WO2012038943A1 - Matrix metalloproteinase inhibitors - Google Patents

Matrix metalloproteinase inhibitors Download PDF

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Publication number
WO2012038943A1
WO2012038943A1 PCT/IB2011/054228 IB2011054228W WO2012038943A1 WO 2012038943 A1 WO2012038943 A1 WO 2012038943A1 IB 2011054228 W IB2011054228 W IB 2011054228W WO 2012038943 A1 WO2012038943 A1 WO 2012038943A1
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Prior art keywords
compound
phenyl
carbamoyl
formula
oxy
Prior art date
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PCT/IB2011/054228
Other languages
French (fr)
Inventor
Manoj Kumar Khera
Jitendra Sattigeri
Neeraj Kumar Yadav
Abdul Rehman Abdul Rauf
Ian A. Cliffe
Pradip Kumar Bhatnagar
Abhijit Ray
Punit Srivastava
Sunanda Ghosh Dastidar
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Ranbaxy Laboratories Limited
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Publication date
Priority to SG2013021696A priority Critical patent/SG188644A1/en
Priority to KR1020137010202A priority patent/KR20130137174A/en
Priority to AU2011306397A priority patent/AU2011306397A1/en
Priority to EP11776884.6A priority patent/EP2619177A1/en
Priority to JP2013529762A priority patent/JP2013538820A/en
Priority to BR112013006929A priority patent/BR112013006929A2/en
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to EA201390405A priority patent/EA201390405A1/en
Priority to CA2812361A priority patent/CA2812361A1/en
Priority to CN2011800564174A priority patent/CN103221386A/en
Priority to MX2013003360A priority patent/MX2013003360A/en
Publication of WO2012038943A1 publication Critical patent/WO2012038943A1/en
Priority to IL225527A priority patent/IL225527A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
    • C07C321/28—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • 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.

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 METALLOPROTEINASE INHIBITORS
Field of the Invention
The present invention relates to certain sulfone acetic acid derivatives as MMP inhibitor and processes for its syntheses. The invention also relates to pharmacological compositions containing the compounds of the present invention and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple scleorisis, gingivitis, atherosclerosis, dry eye, and neointimal proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders characterized by over expression and over activation of a matrix metalloproteinase using the compounds.
Background of the Invention
Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases (enzymes) found in most mammals. The superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types; sharing structural and functional features. Based on structural and functional considerations proteinases have been classified into different families and subfamilies (Vartak et ah, J. Drug Targeting, 15, p. 1-20 (2007), and Hopper, FEBS, 354, p. 1-6 (1994), such as collagenases (MMP-1, -8 and -13), gelatinases (MMP-2, and -9), metalloelastases (MMP-12), the MT-MMPs (MMP-14, -15, -16, -17, -24 and -25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10 and
-11) and sheddases such as TNF-converting enzymes (TACE, and ACE).
Metalloproteinases are believed to be important in physiological disease processes that involve remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. One major biological function of MMPs is to catalyze the breakdown of connective tissues or extra-cellular matrix by their ability to hydrolyze various components of tissue or matrix. Apart from their role in degrading connective tissue, MMPs are involved in the activation of zymogen (pro) forms of other MMPs thereby inducing MMP activation. They are also involved in the biosynthesis of TNF- alpha which is implicated in many pathological conditions. MMP-9 (gelatianse B) has been implicated in pathogenesis of COPD, MS and other inflammatory disorders. MMP-9 is secreted as proenzyme and upon activation, exhibits distinct roles in the progression of both disease states. For example, leukocyte mediated activation of MMP-9 exhibits during the inflammatory response associated with COPD, marks the onset of processes linked to airway obstruction. MMP-9 is the primary pro-inflammatory mediator of the inflammation and its expression goes higher in all inflammatory diseases, like COPD, MS, arthritis, psoriasis, etc. Other MMPs are also involved in some vital and regulatory functions of the cell, so an MMP-9 selective inhibitor would only target the inflammation component of the disease and would be free of undesirable toxicity.
Over-expression or over-activation of an MMP, or an imbalance between an MMP and a natural {i.e., endogenous) tissue inhibitor of a matrix metalloproteinase (TIMP) has been linked to a pathogenesis of diseases characterized by the breakdown of connective tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, autoimmune and allergic diseases such as, inflammation of the joint, inflammation of the GI tract, inflammation of the skin, collagen remodeling, wound healing disorders, etc.
The design and therapeutic application of MMP inhibitors has revealed that the requirement of a molecule to be an effective inhibitor of MMP class of enzymes is a functional group {e.g., carboxylic acid, hydroxamic acid or sulphydryl) capable of chelating to the active site Zn2+ ion (Whittaker et al, Chem. Rev., 99; p. 2735-76 (1999).
WO 03/82841 discloses new 5-substituted l,l-dioxo-l,2,5-thiazolidine-3-one derivatives as protein tyrosine phosphatase inhibitors used for treating, e.g., diabetes, metabolic disorders, obesity and ischemic disease. EP 0 507 238 discloses R- and 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.
Research has been carried out into the identification of inhibitors that are selective, e.g. , for a few of the MMP subtypes. An MMP inhibitor of improved selectivity would avoid potential side effects associated with inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
Further, use of more selective MMP inhibitors would require administration of a lower amount of the inhibitor for treatment of disease than would otherwise be required and, after administration, partitioned in vivo among multiple MMPs. Still further, the administration of a lower amount of compound would improve the margin of safety between the dose of the inhibitor required for therapeutic activity and the dose of the inhibitor at which toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules, i.e., chiral and will therefore have several stereoisomers depending upon the number of chiral centers present. The importance of evaluating new chemical entities having chiral centers as single isomers is to understand their effect on pharmacological and toxicological aspects. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between
enantiomers/diastereomers. Even if natural physiological mediators are achiral, based on their target environment, their receptors/enzymes may demonstrate a preference for only one optically pure enantiomer of agonists, antagonists or inhibitors. From a
pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure single isomers may also offer advantages in terms of these pharmacokinetic parameters thus enabling better developability of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn have profound effects on the pharmacokinetics and developability of the molecule. Besides those mentioned above, regulatory principles guide one to preferably develop single isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to interactions of an unwanted isomer with undesirable molecular targets.
In this context, synthetic strategies to produce pure single isomers offer advantages over analytical techniques of separation of isomer not only in terms of cost and efficiency but larger amounts of compound can be prepared for elaborate pharmaceutical testing. Thus, compounds of present invention, which are single chiral isomers, have improved potency, improved pharmacokinetics and/or improved physicochemical properties as compared to racemic compounds. The present invention is directed to overcoming problems encountered in the art.
Summary of the Invention
The present invention provides sulfone acetic acid derivatives as matrix metaIloproteinase-9 inhibitors which are effective therapeutic or prophylactic agents for the treatment of various inflammatory and allergic diseases. Also provides are processes for synthesizing such compounds.
The compounds of the present invention are useful for the treatment of inflammatory and autoimmune diseases.
Pharmaceutical compositions containing such compounds are provided together with the pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory and autoimmune diseases. These pharmaceutical compositions may be administered or co-administered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or by parenteral route. The composition may also be administered or co-administered in slow release dosage forms.
Although, the specific enantiomers have been shown by way of examples, racemates, diastereomers, and pharmaceutically acceptable salts are also provided.
Pharmaceutical compositions comprising such compounds, their racemates, enantiomers, diastereomers, and pharmaceutically acceptable salts are also included.
The therapeutically effective amount of one or more compounds of the present invention 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.
Other objects will be set forth in accompanying description and in the part will be apparent from the description or may be by the practice of the invention.
Detailed Description of the Invention
In accordance with one aspect there is provided a compounds having structure of Formula I: COOH
Formula I
including racemates, enantiomers and diastereomers, thereof or a pharmaceutically acceptable salts thereof.
