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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to certain hydroxy propionic acid derivatives and the processes for the synthesis of the same.
• This 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 sclerosis, gingivitis, atherosclerosis, dry eye, neointimal
• 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 and sharing structural and functional features. Based on structural and functional considerations, proteinases have been classified into different families and subfamilies (Vartak et al. , 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-12 the MT-MMPs
• MMP-14, -15, -16, -17, - 24 and 25 matrilysins
• MMP-7 and -26 matrilysins
• MMP- 3, -10 and -11 sheddases
• TACE TNF-converting enzymes
• MMPs are believed to be important in physiological and disease processes that involve remodeling, such as airway diseases, 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 which belongs to the gelatinase family, plays a major role in chronic inflammatory disorders like COPD, asthma and rheumatoid arthritis.
• the concentration of MMP-9 has been reported to increase in diseases like asthma, interstitial pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS), and in chronic obstructive pulmonary disease (COPD).
• IPF interstitial pulmonary fibrosis
• ARDS adult respiratory distress syndrome
• COPD chronic obstructive pulmonary disease
• MMP-9 Because of its proteolytic ability, MMP-9 has been implicated in tissue remodeling of the airways and lungs in chronic inflammatory diseases such as severe asthma and COPD.
• MMP-9 is also likely to be physiologically important because of its ability to regulate the digestion of components of the extracellular matrix as well as the activity of other proteases and cytokines.
• MMP-9 is secreted in neutrophils, macrophages, and osteoclasts, which are easily induced by cytokines and growth factors
• MMP-12 also known as macrophage elastase or metalloelastase, is expressed in activated macrophages and has been shown to be secreted from alveolar macrophages from smokers, as well as in foam cells in atherosclerotic lesions. MMP-12 knockout mouse studies have shown the development of significant emphysema, thus supporting its role in COPD.
• MMP-9 gelatinase B, 92 kDa Type IV collagenase
• MMP-9 is one member of the MMP family that is released as a proenzyme and subsequently activated via a protease cascade in vivo.
• TMP matrix metalloproteinase
• Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, autoimmue 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 2004/014310 discloses processes for the preparation of peripheral opioid antagonist compounds useful for gastrointestinal motility disorders.
• WO 02/060888 discloses processes for preparing chromanylbenzoic acids.
• WO 94/20455 discloses styryl derivatives as PDE-IV inhibitors useful in the prophylaxis and treatment of diseases such as asthma, where an unwanted inflammatory response or muscular spasm is present.
• WO 2004/1 10974 discloses compounds and their physiologically functional derivatives described as inhibitors of matrix metalloproteinase enzymes.
• WO 2004/1 13279 discloses inhibitors of matrix metalloproteinase.
• WO 2005/026120 discloses compounds described as inhibitors of matrix metalloproteinase.
• 2003/0139453 discloses diflourobutyric acid compounds useful for treating diseases associated with zinc metalloprotease activity.
• WO 2006/090235 describes 5-phenyl-pentanoic acid derivatives described as matrix metalloproteinase inhibitors for the treatment of asthma and other diseases.
• WO 2008/023336 discloses ⁇ -hydroxy and amino-substituted carboxylic acids, which act as matrix metalloproteinase inhibitors.
• 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 is directed to overcoming problems encountered in the art. Summary of the Invention
• the present invention provides some hydroxy propionic acid derivatives, which act as matrix metalloprotease inhibitors, corresponding processes for the synthesis of and pharmaceutical compositions containing the compounds of the present invention.
• the present invention relates to matrix metalloproteinase inhibitors useful as effective therapeutic or prophylactic agents in treatment of various inflammatory, autoimmune, and allergic diseases and other inflammatory disorders characterized by the over-expression and over- activation of a matrix metalloproteinase using the compounds.
• the present invention discloses a novel class of compounds that are dual MMP- 9/12 inhibitors and have desirable activity profiles.
• the compounds of this invention have beneficial potency and/or selectivity.
• 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 or autoimmune diseases.
• These pharmaceutical compositions may be administered or coadministered 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.
