MX2013003360A - Matrix metalloproteinase inhibitors. - Google Patents

Matrix metalloproteinase inhibitors.

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Publication number
MX2013003360A
MX2013003360A MX2013003360A MX2013003360A MX2013003360A MX 2013003360 A MX2013003360 A MX 2013003360A MX 2013003360 A MX2013003360 A MX 2013003360A MX 2013003360 A MX2013003360 A MX 2013003360A MX 2013003360 A MX2013003360 A MX 2013003360A
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Mexico
Prior art keywords
compound
phenyl
carbamoyl
formula
acid
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MX2013003360A
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Spanish (es)
Inventor
Jitendra Sattigeri
Manoj Kumar Khera
Abhijit Ray
Abdul Rehman Abdul Rauf
Neeraj Kumar Yadav
Ian A Cliffe
Pradip Kumar Bhatnagar
Punit Srivastava
Sunanda Ghosh Dastidar
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Ranbaxy Lab Ltd
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Publication of MX2013003360A publication Critical patent/MX2013003360A/en

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    • C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings

Abstract

The present invention relates to certain sulfone acetic acid derivatives of formula I 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, 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.

Description

MATRIX METALOPROTEINASE INHIBITORS Field of the Invention The present invention relates to certain sulfone acetic acid derivatives as inhibitors of MMP and processes for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the present invention and methods for treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, lung inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye and neointima proliferation leading to restenosis and ischemic heart failure, stroke, kidney 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; that share structural and functional characteristics. Based on structural and functional considerations, proteinases have been classified into different families and subfamilies (Vartak et al., J. Drug Targeting, 15, pages 1-20 (2007) and Hopper, FEBS, 354, pages 1-6 (1994)). , such as collagenases (MMP-1, -8 and -13), gelatinases (MMP-2 and -9), metalloelastases (MMP-12), MT-MMPs (MMP-14, -15, -16, -17 , -24 and -25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10 and -11) and shedasas such as enzymes that convert TNF (TACE and ACE).
Metalloproteinases are believed to be important in the processes of physiological disease involving remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. A major biological function of M Ps is to catalyze the decomposition of connective tissues or extra-cellular matrix by its ability to hydrolyze various tissue or matrix components. Apart from its role in degrading the connective tissue, MMPs are involved in the activation of (pro) forms of zymogen from other MMPs in order to induce the activation of MMP. They are also involved in the biosynthesis of TNF-alpha that is involved in many pathological conditions.
MMP-9 (gelatinase B) has been implicated in the pathogenesis of COPD, MS and other inflammatory disorders. MMP-9 is secreted as the proenzyme and, in activation, exhibits different functions in the progression of both disease states. For example, leukocyte-mediated activation of MMP-9 is exhibited during the inflammatory response associated with COPD, marking the beginning of processes linked to airway obstruction. MMP-9 is the main pro-inflammatory mediator of inflammation and its expression is higher in all inflammatory diseases, such as COPD, MS, arthritis, psoriasis, etc. Other MMPs are also involved in some vital and regulatory functions of the cell, so a selective inhibitor of MMP-9 would only direct the inflammation component of the disease and be free of undesirable toxicity.
Overexpression or over-activation of an MMP, or an imbalance between a MMP and a natural (ie, endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has been linked to a pathogenesis of diseases characterized by decomposition of the connective tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in the treatment of various inflammatory, autoimmune and allergic diseases such as, joint inflammation, GI tract inflammation, skin inflammation, collagen remodeling, healing disorders. of wounds, etc.
The design and therapeutic application of MMP inhibitors have revealed that the requirement of a molecule to be an effective inhibitor of the MMP class of enzymes is a functional group (eg, carboxylic acid, hydroxamic acid or sulfhydryl) capable of chelating at active site Zn2 + ion (Whittaker et al., Chem. Rev., 99; pages 2735-76 (1999).
WO 03/82841 discloses new 5-substituted 1, 1-dioxo-l, 2, 5-thiazolidin-3-one derivatives as inhibitors of tyrosine phosphatase protein used to treat, eg, diabetes, metabolic disorders, obesity and disease ischemic EP 0 507 238 discloses R- and S-carboxylic 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 lipid metabolism diseases.
Research has been carried out on the identification of inhibitors that are selective, for example, for a few of the MMP subtypes. An MMP inhibitor of improved selectivity will avoid potential side effects associated with the inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
In addition, the use of more selective MMP inhibitors would require the administration of a lower amount of the inhibitor for the treatment of the disease than would otherwise be required and, after administration, divided in vivo by multiple MMPs. Still further, administration of a lower amount of the compound would improve the safety margin between the dose of the inhibitor required for the therapeutic activity and the dose of the inhibitor at which the toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules, that is, chiral and therefore will have several stereoisomers depending on the number of chiral centers present. The importance of evaluating new chemical entities that have chiral centers as individual isomers is to understand their effect in pharmacological and toxicological aspects. Frequently there are pharmacodynamic, pharmacokinetic and / or toxicological differences between the enantiomers / diastereomers. Even if the natural physiological mediators are achiral, based on their target environment, their receptors / enzymes may demonstrate a preference for only an optically pure enantiomer of agonists, antagonists or inhibitors. From a pharmacokinetic point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure individual isomers may also offer advantages in terms of these pharmacokinetic parameters thus allowing greater capacity for development 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 has profound effects on the pharmacokinetics and capacity for the development of the molecule. In addition to those mentioned in the foregoing, the regulatory principles guide the development of preferably individual isomers as drug candidates to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to the interactions of an unwanted isomer with undesirable molecular targets.
In this context, synthetic strategies for producing pure individual isomers offers advantages over analytical techniques of isomer separation not only in terms of cost and efficiency but larger quantities of the compound can be prepared to make the pharmaceutical test. In this manner, the compounds of the present invention, which are individual chiral isomers, have improved potency, improved pharmacokinetic and / or physicochemical properties as compared to the racemic compounds.
The present invention is directed to overcome the problems encountered in the art.
Brief Description of the Invention The present invention provides sulphone acetic acid derivatives as matrix metalloproteinase-9 inhibitors which are effective therapeutic or prophylactic agents for the treatment of various inflammatory and allergic diseases. Processes are also provided to synthesize 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 pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory and autoimmune diseases. These pharmaceutical compositions can be administered or co-administered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or parenteral route. The composition can also be administered or co-administered in slow release dosage forms.
Although, the specific enantiomers have been shown by way of example, racemates, diastereomers and pharmaceutically acceptable salts are also provided. Also included are pharmaceutical compositions comprising such compounds, their racemates, enantiomers, diastereomers and pharmaceutically acceptable salts.
The therapeutically effective amount of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, inhibitors of protein synthesis, amino glycosides, cell wall synthesis inhibitor (glycopeptides, beta -lactams, etc.), inhibitors of RNA and DNA synthesis or inhibitors of fatty acid synthesis.
Other objects will be set forth in the accompanying description and in part will be apparent from the description or may be by the practice of the invention.
Detailed description of the invention According to one aspect, a compound having the structure of Formula I is provided: Formula I which includes racemates, enantiomers and diastereomers thereof or a pharmaceutically acceptable salt thereof.