Wherein,
X can be S, SO or S02;
L1 can be selected from bond, -0-, -S-, -SO, -SO2, -CH2, -NR4, -NHCO(CH2)„-, -(CH2)nCONH-, -NHCONH-, -S02NH-, -NHSO2-, -NHCO(O)-, -0-(CH2)„, -(CH2)„-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;
R1 can be -OCONHR3, OCSNHR3, OC¾R3;
When R1 is OCONHR3 or OCSNHR3 then R1 can be hydrogen, Ci-Cealkyl, hydroxy!, CpQalkoxy, cyano, nitro, halogen, halogeno Ci-C6alk l, Ce-C^ aryl, C3-C8cycloalkyl, C5-C12 heteroaryl wherein Ci-C[2 aryl, C3-C8cycloalkyl, C5-C12 heteroaryl is optionally substituted with one or more times with R5;
When R1 is OCH2R3, then R1 can be C6-Ci2 aryl, C3-C8 cycloalkyl, Q-C12 heteroaryl;
R3 is alkyl, alkenyl, alkynyl, Ce-C^ ary], C3-C8 cycloalkyl, C5-C12 heteroaryl, C3- C12 heterocyclyl which may optionally be substituted one or more times with R5;
R4 can be H, Ci-ealkyl, Ci- alkylaryl;
R5 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- Ci-C6 alkyl, halogeno-Ci-C& aikoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0 Rf, -COORf, -NRfRq,
Figure imgf000006_0001
-(CH2)n- O- Ci^N f ,, (CH2)„ NHC^NRfR,,, -(CH2)0-0-C(=0 Rf, -iCH2)„-NH-C(=0> Rf or -(CH2)nS(=0)m-NRrRq {wherein Rf and R<, are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2}; In one aspect the invention encompasses compounds that include, for example,
4- { [(4-Chlorophenyl)carbamoyl]oxy} -2-[(4-chlorophenyl)sulfanyl]butanoic acid (Compound no. 1);
2-[(4-Chlorophenyl)sulfanyl]-4- { [(4-fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 2);
4- { [(4-Chlorophenyl)carbamoyl]oxy} -2-[(4-chlorophenyl)sulfony1]butanoic acid (Compound no. 3);
2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 4);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(4-fluorophenyl carbamoyl]oxy}butanoic acid (Compound no. 5);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
2- [(4- { [(4-Chlorophenyl)carbonyl] amino} phenyl)sulfanyl] -4- { [(3 , 5 - dimethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 7);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
2- [(4- { [(4-Chlorophenyl)carbonyl] amino} phenyl)sulfanyl] -4- { [(2-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 9);
4-{ [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2- [(4- { [(4-chlorophenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3- ethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 11);
4- { [(3-Chlorophenyl)carbamoyl]oxy} -2-[(4- { [(4- chlorophenyl)carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 12);
4- { [(4-Chlorophenyl)carbamothioyl]oxy} -2-[(4- { [(4-chlorophenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 13);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3-cyanophenyl) carbamothioyl]oxy}butanoic acid (Compound no. 14);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{ [(4-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 15);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 16);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
4- { [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4- { [(4- chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 19); 4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 20);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(3-cyanophenyl) carbamothioyl]oxy}butanoic acid (Compound no. 21);
4-(Benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 22;)
4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 23);
4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 24);
4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 25);
4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino}phenyl)
sulfonyl]butanoic acid (Compound no. 26);
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 27)
4-(Benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid (Compound no. 28);
4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 29);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 30);
4- { [(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 31);
4- { [(4-Chlorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl)
carbonyl] amino }phenyl)sulfanyl]butanoic acid (Compound no. 32);
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 33);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 34);
4- { [(2,6-Dichlorophenyl)carbamoyl]oxy } -2-[(4-{ [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 35);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(2-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 36);
4- { [(4-Methoxyphenyl)carbamoyl]oxy} -2-[(4-{ [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 37);
4-[(fert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)
carbonyl] amino }phenyl)sulfanyl]butanoic acid (Compound no. 38);
4- { [(2,4-Difluorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 39); 4- { [(2-Fluorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 40);
4- { [(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 41);
4- { [(3 ,4-Dichlorophenyl)carbamoy] ]oxy } -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 42);
4- { [(3 ,4-Dichlorophenyl)carbamoyl]oxy } -2- [(4- { [(4-methylphenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl) carbony1]amino}phenyl)sulfanyl]butanoic acid (Compound no. 44);
4- { [(4-Chlorophenyl)carbamoyl]oxy) -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 45);
4- { [(4-Ethylphenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 46);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
4- { [(2,6-Dichlorophenyl)carbamoyl]oxy } -2-[(4- {[(4-methoxyphenyl) carbonyl]aminophenyl)}sulfonyl]butanoic acid (Compound no. 48);
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49);
4- [(tert-Butylcarbamoy l)oxy] -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 50);
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 51);
4- { [(2-Fluorophenyl)carbamoyl] oxy } -2- [(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 52);
4- { [(3 -Fluorophenyl)carbamoyl] oxy} -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 53);
4- { [(5-Chloro-2-methoxyphenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 54);
4- { [(3 ,4-Dichlorophenyl)carbamoyl ]oxy } -2- [(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55);
4-{ [(3,4-Dichlorophenyl)carbamoyl]oxy} -2-[(4-{ [(4-methylphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56);
4- { [(2,4-Difluorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methylphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
4-{ [(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 58);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 59); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 60);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(propan-2-yl)phenyl] carbamoyl }oxy)butanoic acid (Compound no. 61);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methoxyphenyl) carbamoyl]oxy}butanoic acid (Compound no. 62);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(3- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 64);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(4- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 65);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(2,4- difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 67);
2-( {4-[(4-Chlorophenyl)carbamoy] ]phenyl} sulfanyl)-4-{ [(4- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 68);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(2,6- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 69);
4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl }sulfanyl)butanoic acid (Compound no. 70);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(3,4- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 71);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 72);
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-({4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 73);
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 74);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 75);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 76);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 77);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(4- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 78);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl } sulfonyl)-4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4- difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(4- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 81);
2-( {4-[(4-Chlorophenyl)carbamoyl ]phenyl} sulfonyl)-4-{ [(2,6- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 82);
4- [(tert-Butylcarbamoyl)oxy] -2-( {4- [(4-chlorophenyl)carbamoyl]
phenyl }sulfonyl)butanoic acid (Compound no. 83);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(3,4-dichlorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 84);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 85);
4- { [(3 -Chlorophenyl)carbamoyl]oxy} -2-( {4-[(4-chlorophenyl)carbamoyl] phenyl} sulfonyl)butanoic acid (Compound no. 86);
4-[(Butylcarbamoyl)oxy] -2-( {4-[(4- chlorophenyl)carbamoyl]phenyl}sulfonyl)butanoic acid (Compound no. 87);
2-[(4-{[(2-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 89);
2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 90);
2-( {4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({ [4- (trifluoromethyl)phenyl carbamoyl }]oxy)butanoic acid (Compound no. 91);
2-[(4-{[(2-Methylphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 92);
2- [(4- { [(2-Ethoxyphenyl)carbonyl] amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 93);
2-[(4-{[(2,3-Difluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 94);
2-[(4- { [(3 ,4-Dichlorophenyl)carbony 1] amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl] carbamoyl }oxy)butanoic acid (Compound no. 95);
2- [(4- { [(4-Ethoxyphenyl)carbonyl] amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 96);
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-({[4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 97);
2- [(4- { [(2,4-Dichlorophenyl)carbony l]amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98). In another aspect, provided herein, are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided herein are methods for treating or preventing various inflammatory and allergic diseases comprising administering to a mammal in need thereof therapeutically effective amount of one or more compounds of Formula 1 described herein.
In yet another aspect, the present invention relates to the therapeutically effective amount of compounds of Formula I in combination with one or more of other therapeutic agents used in treating various inflammatory and allergic diseases. Examples of such therapeutic agents includes but are not limited to:
a) anti-inflammatory agents, experimental or commercial (i) such as
nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5- lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors, (iv) MMP inhibitors, and (v) interleukin-I inhibitors;
b) antihypertensive agents, (i) ACE inhibitors, e.g., enalapril, lisinopril,
valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) β-blockers, and (iv) calcium channel blockers.
c) immunosuppressive agents such as cyclosporine, azathioprine and
methotrexate, and anti inflammatory corticosteroids.
The following definitions apply to terms as used herein.
The term "alkyl" unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. The term "alkenyl" unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
The term "aikynyl" unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
The term "cycloalkyl" unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyi, and the like or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included.
The term "aryl" unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, CI, Br, I), hydroxy, alkyl, alkenyl, aikynyl, cycloalkyl, alkoxy, acyl, aryloxy, CFj, cyano, nitro, COORy, NHC(=0)RJL, -NRJLR„, -C(=0)NRxR», -NHC(=0)NRxRx, -0-C(=0)NR¾R„, -SOmRy, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalk l or amino carbonyl amino, mercapto, haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, -CONHR,, -OCOR,, -COR«, -NHSChR* or -SOaNHR. (wherein Rx, R», m and Ry are the same as defined earlier). Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
The term "aralkyl" unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined above. Examples of aralkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl, and the like. The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined above.
The term "heteroaryl" unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S. Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or benzoxazolyl, and the like.
The term "heterocyclyl" unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members. Examples of heterocyclyl groups include benzotriazinone, isoindoledione, pyrimidinedione, 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.
The term "cycloalkylalkyl" refers to cycloalkyl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and cycloalkyl are the same as defined earlier.
The term "heteroarylalkyl" refers to heteroaryl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heteroaryl are the same as defined earlier. The term "heterocyclylalkyl" refers to heterocyclyl group linked through alkyl portion, wherein the alkyl having 1 to 6 carbon atoms and heterocyclyl are the same as defined earlier.
The term "amino" refers to— NH2
The term "halogen or Halo" refers to fluorine, chlorine, bromine or iodine;
The term "leaving group" refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (e.g., F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals, and the like.
The term "protecting groups" refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
The compounds of this invention can contain one asymmetric carbon atom and thus may occur as racemic mixtures, enantiomers and diasteromers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are included in the present invention. Each stereogenic carbon atom may be of the R T S configuration. Although the specific compounds exemplified in this application may be depicted in a particular sterochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixture thereof are envisioned as part of the invention.
The term "pharmaceutically acceptable salts" forming part of this invention includes the salts of carboxylic acids moiety, which can be prepared by reacting the compound with appropriate base to provide corresponding base addition salts. Examples of such base are alkali metal hydroxide including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. Further, the salts of organic bases such as lysine, arginine, guanidine, ethanolamine, choline and the like, inorganic bases, e.g., ammonium or substituted ammonium salts are also included. Wherever appropriate, compounds with
pharmaceutically acceptable organic and inorganic acids, e.g., hydro halides, such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts, such as sulphate, nitrate, phosphate etc. and alkyl and mono-arylsulphonates, such as ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids and their corresponding salts, such as acetate, tartaratae, maleate, succinate, citrate, etc.
In another aspect, the compounds disclosed herein may be prepared by following reaction sequences as depicted in Schemes I, and II.
Scheme I
Figure imgf000017_0001
Formula 16
Formula I when L1 is -NHCO and R1 is OC(Z)NHR» 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. Thus, reacting 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 in three ways to give a compound of Formula 8, Formula 9, Formula 15, Formula 16, Formula 19 and Formula 20.
Path A (when Y is COOBT): The reaction of a compound of Formula 3 with a compound of Formula 3' (where R2 is same as defined earlier) to give a compound of Formula 4 which upon reaction with a compound of Formula 4' (wherein R' is alkyl, allyl, benzyl, 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 (where R3 is same as defined earlier and Z is O or S) gives a compound of Formula 7. The hydrolysis of a compound of Formula 7 gives a compound of Formula 8 which upon oxidation gives a compound of Formula 9.