• specific enantiomers have been shown by way of examples, the racemates, diastereomers, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates, having the same type of activity, are also provided.
• Pharmaceutical compositions comprising such compounds, with optionally included excipients are also provided.
• Therapeutically effective amounts of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, other anti-inflammatory agents, beta agonists, antihypertensive agents, immunosuppressive agents and anti-infective agents.
• other therapeutic agents for example, other anti-inflammatory agents, beta agonists, antihypertensive agents, immunosuppressive agents and anti-infective agents.
• R f and R q are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as defined earlier and m is an integer 0-2 ⁇ ; can be selected from heteroaryl or heterocyclyl.
• G_ can be selected from phenyl, fluorophenyl, heteroaryl or heterocyclyl;
• R f and R q are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and
• alkylheterocyclyl n is as defined earlier and m is an integer 0-2 ⁇ ; can be selected from heteroaryl or heterocyclyl.
• the current invention provides a compound of Formula lb:
• Ra can be hydrogen or fluorine
• L ⁇ nd _ are as defined earlier.
• the current invention provides a compound of Formula Ic:
• L la is selected from S(0) n , NHCO(CH 2 ) consult and NHCO(O); are as defined earlier.
• the enantiomers, diastereomers, rotational isomers, TV-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds, prodrugs and metabolites having the same type of activity are also provided, as well as pharmaceutical compositions comprising the compounds, their metabolites, enantiomers, diastereomers, conformational isomers, TV-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
• the invention encompasses compounds of Formula (I), which may include, but are not limited to the following, for example
• compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
• compounds according to Formula I/Ia/Ib/Ic for use in treating or preventing various inflammatory and allergic diseases comprising administering to a mammal in need thereof.
• inflammatory and allergic diseases are 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 tumour metastasis.
• the present invention relates to the therapeutically effective dose of a compound of Formula I/Ia/Ib/Ic in combination with one or more of other therapeutic agents used for treating various inflammatory and allergic diseases.
• therapeutic agents include, but are not limited to: ) Anti-inflammatory agents, experimental or commercial (i) such as nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, phosphodiesterase inhibitors including PDE-4 inhibitors, p38 MAP Kinase/Cathepsin inhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists, cell adhesion inhibitors (specially ICAM), adenosine 2a agonists, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors, 5 -lipoxygenase inhibitors
• dexbudesonide diflorasone, difluprednate, fluticasone, flunisolide
• halometasone haloperedone, hydrocortisone, methylprednisolone,
• Preferred corticosteroids include, for example, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone;
• Beta-agonists experimental or commercial
• suitable p2-agonists include, for example, one or more of albuterol, salbutamol, biltolterol, pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol, salmeterol, carmoterol, arformoterol, formoterol, and their pharmaceutically acceptable salts or solvates thereof one or more ⁇ 2- agonists may be chosen from those in the art or subsequently discovered,
• the p2-agonists may include one or more compounds described in, for example, U.S. Patent Nos.
• antihypertensive agents e.g., 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) ⁇ - blockers, and (iv) calcium channel blockers; 4) immunosuppressive agents, for example, cyclosporine, azathioprine and methotrexate, anti-inflammatory corticosteroids; and
• anti-infective agents e.g. , antibiotics, antivirals.
• alkyl refers to a straight or branched fully saturated hydrocarbon chain which is optionally substituted by one or more halo atom, and which has 1 to 20 carbon atoms unless otherwise specified. This term is exemplified by groups such as methyl, ethyl, ⁇ -propyl, so-propyl, «-butyl, so-butyl, t-butyl, «-hexyl, «-decyl, «-tetradecyl, trifluoromethyl, chloroethyl, and the like.
• alkenyl refers to a branched or unbranched unsaturated hydrocarbon group containing at least one double bond with cis or trans geometry and preferably having 2 to 20 carbon atoms. Examples of alkenyl group include ethenyl, 2-propenyl and isopropenyl.