Where, X can be S, SO or S02; L1 can be selected from the bond, -O-, -S-, -SO, -S02, -CH2, -NR4, -NHCO (CH2) n-, - (CH2) nCONH-, -NHCONH-, -S02NH-, -NHS02-, -NHCO (O) -, -0- (CH2) n, - (CH2) n-0-, -OC (0) NH-, -C (S) NH-, -NHC (S), -NHC (S) NH-, -COO- where n can be zero or an integer between 1 and 2; R1 can be -OCONHR3, OCSNHR3, 0CH2R3; When R1 is OCONHR3 or OCSNHR3 then R1 can be hydrogen, C1-C6 alkyl, hydroxyl, Ci-C6 alkoxy, cyano, nitro, halogen, halogen-C1-C6 alkyl, C6-C12 aryl, C3-cycloalkyl C8, C5-C12 heteroaryl wherein C6-Ci2 aryl, C3-C8 cycloalkyl, C5-C12 heteroaryl is optionally substituted with one or more times with R5; When R1 is OCH2R3, then R2 can be C6-Ci2 aryl, C3-Cg cycloalkyl, C6-Ci2 heteroaryl; R3 is alkyl, alkenyl, alkynyl, C6-Ci2 aryl / C3-C8 cycloalkyl, C5-C12 heteroaryl, C3-Ci2 heterocyclyl which may be optionally substituted one or more times with R5; R4 can be H, Ci-C alkyl < Ci-C4 alkylaryl; R5 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-Ci-C6 alkyl, halogen-Ci-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C ( = 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) n-NHC (= 0) Rf, - (CH2) n-0-C (= 0) - NRfRq, (CH2) nNHC (= 0) NR £ Rq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0) m-NRfRq. { wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is an integer of 0-2}; In one aspect the invention encompasses compounds that include, for example, 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4-chlorophenyl) -sulfanyl] butanoic (Compound No. 1); 2- [(4-chlorophenyl) sulfanyl] -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 2); 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4-chlorophenyl) -sulfonyl] butanoic (Compound No. 3); 2- [(4-chlorophenyl) sulfonyl] -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 4); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] -4- acid. { [(-fluorophenylcarbamoyl] oxy] butanoic (Compound No. 5); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] -4- ( { [2-fluoro-5- (trifluoromethyl) phenyl] carbamoyl} oxy] ) butanoic (Compound No. 6); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] -4- acid. { [(3,5-dimethoxyphenyl) carbamoyl] oxybutanoic (Compound No. 7); 2- [(- { [(4-chlorophenyl) carbonyl] amino] phenyl) sulfanyl] -4- acid. { [(5-fluoro-2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 8); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 9); 4- Acid. { [(3-chloro-4-methoxyphenyl) carbamoyl] oxy) -2- [(4. {[[(4-chlorophenyl) carbonyl] amino] phenyl) sulfanyl] butanoic (Compound 10); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] -4- acid. { [(3-ethoxyphenyl) carbamoyl] oxy} butanoic (Compound No. 11); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- [(4- { [(4-chlorophenyl) carbonyl] aminojphenyl) sulfanyl] butanoic (Compound no. 12); 4- Acid. { [(4-chlorophenyl) carbamothioyl] oxy} -2- [(4- {[[(-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound no. 13); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] -4- acid. { [(3-cyanophenyl) carbamothioyl] oxy} butanoic (Compound No. 14); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 15); 2- [(- { [(4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] -4- ( { [2-fluoro-5- (trifluoromethyl) phenyl] carbamoyl.} Oxy] butanoic (Compound No. 16); 2- [(- { [(4-chlorophenyl) carbonyl] amino] phenyl) sulfonyl] -4- acid. { [(5-fluoro-2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 17); 4- Acid. { [(3-chloro-4-methoxyphenyl) carbamoyl] oxy} -2- [(4-. {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound do not. 18); 2- (4- {[[(-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 19); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-chloro-phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound no. twenty); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] -4- acid. { [(3-cyanophenyl) carbamothioyl] oxybutanoic (Compound no. twenty-one); 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- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfanyl] utanoic (Compound do not . 29); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound no. 30); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-methyl-phenyl) carbonyl] aminojphenyl) sulfonyl] butanoic (Compound no. 31); 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} enyl) sulfanyl] butanoic (Compound No. 32); 4- Acid. { [(4-ethylphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 33); 2- [(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-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic acid (Compound no. 35); 2- [(4- {[[(-methoxyphenyl) carbonyl] amino} phenyl) sulfanyl] -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 36); 4- Acid. { [(-methoxyphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 37); 4- [(tert-Butylcarbamoyl) oxy] -2- [(4- {[[(4-methoxyphenyl) -carbonyl] amino} phenyl) sulfanyl] butanoic acid (Compound No. 38); 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 39); Acid 4 -. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound no. 40); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound no. 41); 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound no. 42); 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[(-methyl-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 43); 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound no. 44); 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy) -2- [(4. {[[(4-methoxy-phenyl) carbonyl] amino] phenyl) sulfonyl] butanoic (Compound no.
Four. Five); 4- Acid. { [(4-ethylphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 46); 2- [(4. {[[(4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy} utanoic acid (Compound No. 47); 4- Acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] aminophenyl)} sulfonyl] butanoic (Compound No. 48); 2- [(4- {[[(4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 49); 4- [(tert-Butylcarbamoyl) oxy] -2- [(4- {[[(4-methoxyphenyl) -carbonyl] amino} phenyl) sulfonyl] butanoic acid (Compound No. 50); 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methoxyphenyl) -carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 51); 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy) -2- [(4. {[[(4-methoxyphenyl) carbonyl] amino] phenyl) sulfonyl] butanoic (Compound No. 52); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2 - [(4- {[[(4-methoxyphenyl) carbonyl] aminojphenyl) sulfonyl] butanoic (Compound No. 53); 4- Acid. { [(5-chloro-2-methoxyphenyl) carbamoyl] oxy} -2- [(4- {[[(4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 54); 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(-. {[[(-methoxyphenyl) carbonyl] amino] phenyl) sulfonyl] butanoic (Compound No. 55); 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound no. 56); 4- Acid. { [(2, -difluorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-methyl phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound no. 57); 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-methyl phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound no. 58); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(2-fluorophenyl) carbamoyl] oxy -butanoic (Compound No. 59); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-ethylphenyl) carbamoyl] oxy} butanoic (Compound No. 60); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfane) -4- ( { [4 (propan-2-yl) phenyl] carbamoyl} oxy) butanoic acid (Compound no 61); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-methoxyphenyl) carbamoyl] oxy Jbutanoic (Compound No. 62); 2- ((4- [(4-Chlorophenyl) carbamoyl] phenyl} sulfane) -4-. {[[(2-methylphenyl) carbamoyl] oxy} butanoic acid (Compound No. 63); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(3-fluorophenyl) carbamoyl] oxy-J-butanoic (Compound No. 64); 2- ((4- [(4-Chlorophenyl) carbamoyl] phenyl} sulfane) -4-. {[[(4-methylphenyl) carbamoyl] oxybutanoic acid (Compound No. 65); 2- ( { 4 - [(-chlorophenyl) carbamoyl] phenyl} sulfane) -4- ( { [4 (trifluoromethyl) phenyl] carbamoyl.} Oxy] butanoic acid (Compound no. 66); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(2,4-difluorophenyl) carbamoyl] oxy} butanoic (Compound no. 67); "2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 68); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 69); 4- [(tert-Butylcarbamoyl) oxy] -2- ({4- [(4-chlorophenyl) -carbamoyl] phenyl} sulfanyl) butanoic acid (Compound No. 70); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 71); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- [(pentylcarbamoyl) oxy] butanoic acid (Compound No. 72); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- ({4- [(4-chlorophenyl) -carbamoyl] phenyl} sulfanyl) butanoic (Compound No. 73); 4- [(Butylcarbamoyl) oxy] -2- ({4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) butanoic acid (Compound No. 74); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 75); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-Ethylphenyl) carbamoyl] oxy Jbutanoic (Compound No. 76); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 77); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 78); 2- ( {4 - [(4-Chlorophenyl) carbamoyl] phenyl} sulfonyl) -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy) butanoic acid (Compound no. 79); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2,4-difluorophenyl) carbamoyl] oxy} butanoic (Compound no. 80); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 81); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 82); 4- [(tert-Butylcarbamoyl) oxy] -2- (. {4- [4-chlorophenyl] -carbamoyl] phenyl] sulfosyl) butanoio (Compound No. 83); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 84); 2- ( {4 - [(4-chlorophenyl) carbamoyl] phenyl} sulfonyl) -4- [(pentylcarbamoyl) oxy] butanoic acid (Compound No. 85); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- ({4- [(4-chlorophenyl) -carbamoyl] phenyl} sulfonyl) butanoic (Compound No. 86); 4- [(Butylcarbamoyl) oxy] -2- ( { - [(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, β-dimethoxyphenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy] -butanoic (Compound No. 90); 2- ( { 4- [(Cyclopropylcarbonyl) amino] phenyl} sulfanyl) -4- ({[[4- (trifluoromethyl) phenylcarbamoyl}]] oxy) butanoic acid (Compound No. 91); 2- [(- { [(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} utanoic acid (Compound No. 93); 2- [(4- {[[(2,3-difluorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy] -butanoic (Compound No. 94); 2- [(4- {[[(3,4-Dichlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ( { [4 - (trifluoromethyl) phenyl] carbamoyl} oxy] acid) -butanoic (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} sulfane) -4- ({[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} butanoic acid (Compound No. 97); 2- [(4- {[[(2,4-Dichlorophenyl) carbonyl] amino} phenyl) -sulfañyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy] acid) -butanoic (Compound No. 98).
In another aspect, there are provided herein, 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, methods for treating or preventing various inflammatory and allergic diseases comprising administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of Formula 1 described herein are provided 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 other therapeutic agents used in treating various inflammatory and allergic diseases. Examples of such therapeutic agents include but are not limited to: a) anti-inflammatory, experimental or commercial agents (i) such as non-steroidal anti-inflammatory agents of piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, inhibitors of MAP PDE-4 / p38 kinase / cathepsin, (ii) LTC4 / LTD4 / LTE4 / LTB4 inhibitors of leukotrienes, 5-lipoxygenase inhibitor and PAF receptor antagonists, (iii) Cox-2 inhibitors, (iv) inhibitors of MP and (v) interleukin-I inhibitors; b) antihypertensive agents, (i) ACE inhibitors, for example enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, for example losartan, candesartan, irbesartan, valsartan and eprosartan, (iii) ) ß-blockers and (iv) calcium channel blockers. c) immunosuppressive agents such as cyclosporine, azathioprine and methotrexate and anti-inflammatory corticosteroids.
The following definitions apply to the terms as used herein.
The term "alkyl" unless otherwise specified, refers to a branched or unbranched monorradical 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 monororadical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
The term "alkynyl" unless otherwise specified, refers to a monororadical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
The term "cycloalkyl" unless otherwise specified, refers to cyclic alkyl groups of 3 to 20 carbon atoms having a single cyclic ring or multiple fused rings, which may optionally contain one or more olefinic bonds, unless they are otherwise limited by definition. Such cycloalkyl groups may include, for example, only ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl and the like or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups at which fuses 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 the aromatic system having 6 to 14 carbon atoms, wherein the ring system may 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, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COOR ,,,, NHC (= 0) R > . , -NR¾RN, - C (= 0) NRXRIT, -NHC (= 0) NR \ RN, -0-C (= 0) NRA, -S0MR (| J, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or aminocarbonyl amino, mercapto, haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, -CONH RJJ, -OCOR ,,, -C0R ", -NHS02RRT or -S02NHRn (wherein Rx, N, my RV are the same as defined in the above) Aryl groups may optionally be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from 0, 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. Carbon and aryl is as defined in the above. Examples of aralkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl and the like.