Path B (when Y is N02): The reduction of a compound of Formula 3 gives a compound of Formula 10 which upon reaction with a compound of Formula 11 (wherein R2 is same as defined earlier and U is a leaving group such as halide, alkyloxy, aryloxy) gives a compound of Formula 12. The compound of Formula 12 upon reaction with a compound of Formula 4' (wherein R' and Hal are same as defined earlier) gives a compound of Formula 13. The reaction of a compound of Formula 13 with a compound of Formula 6 (wherein R3 and Z are same as defined earlier) gives a compound of Formula 14. The hydrolysis of a compound of Formula 14 gives a compound of Formula 15 which upon oxidation gives a compound of Formula 16.
Path C (when Y is halogen): The reaction of a compound of Formula 3 with a compound of Formula 4' (wherein R' and Hal is same as defined earlier) gives a compound of Formula 17 which upon reaction with a compound of Formula 6 (wherein R3 and Z are same as defined as earlier) gives a compound of Formula 18. The hydrolysis of a compound of Formula 18 gives a compound of Formula 19 which upon oxidation gives a compound of Formula 20.
The reaction of a compound of Formula 2 with alpha bromo lactone to give a compound of Formula 3 can be carried out in the presence of organic base, for example, triethylamine, pyridine, 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.
The reaction of a compound of Formula 3 (Path A) with a compound of Formula 3' to give a compound of Formula 4 can be carried out using base selected from
triethylamine, pyridine, NN-dimethylaminopyridine, 2,6-lutidine, 1-methylpiperidine, N- ethyldiisopropylamine or N-methylmorpholine, in the presence of a additives, for example, hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo- 1 ,2,3-benzotriazine, 2- hydroxypyridine, N-hydroxysuccinimide or l-hydroxy-7-azabenzotriazole, with a suitable condensing agent, for example, dicyclohexyl carbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, chlorotripyrrolidinophosphonium hexafluorophosphate or (benzotriazol- 1 -yloxy)ira-(dimethylamino)phosphonium hexafluorophosphate.
The reaction of a compound of Formula 4 with a compound of Formula 4' to give a compound of Formula 5 can be carried out in the presence of 18-crown-6 using one or more inorganic base selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide in the presence of a solvent, selected from, N, N- dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture thereof.
The reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7 can be carried out in the presence of organic base selected from, for example, triethylamine, pyridine, 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.
The hydrolysis of a compound of Formula 7 to give a compound of Formula 8 can be carried out in the presence of inorganic base selected from, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide in solvents for example, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol, dimethylsulfoxide, or mixture(s) thereof.
The oxidation of a compound of Formula 8 to give a compound of Formula 9 can be carried out with oxidizing agents, for example, meta-chloroperbenzoic acid or oxone in a solvent, selected from, chloroform, dichloromethane, methanol, water, carbon tetrachloride, or mixture(s) thereof.
The reduction of a compound of Formula 3 (Path B) to give a compound of Formula 10 can be carried out using reducing agent selected from, for example, Pd/C, lithium aluminum hydride, Raney Nickel in the presence of hydrazine hydrate, zinc, tin or iron in the presence of hydrochloric acid in a solvent selected from tetrahydrofuran, methanol, ethanol, dichloromethane, or mixture(s) thereof.
The reaction of a compound of Formula 10 with a compound of Formula 11 to give a compound of Formula 12 can be carried out in the presence of organic base, for example, triethylamine, pyridine,
Figure imgf000020_0001
2,6-lutidine, 1- methylpiperidine, N-ethyldiisopropylamine or N-methylmorpholine in a solvent selected from, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or mixture(s) thereof.
The ring opening of a compound of Formula 12 with a compound of Formula 4' to give a compound of Formula 13 can be carried out under similar conditions as described for the reaction of a compound of Formula 4 with a compound of Formula 4' to give a compound of Formula 5.
The reaction of a compound of Formula 13 with a compound of Formula 6 to give a compound of Formula 14 can be carried out under similar conditions as described for the reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7.
The hydrolysis of a compound of Formula 14 to give a compound of Formula 15 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 to give a compound of Formula 8.
The oxidation of a compound of Formula 15 to give a compound of Formula 16 can be carried out under similar conditions as described for the compound of Formula 8 to give a compound of Formula 9.
The reaction of a compound of Formula 3 (Path C) with a compound of Formula 4' to give a compound of Formula 17 can be carried out under similar conditions as described for the reaction of compound of Formula 4 with a compound of Formula 4' to give a compound of Formula 5. The reaction of a compound of Formula 17 with a compound of Formula 6 to give a compound of Formula 18 can be carried out under similar conditions as described for the reaction of a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7.
The hydrolysis of a compound of Formula 18 to give a compound of Formula 19 can be carried out under similar conditions as described for the hydrolysis of a compound of Formula 7 to give a compound of Formula 8.
The oxidation of a compound of Formula 19 to give a compound of Formula 20 can be carried out under similar conditions as described for the compound of Formula 8 to give a compound of Formula 9.
Scheme Π
Figure imgf000021_0001
Formula 29 Formula 28 Formula 27
The compound of Formula 27 (Path D) and Formula 30 (Path E) can be prepared according to Scheme II. Thus, reaction of a compound of Formula 21 with a compound of Formula 22 (wherein R' and Hal are same as defined earlier) gives a compound of Formula 23 which upon oxidation gives a compound of Formula 24. The reaction of a compound of Formula 24 with a compound of Formula 25 (Bn is benzyl group and Hal is same as defined earlier) forms a compound of Formula 26. The compound of Formula 26 can be reacted in two ways to give a compound of Formula 27 and Formula 30.
Path D: The hydrolysis of a compound of Formula 26 gives a compound of Formula 27.
Path E: The reduction of a compound of Formula 26 gives a compound of Formula 28 which upon reaction with a compound of Formula 11 (wherein R2 and U are same as defined earlier) gives a compound of Formula 29. The compound of Formula 29 upon hydrolysis gives a compound of Formula 30.
The reaction of a compound of Formula 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.
The oxidation of a compound of Formula 23 to form a compound of Formula 24 can be carried out under similar conditions as described for the compound of Formula 8 to give a compound of Formula 9.
The reaction of a compound of Formula 24 with a compound of Formula 25 to give a compound of Formula 26 can be carried out using tetrabutylammonium iodide in the presence of inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate using a solvent selected from, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dimethylsulfoxide, or mixture(s) thereof.
The hydrolysis of a compound of Formula 26 (Path D) to give a compound of Formula 27 can be carried out under similar conditions as described for the compound of Formula 7 to give a compound of Formula 8.
The reduction of a compound of Formula 26 (Path E) to give a compound of
Formula 28 can be carried out using reducing agent selected from, for example, lithium aluminum hydride, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or iron in the presence or in the absence of hydrochloric acid.
The reaction of a compound of Formula 28 with a compound of Formula 11 to give a compound of Formula 29 can be carried out under similar conditions as described for the reaction of a compound of Formula 10 with a compound of Formula 11 to give a compound of Formula 12.
The hydrolysis of a compound of Formula 29 to give a compound of Formula 30 can be carried out under similar conditions as described for the compound of Formula 7 to give a compound of Formula 8. In the above schemes, where specific reagents, for example, bases, acids, solvents, condensing agents, hydrolyzing agents, catalysts, etc., as mentioned, is to be understood that other reagents, e.g., other acids, bases, solvents, condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, catalysts, etc., known to one of ordinary skill in the art may be used. Similarly, reaction temperatures and durations may be adjusted according to the desired needs without undue experimentation and well within the abilities of one of ordinary skill in the art.
The compounds described herein may be administered to an animal for treatment orally, topically, rectally, intemasally or by parenteral route. Pharmaceutical compositions disclosed herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, lozenges, troches, cachets and suppositories. For solid form preparations, active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier. Tablets and capsules for oral administration may contain conventional excipients, such as binding agents and/or dissolution enhancers, for example, polyvinyl pyrrolidine, cellulose, mucilage of starch, gelatin, sorbitol, syrup, acacia or tragacanth; fillers or bulking agents, for example, microcrystalline cellulose, sugar, maize-starch, calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethyleneglycol, magnesium stearate or stearic acid; disintegrating agents and binder, for example, croscarmellose sodium, pregelatinized starch, sodium starch gylcollate or potato starch; glidants, for example, colloidal silicon dioxide or talc; antiadherants, for example, magnesium stearate or sodium luaryl sulfate; and coating materials.
Capsules, tablets or pills may also comprise buffering agents.
Tablets, capsules, pills or granules can be prepared using one or more coatings or shells to modulate the release of active ingredients, for example, enteric coatings or other coatings known to one of ordinary skill in the art. General Example
A formulation of a tablet could typically contain from 0.01 mg to 500 mg of active compound whilst tablet fill weight may range from 50 mg to 1000 mg. An example is illustrated below.
Ingredients Amount % w/w
Active Compound 0.01 to 20 mg
Microcrystalline Cellulose about 50% to about 90%
Croscarmellose Sodium about 1% to about 10%
Pregelatinized Starch about 1% to about 15% Polyvinyl Pyrrolidone (K-30) about 5% to about 12%
Talc about 0.1% to about 2%
Magnesium Stearate about 0.1% to about 2%
Colloidal Silicon Dioxide about 0.1% to about 2%
Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, active compounds can be mixed with water or one or more non-toxic solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan, or mixtures thereof. Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, or mixtures thereof.
Injectable preparations, for example, sterile injections, and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents.
Acceptable vehicles and solvents that may be employed include one or more of water, Ringer's solution, isotonic sodium chloride, or mixtures thereof. Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable nonirritating excipients such as coca butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the rectum and release the drug.
Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Active compounds can be admixed under sterile condition with one or more pharmaceutically acceptable carriers and optionally any preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
Pharmaceutical preparations may be in unit dosage form. In unit dosage form, the preparations can be subdivided into unit doses containing appropriate quantities of active components. Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms.
The following examples are set forth to demonstrate general synthetic procedures for the preparation of representative compounds of the present invention. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention.