• cycloalkyl refers to a non aromatic cyclic group having 3 to 20 ring carbon atoms and form one to three rings and may optionally contain one or more olefinic bonds. Polycyclic ring systems may be a spiro, fused or bridged arrangement.
• Cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, adamantyl, bicyclo[2.2./]heptanyl, bicyclo[2.2.2]octane, tricycle[3JJ.i]decane, and the like.
• aryl refers to an aromatic system having from 6 to 14 carbon atoms and up to three rings which may be fused or directly joined.
• Representative examples of such aryl group include, but are not limited to, phenyl, biphenyl, naphthyl, phenanthrene, anthracenyl, azulenyl, and indanyl.
• Aryl group may also comprise one or more rings which are not fully aromatic and examples of such system are indane, indene, 2, 3 dihydrobenzofuran and 1 ,2,3,4-tetrahydronaphthalene
• heteroaryF refers to an aromatic system having from 5 to 14 membered carbon atoms and up to three rings, which may be fused or directly joined, and containing from one to eight heteroatoms selected from N, O and S.
• heteroaryl groups are pyridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, thiophenyl, 1,2,3-triazolyl, 1 ,2,4- triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
• heterocyclyl refers to a non-aromatic monocyclic or polycyclic ring system, which may be fused spiro or bridged, having 3 to 12 ring atoms and up to eight heteroatoms selected from N, O and S.
• heterocyclyl ring systems include piperidine, morpholine, piperazine, isoquinoline, oxazolidine, tetrahydrofuran, dihydrofuran, dihydropyridine, dihydroisoxazole, dihydrobenzofuran, azabicyclohexane, dihydroindole, tetrahydroquinoline, pyrrolidine, azepine, azetidine, aziridine,
• cycloalkylalkyl refers respectively, to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked to the remainder of the molecule via an alkyl group.
• amino refers to -NH 2 .
• alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
• halogen or halo refers to fluorine, chlorine, bromine or iodine.
• halogeno-Ci-C 6 alkyF refers to Ci-C 6 alkyl of which one or more hydrogen(s) is/are replaced by halogen.
• halogeno Ci-C ⁇ alkoxy refers to as halogen atom bonded to C C 6 alkoxy group. Examples of such groups include trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy etc.
• hydroxyl or "hydroxy” refers to -OH.
• thiol refers to the group -SH.
• alkylthiol refers to a thiol group when hydrogen is replaced by alkyl, for example, methylthio, ethylthio, propylthio, t-butylthio, cyclopropylthio, and the like.
• cyano refers to as C ⁇ N.
• 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.
• 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. 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 are/is stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
• Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned.
• salts of carboxylic acid moiety which may be prepared by reacting the compound with appropriate base to provide corresponding base addition salts.
• bases are 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.
• compounds of the present invention may also form the acid addition salts by treating the said compounds with pharmaceutically acceptable organic and inorganic acids, e.g., hydrohalides 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, tartarate, maleate, succinate, citrate, etc.
• the salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for the purpose of this invention.
• solvates refers to solvates with water ⁇ i.e., hydrates) or pharmaceutically acceptable solvents, for example, solvates with ethanol, and the like. Such solvates are also encompassed within the scope of the disclosure.
• polymorphs includes all crystalline forms as well as amorphous forms for compounds described herein and as such are included in the present invention.
• pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
• pharmaceutically acceptable means approved by the regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
• inflammatory conditions and autoimmune disorders in which the compounds of the invention have potentially beneficial effects in treatment methods may include, but are not limited to diseases of the respiratory tract such as asthma (including allergen-induced asthmatic reactions), cystic fibrosis, bronchitis (including chronic bronchitis), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), chronic pulmonary inflammation, rhinitis and upper respiratory tract inflammatory disorders (URID), ventilator induced lung injury, silicosis, pulmonary sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, arthritis, e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, Reiter's syndrome, gouty arthritis and prosthetic joint failure, gout, acute synovitis, spondylitis and non-articular inflammatory conditions, e.g.
