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WO2012038944A1 - Inhibiteurs de métalloprotéinase matricielle - Google Patents

Inhibiteurs de métalloprotéinase matricielle Download PDF

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Publication number
WO2012038944A1
WO2012038944A1 PCT/IB2011/054229 IB2011054229W WO2012038944A1 WO 2012038944 A1 WO2012038944 A1 WO 2012038944A1 IB 2011054229 W IB2011054229 W IB 2011054229W WO 2012038944 A1 WO2012038944 A1 WO 2012038944A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
amino
methylsulfonyl
oxo
Prior art date
Application number
PCT/IB2011/054229
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English (en)
Inventor
Manoj Kumar Khera
Venkata P. Palle
Viswajanani Sattigeri
Jitendra Sattigeri
Ajay Soni
Abdul Rehman Abdul Rauf
R. Sivakumar
Ranadheer R. Reddy
Arpita Musib
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
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to BR112013008008A priority Critical patent/BR112013008008A2/pt
Priority to JP2013529763A priority patent/JP2013538821A/ja
Priority to SG2013021654A priority patent/SG188641A1/en
Priority to KR1020137010369A priority patent/KR20140045287A/ko
Priority to EP11776885.3A priority patent/EP2619179A1/fr
Priority to AU2011306398A priority patent/AU2011306398A1/en
Priority to MX2013003362A priority patent/MX2013003362A/es
Priority to CN2011800564244A priority patent/CN103249719A/zh
Priority to CA2812362A priority patent/CA2812362A1/fr
Publication of WO2012038944A1 publication Critical patent/WO2012038944A1/fr
Priority to IL225526A priority patent/IL225526A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/04—1,2,3-Triazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to methyl sulfonamides and N-formamides derivatives and to processes for their syntheses.
  • the invention also relates to
  • 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 -1 1 sheddases
  • TACE and ACE TNF -converting enzymes
  • MMPs are believed to be important in physiological disease processes that involve remodeling, such as, airway diseases, embryonic development, bone formation and uterine remodelling 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.
  • 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). Because of its proteolytic ability, MMP-9 has been implicated in tissue remodelling 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, osteoclasts, which are easily induced by cytokines and growth factors, and plays a role in various physiological and pathological processes.
  • IPF interstitial pulmonary fibrosis
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • 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.
  • TIMP 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 have 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),.
  • WO 95/35276 discloses N-substituted arylsulphonyl amino acid and their hydroxamic acid derivatives as matrix metallo -proteinase inhibitors.
  • WO 00/06561 discloses tricyclic sulfonamides compounds as matrix metalloproteinases.
  • Patent No. 6,366,675 discloses N-sulphonyl-diamino: carboxylic acid derivatives used as matrix metalloprotease inhibitors.
  • WO 2004/1 13279 discloses substituted glycine derivatives, useful for treating inflammatory conditions or autoimmune disorders 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.
  • the present invention provides the methyl sulfonamide and formamides derivatives as matrix metalloproteinase 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
  • MMP9/12 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 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.
  • 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, other anti-inflammatory agents, antihypertensive agents and immunosuppressive agents
  • L 1 can be selected from bond, O, S, CH 2 , NR 4 , NHCO(CH 2 ) n , (CH 2 ) n CONH, NHCONH, S0 2 NH, NHSO2, NHCO(O), -0-(CH 2 ) n , -(CH 2 ) n -0-, -OC(0)NH-, C(S)NH, NHC(S), NHC(S)NH or -COO- wherein n can be zero or an integer between 1 and 2;
  • R 1 can be selected from hydrogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, cyano, nitro, halogen, halogeno Ci-C6alkyl, C5-C12 aryl, Ce-Cn heteroaryl, C3-C6 cycloalkyl wherein aryl, heteroaryl, cycloalkyl is optionally substituted by one or more substitutents independently selected from R 5 ;
  • R 2 can be CHO or S0 2 Ci_ 6 alkyl
  • R 3 can be unsubstituted or substituted heteroaryl or -OCONHR' where R' is Ce- C12 aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more substitutents independently selected from R 5 ;
  • R 4 can be H or Ci_ 6 alkyl
  • R f and R q are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and
  • n is as defined earlier and m is an integer 0-2 ⁇ .