Experimental
Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc., were dried using various drying reagents according to procedure as described in the literature.
Example 1 : Synthesis of 2-(i4-[(4-chlorophenvncarbamoyl1phenyl}sulfanyl)-4-ir(4- fluoro phenyl)carbamoyl1oxy}butanoic acid (Compound no. 68) (Scheme L Path A, Formula 8)
Step a: Preparation of 4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]benzoic acid
To an ice cooled solution of 4-mercaptobenzoicacid (0.5 g, 0.003 moles) in dichloromethane (5 mL) under argon atmosphere were added triethylamine (0.909 g, 0.009 moles) and a solution of bromo lactone (0.53 g, 0.003 moles) in dichloromethane (5 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes. After completion, reaction mixture was diluted by adding water and extracting in
dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 70% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.800 g
LCMS: 239.16 (M+l)
Step b: Preparation of N-(4-chlorophenyl)-4-[(2-oxotetrahydrofuran-3-yl)sulfanyl] benzamide
To the solution of compound obtained from Step a (15.0 g, 0.0630 moles) in dichloromethane (150 mL) were added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDCI, 18.0 g, 0.0942 moles), hydroxybenzotriazole (HOBT 10.2 g, 0.0689 moles), 4- dimethylaminopyridine (DMAP 1.5 g, 0.0122 moles) and stirred for about 30 minutes under argon atmosphere. After 30 minutes, 4-chloroaniline (8.0 g, 0.0630 moles) was added and again stirred for about 12 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude compound which was purified by column chromatography using 40% ethyl acetate in hexane as eluent to get desired compound.
Yield: 13.0 g
LCMS: 348.05 (M+l)
Step c: Preparation of methyl 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)-4- hydroxybutanoate
To a solution of compound obtained from Step b (13.0 g, 0.037 mole) in N,N- dimethylformamide (52 mL) and water (13 mL) was added sodium hydroxide (1.70 g, 0.044 moles). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (3.7 g, 0.044 moles), 18 crown 6 (0.970 g, 0.0037 moles) and methyl iodide (7.80 g, 0.055 moles) were added and stirred for overnight. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 30% ethyl acetate in hexane as eluent to get desired compound.
Yield: 8.0 g
Step d: Preparation of methyl 2-({4-[(4-chlorophenyl)carbamoyl] phenyl} sulfanyl)-4- {[(4-fluorophenyl)carbamoyl]oxy}butanoate
To a solution of compound obtained from Step c (0.500 g, 0.0013 moles) in tetrahydrofuran (5 mL) under argon atmosphere were added triethylamine (0.393 g, 0.0038 moles) and 4-fluoro-isocyanate (0.213 g, 0016moles) and stirred for about 2 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 30% ethyl acetate in hexane as eluent to afford desired compound.
Yield: 0.3 g
Step e: Preparation of 2-({4-[(4-chlorophenyl)carbamoyI]phenyl}sulfanyl)-4-{[(4- fluorophenyl)car bamoy 1] oxy } butanoic acid
To a solution of compound obtained from Step d (0.300 g, 0.0005 moles) in tetrahydrofuran (5ml)/methanol (5ml) was added a solution of lithium hydroxide (0.036 g, 0.0006 moles) in water (1 mL) and stirred for about one hour at room temperature. After completion, reaction mixture was acidify by adding sodium bisulphite solution and extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get a compound which was purified by preparative TLC eluted using 10% methanol in dichloromethane.
Yield: 0.050 g
LCMS: 501.15 (M-l)
JH NMR (400 MHz, DMSO-</6)-5: 10.28 - 10.35 (1H, s), 9.67 (1H, s), 7.76 - 7.78 (4H, m), 7.53 - 7.55 (2H, m), 7.32 - 7.44 (3H, m), 7.07 - 7.20 (3H, m), 4.18 - 4.21 (2H, m), 3.98 - 4.02 (1H, m), 1.90 -2.23 (2H, m).
The following compounds can be prepared by following the above synthetic route.
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 59); LCMS: 501.17 (M-l)
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 60);
LCMS: 511.22 (M-2)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4-(propan-2-yl)phenyl] carbamoyl }oxy)butanoic acid (Compound no. 61);
LCMS: 525.19 (M-2)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methoxyphenyl) carbamoyl]oxy}butanoic acid (Compound no. 62);
LCMS: 513.18 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
LCMS: 497.18 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3-fluoro phenyl) carbamoyl]oxy}butanoic acid (Compound no. 64);
LCMS: 501.16 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(4-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 65);
LCMS: 417.17 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);
LCMS: 551.09 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,4-difluorophenyl) carbamoyl] oxy}butanoic acid (Compound no. 67);
LCMS: 519.15 (M-l)
2-( { 4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(2,6- dichlorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 69);
LCMS: 553.06 (M)
4-[(rert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl butanoic acid (Compound no. 70);
LCMS: 463.20 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3,4- dichlorophenyl)carbamoyl]oxy} butanoic acid (Compound no. 71);
LCMS: 553.03 (M)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 72);
LCMS: 477.19 (M-l) 4- { [(3 -Chlorophenyl)carbamoy1 ] oxy } -2-( { 4- [(4-chlorophenyl)carbamoy l]phenyl } sulfanyl)butanoic acid (Compound no. 73);
LCMS: 519.10 (M)
4-[(Butylcarbamoyl)oxy]-2-({4-[(4- chlorophenyl)carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 74);
LCMS: 463.17 (M-l)
Example 2: Synthesis of 2-({4-r(4-chlorophenyl)carbamoyl1phenyl?sulfonyl)-4-{[(4- fluorophenvDcarbamoylloxylbutanoic acid (Compound no. 81) (Scheme I, Path A, Formula 9)
To an ice-cooled solution of 2-({4-[(4-chlorophenyl)carbamoyl]phenyl}sulfanyl)- 4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid (0.050 g, 0.00009 moles) in chloroform (5 mL) was added metachloroperbenzoic acid (0.065 g, 0.00037 moles) and stirred for 1 hour at room temperature. The reaction mixture was quenched by adding sodium metabisulphite solution and then extracted in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC eluted in 12% methanol in dichloromethane. Yield: 0.030 g
LCMS: 533.18 (M-l)
!H NMR (400 MHz, DMSO-e ) -δ: 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} sulfonyl)-4- { [(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 75);
LCMS: 533.21 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4- ethylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 76);
LCMS: 543.24 (M-2)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 77);
LCMS: 529.22 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(4- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 78);
LCMS: 529.20 (M-l) 2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79);
LCMS: 583.21 (M-l)
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4- difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80);
LCMS: 551.19 (M-l)
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(2,6-dichlorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 82);
LCMS: 541.11 (M-44)
4-[(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}sulfonyl)-4-{[(3,4-dichlorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 84);
LCMS: 585.09 (M)
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- [(pentylcarbamoyl)oxy]butanoic acid (Compound no. 85);
LCMS: 509.24 (M-l)
4- { [(3 -Chlorophenyl)carbamoyl]oxy } -2-( {4- [(4-chlorophenyl)carbamoyl]phenyl } sulfonyl butanoic acid (Compound no. 86);
LCMS: 551.11 (M)
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]phenyl}
sulfonyl)butanoic acid (Compound no. 87);
LCMS: 495.24
Example 3: Synthesis of 2-[(4-{[(4-chlorophenyl)carbonyl1amino|phenyl)sulfanyll-4- {[(4-fluoro phenyl)carbamoyl]oxyl butanoic acid (Compound no. 5) (Scheme I, Path B, Formula 15)
Step a: Preparation of 3-[(4-nitrophenyl)sulfanyl]dihydrofuran-2(3H)-one
To an ice-cooled solution ofp-nitro thiophenol (10.0 g, 0.0645 moles) in dichloromethane (75 mL) under argon atmosphere were added triethylamine (19.4 g, 0.1935 moles) and a solution of bromo-lactone (11.1 g, 0.067 moles) in dichloromethane (75 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes at room temperature. After completion, reaction mixture was diluted with water and extracted in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product. The crude product so obtained was purified by silica gel column using 30% ethyl acetate in hexane as eluent to get title compound.
Yield: 11 g
Step b: Preparation of 3-[(4-aminophenyl)sulfanyl]dihydrofuran-2(3H)-one
To the solution of compound obtained from Step a (10.0 g, 0.04184 moles) in tetrahydrofuran/methanol (100 mL: 100 mL) was added Pd/C (4 g) under vacuum and hydrogen pressure was applied using balloon. The reaction mixture was allowed to stir for about 2 hours at room temperature. After completion, reaction mixture was filtered through celite and concentrated to get desired compound.
Yield: 5.0 g
LCMS: 210 (M+1)
Step c: Preparation of 4-chloro-N-{4-[(2-oxotetrahydrofuran-3-yl)sulfanyl]phenyl} benzamide
To a solution of compound obtained from Step b (4.86 g, 0.0232 moles) in dichloromethane (100 mL) under argon atmosphere was added triethylamine (7.04 g,
0.0697 moles) and cooled to 0°C and then 4-chlorobenzoyl chloride (4.27 g, 0.024 moles) was added slowly drop wise. The reaction mixture was allowed to stir for 10 minutes at room temperature. After completion, reaction mixture was diluted with water and extracting in dichloromethane. The organic layer was washed with sodium bicarbonate and separated. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product. The crude product obtained was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
Yield: 4.0 g
LCMS: 348 (M+l)
Step d: Preparation of methyl 2-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl) sulfanyl]-4-hydroxybutanoate
To a solution of compound obtained from Step c (8.2 g, 0.0236 moles) in N, ΛΓ- dimethylformamide (32 mL) and water (8 mL) was added sodium hydroxide (1.12 g, 0.0283 moles). The reaction mixture was allowed to stir for about 30 minutes at room temperature. After 30 minutes, sodium bicarbonate (2.3 g, 0.0283 moles), 18 crown 6 (0.620 g, 0.0023 moles) and methyl iodide (5.02 g, 0.0354 moles) were added to reaction mixture and stirred for overnight at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent.
