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  • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • 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
  • C07C309/60—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 the carbon skeleton being further substituted by singly-bound oxygen atoms
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  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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  • C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
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  • C07C323/50—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
  • C07C323/51—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
  • C07C323/52—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 the carbon skeleton being acyclic and saturated
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  • C07C323/50—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
  • C07C323/51—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
  • 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

Definitions

• the present invention relates to certain sulfone acetic acid derivatives as MMP inhibitor and processes for its syntheses.
• the invention also relates to pharmacological compositions containing the compounds of the present invention and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple scleorisis, gingivitis, atherosclerosis, dry eye, and neointimal proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders characterized by over expression and over activation of a matrix metalloproteinase using the compounds.
• MMPs Metalloproteinases
• Enzymes a naturally occurring superfamily of proteinases (enzymes) found in most mammals.
• the superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types; sharing structural and functional features. Based on structural and functional considerations proteinases have been classified into different families and subfamilies (Vartak et ah, J. Drug Targeting, 15, p. 1-20 (2007), and Hopper, FEBS, 354, p.
• MMP-1, -8 and -13 collagenases
• MMP-2, and -9 gelatinases
• MMP-12 metalloelastases
• MMP-14, -15, -16, -17, -24 and -25 MT-MMPs
• MMP-7 and -26 matrilysins
• MMP-3, -10 stromelysins
• TACE TNF-converting enzymes
• MMPs are believed to be important in physiological disease processes that involve remodeling such as embryonic development, bone formation and uterine remodeling during menstruation.
• One major biological function of MMPs is to catalyze the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze various components of tissue or matrix.
• MMPs are involved in the activation of zymogen (pro) forms of other MMPs thereby inducing MMP activation. They are also involved in the biosynthesis of TNF- alpha which is implicated in many pathological conditions.
• MMP-9 gelatianse B
• MMP-9 has been implicated in pathogenesis of COPD, MS and other inflammatory disorders.
• MMP-9 is secreted as proenzyme and upon activation, exhibits distinct roles in the progression of both disease states.
• leukocyte mediated activation of MMP-9 exhibits during the inflammatory response associated with COPD, marks the onset of processes linked to airway obstruction.
• MMP-9 is the primary pro-inflammatory mediator of the inflammation and its expression goes higher in all inflammatory diseases, like COPD, MS, arthritis, psoriasis, etc.
• Other MMPs are also involved in some vital and regulatory functions of the cell, so an MMP-9 selective inhibitor would only target the inflammation component of the disease and would be free of undesirable toxicity.
• TMP matrix metalloproteinase
• Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, autoimmune and allergic diseases such as, inflammation of the joint, inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound healing disorders, etc.
• MMP inhibitors The design and therapeutic application of MMP inhibitors has revealed that the requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a functional group ⁇ e.g., carboxylic acid, hydroxamic acid or sulphydryl) capable of chelating to the active site Zn 2+ ion (Whittaker et al, Chem. Rev., 99; p. 2735-76 (1999).
• a functional group ⁇ e.g., carboxylic acid, hydroxamic acid or sulphydryl
• WO 03/82841 discloses new 5-substituted l,l-dioxo-l,2,5-thiazolidine-3-one derivatives as protein tyrosine phosphatase inhibitors used for treating, e.g., diabetes, metabolic disorders, obesity and ischemic disease.
• EP 0 507 238 discloses R- and 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 diseases of lipid metabolism.
• MMP inhibitors that are selective, e.g. , for a few of the MMP subtypes.
• An MMP inhibitor of improved selectivity would avoid potential side effects associated with inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
• use of more selective MMP inhibitors would require administration of a lower amount of the inhibitor for treatment of disease than would otherwise be required and, after administration, partitioned in vivo among multiple MMPs. Still further, the administration of a lower amount of compound would improve the margin of safety between the dose of the inhibitor required for therapeutic activity and the dose of the inhibitor at which toxicity is observed.
• chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure single isomers may also offer advantages in terms of these pharmacokinetic parameters thus enabling better developability of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn have profound effects on the pharmacokinetics and developability of the molecule. Besides those mentioned above, regulatory principles guide one to preferably develop single isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to interactions of an unwanted isomer with undesirable molecular targets.
• the present invention provides sulfone acetic acid derivatives as matrix metaIloproteinase-9 inhibitors which are effective therapeutic or prophylactic agents for the treatment of various inflammatory and allergic diseases. Also provides are processes for synthesizing such compounds.
• the compounds of the present invention are useful for the treatment of inflammatory and autoimmune diseases.
• compositions containing such compounds are provided together with the pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory and autoimmune diseases.
• These pharmaceutical compositions may be administered or co-administered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or by parenteral route.
• the composition may also be administered or co-administered in slow release dosage forms.
• compositions comprising such compounds, their racemates, enantiomers, diastereomers, and pharmaceutically acceptable salts are also included.
• the therapeutically effective amount of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, protein synthesis inhibitors, amino glycosides, cell wall synthesis inhibitor (glycopeptides, beta-lactams, etc.), R A, and DNA synthesis inhibitors or fatty acid synthesis inhibitors.
• protein synthesis inhibitors amino glycosides
• cell wall synthesis inhibitor glycopeptides, beta-lactams, etc.
• R A DNA synthesis inhibitors or fatty acid synthesis inhibitors.
• X can be S, SO or S0 2 ;
• L 1 can be selected from bond, -0-, -S-, -SO, -SO2, -CH 2 , -NR 4 , -NHCO(CH 2 ) lake-, -(CH 2 ) n CONH-, -NHCONH-, -S0 2 NH-, -NHSO2-, -NHCO(O)-, -0-(CH 2 ) resort, -(CH 2 ) hinder-0-, -OC(0)NH-, -C(S)NH-, -NHC(S), -NHC(S)NH-, -COO- wherein n can be zero or an integer between 1 and 2;
• R 1 can be -OCONHR 3 , OCSNHR 3 , OC3 ⁇ 4R 3 ;
• R 1 can be hydrogen, Ci-Cealkyl, hydroxy!, CpQalkoxy, cyano, nitro, halogen, halogeno Ci-C6alk l, Ce-C ⁇ aryl, C 3 -C 8 cycloalkyl, C5-C12 heteroaryl wherein Ci-C[ 2 aryl, C 3 -C 8 cycloalkyl, C5-C12 heteroaryl is optionally substituted with one or more times with R 5 ;
• R 1 When R 1 is OCH 2 R 3 , then R 1 can be C 6 -Ci 2 aryl, C 3 -C 8 cycloalkyl, Q-C12 heteroaryl;
• R 3 is alkyl, alkenyl, alkynyl, Ce-C ⁇ ary], C3-C8 cycloalkyl, C5-C12 heteroaryl, C 3 - C12 heterocyclyl which may optionally be substituted one or more times with R 5 ;
• R 4 can be H, Ci-ealkyl, Ci- alkylaryl
• compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
• provided herein are methods for treating or preventing various inflammatory and allergic diseases comprising administering to a mammal in need thereof therapeutically effective amount of one or more compounds of Formula 1 described herein.
• the present invention relates to the therapeutically effective amount of compounds of Formula I in combination with one or more of other therapeutic agents used in treating various inflammatory and allergic diseases.
• therapeutic agents includes but are not limited to:
• nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5- lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors, (iv) MMP inhibitors, and (v) interleukin-I inhibitors;
• ACE inhibitors e.g., enalapril, lisinopril
• valsartan telmisartan and quinapril
• angiotensin II receptor antagonists and agonists e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan
• ⁇ -blockers e.g., calcium channel blockers
• immunosuppressive agents such as cyclosporine, azathioprine and
• methotrexate and anti inflammatory corticosteroids.
• alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
• alkenyl unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
• alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
• cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
• Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyi, and the like or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included.
• aryl refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
• Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
• Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
• aralkyl refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined above.
• alkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl, and the like.
• aryloxy denotes the group O-aryl wherein aryl is the same as defined above.
• heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S. Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
• heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or benzoxazolyl, and the like.