• diseases of the respiratory tract such as asthma (including aller
• herniated/ruptured/prolapsed intervertebral disk syndrome bursitis, tendonitis, tenosynovitic, fibromyalgic syndrome and other inflammatory conditions associated with ligamentous sprain and regional musculoskeletal strain, inflammatory disorders of the gastrointestinal tract, e.g.
• ulcerative colitis ulcerative colitis
• diverticulitis Crohn's disease
• inflammatory bowel diseases irritable bowel syndrome and gastritis
• multiple sclerosis systemic lupus erythematosus, scleroderma, autoimmune exocrinopathy, autoimmune encephalomyelitis, diabetes, tumor angiogenesis and metastasis, cancer including carcinoma of the breast, colon, rectum, lung, kidney, ovary, stomach, uterus, pancreas, liver, oral, laryngeal and prostate, melanoma, acute and chronic leukemia, periodontal disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy, muscle degeneration, inguinal hernia, retinal degeneration, diabetic retinopathy, macular degeneration, inguinal hernia, ocular inflammation, bone resorption diseases, osteoporosis, osteopetrosis, graft vs.
• the compound of Formula II (wherein _ is as defined earlier, X is O or S and R k is H, halo, alkyl, alkoxy, cyano, halogeno-Ci-C 6 alkyl or halogeno-Ci-C6 alkoxy and z is 0-4) can react with a compound of Formula III to give a compound of
• Path A (When X is S): The compound of Formula VI undergoes hydrolysis to give a compound of Formula VII, which then further undergoes oxidation to give a compound of Formula VIII.
• Path B (When X is O): The compound of Formula VI undergoes hydrolysis to give a compound of Formula IX.
• the reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in the presence of a base, for example, potassium carbonate, cesium carbonate, sodium acetate or potassium acetate in a solvent, for example, dimethylformamide, acetonitrile, toluene, tetrahydrofuran, acetone, dioxane, or mixture(s) thereof.
• a base for example, potassium carbonate, cesium carbonate, sodium acetate or potassium acetate
• a solvent for example, dimethylformamide, acetonitrile, toluene, tetrahydrofuran, acetone, dioxane, or mixture(s) thereof.
• asymmetric aldol addition of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI can be carried out by generating the enolates with titanium tetrachloride, dibutyl boron triflate, dialkyl boron chloride or tin(II) triflate, in the presence of a base, for example, tetramethylethylenediamine,
• Hydrolysis of a compound of Formula VI (Path A, when X is S) to give a compound of Formula VII can be carried out with hydrogen peroxide and lithium hydroxide, in the presence of a solvent, for example, tetrahydrofuran, water, or mixture(s) thereof.
• a solvent for example, tetrahydrofuran, water, or mixture(s) thereof.
• Oxidation of a compound of Formula VII to give a compound of Formula VIII can be carried out with an oxidizing agent, for example, meta chloro perbenzoic acid, oxone or hydrogen peroxide, in a solvent, for example, chloroform, dichoromethane, methanol, water, tetrachloromethane, or mixture(s) thereof.
• an oxidizing agent for example, meta chloro perbenzoic acid, oxone or hydrogen peroxide
• a solvent for example, chloroform, dichoromethane, methanol, water, tetrachloromethane, or mixture(s) thereof.
• the compound of Formula V undergoes aldol addition with a compound of Formula X (wherein G can be nitro or C(O)O-benzyl) to give a compound of Formula XI, which then can be reduced to give a compound of Formula XII (wherein G 1 can be amino or COOH).
• Aldol addition of a compound of Formula X to a compound of Formula V to give a compound of Formula XI can be carried out in a similar way as the aldol addition of a compound of Formula IV with a compound of Formula V to give a compound of Formula VI.
• Reduction of a compound of Formula XI to give a compound of Formula XII can be carried out with one or more reducing agents, for example, palladium-carbon/hydrogen, Raney nickel/hydrogen, platinum/hydrogen or mixture thereof in a solvent, for example, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, or mixtures thereof.