Yield: 8.0 g
Step e: Preparation of methyl 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4- chlorophenyl)carbony 1] amino} phenyl)sulfany 1] butanoate
To a solution of compound obtained from Step d (0.500 g, 0.00131 moles) in tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.266 g, 0.0026 moles) and l-chloro-4-isocyanatobenzene (0.211 g, 0.0015 moles) and stirred for about 2 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 15% ethyl acetate in hexane as eluent.
Yield: 0.4 g
Step f: Preparation of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl) carbonyl] amino} phenyl)sulfanyl] butanoic acid
To a solution of compound obtained from Step e (0.300 g, 0.0005 moles) in tetrahydrofuran /methanol (5 mL:5 mL) was added a solution of lithium hydroxide (0.034 g, 0.0008 moles) in water and stirred at room temperature for about one hour. After completion, reaction mixture was acidify with sodium bisulphite solution and then extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol/dichloromethane as eluent.
Yield: 0.080 g
LCMS: 503 (M+l), 520 (M+18)
!H NMR (400 MHz, DMSO-<¾) δ 10.4 (1H, s), 9.66 (1H, s), 7.95 - 7.97 (2H, d, J= 8.4 Hz), 7.73 - 7.76 (2H, d, J= 8.4 Hz), 7.59 - 7.61 (2H, d, J= 8.4 Hz), 7.43 - 7.49 (4H, d, J= 8.4 Hz), 7.06 - 7.15 (2H, d, J= 4.0 Hz), 5.7 (1H, s), 4.12 - 4.23 (2H, m), 3.72 - 3.76 (1H, m), 2.07 - 2.12 (1H, m), 1.89 -1.96 (1H, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[2-fluoro-5- (trifluoro methyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
LCMS: 571.11 (M+l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3,5- dimethoxyphenylcarbamoyl]oxy}butanoic acid (Compound no. 7);
LCMS: 545.11 (M)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
LCMS: 517.17 (M+l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 9);
LCMS: 503.11 (M+l)
4- { [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4- { [(4-chlorophenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
LCMS: 549.03 (M)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3-ethoxyphenyl) carbamoyl]oxy}butanoic acid (Compound no. 11);
LCMS: 529.15 (M), 546.19 (M+l 7)
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 12);
LCMS: 519.07 (M), 536.11 (M+l 7)
4- { [(4-Chlorophenyl)carbamothioyl]oxy} -2-[(4- { [(4-chlorophenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 13);
LCMS: 535.03 (M)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3- cyanophenyl)carbamothioyl]oxy}butanoic acid (Compound no. 14);
LCMS: 527.12 (M+l)
4- { [(2-Fluorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methylphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 29) ;
LCMS: 483.14 (M+l)
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 30);
LCMS: 483.21 (M+l) 4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 32);
LCMS: 513.22 (M-l)
4- { [(4-Ethylphenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 33);
LCMS: 507.28 (M-l)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 34);
LCMS: 547.20 (M-l)
4- { [(2,6-Dichlorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 35);
LCMS: 547.3 (M-2)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(2-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 36);
LCMS: 493.22 (M-l)
4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 37);
LCMS: 509.26 (M-l)
4-[(/ert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]amino}phenyl) sulfanyl]butanoic acid (Compound no. 38);
LCMS: 459.24 (M-l)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 39);
LCMS: 515.20 (M-l)
4-{ [(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 40);
LCMS: 497.25 (M-l)
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfanyl]butanoic acid (Compound no. 41);
LCMS: 497.25 (M-l)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 42);
LCMS: 547.14 (M-2)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
LCMS: 535.09 (M+2)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 44); LCMS: 501.15 (M+l)
2-[(4-{[(2-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88);
LCMS: 535.27 (M-l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 89);
LCMS: 551.27 (M-l)
2-[(4-{[(2,6-Dimethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 90);
LCMS: 577.29 (M-l)
2-( {4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 91);
LCMS: 483.19 (M+l)
2- [(4- { [(2-Methylphenyl)carbonyl]amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl] carbamoyl} oxy)butanoic acid (Compound no. 92);
LCMS: 531.25 (M-l)
2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 93);
LCMS: 561.27 (M-l)
2-[(4- { [(2,3-Difluorophenyl)carbonyl]amino} phenyl)sulfanyl]-4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 94);
LCMS: 553.21 (M-l)
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 95);
LCMS: 585.21 (M-2)
2-[(4-{[(4-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 96);
LCMS: 561.28
2-({4-[(Cyclohexylcarbonyl)amino]phenyl}sulfanyl)-4-({[4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 97);
LCMS: 523.33 (M-l)
2- [(4- { [(2,4-Dichlorophenyl)carbonyl] amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98);
LCMS: 585.19 (M-2), 587.15 (M).
Example 4: Synthesis of 2- (4-{ (4-chlorophenyl)carbonyllamino}phenyl)sulfonvn-4- f [(4-fluoro phenyl)carbamoyl]oxy}butanoic acid (Compound no. 15) (Scheme I, Path B,
Formula 16) To an ice-cooled solution of 4-{[(4-fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4- chlorophenyl)carbonyl]amino}phenyl)sulfanyl]butanoic acid (0.080 g, 0.00015 moles) was added meta-chloroperbenzoic acid (0.101 g, 0.00059 moles) and stirred for about one hour at room temperature. After completion, reaction mixture was quenched by adding sodium metabisulphite solution and then extracted in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent.
Yield: 0.020 g
LCMS: 535 (M+l), 557 (M+23)
NMR (400 MHz, DMSO-c¾-5 11.00 (IH, s), 9.67 (1H, s), 7.98 - 8.05 (4H, d, J= 8.4 Hz), 7.78 -7.80 (2H, d, J= 9.2 Hz), 7.57 - 7.60 (2H, d, J= 8.4 Hz), 7.42 - 7.45 (2H, d, J= 8.8 Hz), 7.05 - 7.10 (2H, d, J= 8.8 Hz), 4.17 - 4.19 (IH, m), 3.97 - 4.03 (IH, m), 3.70 - 3.79 (1H, m), 2.07 - 2.11 (2H, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 16);
LCMS: 603.22 (M+l), 620.22 (M+18)
2-[(4- { [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4- { [(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
LCMS: 548.03 (M)
4- { [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4- { [(4- chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18);
LCMS: 581.33 (M), 603.08 (M+l)
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 19);
LCMS: 535.22 (M+l), 552.28 (M+18)
4-{[(3-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 20);
LCMS: 552.01 (M+l), 573.14 (M+22)
2-[(4- { [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4- { [(3-cyanophenyl) carbamothioyl]oxy}butanoic acid (Compound no. 21);
LCMS: 564.12 (M+6), 542.24 (M-16)
4- { [(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)carbonyl] amino}phenyl)sulfonyl]butanoic acid (Compound no. 31); LCMS: 515.09 (M+l)
4- { [(4-Chlorophenyl)carbamoyl] oxy} -2-[(4- { [(4-methoxypheny l)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 45);
LCMS: 547.20 (M+l)
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 46);
LCMS: 540.25 (M)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
LCMS: 579.24 (M-l)
4- { [(2,6-Dichlorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 48);
LCMS: 579.18 (M-20)
2-[(4-{[(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49);
LCMS: 525.24 (M-l)
4- [(tert-Butylcarbamoyl)oxy] -2-[(4- { [(4-methoxyphenyl)carbonyl] amino} phenyl) sulfonyl]butanoic acid (Compound no. 50);
LCMS: 491.29 (M-l)
4-{[(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 51);
LCMS: 547.22 (M-l)
4- { [(2-Fluorophenyl)carbamoyl] oxy} -2-[(4- { [(4-methoxyphenyl)carbonyl ] amino } phenyl)sulfonyl]butanoic acid (Compound no. 52);
LCMS: 529.22 (M-l)
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 53);
LCMS: 529.25 (M-l)
4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 54);
LCMS: 575.23 (M-2), 577.17 (M)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55);
LCMS: 579.14 (M-2), 581.16 (M)
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56);
LCMS: 565.06 (M) 4- { [(2,4-Difluorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
LCMS: 533.10 (M+l)
4- { [(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 58);
LCMS: 515.15 (M+l)
Example 5: Synthesis of 4-([(4-chlorophenyl)carbamoylloxy)-2-[(4-chlorophenyl) sulfanyl]butanoic acid (Compound no. 1) (Scheme L Path C Formula 19)
Step a: Preparation of 3-[(4-chlorophenyl)sulfanyljdihydrofuran-2(3H)-one
To an ice cooled solution of j9-chloro thiophenol (10.0 g, 0.069 moles) in dichloromethane (75 mL) under argon atmosphere were added triethylamine (21.0 g, 0.208 moles) and a solution of bromo lactone (12.0 g, 0.072 moles) in dichloromethane (75 mL) drop wise. The reaction mixture was allowed to stir for about 30 minutes at 0°C. After completion, reaction mixture was diluted by adding water and extracting in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
Yield: 13.9 g
Step b: Preparation of methyl 2-[(4-chlorophenyl)sulfanyll-4-hvdroxybutanoate
To a solution of compound obtained from Step a (5.0 g, 0.0219 moles) in N, N- dimethylformamide (20ml) and water (5ml) was added sodium hydroxide (1.05 g, 0.0263 moles). The reaction mixture was allowed to stir for about 30 minutes at room
temperature. After 30 minutes, sodium bicarbonate (1.74 g, 0.0208 moles), 18 crown 6 (0.45 g, 0.0017 moles) and methyl iodide (3.68 g, 0.0259 moles) were added to reaction mixture and again stirred for overnight at room temperature. After completion, reaction mixture was diluted by addition of water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to obtain a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent to get a title compound.