  • the invention encompasses compounds that include, 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.
  • kits for treating or prophylaxis of an animal or a human suffering from various inflammatory or allergic diseases comprising administering to a mammal in need thereof therapeutically effective amount of one or more compounds of Formula 1 , described herein.
  • the diseases or conditions of inflammation and associated pathologies are selected from 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 which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders
  • 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.
  • the following definitions apply to terms, as used herein.
  • 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 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, cyclopentenyl, 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 include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring, 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 and optionally are benzofused or fused heteroaryl having 5-6 ring members.
  • 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.
  • 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
  • halogen 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. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moiety/moieties 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 or more 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 or S configuration.
  • 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.
  • 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.
  • 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.
  • alkyl and mono-arylsulphonates such as ethane sulphonate, toluene sulphonate and benzene sulphonate
  • other organic acids and their corresponding salts such
  • the compounds, disclosed herein may be prepared by following reaction sequences as depicted in Schemes I, II, III, IV, V and VI.
  • Formula 10 Formula 12 Formula 13 ⁇ Formula 1 when R 3 is ⁇ Formula 1 when R 3 is heteroaryl, L 1 is bond ⁇ OCONHR, L 1 is bond ⁇
  • Formula 2 (wherein is aryl or heteroaryl ring and R 6 is hydrogen, alkyl, halogen,
  • the coupling of 4-bromo-nitrobenzene with a compound of Formula 2 to give a compound of Formula 3 can be carried out in the presence of inorganic base selected from, for example, potassium carbonate, sodium carbonate, sodium acetate, potassium acetate in presence of a solvent selected from, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, toluene, or mixture(s) thereof.
  • inorganic base selected from, for example, potassium carbonate, sodium carbonate, sodium acetate, potassium acetate in presence of a solvent selected from, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, toluene, or mixture(s) thereof.
  • the reduction of a compound of Formula 3 to give a compound of Formula 4 can be carried out using reducing agent selected from, for example, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or iron in the presence of hydrochloric acid or lithium aluminum hydride, Pd/C in H2 in the presence of a solvent, for example, tetrahydrofuran, methanol, ethanol, diethyl ether, dioxane, or mixture(s) thereof.
  • reducing agent selected from, for example, Raney Nickel in hydrazine hydrate or ammonium formate, zinc, tin or iron in the presence of hydrochloric acid or lithium aluminum hydride, Pd/C in H2 in the presence of a solvent, for example, tetrahydrofuran, methanol, ethanol, diethyl ether, dioxane, or mixture(s) thereof.
  • the coupling of a compound of Formula 4 with alpha-bromolactone to give a compound of Formula 5 can be carried out using inorganic base selected from, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate using solvent selected from, for example, acetonitrile, water, or mixture(s) thereof.
  • the formylation of a compound of Formula 5 to give a compound of Formula 6 can be carried out using formylating agent selected from, for example, formic acid, acetic formic anhydride, chloral, activated formic acid using N, N-dicyclohexylcarbodiimide
  • DCC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • EDCI l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • the ring opening of a compound of Formula 6 to give a compound of Formula 7 can be carried out with alkyl/aryl halide 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, for example, N, N-dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture(s) thereof.
  • a solvent for example, N, N-dimethylformamide, methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile, water, or mixture(s) thereof.
  • the coupling of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9 can be carried out in the presence of redox couple.
  • the oxidizing part of the redox couple is selected from, for example, 1,1 ' -(azodicarbonyl)piperidine (ADDP), 4,7-dimethyl-3,5,7-hexahydro- l,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,N,N- tetramethylazodicarboxamide (TMAD), N,N,N,N-tetraisopropylazodicarboxamide (TIP A), diethyl azodicarboxylate (DEAD), di-Z-butylazodicarboxylate or
  • the reducing part of the redox couple is selected from, for example, tributylphosphine, triphenylphosphine, / (dimethylaminophenyl) or triscyclohexylphosphine in the presence of a solvent, for example, tetrahydrofuran, dimethylsulfoxide, N, V-dimethylformamide, acetonitrile, or mixture(s) thereof.