The term "aryloxy" represents the O-aryl group 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 limited by definition, substituents are attached to an atom on the ring, i.e., carbon or ring hetero atom . Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2-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 members in the ring. Examples of heterocyclyl groups include benzotriazinone, isoindoledione, pyrimidinedione, aza-spiro [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, isoindol 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo [, 5-6] pyridine, isoquinolinyl, 1H-pyrrolo [2, 3-6 ] pyridine or piperazinyl and the like.
The term "cycloalkylalkyl" refers to the cycloalkyl group linked through the alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and cycloalkyl are the same as defined above.
The term "heteroarylalkyl" refers to the heteroaryl group linked through the alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heteroaryl are the same as defined above.
The term "heterocyclylalkyl" refers to the heterocyclyl group linked through the alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heterocyclyl are the same as defined above.
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 synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (for example F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy or hydroxy radicals and the like.
The term "protecting groups" refers to portions that prevent the chemical reaction at a location of a molecule proposed to be left unaffected during chemical modification of such a molecule. Unless otherwise specified, the protecting groups can be used in 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", 2- 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 used are not critical, since the portions / portion derived (s) are / are stable to subsequent reaction conditions and can be removed without interrupting the remainder of the molecule.
The compounds of this invention may contain an asymmetric carbon atom and thus may occur as racemic mixtures, enantiomers and diastereomers. These compounds can also exist as conformers / rotamers. All of these isomeric forms of these compounds are included in the present invention. Each stereogenic carbon atom can be of the RT S configuration. Although the specific compounds exemplified in this application can be represented in a particular stereochemical configuration, the compounds having either the opposite stereochemistry at any given chiral center or mixture thereof are contemplate as part of the invention.
The term "pharmaceutically acceptable salts" forming part of this invention includes the salts of the carboxylic acid moiety, which can be prepared by reacting the compound with the 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. Additionally, salts of organic bases such as lysine, arginine, guanidine, ethanolamine, choline and the like, inorganic bases, for example also include ammonium or substituted ammonium salts. If appropriate, compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrohalides, such as hydrochloride, hydrobromide, iodide; other mineral acids and their corresponding salts, such as sulfate, nitrate, phosphate etc. and alkyl and mono-arylsulfonates, such as ethane sulfonate, toluene sulfonate and benzene sulfonate; and other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citrate, etc.
In another aspect, the compounds disclosed herein can be prepared by the following reaction sequences as depicted in Schemes I and II.
Scheme I Formula 15 Formula 20 Formula I when L '" enlactyRte¡OC (Z) NHRJ Formula 16 Formula 1 when L 'e? -NHCO and R'esOC (Z) NHR ' The compound of Formula 8 (Route A), Formula 9 (Route A), Formula 15 (Route B), Formula 16 (Route B), Formula 19 (Route C) and Formula 20 (Route C) may be prepared in accordance to Scheme I. In this manner, the reaction of a compound of Formula 2 (wherein Y is N02, Hal and COOH) with alpha bromo lactone gives a compound of Formula 3. The compound of Formula 3 can react by three. Ways to give a compound of Formula 8, Formula 9, Formula 15, Formula 16, Formula 19 and Formula 20.
Route A (when Y is COOH): The reaction of a compound of Formula 3 with a compound of Formula 3 '(where R2 is the same as defined above) to give a compound of Formula 4 which in the reaction with a compound of Formula 4 '(wherein R' is alkyl, allyl, benzyl, t-butyl, 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 (wherein R 3 is the same as defined above and Z is O or S) gives a compound of Formula 7. L hydrolysis of a compound of Formula 7 a compound of Formula 8 which in oxidation gives a compound of Formula 9.
Route B (when Y is N02): Reduction of a compound of Formula 3 gives a compound of Formula 10 that in the reaction with a compound of Formula 11 (wherein R2 is the same as defined above) and U is a leaving group such as halide, alkyloxy, aryloxy) gives a compound of Formula 12. The compound of Formula 12 in the reaction with a compound of Formula 4 '(wherein R' and Hal are the same as defined in the foregoing) gives a compound of Formula 13. The reaction of a compound of Formula 13 with a compound of Formula 6 (wherein R 3 and Z are the same as defined above) gives a compound of Formula 14. Hydrolysis of a compound of Formula 14 gives a compound of Formula 15 which on oxidation gives a compound of Formula 16.
Route C (when Y is halogen): The reaction of a compound of Formula 3 with a compound of Formula 4 '(wherein R' and Hal is the same as defined above) gives a compound of the Formula 17 that in the reaction with a compound of Formula 6 (wherein R3 and Z are the same as defined above) gives a compound of Formula 18. Hydrolysis of a compound of Formula 18 gives a compound of the Formula 19 which in 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 the organic base, for example, triethylamine, pyridine,?, - V'-dimethylaminopyridine, , 6-lutidine, 1-methylpiperidine,? -ethyldiisopropylamine 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 (Route A) with a compound of Formula 3 'to give a compound of Formula 4 can be carried out using selected base of triethylamine, pyridine, N, N-dimethylamino-pyridine, 2, 6-lutidine, 1-methylpiperidine, W-ethyldiisopropyl-amine or N-methylmorpholine, in the presence of an additive, 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, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, hexafluoro-phosphate of chlorotripyrrolidino-phosphonium or (benzotriazol-1-yloxy) tris- (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 bases selected from sodium bicarbonate , sodium hydroxide, potassium hydroxide, lithium hydroxide in the presence of a solvent, selected from,,? - dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water or mixtures 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 the organic base selected from, for example, triethylamine, pyridine, N, N- dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N-ethyldiisopropylamine or W-methylmorpholine in a solvent selected from tetrahydrofuran, dimethyl sulfoxide, acetonitrile, N, N-dimethylformamide or mixture (s) thereof.
Hydrolysis of a compound of Formula 7 to give a compound of Formula 8 can be carried out in the presence of the inorganic base selected from, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxide barium in solvents for example, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol, dimethyl sulfoxide or mixture (s) thereof.
Oxidation of a compound of Formula 8 to give a compound of Formula 9 can be carried out with oxidation 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 (Route B) to give a compound of Formula 10 can be carried out using the reducing agent selected from, for example, Pd / C, lithium aluminum hydride, Raney Nickel in the presence of hydrazine, zinc, tin or iron hydrate 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 12 can be carried out in the presence of the organic base, for example, triethylamine, pyridine, N, N-dimethylaminopyridine, 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 the formula Formula 6 to give a compound of Formula 7.
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.
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 (Route 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 the 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 the formula Formula 6 to give a compound of Formula 7.
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.
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 II Formula 30 Formula 29 Formula 28 Formula 27 Formula 1 when L1 -NHCO and 1 is OBn The compound of Formula 27 (Route D) and the Formula 30 (Route E) can be prepared according to Scheme II. In this way, the reaction of a compound of Formula 21 with a compound of Formula 22 (wherein R 'and Hal are the same as defined above) give a compound of Formula 23 which on oxidation gives a compound of the Formula 24. The reaction of a compound of Formula 24 with a compound of Formula 25 (Bn is benzyl group and Hal is the same as defined above) forms a compound of Formula 26. The compound of Formula 26 it can be reacted in two ways to give a compound of Formula 27 and Formula 30.
Route D: Hydrolysis of a compound of Formula 26 yields a compound of Formula 27.
Route E: Reduction of a compound of Formula 26 gives a compound of Formula 28 which in the reaction with a compound of Formula 11 (wherein R2 and U are the same as defined above) gives a compound of Formula 29. The compound of Formula 29 in hydrolysis gives a compound of Formula 30.
The reaction of a compound of Formula 21 with a compound of Formula 22 to give a compound of Formula 23 can be carried out in the presence of the organic base selected from, for example, triethylamine, pyridine,?,? ' dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from dichloromethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, N, N'-dimethylformamide, or mixture (s) thereof.
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 the selected inorganic base of lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate using a solvent selected from, N, W-dimethylformamide, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, or mixture (s) thereof.
Hydrolysis of a compound of Formula 26 (Route 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 (Route E) to give a compound of Formula 28 can be carried out using the 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 the formula Formula 11 to give a compound of Formula 12.
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 the specific reagents, for example, bases, acids, solvents, condensing agents, hydrolyzing agents, catalysts, etc. , as mentioned, it is to be understood that other reagents, for example other acids, bases, solvents, condensation agents, reducing agent, deprotection agent, hydrolyzing agent, catalysts, etc., known for one of ordinary skill in the technique can be used. Similarly, the reaction temperatures and durations can 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 can be administered to an animal for treatment orally, topically, rectally, intranasally or by parenteral route. The pharmaceutical compositions disclosed herein comprise pharmaceutically effective amounts of the compounds described in the present formulation together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, pills, troches, wafers and suppositories. For solid form preparations, the active compounds can be mixed with one or more pharmaceutically acceptable, inert excipients or carriers. Tablets and capsules for oral administration may contain conventional excipients, such as binding agents and / or dissolution enhancers, for example, polyvinyl pyrrolidine, cellulose, starch mucilage, gelatin, sorbitol, syrup, acacia or tragacanth.; fillers or thickening agents, for example, microcrystalline cellulose, sugar, corn starch, calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethylene glycol, magnesium stearate or stearic acid; disintegrating agents and binder, for example, croscarrosose sodium, pregelatinized starch, sodium starch glycolate or potato starch; slip agents, for example, colloidal silicon dioxide or talc; non-stick, for example, magnesium stearate or sodium lauryl sulfate; and coating materials.
The capsules, tablets or pills may also comprise regulatory agents.
The tablets, capsule, pills or granules can be prepared using one or more coatings or coatings to modulate the release of the 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 the active compound while the weight of the tablet filling can vary from 50 mg to 1000 mg. An example is illustrated below.