• one or more reducing agents for example, palladium-carbon/hydrogen, Raney nickel/hydrogen, platinum/hydrogen or mixture thereof in a solvent, for example, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, or mixtures thereof.
• the compound of Formula XII (when G] is amino) can react through two pathways.
• Path C Compound of Formula XII couples with a compound of Formula XIII (wherein Rk and z are as defined earlier) to give a compound of Formula XIV, which then undergoes hydrolysis to give a compound of Formula XV.
• Path D Compound of Formula XII couples with a compound of Formula XVI (wherein X is a leaving group for example halogen and R j is -(CH 2 ) 0-1 -CO-, -C(0)O, -S0 2- , and R k is as defined earlier) to give a compound of Formula XVII, which then undergo hydrolysis to give a compound of Formula XVIII.
• X is a leaving group for example halogen and R j is -(CH 2 ) 0-1 -CO-, -C(0)O, -S0 2- , and R k is as defined earlier
• a suitable base for example, potassium carbonate ⁇ sodium carbonate, triethylamine, diisopropylethyl amine, etc. in the presence of solvents like acetonitrile, dimethylformamide, toluene,
• a base for example, triethylamine (TEA), N-methyl-morpholine (NMM), N,N-dimethylaminopyridine
• the compound of Formula XII (when Gi is COOH) can couple with a compound of Formula XIX to give a compound of Formula XX, which then undergoes hydrolysis to give a compound of Formula XXI.
• the coupling of compound of Formula XII with a compound of Formula XIX to give a compound of Formula XX can be carried out in the presence of a coupling agent 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) or N ⁇ V-dicyclohexylcarbodiimide (DCC) and optionally activating catalyst HOBT and an organic base
• a coupling agent 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) or N ⁇ V-dicyclohexylcarbodiimide (DCC) optionally activating catalyst HOBT and an organic base
• XII can also be activated by converting to the corresponding acid chloride (using thionyl chloride, oxalyl chloride, etc.) or the anhydride (pivaloyl chloride, etc.) and coupled with the corresponding anilines.
• Hydrolysis of compound of Formula XX to give a compound of Formula XXI can be carried out in a similar way as the hydrolysis of compound of Formula VI to give a compound of Formula VII.
• Table 1 lists the type of compounds synthesized by using the synthetic procedure as demonstrated in Schemes I-IV.
• 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, and cachets.
• active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate and/or fillers or extenders (for example, starches, lactose, sucrose, glucose, mannitol, silicic acid, or mixtures thereof); binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate, or mixtures thereof; absorption acceletors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol mono stearate or mixtures thereof; adsorbants, for example, sodium
• 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.
• 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.
• solubilizing agents or emulsifiers for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,
• 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.
• 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 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 cocoa 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.
• suitable nonirritating excipients such as cocoa 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 packed preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packed forms.
• Step 1 Synthesis of 4-[(4-chlorophenyl)sulfanyl]benzaldehyde To a solution of 4-chlorothiophenol (1.0 g, 0.0069 mol) in dimethylformamide
• Step 2 Synthesis of 3- ⁇ (3S)-4-[(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3-yl]-3-[(S)- ⁇ 4-[(4- chlorophenyl)sulfanyl]phenyl ⁇ (hydroxy)methyl]-4-oxobutyl ⁇ -l,2,3-benzotriazin- 4(3H)-one