  • a solvent for example, tetrahydrofuran, dimethylsulfoxide, N, V-dimethylformamide, acetonitrile, or mixture(s) thereof.
  • the deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out can be carried out in the presence of mineral acid, for example, hydrochloric, hydrobromic, hydroiodic acid in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • mineral acid for example, hydrochloric, hydrobromic, hydroiodic acid in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • the deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of one or more organic acid(s), for example, trifluoroacetic acid, / toluenesulphonic acid or camphor sulphonic acid, in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • organic acid(s) for example, trifluoroacetic acid, / toluenesulphonic acid or camphor sulphonic acid
  • a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • the deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of inorganic base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • inorganic base for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • the deprotection of a compound of Formula 9 to give a compound of Formula 10 can be carried out in the presence of deprotecting agent, for example, Pd/C in presence of I3 ⁇ 4, Pd/C with ammonium formate, Pd/C in presence of triethylsilane, ozone, boron trichloride dimethylsulfide (BCl3.SMe2), 2,3-dichloro-5,6-dicyano-/ benzoquinone (DDQ), tetrakis triphenylphosphine in the presence of morpholine using solvent selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, methanol, ethanol, acetonitrile, tetrahydrofuran, or mixture(s) thereof.
  • deprotecting agent for example, Pd/C in presence of I3 ⁇ 4, Pd/C with ammonium formate, Pd/C in presence of triethylsilane
  • the reaction of a compound of Formula 7 with a compound of Formula 11 to give a compound of Formula 12 can be carried out in the presence of base selected from, for example, triethylamine, N,N-dimethylaminopyridine, 2,6-lutidine, 1 -methylpiperidine, N- ethyldiisoproylamine, N,N-diisopropylethylamine or N-methylmorpholine in a solvent selected from, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or mixture(s) thereof.
  • base selected from, for example, triethylamine, N,N-dimethylaminopyridine, 2,6-lutidine, 1 -methylpiperidine, N- ethyldiisoproylamine, N,N-diisopropylethylamine or N-methylmorpholine in a solvent selected from, tetrahydro
  • the compound of Formula 20 can be prepared according to Scheme II.
  • the compound of Formula 20 can be prepared according to Scheme II.
  • Path C (when 3 ⁇ 4 is halogen):
  • the compound of Formula 16 react with a compound of Formula 17 to form a compound of Formula 18 which upon coupling with a compound of Formula 2 (wherein ⁇ ⁇ is aryl or heteroaryl ring and R 6 is the same as defined earlier) gives a compound of Formula 19.
  • the compound of Formula 19 on deprotection gives a compound of Formula 20.
  • Path D (when R ⁇ is aryl/heteroaryl substituted with R 6 ):
  • the compound of Formula 16 on reaction with a compound of Formula 17 gives a compound of Formula 19 which upon deprotection gives a compound of Formula 20.
  • the alpha halogenation of a compound of Formula 14 to form a compound of Formula 15 can be carried out in the presence of red phosphorous/Br 2 , in the presence of a solvent selected from, for example, carbon tetrachloride, chloroform, dichloromethane, dichloroethane, or mixture(s) thereof.
  • the O-protection of a compound of Formula 15 to give a compound of Formula 16 can be carried out with carboxy protecting group, for example, methyl, benzyl, allyl, t- butyl, silyl, BOC anhydride in the presence of organic base selected from, for example, triethylamine, N,N-dimethylaminopyridine, 2,6-lutidine, 1 -methylpiperidine, N- ethyldiisoproylamine, N,N-diisopropylethylamine or N-methylmorpholine using solvents selected from, tetrahydrofuran, N, N-dimethylformamide, dimethylsulf oxide, acetonitrile, or mixture(s) thereof.
  • carboxy protecting group for example, methyl, benzyl, allyl, t- butyl, silyl, BOC anhydride
  • organic base selected from, for example, triethylamine, N,N-dimethyl
  • the O-protection of a compound of Formula 15 to give a compound of Formula 16 can be carried out with carboxy protecting group, for example, methyl, benzyl, allyl, Z-butyl, silyl, BOC anhydride in the presence of inorganic base selected from, sodium bicarbonate, lithium bicarbonate, potassium bicarbonate in one or more solvents selected from, for example, N, N-dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, methanol, ethanol, water, or mixture(s) thereof.