Yield: 3.5 g Step c: Preparation of methyl 4-{[(4-chlorophenvDcarbamovnoxy}-2-[(4- chlorophenvDsulfanyllbutanoate
To a solution of compound obtained from Step b (0.425 g, 0.0016 moles) in tetrahydrofuran (10 mL) under argon atmosphere were added triethylamine (0.323 g, 0.0032 moles) and l-chloro-4-isocyanatobenzene (0.293 g, 0.0019 moles) and stirred for about 2 hours at room temperature. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 15% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.600 g
Step d: Preparation of 4-{[(4-chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl) sulfanyljbutanoic acid
To a solution of compound obtained from Step c (0.600 g, 0.0014 moles) in tetrahydrofuran/methanol (5ml:5ml) was added a solution of lithium hydroxide (0.090 g, 0.0021 moles) in water (1 mL) and stirred for about one hour at room temperature. After completion, reaction mixture was acidify with sodium bisulphite solution and then extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to obtain the desired compound.
Yield: 0.100 g
LCMS: 401.23(M+1)
NMR- (400 MHz, DMSO-</6) δ: 9.73 (1H, s), 7.45 - 7.53 (6H, d, J= 8.4 Hz), 7.15 - 7.19 (2H, d, J= 8.4 Hz), 4.17 - 4.30 (2H, m), 3.91 - 3.95 (1H, t, J= 7.2 Hz), 2.15 - 2.24 (1H, m), 1.97 - 2.06 (lH, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4-Chlorophenyl)sulfanyl]-4- { [(4-fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 2);
LCMS: 384.22 (M++1)
Example 6: Synthesis of 4-f 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. After completion, reaction mixture was quenched by sodium metabisulphite solution and extracted in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to get desired compound.
Yield: 0.090 g
LCMS: 432.12 (M), 434 (M+2), 449.17 (M+18)
NMR-(400 MHz, DMSO-i 6) 8: 9.79 (1H, s), 7.73 - 7.82 (2H, d, J= 8.8 Hz), 7.60 - 7.63 (2H, d, J= 8.8 Hz), 7.44 - 7.46 (2H, d, J= 8.8 Hz), 7.29 - 7.31 (2H, d, J= 8.8 Hz), 4.07 - 4.19 (1H, m), 3.97 - 4.03 (1H, m), 3.75 - 3.76 (1H, m), 2.03 - 2.10 (2H, m).
The following compounds can be prepared by following the above synthetic route. 2-[(4-Chlorophenyl)sulfonyl]-4-{[(4-fluorophenyl)carbamoyl]oxy}butanoic acid
(Compound no. 4);
LCMS: 416.13 (M+l)
Example 7: Synthesis of 4-(benzyloxy)-2- (4-nitrophenvnsulfonyllbutanoic acid
(Compound no. 28 (Scheme II, Path D, Formula 27)
Step a: Synthesis of ethyl [(4-nitrophenyI)suIfanyI]acetate
To an ice-cooled solution ofp-nitro thiophenol (5 g, 0.0322 moles) in
dichloromethane (50 mL) under argon atmosphere were added triethylamine (9.7 g, 0.0967 moles) and a solution of ethyl bromoacetate (6.4 g, 0.0387 moles) drop wise. The reaction mixture was allowed to stir for about 5 hours at room temperature. After completion, reaction mixture was diluted with water and extracted in dichloromethane.
The organic layer was dried over sodium sulphate and concentrated to get a crude product. The crude product obtained was purified by silica gel column using 10% ethyl acetate in hexane as eluent.
Yield: 6.5 g
LCMS: 242 (M+l) Step b: Preparation of ethyl [(4-nitrophenyl)sulfonyl]acetate
To an ice-cooled solution of compound obtained from Step a (6.5 g, 0.0269 moles) in chloroform (70 mL) was added meta-chloroperbenzoic acid (18 g, 0.107 moles) and stirred at room temperature for about one hour. After completion, reaction mixture was quenched with sodium metabisulphite solution and then extracted in dichloromethane.
The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to obtain a crude product.
Yield: 6.7 g
LCMS: 274 (M+l)
Step c: Preparation of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate
To a solution of compound obtained from Step b (0.500 g, 0.0018 moles) in N, N- dimethylformamide (5 mL) under argon atmosphere were added potassium carbonate (0.745 g, 0.0054 moles), tetrabutylammonium iodide (0.067 g, 0.00018 moles) and O- benzyl ethyl bromide (0.550 g, 0.0027 moles). The reaction mixture was heated to 50° C and stirred at same temperature for about 4 hours. After completion, reaction mixture was diluted by adding water and extracting in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by silica gel column using 8% ethyl acetate in hexane as eluent to get title compound.
Yield: 0.450 g
LCMS: 408 (M+l)
Step d: Preparation of 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid
To a solution of compound obtained from Step c (0.100 g, 0.00024 moles) in tetrahydrofuran/methanol (5 mL:5 mL) was added a solution of lithium hydroxide (0.015 g, 0.00036 moles) in water (1 mL). The reaction mixture was allowed to stir at room temperature for about one hour. After completion, reaction mixture was acidify with sodium bisulphite solution and then extracted in ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get a crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to get title compound. Yield: 0.040 g
LCMS: 402.12 (M+23)
NMR-(400 MHz, DMSOn_¼) δ: 8.35 - 8.46 (2H, d, J= 8.8 Hz), 8.07 - 8.20 (2H, d, J= 8.8 Hz), 7.28 - 7.33 (5H, m, J= 5.6 Hz), 4.41 (2H, s), 3.80 - 3.84 (1¾ m), 3.45 - 3.51 (4H, m), 2.05 - 2.09 (3H, m), 1.83 (lH, m).
Example 8: Synthesis of 4-fbenzyloxy)-2- (4-(pf4-methylphenvncarbonyl1amino} phenyl)sulfonyl]butanoic acid (Compound no. 22) (Scheme II, Path E, Formula 30)
Step a: Preparation of ethyl 2-[(4-aminophenyl)sulfonyl]-4-(benzyloxy)butanoate
To a solution of ethyl 4-(benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoate (0.500 g, 0.0012 moles) in ethyl acetate (10 mL) was added stannous chloride (0.829 g, 0.0036 moles) and stirred at 80°C for about 2 hours. After completion, reaction mixture was quenched by adding sodium bicarbonate solution and then extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get desired compound.
Yield: 0.450 g
LCMS: 378 (M+l)
Step b: Preparation of ethyl 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl] amino}phenyl)sulfonyl]butanoate
To a solution of compound obtained from Step a (0.500 g, 0.0013 moles) in dichloromethane (10 mL) under argon atmosphere was added pyridine (0.314 g, 0.0039 moles) and cooled to 0°C. To this cooled solution was added 4-methylbenzoyl chloride (0.220 g, 0.0014 moles) slowly drop wise. After completion, reaction mixture was quenched by adding water and extracting in dichloromethane. The organic layer was washed with sodium bicarbonate, dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by silica gel column using 10% ethyl acetate in hexane as eluent to get desired compound.
Yield: 0.400 g
LCMS: 348 (M+l) Step c: Preparation of 4-(benzyloxy)-2-[(4-{[(4-methylphenyl)carbonylJ
amino} phenyl)sulfonyl] butanoic acid
To a solution of compound obtained from Step b (0.100 g, 0.00020 moles) in tetrahydrofuran/methanol (5 mL:5ml) was added a solution of lithium hydroxide (0.012 g, 0.00030 moles) in water (1 mL) and stirred at room temperature for about one hour. After completion, reaction mixture was acidify by adding sodium bisulphite solution and then extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product which was purified by preparative TLC using 10% methanol in dichloromethane as eluent to afford desired compound.
Yield: 0.050 g
LCMS: 467.93 (M), 484.95 (M+17)
*H NMR(400 MHZ, DMSO-i¾) δ: 10.6 (1H, s), 7.98 - 8.00 (2H, d, J= 8.8 Hz), 7.89 - 7.91 (2H, d, J= 8.0 Hz), 7.76 - 7.78 (2H, d, J= 8.4 Hz), 7.24 - 7.35 (7H, d. J= 8.0 Hz), 4.36 (2H, s), 3.77 (1H, m), 3.46 - 3.49 (1H, m), 2.38 (3H, s), 1.99 - 2.01 (2H, t, J= 6.8 Hz), 1.21-1.22 (3H, t, J= 4.0Hz).
The following compounds can be prepared by following the above synthetic route.
4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 23);
LCMS: 470.07 (M-l)
4-(Benzyloxy)-2-[(4-{[(3-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 24);
LCMS: 486.04 (M-l)
4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 25);
LCMS: 480.14 (M-l)
4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino}phenyl)
sulfonyl]butanoic acid (Compound no. 26);
LCMS: 483.98 (M), 500.97 (M+17)
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 27)
LCMS: 470.07 (M-l)
Assay for Matrix Metallo Proteinases (MMPs) NCEs/standards were prepared (stock 10 mM) in 100% DMSO and subsequent dilutions were made in 50% DMSO-50% TCNB (50 mM Tris, 10 mM CaCl2, 150 mM NaCl, 0.05% Brij-35, pH 7.5). 1 μΐ of the compound and 88 μΐ of TCNB was added to wells of 96 well plate to achieve the desired final concentration of NCE (final DMSO concentration should not exceed 0.5%). 1 μΐ of activated, recombinant MMPs was added to each well (20-100 ng/100 μΐ reaction mixture) except the "negative well". (MMP-1, 9 &14 enzymes require prior activation. For this, supplied enzyme was incubated with either APMA, final concentration 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 μΐ of 100 μΜ 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.
Activities for MMP-9 provided IC50 values below 10 nanomolar-10 micromolar.