• heterocyclyl refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members.
• 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, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo[4,5-6]pyridine, isoquinolinyl, lH-pyrrolo[2,3-6]pyridine or piperazinyl, and the like.
• cycloalkylalkyl refers to cycloalkyl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and cycloalkyl are the same as defined earlier.
• heteroarylalkyl refers to heteroaryl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heteroaryl are the same as defined earlier.
• heterocyclylalkyl refers to heterocyclyl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heterocyclyl are the same as defined earlier.
• amino refers to— NH 2
• halogen or Halo refers to fluorine, chlorine, bromine or iodine
• leaving group refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions.
• leaving groups include, but are not limited to, halogen (e.g., F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals, and the like.
• protecting groups refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2 nd Ed., John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
• the compounds of this invention can contain one asymmetric carbon atom and thus may occur as racemic mixtures, enantiomers and diasteromers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are included in the present invention.
• Each stereogenic carbon atom may be of the R T S configuration.
• salts of carboxylic acids moiety which can be prepared by reacting the compound with appropriate base to provide corresponding base addition salts.
• bases alkali metal hydroxide including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide.
• salts of organic bases such as lysine, arginine, guanidine, ethanolamine, choline and the like, inorganic bases, e.g., ammonium or substituted ammonium salts are also included. Wherever appropriate, compounds with
• organic and inorganic acids e.g., hydro halides, such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts, such as sulphate, nitrate, phosphate etc. and alkyl and mono-arylsulphonates, such as ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids and their corresponding salts, such as acetate, tartaratae, maleate, succinate, citrate, etc.
• hydro halides such as hydrochloride, hydrobromide, hydroiodide
• other mineral acids and their corresponding salts such as sulphate, nitrate, phosphate etc. and alkyl and mono-arylsulphonates, such as ethane sulphonate, toluene sulphonate and benzene sulphonate
• organic acids and their corresponding salts such as acetate
• the compounds disclosed herein may be prepared by following reaction sequences as depicted in Schemes I, and II.
• the compound of Formula 8 (Path A), Formula 9 (Path A), Formula 15 (Path B), Formula 16 (Path B), Formula 19 (Path C) and Formula 20 (Path C) can be prepared according to Scheme I.
• reacting a compound of Formula 2 (wherein Y is N0 2 , Hal and COOH) with alpha bromo lactone gives a compound of Formula 3.
• the compound of Formula 3 can react in three ways to give a compound of Formula 8, Formula 9, Formula 15, Formula 16, Formula 19 and Formula 20.
• Path A (when Y is COOBT): The reaction of a compound of Formula 3 with a compound of Formula 3' (where R 2 is same as defined earlier) to give a compound of Formula 4 which upon reaction with a compound of Formula 4' (wherein R' is alkyl, allyl, benzyl, t- butyl, silyl and Hal is F, CI, Br, I) gives a compound of Formula 5.
• R' is alkyl, allyl, benzyl, t- butyl, silyl and Hal is F, CI, Br, I
• R 3 is same as defined earlier and Z is O or S
• the hydrolysis of a compound of Formula 7 gives a compound of Formula 8 which upon oxidation gives a compound of Formula 9.
• Path B (when Y is N0 2 ):
• the reduction of a compound of Formula 3 gives a compound of Formula 10 which upon reaction with a compound of Formula 11 (wherein R 2 is same as defined earlier and U is a leaving group such as halide, alkyloxy, aryloxy) gives a compound of Formula 12.
• the compound of Formula 12 upon reaction with a compound of Formula 4' (wherein R' and Hal are same as defined earlier) gives a compound of Formula 13.
• the reaction of a compound of Formula 13 with a compound of Formula 6 (wherein R 3 and Z are same as defined earlier) gives a compound of Formula 14.
• the hydrolysis of a compound of Formula 14 gives a compound of Formula 15 which upon oxidation gives a compound of Formula 16.
• Path C (when Y is halogen):
• the reaction of a compound of Formula 3 with a compound of Formula 4' gives a compound of Formula 17 which upon reaction with a compound of Formula 6 (wherein R 3 and Z are same as defined as earlier) gives a compound of Formula 18.