  • carboxy protecting group for example, methyl, benzyl, allyl, Z-butyl, silyl, BOC anhydride
  • inorganic base selected from, sodium bicarbonate, lithium bicarbonate, potassium bicarbonate in one or more solvents selected from, for example, N, N-dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, methanol
  • C) to give a compound of Formula 18 can be carried out in the presence of inorganic base selected from, for example, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, barium carbonate using solvent, for example, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, or mixture(s) thereof.
  • inorganic base selected from, for example, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, barium carbonate using solvent, for example, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide, or mixture(s) thereof.
  • the coupling of a compound of Formula 18 with a compound of Formula 2 to give a compound of Formula 19 can be carried out in the presence of inorganic catalyst selected from, for example, te-(diphenylphosphino)ferrocence palladium II dichloride
  • D) to give a compound of Formula 19 can be carried out in the presence of inorganic base selected from, for example, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate in a solvent, for example, acetonitrile, tetrahydrofuran, ⁇ , ⁇ '- dimethylformamide, dimethylsulfoxide, or mixture(s) thereof.
  • inorganic base selected from, for example, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate in a solvent, for example, acetonitrile, tetrahydrofuran, ⁇ , ⁇ '- dimethylformamide, dimethylsulfoxide, or mixture(s) thereof.
  • the compound of Formula 26b (Path E), Formula 29 (Path F), Formula 31 (Path G), Formula 36 (Path H) can be prepared according to Scheme III.
  • a compound of Formula 17a (wherein 3 ⁇ 4 ' is hydrogen, halogen, alkoxy, aryloxy, aryl, carboxy) with alpha-hydroxy lactone gives a compound of Formula 21 which upon ring opening gives a compound of Formula 22.
  • the carboxy-protection of compound of Formula 22 gives a compound of Formula 23 (wherein R p is same as defined earlier).
  • Path E when is halogen: the compound of Formula 23 upon hydroxy protection gives a compound of Formula 24 (wherein R p > is hydroxy protecting group).
  • R p > is hydroxy protecting group.
  • the coupling of a compound of Formula 24 with a compound of Formula 24a gives a compound of Formula 25 which upon deprotection gives a compound of Formula 26.
  • the reaction of a compound of Formula 26 with a compound of Formula 27 gives a compound of Formula 26a.
  • the deprotection of a compound of Formula 26a gives a compound of Formula 26b.
  • Path F when is alkoxy/aryloxy/halogen/hydrogen: the reaction of a compound of Formula 23 with a compound of Formula 27 gives a compound of Formula 28 which upon deprotection gives a compound of Formula 29.
  • Path G (when is aryl substituted with halogen and R p is allyl): the reaction of a compound of Formula 23 with a compound of Formula 27 gives a compound of Formula 30 which upon deprotection gives a compound of Formula 31.
  • Path H (when is COOR p ): the coupling of a compound of Formula 23 with a compound of Formula 27 gives a compound of Formula 32 which upon deprotection gives a compound of Formula 33.
  • the coupling of a compound of Formula 33 with a compound of Formula 34 gives a compound of Formula 35 which finally upon deprotection forms a compound of Formula 36.
  • reaction of a compound of Formula 17a with oc-hydroxy lactone to give a compound of Formula 21 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the ring-opening of a compound of Formula 21 to give a compound of Formula 22 can be carried out as described for the compound of Formula 6 to give a compound of Formula 7.
  • the hydroxy-protection of a compound of Formula 23 to give a compound of Formula 24 (Path E) can be carried out using protecting group selected from, for example, tert-butyldimethylsilylchloride (TBDMSC1), trimethylsilylchloride (TMSC1), tert- butyldimethylsilyloxymethylchloride (TOMC1), triisopropylsilylchloride (TIPSC1), benzoyl chloride in the presence of base, for example, imidazole, N-methylimidazole, triethylamine, pyridine, diisopropylethylamine, N,Ndimethylaminopyridine in the presence of solvent, for example, N, N-dimethylformamide, toluene, acetonitrile, dichloromethane, or mixture thereof.