Claims

We claim:
1. A compound of Formula I:
Figure imgf000045_0001
Formula I
luding racemates, enantiomers and diastereomers, thereof or a pharmaceutically ;eptable salts thereof, wherein,
X is S, SO or SC ;
L1 is selected from bond, -0-, -S-, -SO, -S02, -CH2, -NR*. -NHCO(CH2)„-. -(CH2)nCONH-, -NHCONH-, -S02NH-, -NHSO2-, -NHCO(0)-, -0-(CH2)n, -(CH2VO-, -OC(0)NH-, -C(S)NH-, -NHC(S), -NHC(S)NH-, -COO- wherein n is zero or an integer between 1 and 2;
R1 is -OCONHR3, OCSNHR3, OCH2R3;
When R1 is OCONHR3 or OCSNHR3 then R2 is hydrogen, Ci-C6alkyl, hydroxyl, Ci-Cealkoxy, cyano, nitro, halogen, halogeno Ci-Csalkyl, Ce-Cn aryl, C3- Cgcycloalkyl, C5-C12 heteroaryl wherein C6-Ci2 aryl, Cj-Cgcycloalkyl, C5-C12 heteroaryl is optionally substituted with one or more times with R5;
When R1 is OCH2R3, then R2 is C6-Ci2 aryl, C3-Cg cycloalkyl, Ce-Ci2 heteroaryl;
R3 is alkyl, alkenyl, alkynyl, C6-Ci2 aryl, C3-Cg cycloalkyl, Cj-Ci2 heteroaryl, C3- C|2 heterocyclyl which is optionally substituted one or more times with R5;
R* is H, Ci-ealkyl, C alkylaryl;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-Ce alkyl, halogeno-Ci-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0>Rf, -COORf, -NRjRq, -(CH2)a-C(=0)NRii<I, -(CH2)„-NHC(=0)-Rf, -(CH2)„- O-
Figure imgf000045_0002
Rf or -(CH2)nS(=0)m-NR^l<] {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2}. A compound of Formula I, which is:
4-{ [(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-chlorophenyl)sulfanyl]butanoic acid (Compound no. 1);
2-[(4-Chlorophenyl)sulfanyl]-4-{ [(4-fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 2);
4- { [(4-Chlorophenyl)carbamoyl]oxy} -2-[(4-chlorophenyl)sulfonyl]butanoic acid (Compound no. 3);
2-[(4-Chlorophenyl)sulfonyl]-4-{ [(4-fluorophenyl)carbamoy]]oxy}butanoic acid (Compound no. 4);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(4-fluorophenyl carbamoyl]oxy}butanoic acid (Compound no. 5);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({ [2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 6);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{[(3,5- dimethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 7);
2-[(4- { [(4-Chlorophenyl)carbonyl]amino) phenyl)sulfanyl]-4- { [(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 8);
2-[(4-{ [(4-Chlorophenyl)carbony]]amino}phenyl)sulfanyl]-4-{ [(2-fluoro phenyl) carbamoyl]oxy}butanoic acid (Compound no. 9);
4-{[(3-Chloro-4-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-chlorophenyl) carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 10);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-{ [(3- ethoxyphenyl)carbamoyl]oxy}butanoic acid (Compound no. 11);
4-{ [(3-Chlorophenyl)carbamoyl]oxy} -2- [(4- { [(4-chlorophenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 12);
4-{ [(4-Chlorophenyl)carbamothioyl]oxy}-2-[(4-{ [(4-chlorophenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 13);
2-[(4-{[(4-Chlorophenyl)carbony]]amino}phenyl)sulfanyl]-4-{[(3-cyanophenyl) carbamothioyl]oxy}butanoic acid (Compound no. 14);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{ [(4-fluorophenyl) carbamoyl] oxy }butanoic acid (Compound no. 15);
2-[(4-{ [(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-({ [2-fluoro-5- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 16);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(5-fluoro-2-methyl phenyl)carbamoyl]oxy}butanoic acid (Compound no. 17);
4-{ [(3-Chloro-4-methoxyphenyl)carbamoyl]oxy} -2-[(4-{ [(4- chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 18); 2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 19); 4- { [(3 -Chlorophenyl)carbamoyl] oxy } -2-[(4- { [(4-chlorophenyl)carbonyl] amino} phenyl)sulfonyl]butanoic acid (Compound no. 20);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfonyl]-4-{[(3- cyanophenyl)carbamothioyl]oxy}butanoic acid (Compound no. 21);
4-(Benzyloxy)-2-[(4-{[(4-methylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 22;)
4-(Benzyloxy)-2-[(4-{[(3-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 23);
4-(Benzyloxy)-2-[(4- { [(3-chlorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 24);
4-(Benzyloxy)-2-[(4-{[(4-ethylphenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 25);
4-(Benzyloxy)-2-[(4-{[(3-methoxyphenyl)carbonyl]amino}phenyl)
sulfonyl]butanoic acid (Compound no. 26);
4-(Benzyloxy)-2-[(4-{[(2-fluorophenyl)carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 27)
4-(Benzyloxy)-2-[(4-nitrophenyl)sulfonyl]butanoic acid (Compound no. 28); 4- { [(2-Fluorophenyl)carbamoyl] oxy} -2- [(4- { [(4-methylphenyl)carbonyl] amino} phenyl)sulfanyl]butanoic acid (Compound no. 29);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 30);
4- { [(3 -Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)carbonyl] amino}phenyl)sulfonyl]butanoic acid (Compound no. 31);
4-{[(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 32);
4-{[(4-Ethylphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 33);
2- [(4- { [(4-Methoxyphenyl)carbonyl] amino} phenyl)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 34);
4-{[(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 35);
2-[(4- { [(4-Methoxyphenyl)carbonyl] amino} phenyl)sulfanyl] -4- { [(2-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 36);
4-{[(4-Methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 37);
4-[(/er/-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfanyl]butanoic acid (Compound no. 38);
4- { [(2,4-Difluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 39); 4- { [(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 40);
4- { [(3-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methoxyphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 41 );
4- { [(3 ,4-Dichlorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfanyl]butanoic acid (Compound no. 42);
4- { [(3,4-Dichlorophenyl)carbamoyl]oxy } -2-[(4- { [(4-methylphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 43);
4-{ [(2,4-Difluorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methylphenyl)carbonyl] amino}phenyl)sulfanyl]butanoic acid (Compound no. 44);
4-{ [(4-Chlorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)carbonyl] amino}phenyl)sulfonyl]butanoic acid (Compound no. 45);
4- { [(4-Ethylphenyl)carbamoyl]oxy } -2-[(4- { [(4-methoxyphenyl)carbonyl] amino}phenyl)sulfonyl]butanoic acid (Compound no. 46);
2-[(4-{ [(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-({ [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 47);
4-{ [(2,6-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{ [(4-methoxyphenyl)
carbonyl]aminophenyl)} sulfonyl]butanoic acid (Compound no. 48);
2-[(4-{ [(4-Methoxyphenyl)carbonyl]amino}phenyl)sulfonyl]-4-{ [(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 49);
4-[(tert-Butylcarbamoyl)oxy]-2-[(4-{[(4-methoxyphenyl)carbonyl]
amino}phenyl)sulfonyl]butanoic acid (Compound no. 50);
4- { [(2,4-Difluorophenyl)carbamoyl] oxy } -2-[(4- { [(4-methoxyphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 51);
4-{[(2-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl]amino} phenyl)sulfonyl]butanoic acid (Compound no. 52);
4-{[(3-Fluorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl)carbonyl] amino}phenyl)sulfonyl]butanoic acid (Compound no. 53);
4-{[(5-Chloro-2-methoxyphenyl)carbamoyl]oxy}-2-[(4-{[(4-methoxyphenyl) carbonyl] amino }phenyl)sulfonyl]butanoic acid (Compound no. 54);
4- { [(3 ,4-Dichlorophenyl)carbamoyl] oxy} -2-[(4- { [(4-methoxyphenyl) carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 55);
4-{[(3,4-Dichlorophenyl)carbamoyl]oxy}-2-[(4-{[(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 56);
4- { [(2,4-Difluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 57);
4- { [(2-Fluorophenyl)carbamoyl]oxy} -2-[(4- { [(4-methylphenyl)
carbonyl]amino}phenyl)sulfonyl]butanoic acid (Compound no. 58);
2-( {4-[(4-Chlorophenyl)carbamoy]]phenyl} sulfanyl)-4- { [(2- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 59); 2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(4-ethylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 60);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-({ [4-(propan-2-yl)phenyl] carbamoyl} oxy)butanoic acid (Compound no. 61 );
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{ [(4-methoxyphenyl) carbamoyl]oxy}butanoic acid (Compound no. 62);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(2- methylphenyl)carbamoyl]oxy}butanoic acid (Compound no. 63);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(3 -fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 64);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4- { [(4-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 65);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-( { [4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 66);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,4-difluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 67);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfanyl)-4-{ [(4-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 68);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(2,6- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 69);
4-[(tert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl} sulfanyl)butanoic acid (Compound no. 70);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-{[(3,4- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 71);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfanyl)-4-[(pentylcarbamoyl) oxy]butanoic acid (Compound no. 72);
4- { [(3 -Chlorophenyl)carbamoyl] oxy } -2-( {4-[(4-chlorophenyl)
carbamoyl]phenyl}sulfanyl)butanoic acid (Compound no. 73);
4-[(Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl }sulfanyl)butanoic acid (Compound no. 74);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(2-fluorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 75);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(4-ethylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 76);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 77);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(4-methylphenyl) carbamoyl]oxy}butanoic acid (Compound no. 78);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4-( { [4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 79); 2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,4- difluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 80);
2-( {4-[(4-Chlorophenyl)carbamoyl]phenyl} sulfonyl)-4- { [(4- fluorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 81);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(2,6- dichlorophenyl)carbamoyl]oxy}butanoic acid (Compound no. 82);
4-[(fert-Butylcarbamoyl)oxy]-2-({4-[(4-chlorophenyl)carbamoyl]
phenyl } sulfonyl)butanoic acid (Compound no. 83);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-{[(3,4-dichlorophenyl) carbamoyl]oxy}butanoic acid (Compound no. 84);
2-({4-[(4-Chlorophenyl)carbamoyl]phenyl}sulfonyl)-4-[(pentylcarbamoyl) oxy]butanoic acid (Compound no. 85);
4- { [(3-Chlorophenyl)carbamoyl]oxy } -2-( {4-[(4-chlorophenyl)carbamoyl] phenyl} sulfonyl)butanoic acid (Compound no. 86);
4-[(Butylcarbamoyl)oxy]-2-( {4-[(4-chlorophenyl)carbamoyl]phenyl}
sulfonyl)butanoic acid (Compound no. 87);
2-[(4-{[(2-Fluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4-(trifluoromethyl) phenyl]carbamoyl}oxy)butanoic acid (Compound no. 88);
2-[(4-{[(4-Chlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 89);
2-[(4- { [(2,6-Dimethoxyphenyl)carbonyl]amino} phenyl)sulfanyl]-4-( { [4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 90);
2-({4-[(Cyclopropylcarbonyl)amino]phenyl} sulfanyl)-4-({ [4- (trifluoromethyl)phenylcarbamoyl}]oxy)butanoic acid (Compound no. 91);
2-[(4-{[(2-Methylphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl } oxy)butanoic acid (Compound no. 92);
2-[(4-{[(2-Ethoxyphenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 93);
2-[(4-{[(2,3-Difluorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl} oxy)butanoic acid (Compound no. 94);
2-[(4-{[(3,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 95);
2-[(4-{ [(4-Ethoxyphenyl)carbonyl] amino } pheny l)sulfanyl] -4-( { [4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 96);
2-( {4-[(Cyclohexylcarbonyl)amino]phenyl} sulfanyl)-4-( { [4-(trifluoromethyl) phenyl]carbamoyl} oxy)butanoic acid (Compound no. 97);
2-[(4-{[(2,4-Dichlorophenyl)carbonyl]amino}phenyl)sulfanyl]-4-({[4- (trifluoromethyl)phenyl]carbamoyl}oxy)butanoic acid (Compound no. 98).