Ingredients Quantity% p / p Active Compound 0.01 to 20 mg Approximately 50% icrocrystalline cellulose Approximately 90% Croscarmellose Sóxica approximately 1% approximately 10% Pregelatinized starch about 1% Approximately 15% Polyvinyl pyrrolidone (K- approximately 5% approximately 12% Talc approximately 0.1% approximately 2% Magnesium stearate approximately 0.1% approximately 2% Colloidal Silicon Dioxide approximately 0.1% approximately 2% Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, the active compounds can be mixed with water or one or more non-toxic solvents, solubilizing or emulsifying agents, 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, peanut, corn, germ, olive, castor oil and sesame, glycerol, sorbitan fatty acid esters or mixtures thereof . The oral compositions may 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. Suitable 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 non-irritating excipients such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and therefore melt in the body. straight 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. The active compounds can be mixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any of the preservatives or buffer solutions as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
The pharmaceutical preparations can be. in unit dosage form. In the unit dosage form, the preparations can be subdivided into unit doses containing appropriate amounts of active components. The 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 the general synthetic procedures for the preparation of representative compounds of the present invention. The examples are provided to illustrate the particular aspect of the description and not to limit the scope of the present invention.
Experimental Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc., were dried using various drying reagents according to the procedure as described in the literature.
Example 1: Synthesis of 2- ((4- [(4-chlorophenyl) -carbamoyl] phenyl} sulfanyl) -4- {[[4-fluorophenyl) -carbamoyl] oxy} -butanoic acid (Compound No. 68) (Scheme I, Route A, Formula 8) Step a: Preparation of 4- [(2-Oxotetrahydrofuran-3-11) s lphaneyl] benzoic acid To an ice cooled solution of 4-mercaptobenzoic acid (0.5 g, 0.003 mole) in dichloromethane (5 mL) under argon atmosphere were added triethylamine (0.909 g, 0.009 mole) and a solution of bromo lactone (0.53 g, 0.003 mole). ) in dichloromethane (5 mL) dropwise. The reaction mixture was allowed to stir for about 30 minutes. After completion, the reaction mixture was diluted by adding water and extracting in dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by column on silica gel using 70% ethyl acetate in hexane as eluent to obtain the compound wanted .
Yield: 0.800 g LCMS: 239.16 (M + l) Step b: Preparation of N- (4-chlorophenyl) -4- [(2-oxotetra-hydro-furan-3-yl) sulfanyl] benzamide To the solution of the compound obtained from Step a (15.0 g, 0.0630 mol) 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 mol) was added and again stirred for approximately 12 hours at room temperature. After completion, the reaction mixture was diluted by adding water and extracting in dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude compound which was purified by column chromatography using 40% ethyl acetate in hexane as eluent to obtain the desired compound.
Yield: 13.0 g LCMS: 348.05 (M + l) Step c: Preparation of 2- ( { 4- [(4-chlorophenyl) carbamoyl] -phenyl} sulphane) methyl-4-hydroxybutanoate To a solution of the compound obtained from Step b (13.0 g, 0.037 mol) in?, - V'-dimethylformamide (52 mL) and water (13 mL) was added sodium hydroxide (1.70 g, 0.044 mol). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (3.7 g, 0.044 mole), 18 crown 6 (0.970 g, 0.0037 mole) and methyl iodide (7.80 g, 0.055 mole) were added and stirred overnight. After completion, the reaction mixture was diluted by adding water and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by column on silica gel using 30% ethyl acetate in hexane as the eluent to obtain the desired compound.
Yield: 8.0 g Step d: Preparation of 2- ( { 4- [(4-chlorophenyl) carbamoyl] -phenyl} sulfane) -4-. { [(4-fluorophenyl) carbamoyl] ox ±} b methyl tannate To a solution of the compound obtained from Step c (0.500 g, 0.0013 mol) in tetrahydrofuran (5 mL) under argon atmosphere were added triethylamine (0.393 g, 0.0038 mol) and 4-fluoro-isocyanate (0.213 g, 0016 mol) and stirred for about 2 hours at room temperature . After completion, the reaction mixture was diluted by adding water and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by column on silica gel using 30% ethyl acetate in hexane as eluent to provide the desired compound.
Yield: 0.3 g Step e: Preparation of 2- (. {4- [(4-chlorophenyl) -carbamoyl] phenyl] sulfane) -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} -butañoico To a solution of the compound obtained from Step d (0.300 g, 0.0005 mol) in tetrahydrofuran (5 ml) / methanol (5 ml) was added a solution of lithium hydroxide (0.036 g, 0.0006 mol) in water (1 ml) and stirred for about one hour at room temperature. After completion, the reaction mixture was acidified by adding sodium bisulfite solution and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a compound which was purified by preparative TLC eluted using 10% methanol in dichloromethane.
Yield: 0.050 g LCMS: 501.15 (M-l) XH NMR (400 MHz, DMSO-d6) -d: 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] sulfane) -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound no. 59); LCMS: 501.17 (M-l) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-ethylphenyl) carbamoyl] oxy} utanoic (Compound no. 60); LCMS: 511.22 (M-2) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfane) -4- ( { [4- (Propan-2-yl) phenyl] carbamoyl.} Oxy] butanoic acid (Compound No. 61); LCMS: 525.19 (M-2) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-methoxyphenyl) carbamoyl] oxy} butanoic (Compound no. 62); LCMS: 513.18 (M-l) 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound no. 63); LCMS: 497.18 (M-l) 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4-. { [(3-fluorophenyl) carbamoyl] oxy Jbutanoic (Compound no. 64); LCMS: 501.16 (M-l) 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(4-methylphenyl) carbamoyl] oxy} butanoic (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- acid. { [(2,4-difluorophenyl) carbamoyl] oxy [butanoic (Compound No. 67); LCMS: 519.15 (M-l) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 69); LCMS: 553.06 (M) 4- [(er-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- acid. { [(3,4-dichlorophenyl) carbamoyl] oxy Jbutanoic (Compound No. 1); LCMS: 553.03 (M) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- [(pentylcarbamoyl) oxy] utanoic acid (Compound No. 72); LCMS: 477.19 (M-l) 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- ( { - [(4-Chloro-phenyl) carbamoyl] phenyl} sulfanyl) butanoic (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) -carbamoyl] phenyl] -sulfonyl) -4- acid. { [(-florophenyl) carbamoyl] oxy} -butanoic (Compound No. 81) (Scheme I, Route A, Formula 9) To an ice-cooled solution of 2- (. {4- [(4-chlorophenyl) carbamoyl] phenyl] sulphanil) -4-. { [(4-fluorophenyl) -carbamoyl] oxybutanoic acid (0.050 g, 0.00009 mol) in chloroform (5 mL) was added metachloroperbenzoic acid (0.065 g, 0.00037 mol) and stirred for 1 hour at room temperature. The reaction mixture was rapidly cooled by adding sodium metabisulfite solution and then extracted into dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by preparative TLC eluted in 12% methanol in dichloromethane.
Yield: 0.030 g LCMS: 533.18 (-l) 1 H NMR (400 MHz, DMSO-d 6) -5: 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), 2.11 ( 2H, m).
The following compounds can be prepared by following the above synthetic route. 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound no. 75); LCMS: 533.21 (M-l) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-ethylphenyl) carbamoyl] oxy Jbutanoic (Compound No. 76); LCMS: 543.24 (M-2) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyljsulfonyl) -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound no. 77); LCMS: 529.22 (M-l) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-methylphenyl) carbamoyl] oxy Jbutanoic (Compound no. 78); LCMS: 529.20 (M-l) 2- ( {4 - [(4-chlorophenyl) carbamoyl] phenyl} sulfonyl) -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy) utanoic acid (Compound No. 79); LCMS: 583.21 (M-l) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2,4-difluorophenyl) carbamoyl] oxy} butanoic (Compound No. 80); LCMS: 551.19 (M-l) 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 82); LCMS: 541.11 (M-44) 4- [(tert-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] sulphonyl) -4- acid. { [(3, -dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 84); LCMS: 585.09 (M) 2- ( {4 - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- [(pentylcarbamoyl) oxy] butanoic acid (Compound No. 85); LCMS: 509.24 (M-l) 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- ( { - [(4-chlorophenyl) carbamoyl] phenyl} sulfonyl butanoic (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) -carbonyl] amino} phenyl) sulfañyl] -4- acid. { [(4-fluoro-phenyl) -carbamoyl] oxy]} butanoic (Compound No. 5) (Scheme I, Route B, Formula 15) Step a: Preparation of 3- [(4-nifcrofenil) sulfañil] -dihidro-furan-2 (3H) -one To an ice-cooled solution of p-nitro thiophenol (10.0 g, 0.0645 mol) in dichloromethane (75 mL) under argon atmosphere were added triethylamine (19.4 g, 0.1935 mol) and a solution of bromo-lactone (11.1 g, 0.067 g). moles) in dichloromethane (75 mL) dropwise. The reaction mixture was allowed to stir for about 30 minutes at room temperature. After completion, the reaction mixture was diluted with water and extracted into dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product thus obtained was purified by column on silica gel using 30% ethyl acetate in hexane as eluent to obtain the title compound.
Yield: 11 g Step b: Preparation of 3- [(4-aminophenyl) sulfañyl] -dihydrofuran-2 (3H) -one To the solution of the compound obtained from Step a (10.0 g, 0.04184 mol) in tetrahydrofuran / methanol (100 mL: 100 mL) was added Pd / C (4 g) under vacuum and hydrogen pressure was applied using a balloon. The reaction mixture was allowed to stir for about 2 hours at ambient temperature. After completion, the reaction mixture was filtered through celite and concentrated to obtain the desired compound.