  • protecting group selected from, for example, tert-butyldimethylsilylchloride (TBDMSC1), trimethyl
  • deprotection of a compound of Formula 25 to give a compound of Formula 26 can be carried out using deprotecting agent selected from, for example, boron trifluoride ethearte (BF 3 .0Et2), HF-pyridine, boron trichloride, boron tribromide, cesium fluoride (CsF), potassium fluoride (KF), «-tetrabutylammonium fluoride, Pd/C in !3 ⁇ 4, potassium carbonate in presence of solvent, for example, dichloromethane, N, N-dimethylformamide, acetonitrile, methanol, ethanol, acetone, tetrahydrofuran, or mixture thereof.
  • deprotecting agent selected from, for example, boron trifluoride ethearte (BF 3 .0Et2), HF-pyridine, boron trichloride, boron tribromide, cesium fluoride (CsF), potassium fluoride (KF
  • reaction of a compound of Formula 26 with a compound of Formula 27 to give a compound of Formula 26a can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the deprotection of a compound of Formula 26a to give a compound of Formula 26b can be out under similar conditions as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.
  • reaction of a compound of Formula 23 (Path F) with a compound of Formula 27 to give a compound of Formula 28 can be carried out under similar condition as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the deprotection of a compound of Formula 28 to give a compound of Formula 29 can be out under similar conditions as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.
  • reaction of a compound of Formula 23 (Path G) with a compound of Formula 27 to give a compound of Formula 30 can be carried out under similar conditions as described for reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the deprotection of a compound of Formula 30 to give a compound of Formula 31 can be carried out under similar conditions as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.
  • reaction of a compound of Formula 23 (Path H) with a compound of Formula 27 to give a compound of Formula 32 can be carried out under similar conditions as described for the compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the coupling of a compound of Formula 33 with a compound of Formula 34 to give a compound of Formula 35 can be carried out using base selected from triethylamine, N,N-dimethylaminopyridine, 2,6-lutidine, 1 -methylpiperidine, N-ethyldiisoproylamine, N,N-diisopropylethylamine or N-methylmorpholine, in the presence of a additives for example hydroxybenzotriazole, 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine, 2- hydroxypyridine, N-hydroxysuccinimide or 1 -hydroxy-7-azabenzotriazole, with a suitable condensing agent, for example, dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, chlorotripyrrolidinophosphonium hexa
  • R 1 is aryl/heteroaryl ⁇
  • the compound of Formula 43 can be prepared according to Scheme IV.
  • protecting a compound of Formula 37 (wherein R p is same as defined earlier) gives a compound of Formula 38 (wherein R p > is same as defined earlier) which on reaction with a compound of Formula 39 (Wherein R 6 is alkyl and Ak is same as defined earlier) gives a compound of Formula 40.
  • the compound of Formula 40 on deprotection gives a compound of Formula 41 which on reaction with a compound of Formula 27 (wherein R 5 is same as defined earlier) forms a compound of Formula 42.
  • the deprotection of a compound of Formula 42 gives a compound of Formula 43.
  • reaction of a compound of Formula 38 with a compound of Formula 39 to give a compound of Formula 40 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • reaction of a compound of Formula 41 with a compound of Formula 27 to give a compound of Formula 42 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • L 1 is bond and R 1 is aryl/heteroaryl]
  • the compound of Formula 52 can be prepared according to Scheme V.
  • Scheme V Thus reacting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane with a compound of Formula 44 gives a compound of Formula 45 which upon ring opening gives a compound of Formula 46.
  • the compound of Formula 46 on O-protection gives a compound of Formula 47 (wherein R p > is same earlier) which upon reaction with a compound of Formula 48 (wherein Hal and Ak are same as defined earlier) gives a compound of Formula 49.
  • the coupling of a compound of Formula 49 with a compound of Formula 2 gives a compound of Formula 50.
  • the compound of Formula 50 on deprotection forms a compound of Formula 51 which finally on oxidation gives a compound of Formula 52.