• the hydrolysis of a compound of Formula 18 gives a compound of Formula 19 which upon oxidation gives a compound of Formula 20.
• reaction of a compound of Formula 2 with alpha bromo lactone to give a compound of Formula 3 can be carried out in the presence of organic base, for example, triethylamine, pyridine, NiV-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.
• reaction of a compound of Formula 3 (Path A) with a compound of Formula 3' to give a compound of Formula 4 can be carried out using base selected from
• reaction of a compound of Formula 4 with a compound of Formula 4' to give a compound of Formula 5 can be carried out in the presence of 18-crown-6 using one or more inorganic base selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide in the presence of a solvent, selected from, N, N- dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture thereof.
• inorganic base selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide in the presence of a solvent, selected from, N, N- dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture thereof.
• reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7 can be carried out in the presence of organic base selected from, for example, triethylamine, pyridine, NiV-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from tetrahydrofuran, dimethylsulfoxide, acetonitrile, N, N-dimethylformamide, or mixture(s) thereof.
• organic base selected from, for example, triethylamine, pyridine, NiV-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine
• solvent selected from tetrahydrofuran, dimethylsulfoxide, acetonitrile, N, N-dimethylformamide, or mixture(s)
• the hydrolysis of a compound of Formula 7 to give a compound of Formula 8 can be carried out in the presence of inorganic base selected from, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide in solvents for example, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol, dimethylsulfoxide, or mixture(s) thereof.
• inorganic base selected from, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide in solvents for example, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol, dimethylsulfoxide, or mixture(s) thereof.
• oxidation of a compound of Formula 8 to give a compound of Formula 9 can be carried out with oxidizing agents, for example, meta-chloroperbenzoic acid or oxone in a solvent, selected from, chloroform, dichloromethane, methanol, water, carbon tetrachloride, or mixture(s) thereof.
• oxidizing agents for example, meta-chloroperbenzoic acid or oxone in a solvent, selected from, chloroform, dichloromethane, methanol, water, carbon tetrachloride, or mixture(s) thereof.
• the reduction of a compound of Formula 3 (Path B) to give a compound of Formula 10 can be carried out using reducing agent selected from, for example, Pd/C, lithium aluminum hydride, Raney Nickel in the presence of hydrazine hydrate, zinc, tin or iron in the presence of hydrochloric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, dichloromethane, or mixture(s) thereof.
• reducing agent selected from, for example, Pd/C, lithium aluminum hydride, Raney Nickel in the presence of hydrazine hydrate, zinc, tin or iron in the presence of hydrochloric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, dichloromethane, or mixture(s) thereof.
• 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 organic base, for example, triethylamine, pyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s) thereof.
• organic base for example, triethylamine, pyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine
• 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.
• reaction of a compound of Formula 13 with a compound of Formula 6 to give a compound of Formula 14 can be carried out under similar conditions as described for the reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7.
• reaction of a compound of Formula 3 (Path C) with a compound of Formula 4' to give a compound of Formula 17 can be carried out under similar conditions as described for the reaction of compound of Formula 4 with a compound of Formula 4' to give a compound of Formula 5.
• the reaction of a compound of Formula 17 with a compound of Formula 6 to give a compound of Formula 18 can be carried out under similar conditions as described for the reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7.
• hydrolysis of a compound of Formula 18 to give a compound of Formula 19 can be carried out under similar conditions as described for the hydrolysis of a compound of Formula 7 to give a compound of Formula 8.
• the compound of Formula 27 (Path D) and Formula 30 (Path E) can be prepared according to Scheme II.
• reaction of a compound of Formula 21 with a compound of Formula 22 gives a compound of Formula 23 which upon oxidation gives a compound of Formula 24.
• the reaction of a compound of Formula 24 with a compound of Formula 25 forms a compound of Formula 26.
• the compound of Formula 26 can be reacted in two ways to give a compound of Formula 27 and Formula 30.
• Path D The hydrolysis of a compound of Formula 26 gives a compound of Formula 27.