Yield: 5.0 g LCMS: 210 (M + l) Step c: Preparation of 4-chloro-N-. { 4- [(2-Oxotetrahydrofuran-3-yl) sulfanyl] phenyl} benzamide To a solution of the compound obtained from Step b (4.86 g, 0.0232 mol) in dichloromethane (100 mL) under argon atmosphere was added triethylamine (7.04 g, 0.0697 mol) and cooled to 0 ° C and then chloride was added. 4-Chlorobenzoyl (4.27 g, 0.024 mole) slowly dropwise. The reaction mixture was allowed to stir for 10 minutes at room temperature. After completion, the reaction mixture was diluted with water and extracted into dichloromethane. The organic layer was washed with sodium bicarbonate and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by column in silica gel using 10% ethyl acetate in hexane as eluent.
Performance: 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 the compound obtained from Step c (8.2 g, 0.0236 moles) in?,? ' Dimethylformamide (32 mL) and water (8 mL) were added with sodium hydroxide (1.12 g, 0.0283 mol). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (2.3 g, 0.0283 mol), 18 crown 6 (0.620 g, 0.0023 mol) and methyl iodide (5.02 g, 0.0354 mol) were added to the reaction mixture and stirred overnight at room temperature. After completion, the reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by column on silica gel using 8% ethyl acetate in hexane as eluent. Yield: 8.0 g Stage e: Preparation of 4-. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) sulfanylbutanoate methyl To a solution of the compound obtained from Step d (0.500 g, 0.00131 mol) in tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.266 g, 0.0026 mol) and l-chloro-4-isocyanatobenzene (0.211 g, 0.0015). moles) and stirred for about 2 hours at room temperature. After completion, the reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by column on silica gel using 15% ethyl acetate in hexane as eluent.
Yield: 0.4 g Step f: Preparation of acid 4-. { [(4-chlorophenyl) carbamoyl] -oxi} -2- [(4- { [(4-chlorophenyl) carbonyl] amino.}. Phenyl) sulfanyl] -butanoic To a solution of the compound obtained from Step e (0.300 g, 0.0005 mole) in tetrahydrofuran / methanol (5 mL: 5 mL) was added a solution of lithium hydroxide (0.034 g, 0.0008 mole) in water and stirred at room temperature. environment for about an hour. After completion, the reaction mixture was acidified with sodium bisulfite solution and then extracted into ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the 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) XH NMR (400 Hz, D SO-d6) -6: 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- (trifluoromethyl) phenyl] carbamoyl}. oxy) butanoic (Compound No. 6); LCMS: 571.11 (M + l) 2 - [(4- {[[(4-chlorophenyl) carbonyl] amino] phenyl) -sulfanyl] -4- acid. { [(3, 5-dimethoxyphenylcarbamoyl] oxy] butanoic (Compound No. 7); LCMS: 545.11 (M) 2- [(4- {[[(4-chlorophenyl) carbonyl] aminojphenyl) -sulfanyl] -4- acid. { [(5-fluoro-2-methylphenyl) carbamoyl] oxy} - Butanoic (Compound No. 8); LCMS: 517.17 (M + l) 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 9); LCMS: 503.11 (M + l) 4- Acid. { [(3-chloro-4-methoxyphenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 10); LCMS: 549.03 (M) 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- acid. { [(3-ethoxyphenyl) carbamoyl] oxy} butanoic (Compound No. 11); LCMS: 529.15 (M), 546.19 (M + 17) 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] utanoic (Compound No. 12); LCMS: 519.07 (M), 536.11 (M + 17) 4- Acid. { [(4-chlorophenyl) carbamothioyl] oxy} -2- [(4- { [(4-chlorophenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 13); LCMS: 53-5.03 (M) 2- [(4- {[[(4-chlorophenyl) carbonyl] amino) phenyl) -sulfanyl] -4- acid. { [(3-cyanophenyl) carbamothioyl] oxybutanoic (Compound No. 14); LCMS: 527.12 (M + l) 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 29); LCMS: 483.14 (M + l) 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound do not. 30); LCMS: 483.21 (+ l) 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 32); LCMS: 513.22 (M-l) 4- Acid. { [(4-ethylphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 33); LCMS: 507.28 (M-l) 2- [(4- {[[(-methoxyphenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ({[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} butanoic acid ( Compound No. 34); LCMS: 547.20 (M-l) 4- Acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 35); LCMS: 547.3 (M-2) 2- (4- {[[(4-methoxyphenyl) carbonyl] amino} phenyl) -sulfanyl] -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 36); LCMS: 493.22 (M-l) 4- Acid. { [(4-methoxyphenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 37); LCMS: 509.26 (M-l) 4- [(tert-Butylcarbamoyl) oxy] -2- [(4- {[[(4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic acid (Compound No. 38); LC S: 459.24 (M-l) 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 39); LCMS: 515.20 (M-l) 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 40); LCMS: 497.25 (M-l) 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 41); LCMS: 497.25 (M-l) 4- Acid. { [(3, -dichlorophenyl) carbamoyl] oxy} -2 - [(4- {[[(4-methoxyphenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 42); LCMS: 547.14 (M-2) 4- Acid. { [(3, -dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 43); LCMS: 535.09 (M + 2) 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- ([(4-methylphenyl) carbonyl] aminojphenyl) sulfanyl] butanoic (Compound No. 44); LCMS: 501.15 (M + l) 2- [(4- {[[(2-fluorophenyl) carbonyl] aminojphenyl) sulfanyl] -4- ({[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} butanoic acid (Compound No. 88) ); LCMS: 535.27 (M-l) 2- [(4- {[[(4-chlorophenyl) carbonyl] aminojphenyl) 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} - acid butanoic (Compound No. 90); LCMS: 577.29 (M-l) 2- ( { - [(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] aminojphenyl) acid Sulfanyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl.} oxy) butanoic (Compound No. 93); LCMS: 561.27 (M-l) 2- [(4. {[[(2,3-difluorophenyl) carbonyl] amino] phenyl) -sulfanyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy] acid) - butanoic (Compound No. 94); LCMS: 553.21 (M-l) 2- [(-. {[[(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, -dichlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ({[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} - butanoic (Compound No. 98); LCMS: 585.19 (M-2), 587.15 (M).
Example 4: Synthesis of 2- (4- ({(4-chlorophenyl) carbonyl] -amino} phenyl) sulfonyl] -4- acid. { [(4-fluoro-phenyl) carbamoyl] oxy} -butanoic (Compound No. 15) (Scheme I, Route B, Formula 16) To a solution cooled with ice of acid 4-. { [(4-fluorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-chlorophenyl) carbonyl] -aminojphenyl) sulfanyl] butanoic (0.080 g, 0.00015 mol) was added meta-chloroperbenzoic acid (0.101 g, 0.00059 mol) and stirred for about hour at room temperature. After completion, the reaction mixture was rapidly cooled by adding sodium metabisulfite solution and then extracted into dichloromethane. The organic layer was dried over anhydrous sodium sulfate 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-d6) -d 11.00 (1H, 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 (1H , m), 3.97 -4.03 (1H, 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 (Compound No. 16); LCMS: 603.22 (M + l), 620.22 (M + 18) 2- (4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfonyl] -4- acid. { [(5-fluoro-2-methyl phenyl) carbamoyl] oxy} -butanoic (Compound No. 17); LCMS: 548.03 (M) 4- Acid. { [(3-chloro-4-methoxyphenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 18); LCMS: 581.33 (M), 603.08 (M + l) 2- (4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfonyl] -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 19); LCMS: 535.22 (M + l), 552.28 (M + 18) 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 20); LCMS: 552.01 (M + l), 573.14 (M + 22) 2- (4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfonyl] -4- acid. { [(3-cyanophenyl) carbamothioyl] oxybutanoic (Compound No. 21); LCMS: 564.12 (M + 6), 542.24 (M-16) 4- Acid. { t (3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 31); LCMS: 515.09 (M + l) 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 5); LCMS: 547.20 (M + l) 4- Acid. { [(4-ethylphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 46); LCMS: 540.25 (M) 2- [(- { [(4-methoxyphenyl) carbonyl] amino] phenyl) -sulfonyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy) butanoic acid ( Compound No. 47); LCMS: 579.24 (M-l) 4- Acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 48); LCMS: 579.18 (M-20) 2- [(4- {[[(4-methoxyphenyl) carbonyl] amino] phenyl) -sulfonyl] -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 49); LCMS: 525.24 (M-l) 4- [(tert-Butylcarbamoyl) oxy] -2- [(4. {[[(4-methoxyphenyl) carbonyl] amino] phenyl) sulfonyl] butanoic acid (Compound No. 50); LCMS: 491.29 (M-l) 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 51); LCMS: 547.22 (M-l) 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 52); LCMS: 529.22 (M-l) 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 53); LCMS: 529.25 (M-l) 4- Acid. { [(5-chloro-2-methoxyphenyl) carbamoyl] oxy} -2- [(4. {[[(-methoxyphenyl) carbonyl] amino] phenyl) sulfonyl] butanoic (Compound No. 54); LCMS: 575.23 (M-2), 577.17 (M) 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] aminojphenyl) sulfonyl] butanoic (Compound No. 55); LCMS: 579.14 (M-2), 581.16 (M) 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 56); LCMS: 565.06 (M) 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4-. {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 57); LCMS: 533.10 (M + l) 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4- (methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 58); LCMS: 515.15 (M + l) Example 5: Synthesis of 4- ([(-chlorophenyl) carbamoyl] -oxy) -2- [(-chlorophenyl) sulfanyl] butanoic acid (Compound No. 1) (Scheme I, Route C, Formula 19) Step a: Preparation of 3- [(4-chlorophenyl) sulfanyl] -dihydrofuran-2 (3ff) -one To an ice cooled solution of p-chloro thiophenol (10.0 g, 0.069 mol) in dichloromethane (75 L) under argon atmosphere were added triethylamine (21.0 g, 0.208 mol) and a solution of bromo lactone (12.0 g, 0.072 mol). ) in dichloromethane (75 mL) dropwise. The reaction mixture was allowed to stir for about 30 minutes at 0 ° C. After completion, the reaction mixture was diluted by adding water and extracting in dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by column on silica gel using 10% ethyl acetate in hexane as eluent.