  • the ring opening of a compound of Formula 45 to give a compound of Formula 46 can be carried out in the presence of mineral acids selected from, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, or in the presence of catalytic amount of cerium(IV) ammonium nitrate (CAN), cerium(III) trifluoromethane sulfonate using solvent, for example, acetone, nitromethane, acetonitrile, water, or described thereof.
  • mineral acids selected from, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid
  • catalytic amount of cerium(IV) ammonium nitrate (CAN), cerium(III) trifluoromethane sulfonate using solvent, for example, acetone, nitromethane, acetonitrile, water, or described thereof.
  • reaction of a compound of Formula 47 with a compound of Formula 48 to give a compound of Formula 49 can be carried out under similar conditions as described for the reaction of a compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the coupling of a compound of Formula 49 with a compound of Formula 2 to give a compound of Formula 50 can be carried out under similar conditions as described for coupling of a compound of Formula 18 with a compound of Formula 2 to give a compound of Formula 19.
  • the deprotection of a compound of Formula 50 to give a compound of Formula 51 can be carried out under similar condition as described for the deprotection of a compound of Formula 25 to give a compound of Formula 26.
  • oxidation of a compound of Formula 51 to give a compound of Formula 52 can be carried using oxidizing agent, for example, sodium chlorite and sodium
  • the compound of Formula 61 can be prepared according to Scheme VI.
  • protecting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane gives a compound of Formula 53 (wherein R p is same as defined earlier) which upon ring opening forms a compound of Formula 54.
  • the compound of Formula 54 upon further protection gives a compound of Formula 55 (wherein Rp' is same as defined earlier) which on reaction with a compound of Formula 48 (wherein Hal is same as defined earlier) gives a compound of Formula 56.
  • the coupling of a compound of Formula 56 with a compound of Formula 2 gives a compound of Formula 57 which on deprotection forms a compound of Formula 58.
  • the protection of 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane to give a compound of Formula 53 can be carried out using alkyl/aryl halides using inorganic base selected from lithium hydride, sodium hydride or organic base selected from pyridine, triethylamine, trimethylamine, tributylamine, N-ethyldiisopropylamine, 4-N,N- dimethylaminopyridine, N-methylmorpholine or 2,6-lutidine in the presence of a solvent, for example, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, or mixture(s) thereof.
  • inorganic base selected from lithium hydride, sodium hydride or organic base selected from pyridine, triethylamine, trimethylamine, tributylamine, N-ethyldiisopropylamine, 4-N,N- dimethylaminopyridine, N-methylmorpholine or
  • the ring opening of a compound of Formula 53 to give a compound of Formula 55 can be carried out under similar conditions as described for compound of Formula 45 to give a compound of Formula 46.
  • the protection of a compound 54 to give a compound of Formula 55 can be carried out under similar conditions as described for the protection of compound of Formula 23 to give a compound of Formula 24.
  • reaction of a compound of Formula 55 with a compound of Formula 48 to give a compound of Formula 56 can be carried out under similar conditions as described for the compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the deprotection of a compound of Formula 57 to give a compound of Formula 58 can be carried out as described for the deprotection of a compound of Formula 9 to give a compound of Formula 10.
  • the coupling of a compound of Formula 58 with a compound of Formula 27 to gives a compound 59 can be carried out under similar conditions as described for the compound of Formula 7 with a compound of Formula 8 to give a compound of Formula 9.
  • the deprotection of a compound of Formula 59 to give a compound of Formula 60 can be carried out under similar conditions as described fro the compound of Formula 25 to give a compound of Formula 26.
  • the oxidation of a compound of Formula 60 to give a compound of Formula 61 can be carried out under similar condition as described for the compound of Formula 51 to give a compound of Formula 52.
  • 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; antiadherents, 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.
  • a formulation of a tablet could typically contain from 0.01 mg to 500 mg of active compound while tablet fill weight may range from 50 mg to 1000 mg.
  • An example is illustrated below:
  • 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 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 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 organic layer was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum to obtain a crude product.
  • the crude product was purified on silica gel column using 80% ethyl acetate: hexane as eluent to afford the title compound.