• Step 4 Synthesis of (2S)-2-[(S)- ⁇ 4-[(4-chlorophenyl)sulfonyl]phenyl ⁇ (hydroxy) methyI]-4-(4-oxo-l,2,3-benzotriazin-3(4/f)-yl)butanoic acid (Compound No. 2)
• Step 2 Synthesis of 3-[(3S)-4-[(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3-yl]-3- ⁇ (S)- hydroxy[4-(4-methoxyphenoxy)phenyl]methyl ⁇ -4-oxobutyl]-l,2,3-benzotriazin-4(3H - one
• Step 3 Synthesis of (2S)-2- ⁇ (S)-hydroxy[4-(4-methoxyphenoxy)phenyI]methyI ⁇ -4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 56)
• Example III Synthesis of 3-rf35.4 ⁇ 4-AmmophenylV3-(r(4S)-4-benzyl-2-oxo-1.3- thiazolidin-3 -yl] carbonyl ⁇ -4-hydroxybutyl] - 1 ,2,3 -benzotriazin-4(3H)-one
• Step 1 Synthesis of 3- ⁇ (3S)-4-[(4S)-4-benzyl-2-oxo-l, 3-thiazolidin-3-yl]-3-[(S)- hydroxy(4-nitrophenyl)methyl]-4-oxobutyl ⁇ -l,2,3-benzotriazin-4(3H)-one
• Step 1 Synthesis of V- ⁇ 4-[(15,2S)-2- ⁇ [(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3- yl]carbonyl ⁇ -l-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butyl]phenyl ⁇ -2-fluoro-
• Step 2 Synthesis of (2S)-2-[(S)-[4-( ⁇ [2-fIuoro-4-(trifIuoromethyl)phenyl]carbonyl ⁇ amino)phenyl](hydroxy)methyl]-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 46)
• Example V Synthesis of (25 f )-2-[( ' S)-(4- ⁇ [(4-ethylphenyl carbonyllamino ⁇ phenyl (hvdroxy)methyl1-4-(4-oxo- l ,2.3-benzotriazin-3(4H)-yl)butanoic acid (Compound No. 10) Step 1: Synthesis of 3- ⁇ (3S)-4-[(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3-yl]-3-[(S)- hydroxy(4-nitrophenyl)methyl]-4-oxobutyl ⁇ -l,2,3-benzotriazin-4(3H)-one
• Step 3 Synthesis of N- ⁇ 4-[(15,2S)-2- ⁇ [(4S)-4-benzyl-2-oxo-l,3-thiazolidin-3- yl]carbonyl ⁇ -l-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butyl]phenyl ⁇ -4- ethylbenzamide
• MMPs Matrix Metalloproteinases
• New chemical entities of the present invention and corresponding standards used in the present invention were prepared (stock 10 mM) in 100% DMSO and subsequent dilutions were made in MMP assay buffer [50 mM HEPES, 10 mM CaCl 2, 150 nM NaCl, 1 ⁇ Zinc Acetate, 600 ⁇ CHAPS (pH 7.4)].
• Assays used human MMPs expressed either as full length or catalytic domain.
• the Collagenase (MMP-1), Gelatinase (MMP-9), Elastase (MMP- 12) and membrane type-1 (MMP- 14) were cleaved and activated using reagent APMA (4-amino phenyl mercuric acetate) to obtain active catalytic domains.
• reagent APMA 4-amino phenyl mercuric acetate
• IC 5 o values were calculated using least square regression analysis method by Graph-Pad prism version 4.2 software; using a 5-6 point dose response curve in presence of inhibitor. IC 50 values were averaged for duplicate assay data and values tabulated.
• the present invention relates to compounds that act as dual MMP-9/12 inhibitors, which have desirable activity profiles.
• MMP-9 activities of the compounds disclosed in the invention provided IC 50 values from about 10 micromolar to about 1 nM, or from about 1 micromolar to about 1 nM, or from about 650 nM to about 1 nM, or from about 300 nM to about 1 nM, or from about 100 nM to about 1 nM, or from about 50 nM to about 1 nM, or from about 30 nM to about 1 nM, or from about 20 nM to about 1 nM, or from about 12 nM to about 1 nM, as compared to about 1.4 nM to 3.2 nM for marimastat.
• MMP-12 activities of the compounds disclosed in the invention provided IC 50 values from about 10 micromolar to about 1 nM, or from about 1 micromolar to about 1 nM, or from about 300 nM to about 1 nM, or from about 100 nM to about 1 nM, or from about 50 nM to about 1 nM, or from about 30 nM to about 1 nM, or from about 20 nM to about 1 nM, or from about 15 nM to about 1 nM, or from about 7 nM to about 1 nM as compared to 0.2 nM to 0.9 nM for marimastat.

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