Yield: 13.9 g Step b: Preparation of methyl 2- [(4-chlorophenyl) sulfanyl] -4-hydroxybutanoate To a solution of the compound obtained from Step a (5.0 g, 0.0219 moles) in W, N'-dimethylformamide (20 ml) and water (5 ml) was added sodium hydroxide (1.05 g, 0.0263 mol). 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) were added., 0.0259 moles) to the reaction mixture and again stirred overnight at room temperature. After completion, the reaction mixture was diluted by addition of water and extraction in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by column on silica gel using 8% ethyl acetate in hexane as eluent to obtain a title compound. Yield: 3.5 g Stage c: Preparation of 4-. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4-chlorophenyl) sulfañyl] methyl butanoate To a solution of the compound obtained from Step b (0.425 g, 0.0016 mol) in tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.323 g, 0.0032 mol) and l-chloro-4-isocyanatobenzene (0.293 g, 0.0019 mol) and stirred for about 2 hours at room temperature. After completion, the mixture of The reaction was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by column on silica gel using 15% ethyl acetate in hexane as eluent to obtain the desired compound.
Yield: 0.600 g Step d: Preparation of acid 4-. { [(4-chlorophenyl) carbamoyl] -oxi} -2- [(4-chlorophenyl) sulfanyl] butanoic To a solution of the compound obtained from Step c (0.600 g, 0.0014 mol) in tetrahydrofuran / methanol (5ml: 5ml) was added a solution of lithium hydroxide (0.090 g, 0.0021 mol) in water (1 mL) and stirred for about one hour at room temperature. After completion, the reaction mixture was acidified with sodium bisulfite solution and then extracted into ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the 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-df) -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, ra), 1.97 - 2.06 (1H, m).
The following compounds can be prepared by following the above synthetic route. 2- [(4-chlorophenyl) sulfanyl] -4- acid. { [(4-fluorophenyl) -carbamoyl] oxybutanoic (Compound No. 2); LCMS: 384.22 (M ++ l) Example 6: Synthesis of acid 4-. { [(4-chlorophenyl) carbamoyl] -oxi} -2- [(-chlorophenyl) sulfonyl] butanoic (Compound No. 3) (Scheme I, Route C, Formula 20) To a solution cooled with ice of acid 4-. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4-Chlorophenyl) sul anyl] butanoic (0.100 g, 0.0002 mole) in chloroform (10 mL) was added meta-chloroperbenzoic acid (0.172 g, 0.001 mole) and stirred at room temperature for about one hour. After completion, the reaction mixture was rapidly cooled by sodium metabisulfite solution and extracted into dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to obtain the desired compound.
Yield: 0.090 g LCMS: 432.12 (M), 434 (M + 2), 449.17 (M + 18) NMR (400 MHz, DMSO-d6) -d: 9.79 (1 H, s), 7.73 - 7.82 (2 H, d, J = 8.8 Hz), 7.60 - 7.63 (2 H, 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- acid. { [(4-fluorophenyl) -carbamoyl] oxy} butanoic (Compound no.); LCMS: 416.13 (M + l) Example 7: Synthesis of 4- (benzyloxy) -2- (4-nitrophenyl) -sulfonyl] butanoic acid (Compound No. 28 (Scheme II, Route D, Formula 27) Step a: Synthesis of [(4-nitropheni) sulfañil] ethyl acetate To an ice cooled solution of p-nitro thiophenol (5 g, 0.0322 mol) in dichloromethane (50 mL) under argon atmosphere were added triethylamine (9.7 g, 0.0967 mol) and a solution of ethyl bromoacetate (6.4 g, 0.0387). moles) drop, drop. The reaction mixture was allowed to stir for about 5 hours at room temperature. After completion, the reaction mixture was diluted with water and extracted into dichloromethane. The organic layer was dried over sodium sulfate and concentrated to obtain a crude product. The crude product obtained was purified by column on silica gel 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 the compound obtained from Step a (6.5 g, 0.0269 mol) in chloroform (70 mL) was added meta-chloroperbenzoic acid (18 g, 0.107 mol) and stirred at room temperature for about one hour. After completion, the reaction mixture was quenched with sodium metabisulfite solution and then extracted into dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the 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 the compound obtained from Step b (0.500 g, 0.0018 mole) in i \ 7,. V'-dimethylformamide (5 mL) under argon atmosphere were added potassium carbonate (0.745 g, 0.0054 mole), tetrabutylammonium iodide (0.067 g, 0.00018 mole) and bromide of O-benzyl ethyl (0.550 g, 0.0027 mol). The reaction mixture was heated to 50 ° C and stirred at the same temperature for about 4 hours. After completion, the reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by column on silica gel using 8% ethyl acetate in hexane as eluent to obtain the title compound.
Yield: 0.450 g LCMS: 408 (M + l) Step d: Preparation of 4- (benzyloxy) -2- [(4-nitro-phenyl) sulfonyl] butanoic acid To a solution of the compound obtained from Step c (0.100 g, 0.00024 mol) in tetrahydrofuran / methanol (5 mL: 5 mL) was added a solution of lithium hydroxide (0.015 g, 0.00036 mol) in water (1 mL). The reaction mixture was allowed to stir at room temperature for about one hour. After completion, the reaction mixture was acidified with sodium bisulfite solution and then extracted into ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to obtain the title compound.
Yield: 0.040 g LCMS: 402.12 (M + 23) NMR (400 MHz, DMSO-d¿) -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 (1H, m), 3.45 - 3.51 (4H, m), 2.05 - 2.09 (3H, m), 1.83 (1H, m).
Example 8: Synthesis of 4- (benzyloxy) -2- [(4- {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic acid (Compound No. 22) (Scheme II, Route 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 mol) in ethyl acetate (10 mL) was added stannous chloride (0.829 g, 0.0036 mol). and stirred at 80 ° C for about 2 hours. After completion, the reaction mixture was rapidly cooled by adding sodium bicarbonate solution and then extracted into ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the 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 the compound obtained from Step a (0.500 g, 0.0013 mol) in dichloromethane (10 mL) under an argon atmosphere was added pyridine (0.314 g, 0.0039 mol) and cooled to 0 ° C. To this cooled solution was added 4-methylbenzoyl chloride (0.220 g, 0.0014 mol) slowly dropwise. After completion, the reaction mixture was rapidly cooled by adding water and extracting in dichloromethane. The organic layer was washed with sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by column on silica gel using 10% ethyl acetate in hexane as eluent to obtain the compound wanted. Yield: 0.400 g LCMS: 348 (M + l) Step c: Preparation of 4- (benzyloxy) -2- [(4- {[[(4-methylphenyl) carbonyl] amino} -ethenyl) sulfonyl] butanoic acid To a solution of the compound obtained from Step b (0.100 g, 0.00020 mol) in tetrahydrofuran / methanol (5 mL: 5 mL) was added a solution of lithium hydroxide (0.012 g, 0.00030 mol) in water (1 mL) and stirred at room temperature for about one hour. After completion, the reaction mixture was acidified by adding sodium bisulfite solution and then extracted into ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to provide the desired compound.
Yield: 0.050 g LCMS: 467.93 (M), 484.95 (M + 17) : HNR (400 MHz, DMSO-d6) -5: 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 Metallo Matrix Proteinases (MMPs) NCEs / standards were prepared (10 mM extract) in 100% DMSO and subsequent dilutions were made in 50% DMSO-50% TCNB (50 mM Tris, 10 mM CaCl 2, 150 mM NaCl, 0.05% Brij-35 , pH 7.5). 1 μ? of the compound and 88 μ? of TCNB was added to the cavities of the 96-well plate to achieve the desired final concentration of NCE (the final DMSO concentration should not exceed 0.5%). 1 μ? of recombinant, activated MMPs was added to each well (20-100 ng / 100 μl of reaction mixture) except the "negative cavity". (MMP-1, 9 &14 enzymes required before activation.For this, the supplied enzyme was incubated with either APMA, 1 mM final concentration, for a period of 1 hour at 37 ° C). The incubation was done at room temperature (~ 25 ° C) for 4 minutes to 5 minutes. The reaction was started with 10 μ? of substrate 100 μ? (ES001: Aliquots were recently diluted in TCNB, extract: 2 mM) and the increase in florescence was monitored at excitation wavelength 320 nm followed by emission at 405 nm for 25-30 cycles. The increase in fluorescence (RFU) was calculated for positive, negative and NCE / standard cavities. The percent inhibition compared to the controls was calculated and the IC5o values were determined using the Graph-prism software.
Activities for MMP-9 provided low values of 10 nanomolar-10 micromolar.

