from (i) the
nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids,
fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin
inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5-
lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors,
(iv) other MMP inhibitors, and (v) interleukin-I inhibitors;
b) antihypertensive agents, selected from (i) the ACE inhibitors, enalapril,
lisinopril, valsartan, telmisartan and quinapril, (ii) the angiotensin II receptor
antagonists and agonists, losartan, candesartan, irbesartan, valsartan, and
eprosartan, (iii) b-blockers, and (iv) calcium channel blockers.
c) immunosuppressive agents selected from, cyclosporine, azathioprine and
methotrexate, and anti inflammatory corticosteroids.
7. A process for preparing a compound of Formula 9 (Formula I when L1 is -CONH-,
X is S0 2 and R1 is OC(Z)NHR3) comprising:
a) reacting a compound of Formula 2 with alpha bromolactone to give a
compound of Formula 3;
Formula 2 Formula 3
b) reacting a compound of Formula 3 (where Y is COOH) with a compound of
Formula 3' to give a compound of Formula 4;
Formula 3' Formula 4
c) coupling a compound of Formula 4 with a compound of Formula 4' to give a
compound of Formula ;
Formula 4' Formula 5
d) reacting a compound of Formula 5 with a compound of Formula 6 to give a
compound of Formula 7;
o o
R N=C=Z H
Formula 6 Formula 7
e) hydrolyzing a compound of Formula 7 to give a compound of Formula 8;
Formula 8
oxidizing a compound of Formula 8 to give a compound of Formula 9;
o o
R
H
Formula 9
wherein,
R2 is hydrogen, Ci-C alkyl, hydroxyl, Q-Cealkoxy, cyano, nitro, halogen,
halogeno Ci-Cealkyl, C -C12 aryl, C3-C8cycloalkyl, C5-Ci2 heteroaryl wherein
C6-Ci2 aryl, C3-C8cycloalkyl, C -C12 heteroaryl is optionally substituted with
one or more times with R5;
R is alkyl, alkenyl, alkynyl, C -C12 aryl, C3-C8 cycloalkyl, C5-Ci2 heteroaryl,
C3-C12 heterocyclyl optionally substituted one or more times with R5;
Rs is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-
Ci-C6 alkyl, halogeno-Ci-C alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf -
C(=0)-R f, -COORf, -NR Rq, -(CH2)n-C(=0)NR Rq, -(CH2)„-NHC(=0)-Rf,
{whereinRf and R are
independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl,
heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl};
n is zero or an integer between 1 and 2;
m is an integer 0-2;
R' is alkyl, allyl, benzyl, i-butyl, silyl;
Hal is F, CI, Br, I; and
Z isO, S.
8. A process for preparing a compound of Formula 16 (Formula I when L is -
NHCO-, X is S0 and R is OC(Z)NHR3), Formula 20 (Formula I when L is bond, X is
S0 and R is OC(Z)NHR3) comprising:
a) reducing a compound of Formula 3 (where Y is N0 2) to give a compound of
Formul
Formula 3 Formula 10
b) coupling a compound of Formula 10 with a compound of Formula 11 to give
a compound of Formula 12;
Formula 11 Formula 12
c) reacting a compound of Formula 12 with a compound of Formula 4' to give a
compound of Formula 13;
Formula 4' Formula 13
d) coupling a compound of Formula 13 with a compound of Formula 6 to give a
compound of Formula 14;
Formula 6 Formula 14
hydrolyzing a compound of Formula 14 to give a compound of Formula 15;
Formula 15
oxidizing a compound of Formula 15 to ive a compound of Formula 16;
Formula 16
or
g) reacting a compound of Formula 3 (wherein Y is Hal) with a compound of
Formula 4';
Formula 3 Formula 4'
to give a compound of Formula 17;
Formula 17
coupling a compound of Formula 17 with a compound of Formula 6 to give a
compound of Formula 18;
Formula 6 Formula 18
hydrolyzing a compound of Formula 18 to give a compound of Formula 19;
Formula 19
oxidizing a compound of Formula 19 to ive a compound of Formula 20;
Formula 20
wherein,
R3 is alkyl, alkenyl, alkynyl, C6-Ci2 aryl, C3-C8 cycloalkyl, C5- 2heteroaryl,
C3-C2 heterocyclyl optionally substituted one or more times with R5;
R2 is hydrogen, Ci-C alkyl, hydroxy1, - alkoxy, cyano, nitro, halogen,
halogeno Ci-C alkyl, C6- 2 aryl, C3-C8cycloalkyl, C -C 2 heteroaryl,
wherein C6-Ci2 aryl, C3-Cgcycloalkyl, C6-Ci2 heteroaryl is optionally
substituted with one or more times with R5;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-
C C6alkyl, halogeno-CpCe alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf -
C(=0)-R f, -COORf, -NRRq, -(CH2) -C(=0)NR R , -(CH2) -NHC(=0)-R f,
-(CH2)n- O-Ci^-NR , (CH2) NHC(=0)NR Rq , -(CH2) -0-C(=0)- Rf, -
(CH2)n-NH-C(=0)-R f or -(CH2) S(=0)m-NRR {whereinRf and ,each
independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl} ;
n is zero or an integer between 1 and 2;
m is an integer 0-2;
Hal is F, CI, Br, I;
U is halide, alkyloxy, aryloxy;
R' is alkyl, allyl, benzyl, t-butyl, silyl; and
Z isO, S.
9. A process for preparing compounds of Formula 27 (Formula I when L1 is bond, X
is S0 2, R2 is N0 2 and R1 is -OBn) and 30 (Formula I when L1 is -NHCO, X is S0 2 and R
is -OBn) comprising:
a) reacting a compound of Formula 21 with a compound of Formula 22
Formula 2 1 Formula 22
to give a compound of Formula 23;
Formula 23
b) oxidizing a compound of Formula 23 to give a compound of Formula 24;
Formula 24
c) coupling a compound of Formula 24 with a compound of Formula 25 to give
a compound of Formula 26;
Formula 25 Formula 26
d) hydrolyzing a compound of Formula 26 to give a compound of Formula 27;
Formula 27
or
e) reducing a compound of Formula 26 to ive a com ound of Formula 28;
Formula 26 Formula 28
f) reacting a compound of Formula 28 with a compound of Formula 11 to give
a compound of Formula 29;
Formula 11 Formula 29
g) hydrolyzing a compound of Formula 29 to give a compound of Formula 30;
Formula 30
wherein,
R2 is hydrogen, Ci-Qalkyl, hydroxyl, Q-Cealkoxy, cyano, nitro, halogen,
halogeno Q-Cealkyl, C6-C12 aryl, C 3-C8cycloalkyl, C5-Ci2 heteroaryl wherein
C -C12 aryl, C3-C cycloalkyl, C6-C12 heteroaryl is optionally substituted with
one or more times with R5;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-
Ci-C 6 alkyl, halogeno-Q-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)„-ORf; -
C(=0)-R f, -COORf, -NR Rq, -(CH2) -C(=0)NR Rq, -(CH2)n-NHC(=0)-R f,
{whereinRf and R, each
independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl,
heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl} ;
n is zero or an integer between 1 and 2;
m is an integer 0-2;
Hal is F, CI, Br, I;
U is halide, alkyloxy, aryloxy;
Bn is benzyl; and
R' is alkyl, allyl, benzyl, t-butyl, silyl.