• Path E The reduction of a compound of Formula 26 gives a compound of Formula 28 which upon reaction with a compound of Formula 11 (wherein R 2 and U are same as defined earlier) gives a compound of Formula 29.
• the compound of Formula 29 upon hydrolysis gives a compound of Formula 30.
• the reaction of a compound of Formula 21 with a compound of Formula 22 to give a compound of Formula 23 can be carried out in the presence of organic base selected from, for example, triethylamine, pyridine, NN'-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from dichlormethane, dichloroethane, carbon tetrachloride, chloroform, tetrahydrofuran, dimethylsulfoxide, acetonitrile, N, N'-dimethylformamide, or mixture(s) thereof.
• organic base selected from, for example, triethylamine, pyridine, NN'-dimethylaminopyridine, 2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine
• a solvent selected from dichlormethane,
• reaction of a compound of Formula 24 with a compound of Formula 25 to give a compound of Formula 26 can be carried out using tetrabutylammonium iodide in the presence of inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate using a solvent selected from, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dimethylsulfoxide, or mixture(s) thereof.
• Formula 28 can be carried out using reducing agent selected from, for example, lithium aluminum hydride, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or iron in the presence or in the absence of hydrochloric acid.
• 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.
• reaction of a compound of Formula 28 with a compound of Formula 11 to give a compound of Formula 29 can be carried out under similar conditions as described for the reaction of a compound of Formula 10 with a compound of Formula 11 to give a compound of Formula 12.
• compositions disclosed herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.
• Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, lozenges, troches, cachets and suppositories.
• active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier.
• Tablets and capsules for oral administration may contain conventional excipients, such as binding agents and/or dissolution enhancers, for example, polyvinyl pyrrolidine, cellulose, mucilage of starch, gelatin, sorbitol, syrup, acacia or tragacanth; fillers or bulking agents, for example, microcrystalline cellulose, sugar, maize-starch, calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethyleneglycol, magnesium stearate or stearic acid; disintegrating agents and binder, for example, croscarmellose sodium, pregelatinized starch, sodium starch gylcollate or potato starch; glidants, for example, colloidal silicon dioxide or talc; antiadherants, for example, magnesium stearate or sodium luaryl sulfate; and coating materials.
• binding agents and/or dissolution enhancers for example, polyvinyl pyrrolidine
• Capsules, tablets or pills may also comprise buffering agents.
• Tablets, capsules, pills or granules can be prepared using one or more coatings or shells to modulate the release of active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
• coatings or shells to modulate the release of active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
• a formulation of a tablet could typically contain from 0.01 mg to 500 mg of active compound whilst tablet fill weight may range from 50 mg to 1000 mg.
• An example is illustrated below.
• Microcrystalline Cellulose about 50% to about 90%
• Croscarmellose Sodium about 1% to about 10%
• Pregelatinized Starch about 1% to about 15% Polyvinyl Pyrrolidone (K-30) about 5% to about 12%
• Magnesium Stearate about 0.1% to about 2%
• Colloidal Silicon Dioxide about 0.1% to about 2%
• Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
• active compounds can be mixed with water or one or more non-toxic solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan, or mixtures thereof.
• Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, or mixtures thereof.
• Injectable preparations for example, sterile injections, and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents.
• Acceptable vehicles and solvents that may be employed include one or more of water, Ringer's solution, isotonic sodium chloride, or mixtures thereof.
• Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable nonirritating excipients such as coca butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the rectum and release the drug.
• Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any preservatives or buffers as may be required.
• Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
• compositions may be in unit dosage form.
• the preparations can be subdivided into unit doses containing appropriate quantities of active components.
• Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms.