Claims (9)

1. A compound of Formula I: Formula 1 which includes racemates, enantiomers and diastereomers thereof or a pharmaceutically acceptable salt thereof, characterized in that, X is S, SO or S02; L1 is selected from the bond, -0-, -S-, -SO, -S02, -CH2, -NR4, -NHC0 (CH2) n-, - (CH2) nC0NH-, -NHCONH-, -S02NH-, - NHSO2 -, -NHCO (O) -, -0- (CH2) n, - (CH2) n-0-, -0C (0) NH-, -C (S) NH-, -NHC (S), - NHC (S) NH-, -C00- where n is zero or an integer between 1 and 2; R1 is -0C0NHR3, OCSNHR3, OCH2R3; When R1 is OCONHR3 or OCSNHR3 then R1 is hydrogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, cyano, nitro, halogen, halogen-C1-C6 alkyl, C6-Ci2 aryl, C3-C8 cycloalkyl , Cs-Ci2 heteroaryl wherein C6-Ci2 aryl, C3-C8 cycloalkyl, C5-C12 heteroaryl is optionally substituted with one or more times with R5; When R1 is OCH2R3, then R2 is C6-C12 aryl, C3-C8 cycloalkyl, C6-C12 heteroaryl; R3 is alkyl, alkenyl, alkynyl, C6-C12 aryl, C3-C8 cycloalkyl, C5-C12 heteroaryl, C3-C12 heterocyclyl which is optionally substituted one or more times with R5; R 4 is H, C 1 -C 6 alkyl, C 1 -C 4 alkylaryl; R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, ~ (CH2) n- NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq , (CH2) nNHC (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n -NH-C (= 0) -Rf or - (CH2) nS (= 0) m- NRfRq. { wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined above and m is an integer of 0-2};
2. A compound of Formula I, characterized in that it is: Acid 4 -. { [(-chlorophenyl) carbamoyl] oxy} -2- [(4-chlorophenyl) -sulfañyl] butanoic (Compound No. 1); 2- [(4-chlorophenyl) sulfanyl] -4- acid. { [(4-fluorophenyl) -carbamoyl] oxy} butanoic (Compound No. 2); 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4-chlorophenyl) -sulfonyl] butanoic (Compound No. 3); 2- [(4-chlorophenyl) sulfonyl] -4- acid. { [(4-fluorophenyl) -carbamoyl] oxy} butanoic (Compound No. 4); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- acid. { [(4-fluorophenyl carbamoyl) oxy] butanoic (Compound No. 5); 2- [(4. {[[(4-Chlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ( { [2-fluoro-5- (trifluoromethyl) phenyl] -carbamoyl}. oxy) butanoic (Compound No. 6); 2- [(4- {[[(4-chlorophenyl) carbonyl] aminojphenyl) -sulfanyl] -4- acid. { [(3,5-dimethoxyphenyl) carbamoyl] oxy} butanoic (Compound No. 7); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino) phenyl) -sulfanyl] -4- acid. { [(5-fluoro-2-methyl phenyl) carbamoyl] oxy} -butanoic (Compound No. 8); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- acid. { [(2-fluoro-phenyl) carbamoyl] oxy} butanoic (Compound No. 9); 4- Acid. { [(3-chloro-4-methoxyphenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phehyl) sulfanyl] butanoic (Compound No. 10); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- acid. { [(3-Ethoxyphenyl) carbamoyl] oxy Jbutanoic (Compound No. 11); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 12); 4- Acid. { [(4-chlorophenyl) carbamothioyl] oxy} -2- [(4- { [(4-chlorophenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (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- acid. { [(4-fluorophenyl) carbamoyl] oxy Jbutanoic (Compound No. 15); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino] phenyl) -sulfonyl] -4- ( { [2-fluoro-5- (trifluoromethyl) phenyl] -carbamoyl} acid. oxy) butanoic (Compound No. 16); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino] phenyl) -sulfonyl] -4- acid. { [(5-fluoro-2-methyl phenyl) carbamoyl] oxy} -butanoic (Compound No. 17); 4- Acid. { [(3-chloro-4-methoxyphenyl) carbamoyl] oxy} -2- [(- { [(4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 18); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino] phenyl) -sulfonyl] -4- acid. { [(2-fluorophenyl) carbamoyl] oxy Jbutanoic (Compound No. 19); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-chlorophenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 20); 2- [(4- {[[(4-chlorophenyl) carbonyl] amino) phenyl) -sulfonyl] -4- acid. { [(3-cyanophenyl) carbamothioyl] oxy} butanoic (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] butanoio acid (Compound No. 24); 4- (Benzyloxy) -2- [(4- {[[(4-ethylphenyl) carbonyl] amino} - phenyl) sulfonyl] utanoic acid (Compound No. 25); 4- (Benzyloxy) -2- [(4- {[[(3-methoxyphenyl) carbonyl] -amino} phenyl) sulfonyl] butanoic acid (Compound No. 26); 4- (Benzyloxy) -2- [(- { [(2-fluorophenyl) carbonyl] -amino} phenyl) sulfonyl] butanoic acid (Compound No. 27); 4- (Benzyloxy) -2- [(4-nitrophenyl) sulfonyl] butanoic acid (Compound No. 28); Acid4-. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 29); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulphañyl] butanoic (Compound No. 30); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methyl-phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 31); 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 32); 4- Acid. { [(4-ethylphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 33); 2- [(4- {[[(4-methoxyphenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ({{[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} butanoic acid (Compound No. 34); 4- Acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 35); 2- [(- { [(4-methoxyphenyl) carbonyl] amino] phenyl) -sulfanyl] -4- acid. { [(2-me ilphenyl) carbamoyl] oxy} butanoic (Compound No. 36); 4- Acid. { [(4-methoxyphenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 37); 4- [(er-Butylcarbamoyl) oxy] -2- [(4- {[[(4-methoxy-phenyl) carbonyl] amino} phenyl) sulfanyl] butanoic acid (Compound No. 38); 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 39); 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 40); 4- Acid. { [(3-fluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 41); 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] amino.}. Phenyl) sulfanyl] butanoic (Compound No. 42); 4- Acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 43); 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfanyl] butanoic (Compound No. 44); 4- Acid. { [(4-chlorophenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 5); 4- Acid. { [(4-ethylphenyl) carbamoyl] oxy} -2- [(4- {[[(-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 46); 2- [(- { [(-methoxyphenyl) carbonyl] amino] phenyl) -sulfonyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl.} Oxy] butanoic acid (Compound No. 47); 4- Acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] aminophenyl)} sulfonyl] butanoic (Compound No. 48); 2- [(4- {[[(4-methoxyphenyl) carbonyl] amino] phenyl) -sulfonyl] -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound No. 49); 4- [(tert-Butylcarbamoyl) oxy] -2- [(4. {[[(4-methoxyphenyl) carbonyl] amino) phenyl) sulfonyl] butanoic acid (Compound No. 50); 4- Acid. { [(2, -difluorophenyl) carbamoyl] oxy) -2- [(4- {[[(4-methoxyphenyl) carbonyl] aminojphenyl) sulfonyl] butanoic (Compound No. 51); 4- Acid. { t (2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methoxy phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 52); 4- Acid. { [(3-Fluorophenyl) carbamoyl] oxy} -2- [(4- { [(4-methoxyphenyl) carbonyl] aminojphenyl) sulfonyl] butanoic (Compound No. 53); 4- Acid. { [(5-chloro-2-methoxyphenyl) carbamoyl] oxy} -2- [(4- {[[4-methoxyphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 54); 4- Acid. { [(3, -dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methoxy phenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 55); 4- ([(3, -Dichlorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic acid (Compound No. 56); 4- Acid. { [(2,4-difluorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-Methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 57); 4- Acid. { [(2-fluorophenyl) carbamoyl] oxy} -2- [(4- {[[(4-Methylphenyl) carbonyl] amino} phenyl) sulfonyl] butanoic (Compound No. 58); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(2-fluorophenyl) carbamoyl] oxy} butanoic (Compound not 59); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-ethylphenyl) carbamoyl] oxy} butanoic (Compound not 60); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4 ({[[4- (propan-2-yl) phenyl] carbamoyl} oxy} butanoic acid (Compound No. 61); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-methoxyphenyl) carbamoyl] oxijbutanoic (Compound no 62); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(2-methylphenyl) carbamoyl] oxybutanoic (Compound no 63); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(3-fluorophenyl) carbamoyl] oxy} butanoic (Compound not 64); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulfane) -4- acid. { [(4-methylphenyl) carbamoyl] oxybutanoic (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- acid. { [(2,4-difluorophenyl) carbamoyl] oxy} butanoic (Compound No. 67); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(4-fluorophenyl) carbamoyl] oxijbutanoic (Compound No. 68); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(2,6-dichlorophenyl) carbamoyl] oxy (butanoic (Compound No. 69); 4- [(tert-Butylcarbamoyl) oxy] -2- ( { - [(4-chlorophenyl) -carbamoyl] phenyl} sulfanyl) butanoic acid (Compound No. 70); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- acid. { [(3,4-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 71); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) -4- [(pentylcarbamoyl) oxy] butanoic acid (Compound No. 72); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- ({4- [(4-chlorophenyl) carbamoyl] phenyl} sulfanyl) butanoic (Compound No. 73); 4- [(Butylcarbamoyl) oxy] -2- ( { - [(4-chlorophenyl) -carbamoyl] phenyl] sulfane) utanoic acid (Compound No. 74); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2-fluorophenyl) carbamoyl] oxybutanoic (Compound No. 75); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-ethylphenyl) carbamoyl] oxy} butanoic (Compound No. 76); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2-methylphenyl) carbamoyl] oxy} butanoic (Compound no. 77); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-methylphenyl) carbamoyl] oxy} butanoic (Compound no. 78); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl) sulfonyl) -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl.} Oxy] butanoic acid (Compound No. 79); Acid 2-. { . { 4- [(4-chlorophenyl) carbamoyl] phenyl} sulfonyl) -4-. { [(2,4-difluorophenyl) carbamoyl] oxy Jbutanoic (Compound No. 80); 2- ( { 4 - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(4-fluorophenyl) carbamoyl] oxy} butanoic (Compound No. 81); 2- ( { 4 - [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(2,6-dichlorophenyl) carbamoyl] oxy} butanoic (Compound No. 82); 4- [(tert-Butylcarbamoyl) oxy] -2- (. {4 - [(4-chlorophenyl) -carbamoyl] phenyl} sulfonyl) butanoic acid (Compound No. 83); 2- ( { 4- [(4-chlorophenyl) carbamoyl] phenyl] sulphonyl) -4- acid. { [(3,4-dichlorophenyl) carbamoyl] oxy Jbutanoic (Compound No. 84); 2- ( { - [(4-chlorophenyl) carbamoyl] phenyl} sulfonyl) -4- [(pentylcarbamoyl) oxy] butanoic acid (Compound No. 85); 4- Acid. { [(3-chlorophenyl) carbamoyl] oxy} -2- ( { 4- [(4-chloro-phenyl) carbamoyl] phenyl} sulfonyl) butanoic (Compound No. 86); 4- [(Butylcarbamoyl) oxy] -2- ( { - [(4-chlorophenyl) -carbamoyl] phenyl} sulfonyl) utanoic 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] aminojphenyl) -sulfanyl] -4- ({[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} butanoic acid (Compound no. 89); 2- [(4. {[[2,6-dimethoxyphenyl) carbonyl] aminojphenyl) -sulfanyl] -4- ({{[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} butanoic acid (Compound No. 90); 2- ( { 4- [(Cyclopropylcarbonyl) amino] phenyljsulfanyl) -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] acid) - butanoic (Compound No. 94); 2- [(4. {[[(3, -dichlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy} - butanoic (Compound No. 95); 2- [(4- {[[(4-Ethoxyphenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl} oxy] acid) - butanoic (Compound No. 96); 2- ( { 4- [(Cyclohexylcarbonyl) amino] phenyl} sulfanyl) -4- ( { [4- (trifluoromethyl) phenyl] carbamoyl.} Oxy] butanoic acid (Compound No. 97); 2- [(4. {[[(2, -dichlorophenyl) carbonyl] amino} phenyl) -sulfanyl] -4- ({[[4- (trifluoromethyl) phenyl] carbamoyl} oxy} - butanoic (Compound No. 98).
3. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of one or more of the compound of the Formula I according to claims 1 and 2, together with one or more pharmaceutically acceptable carriers, excipients or diluents.
4. A compound according to any of claims 1-2, characterized in that it is 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, characterized in that the inflammatory disease or allergic disease is asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, arthritis psoriatic arthritis, psoriasis, pulmonary fibrosis, lung inflammation, acute respiratory distress syndrome, perodontitis, sclerosis Multiple, gingivitis, atherosclerosis, dry eye, neointima proliferation associated with restenosis and ischemic heart failure, apoplectic attack, kidney disease or tumor metastasis.
6. A pharmaceutical composition according to claim 3, characterized in that it also comprises one or more additional active ingredients selected from: a) anti-inflammatory, experimental or commercial agents (i) selected from (i) the non-spheroidal anti-inflammatory agents of piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, kinase inhibitors / cathepsin of MAP PDE-4 / p38, (ii) LTC4 / LTD4 / LTE4 / LTB4 inhibitors of leukotrienes, 5-lipoxygenase inhibitor and PAF receptor antagonists, (iii) Cox-2 inhibitors, (iv) other MMP inhibitors and (v) interleukin inhibitors. I; b) antihypertensive agents, selected from (i) the ACE inhibitors, enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, losartan, candesartan, irbesartan, valsartan and eprosartan, (iii) ) ß-blockers and (iv) calcium channel blockers. c) immunosuppressive agents selected from, cyclosporine, azathioprine and methotrexate and anti-inflammatory corticosteroids.
. A process for preparing a compound of the Formula 9 (Formula I when L1 is -CONH-, X is S02 and R1 is 0C (Z) NHR3), characterized in that it comprises: 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 coupling a compound of Formula 4 with a compound of Formula 4 'to give a compound of Formula 5; Formula 4 'Formula 5 reacting a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7; R3N = C = Z Formula 6 Formula 7 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; Formula 9 where, R2 is hydrogen, C1-C6 alkyl, hydroxyl, Ci-C6 alkoxy, cyano, nitro, halogen, halogen-Ci-Cg alkyl, C6-C12 aryl, C3-Ce cycloalkyl, C5-C12 heteroaryl in wherein C6-C12 aryl, C3-C8 cycloalkyl, C6-C12 heteroaryl is optionally substituted with one or more times with R5; R3 is alkyl, alkenyl, alkynyl, C6-C12 aryl, C3-Ce cycloalkyl, C5-C12 heteroaryl, C3-C12 heterocyclyl optionally substituted one or more times with R5; R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-Ci-C ^ alkyl, halo-Ci-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C ( = 0) -Rf,. -COORf, -NRfRq, - (CH2) "-C (= 0) NRfRq, - (CH2) n -NHC (= 0) -Rf, - (CH2)" - 0-C (= 0) -NRfRq, ( CH2) nNHC (= 0) NRfRq, - (CH2) "- 0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0) ra-NRfRq. { wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl}; n is zero or n integer between 1 and 2; m is a number of 0-2; R 'is alkyl, allyl, benzyl, t-butyl, silyl; Hal is F, CI, Br, I; Y Z is O, S.
8. A process for preparing a compound of Formula 16 (Formula I when L1 is -NHCO-, X is S02 and R1 is OC (Z) NHR3), Formula 20 (Formula I when L1 is bond, X is S02 and R1 is OC (Z) NHR3), characterized in that it comprises: a) reducing a compound of Formula 3 (where Y is N02) to give a compound of formula 10; Formula 3 Formula 10 coupling a compound of Formula 10 with compound of Formula 11 to give a compound Formula 12; Formula J 1 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 coupling a compound of Formula 13 with a compound of Formula 6 to give a compound of Formula 14; R3N = C = Z Formula 6 Formula 1 hydrolyzing a compound of Formula 14 to give a compound of Formula 15; Formula 15 oxidizing a compound of Formula 15 to give a compound of Formula 16; Formula 16 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 '7 coupling a compound of Formula 17 with a compound of Formula 6 to give a compound of Formula 18; R3N = € = Z 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 give a compound of Formula 20; Formula 20 where, R3 is alkyl, alkenyl, alkynyl, C6-C12 aryl, C3-C8 cycloalkyl, C5-12 heteroaryl, C3-C12 heterocyclyl optionally substituted one or more times with R 2 is hydrogen, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, nitro, halogen, halogen-C 1 -C 6 alkyl, C 6 -C 12 aryl, C 3 -C 8 cycloalkyl, C 5 -C 12 heteroaryl , wherein C6-C12 aryl, C3-C8 cycloalkyl, C6-C12 heteroaryl is optionally substituted with one or more times with R5; R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-C1-C6 alkyl, halo-C1-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -C00Rf, -NRfRq, - (CH2) n ~ C (= 0) NRfRq, - (CH2) n -NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq, (CH2) nNHC (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0) m-NRfRq. { wherein Rf and Rq, each independently represents hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylhetero-aryl and alkylheterocyclyl}; n is zero or an integer between 1 and 2; m is an integer of 0-2; Hal is F, CI, Br, I; ü * is halide, alkyloxy, aryloxy; R 'is alkyl, allyl, benzyl, t-butyl, silyl; Y Z is O, S.
9. A process for preparing compounds of Formula 27 (Formula I when L1 is bond, X is S02, R2 is N02 and R1 is -OBn) and 30 (Formula I when L1 is -NHCO, X is S02 and R1 is -OBn) , characterized in that it comprises: a) reacting a compound of Formula 21 with a compound of Formula 22 Formula 21 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 hydrolyzing a compound of Formula 26 to give a compound of Formula 27; Formula 27 reducing a compound of Formula 26 to give a compound of Formula 28; reacting a compound of Formula 28 with a compound of Formula 11 to give a compound of Formula 29; Formula 11 Formula 29 hydrolyzing a compound of Formula 29 to give a compound of Formula 30; Formula 30 where, R2 is hydrogen, Ci-C6 alkyl, hydroxyl, Ci-C6 alkoxy, cyano, nitro, halogen, halogen-Ci-C6 alkyl, aryl of C6-Ci2, cycloalkyl of C3-C8, heteroaryl of C5-C12 in wherein C6-Ci2 aryl, C3-C8 cycloalkyl, Cg-Ci2 heteroaryl is optionally substituted with one or more times with R5; R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, azido, thiol, alkylthiol, - (CH2) n-ORf, -C (= 0) -Rf, -COORf, -NRfRq, - (CH2) nC (= 0) NRfRq, - (CH2) "- NHC (= 0) Rf, - (CH2) n-0-C (= 0) -NRfRq, (CH2) nNHC (= 0) NRfRq, - (CH2) n-0-C (= 0) -Rf, - (CH2) n-NH-C (= 0) -Rf or - (CH2) nS (= 0) m-NRfRq . { wherein Rf and Rq, each independently represents hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylhetero-aryl and alkylheterocyclyl}; n is zero or an integer between 1 and 2; m is an integer of 0-2; Hal is F, Cl, Br, I; U is halide, alkyloxy, aryloxy; Bn is benzyl; Y R 'is alkyl, allyl, benzyl, t-butyl, silyl.
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