3. A pharmaceutical composition comprising a therapeutically effective amount of one or more of compound of Formula I according to claims 1 and 2, together with one or more pharmaceutically acceptable carrier, excipient or diluents.
4. A compound according to any one of claims 1-2, for use in the treatment or prophylaxis of an animal or a human suffering from an inflammatory or allergic disease.
5. A compound according to claim 4, wherein the inflammatory disease or allergic disease is asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation associated with restenosis and ischemic heart failure, stroke, renal disease or tumor metastasis.
6. A pharmaceutical composition according to claim 3, further comprising one or more of additional active ingredients selected from:
a) anti-inflammatory agents, experimental or commercial, selected from (i) the nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5- lipoxygenase inhibitor and PAF-receptor antagonists, (iii) Cox-2 inhibitors, (iv) other MMP inhibitors, and (v) interleukin-I inhibitors;
b) antihypertensive agents, selected from (i) the ACE inhibitors, enalapril, lisinopril, valsartan, telmisartan and quinapril, (ii) the angiotensin II receptor antagonists and agonists, losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) β-blockers, and (iv) calcium channel blockers. c) immunosuppressive agents selected from, cyclosporine, azathioprine and methotrexate, and anti inflammatory corticosteroids.
7. A process for preparing a compound of Formula 9 (Formula I when L1 is -CONH-, X is S02 and R1 is OC(Z)NHR3) comprising:
a) reacting a compound of Formula 2 with alpha bromolactone to give a
compound of Formula 3;
Figure imgf000052_0001
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;
Figure imgf000052_0002
Formula 3' Formula 4
c) coupling a compound of Formula 4 with a compound of Formula 4' to give a compound of Formula 5 ;
Figure imgf000052_0003
Formula 4' Formula 5
d) reacting a compound of Formula 5 with a compound of Formula 6 to give a compound of Formula 7;
o o R3N=C=Z H
Formula 6 Formula 7
e) hydrolyzing a compound of Formula 7 to give a compound of Formula 8;
Figure imgf000053_0001
Formula 8
oxidizing a compound of Formula 8 to give a compound of Formula 9;
o o
R3-Nv
H
Formula 9
wherein,
R2 is hydrogen, Ci-C6alkyl, hydroxyl, Q-Cealkoxy, cyano, nitro, halogen, halogeno Ci-Cealkyl, C6-C12 aryl, C3-C8cycloalkyl, C5-Ci2 heteroaryl wherein C6-Ci2 aryl, C3-C8cycloalkyl, C6-C12 heteroaryl is optionally substituted with one or more times with R5 ;
R3 is alkyl, alkenyl, alkynyl, C6-C12 aryl, C3-C8 cycloalkyl, C5-Ci2 heteroaryl, C3-C12 heterocyclyl optionally substituted one or more times with R5;
Rs is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- Ci-C6 alkyl, halogeno-Ci-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf; - C(=0)-Rf, -COORf, -NRfRq, -(CH2)n-C(=0)NRfRq, -(CH2)„-NHC(=0)-Rf,
Figure imgf000053_0002
Figure imgf000053_0003
{wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl}; n is zero or an integer between 1 and 2;
m is an integer 0-2;
R' is alkyl, allyl, benzyl, i-butyl, silyl; Hal is F, CI, Br, I; and
Z 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) comprising:
a) reducing a compound of Formula 3 (where Y is N02) to give a compound of Formul
Figure imgf000054_0001
Formula 3 Formula 10 b) coupling a compound of Formula 10 with a compound of Formula 11 to give a compound of Formula 12;
Figure imgf000054_0002
Formula 11 Formula 12
c) reacting a compound of Formula 12 with a compound of Formula 4' to give a compound of Formula 13 ;
Figure imgf000054_0003
Formula 4' Formula 13
d) coupling a compound of Formula 13 with a compound of Formula 6 to give a compound of Formula 14;
Figure imgf000055_0001
Formula 6 Formula 14
hydrolyzing a compound of Formula 14 to give a compound of Formula 15;
Figure imgf000055_0002
Formula 15
oxidizing a compound of Formula 15 to ive a compound of Formula 16;
Figure imgf000055_0003
Formula 16
or
g) reacting a compound of Formula 3 (wherein Y is Hal) with a compound of Formula 4';
Figure imgf000055_0004
Formula 3 Formula 4'
to give a compound of Formula 17;
Figure imgf000056_0001
Formula 17
coupling a compound of Formula 17 with a compound of Formula 6 to give a compound of Formula 18;
Figure imgf000056_0002
Formula 6 Formula 18
hydrolyzing a compound of Formula 18 to give a compound of Formula 19;
Figure imgf000056_0003
Formula 19
oxidizing a compound of Formula 19 to ive a compound of Formula 20;
Figure imgf000056_0004
Formula 20
wherein,
R3 is alkyl, alkenyl, alkynyl, C6-Ci2 aryl, C3-C8 cycloalkyl, C5-Q2 heteroaryl, C3-C 12 heterocyclyl optionally substituted one or more times with R5;
R2 is hydrogen, Ci-C6alkyl, hydroxy 1, Q-Qalkoxy, cyano, nitro, halogen, halogeno Ci-C6alkyl, C6-Q2 aryl, C3-C8cycloalkyl, C5-C12 heteroaryl, wherein C6-Ci2 aryl, C3-Cgcycloalkyl, C6-Ci2 heteroaryl is optionally substituted with one or more times with R5;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- C C6 alkyl, halogeno-CpCe alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf; - C(=0)-Rf, -COORf, -NRfRq, -(CH2)n-C(=0)NRfRq, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O-Ci^-NRfRq, (CH2)n NHC(=0)NRfRq;, -(CH2)n-0-C(=0)- Rf, - (CH2)n-NH-C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {whereinRf and R, each independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl} ;
n is zero or an integer between 1 and 2;
m is an integer 0-2;
Hal is F, CI, Br, I;
U is halide, alkyloxy, aryloxy;
R' is alkyl, allyl, benzyl, t-butyl, silyl; and
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) comprising:
a) reacting a compound of Formula 21 with a compound of Formula 22
Figure imgf000057_0001
Formula 21 Formula 22
to give a compound of Formula 23;
Figure imgf000057_0002
Formula 23
b) oxidizing a compound of Formula 23 to give a compound of Formula 24;
Figure imgf000058_0001
Formula 24
c) coupling a compound of Formula 24 with a compound of Formula 25 to give a compound of Formula 26;
Figure imgf000058_0002
Formula 25 Formula 26
d) hydrolyzing a compound of Formula 26 to give a compound of Formula 27;
Figure imgf000058_0003
Formula 27
or
e) reducing a compound of Formula 26 to ive a com ound of Formula 28 ;
Figure imgf000058_0004
Formula 26 Formula 28
f) reacting a compound of Formula 28 with a compound of Formula 11 to give a compound of Formula 29;
Figure imgf000058_0005
Formula 11 Formula 29
g) hydrolyzing a compound of Formula 29 to give a compound of Formula 30;
Figure imgf000059_0001
Formula 30
wherein,
R2 is hydrogen, Ci- alkyl, hydroxyl, Q-Cealkoxy, cyano, nitro, halogen, halogeno Q-Cealkyl, C6-C12 aryl, C3-C8cycloalkyl, C5-Ci2 heteroaryl wherein C6-C12 aryl, C3-C8cycloalkyl, C6-C12 heteroaryl is optionally substituted with one or more times with R5 ;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- Ci-C6 alkyl, halogeno-Q-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)„-ORf; - C(=0)-Rf, -COORf, -NRfRq, -(CH2)n-C(=0)NRfRq, -(CH2)n-NHC(=0)-Rf,
Figure imgf000059_0002
Figure imgf000059_0003
{wherein Rf and R, each independently represent hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl} ;
n is zero or an integer between 1 and 2;
m is an integer 0-2;
Hal is F, CI, Br, I;
U is halide, alkyloxy, aryloxy;
Bn is benzyl; and
R' is alkyl, allyl, benzyl, t-butyl, silyl.
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