• Step b Preparation of N-(4-chlorophenyl)-4-[(2-oxotetrahydrofuran-3-yl)sulfanyl] benzamide
• Step c Preparation of methyl 2-( ⁇ 4-[(4-chlorophenyl)carbamoyl]phenyl ⁇ sulfanyl)-4- hydroxybutanoate
• Step d Preparation of methyl 2-( ⁇ 4-[(4-chlorophenyl)carbamoyl] phenyl ⁇ sulfanyl)-4- ⁇ [(4-fluorophenyl)carbamoyl]oxy ⁇ butanoate
• Step e Preparation of 2-( ⁇ 4-[(4-chlorophenyl)carbamoyI]phenyl ⁇ sulfanyl)-4- ⁇ [(4- fluorophenyl)car bamoy 1] oxy ⁇ butanoic acid
• Step b Preparation of 3-[(4-aminophenyl)sulfanyl]dihydrofuran-2(3H)-one
• Step c Preparation of 4-chloro-N- ⁇ 4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]phenyl ⁇ benzamide
• Step d Preparation of methyl 2-[(4- ⁇ [(4-chlorophenyl)carbonyl]amino ⁇ phenyl) sulfanyl]-4-hydroxybutanoate
• Step e Preparation of methyl 4- ⁇ [(4-chlorophenyl)carbamoyl]oxy ⁇ -2-[(4- ⁇ [(4- chlorophenyl)carbony 1] amino ⁇ phenyl)sulfany 1] butanoate
• Step f Preparation of 4- ⁇ [(4-chlorophenyl)carbamoyl]oxy ⁇ -2-[(4- ⁇ [(4-chlorophenyl) carbonyl] amino ⁇ phenyl)sulfanyl] butanoic acid
• Step b Preparation of methyl 2-[(4-chlorophenyl)sulfanyll-4-hvdroxybutanoate
• reaction mixture was diluted by addition of water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent to get a title compound.
• Step d Preparation of 4- ⁇ [(4-chlorophenyl)carbamoyl]oxy ⁇ -2-[(4-chlorophenyl) sulfanyljbutanoic acid
• Example 6 Synthesis of 4-f r(4-chlorophenvncarbamoylloxy ⁇ -2-[(4- chlorophenyl)sulfonyl]butanoic acid (Compound no. 3) (Scheme L Path C, Formula 20) To an ice-cooled solution of 4- ⁇ [(4-chlorophenyl)carbamoyl]oxy ⁇ -2-[(4- chlorophenyl)sulfanyl]butanoic acid (0.100 g, 0.0002 moles) in chloroform (10 mL) was added meta-chloroperbenzoic acid (0.172 g, 0.001 moles) and stirred at room temperature for about one hour.
• reaction mixture was quenched by sodium metabisulphite solution and extracted in dichloromethane.
• the organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to get desired compound.
• Step a Synthesis of ethyl [(4-nitrophenyI)suIfanyI]acetate
• dichloromethane 50 mL under argon atmosphere were added triethylamine (9.7 g, 0.0967 moles) and a solution of ethyl bromoacetate (6.4 g, 0.0387 moles) drop wise. The reaction mixture was allowed to stir for about 5 hours at room temperature. After completion, reaction mixture was diluted with water and extracted in dichloromethane.
• the organic layer was dried over sodium sulphate and concentrated to get a crude product.
• the crude product obtained was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
• Step c Preparation of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate
• Step a Preparation of ethyl 2-[(4-aminophenyl)sulfonyl]-4-(benzyloxy)butanoate
• Step b Preparation of ethyl 4-(benzyloxy)-2-[(4- ⁇ [(4-methylphenyl)carbonyl] amino ⁇ phenyl)sulfonyl]butanoate
• MMPs Matrix Metallo Proteinases
• MMP-1 9 &14 enzymes require prior activation.
• supplied enzyme was incubated with either APMA, final concentration 1 mM, for a time period of 1 hour at 37°C). Incubation was done at room temperature ( ⁇ 25°C) for 4 minutes to 5 minutes. Reaction was initiated with 10 ⁇ of 100 ⁇ substrate (ES001: Aliquots were freshly diluted in TCNB; stock: 2 mM) and increase in florescence was monitored at excitation wavelength 320 nm followed by emission at 405 nm for 25-30 cycles. Increase in florescence (RFU) was calculated for positive, negative and NCE/standard wells. The percent inhibition compared to controls was calculated and IC50 values determined using Graph-prism software.

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