  • Step c Preparation of tert-but ⁇ 4- [(methylsulfonyl)amino] benzoate
  • Step d Preparation of tert-but ⁇ 4-[(methylsulfonyl)(2-oxotetrahydrofuran-3- yl)amino] benzoate
  • Step e Preparation of A , -[4-(teri-butoxycarbonyl)phenyl]-A'-(methylsulfonyl) homoserine
  • Step f Preparation of tert-buty ⁇ 4- ⁇ [4-hydroxy-l-oxo-l-(prop-2-en-l-yloxy)butan-2- yl](methylsulfonyl)amino ⁇ benzoate
  • step e To a solution of compound obtained from step e (3 g, 8.04 mmoles) in N, N- dimethylformamide (25 mL) were added sodium bicarbonate (1 g, 12.06 mmoles) and allyl bromide (1.07 g, 8.84 mmoles) at room temperature. The reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of reaction, solvent was evaporated and reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated to get crude product. The crude product was purified on silica gel column using 40% ethyl acetate: hexane to get the desired compound.
  • N-dimethylformamide (15 mL) and water (15 mL) were added 4-chlorophenylboronic acid (2.49 g, 0.016 moles), potassium carbonate (3.3 g, 0.024 moles) and tetrakis triphenylphosphine (277 mg, 0.002 moles).
  • the reaction mixture was heated upto 100°C for about 14 hours. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude product.
  • the crude product was purified on silica gel column using 25% ethyl acetate: hexane as eluent to get title compound.
  • Step b Preparation of A'-(4 , -chlorobiphenyl-4-yl)-A'-(2-oxotetrahydrofuran-3- yl)methane sulfonamide
  • step a To a compound obtained from step a (10 g, 0.035 moles) in tetrahydrofuran (70 mL) were added oc-hydroxy lactone (8.8 g, 0.05 moles) and triphenylphosphine (13.9 g, 0.05 moles) at 0°C. The reaction mixture was allowed to stir for about 10 minutes and diisopropylazodicarboxylate DIAD (10.7 mL, 0.05 moles) was added to it at 0°C. The reaction mixture was again stirred for about 2 hours at room temperature. After completion, solvent was evaporated to obtain a crude product which was purified on silica gel column using 20% ethyl acetate: hexane as eluent to get the desired product.
  • DIAD diisopropylazodicarboxylate
  • Step c Preparation of A'-(4 , -chlorobiphenyl-4-yl)-A'-(methylsulfonyl)homoserine
  • step b To a solution of compound obtained from step b (10 g, 0.0273 moles) in ethanol: water mixture (10: 1) (100ml: lOmL) at 0°C was added sodium hydroxide (1.2g, 0.037 moles) in water (2 mL). The reaction mixture was allowed to stir for about 2 hours at 0°C. After 2 hours, solvent was evaporated under reduced pressure and residues obtained were taken in water and extracted with ethyl acetate. The aqueous layer obtained was acidified by aqueous solution of sodium bisulphite and then extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get title compound.
  • Step d Preparation of prop-2-en-l-yl A'-(4 , -chlorobiphenyl-4-yl)-A'-(methylsulfonyl) homoserinate
  • step c To a compound obtained from step c (10 g, 0.026 moles) in ethanol: water: DMF mixture (60 mL: 6 mL: 60 mL) at room temperature was added sodium bicarbonate (2.1 g, 0.026 moles). The reaction mixture was allowed to stir at room temperature for about 30 minutes. After 30 minutes, the reaction mixture was concentrated under reduced pressure and treated with toluene. The toluene was evaporated and residue so obtained was taken in dry N, N-dimethylformamide (20 mL) at room temperature. To this reaction mixture was slowly added allyl bromide (3.4 g, 0.028 moles) and stirred for overnight at room temperature. After completion, water was added to the reaction mixture and extracted with ethyl acetate.
  • sodium bicarbonate 2.1 g, 0.026 moles
  • Step c Preparation of 3-[(4'-methylbiphenyl-4-yl)amino]dihydrofuran-2(3 )-one
  • Step e Preparation of methyl A'-formyl-7V-(4 , -methylbiphenyl-4-yl)homoserinate
  • Step f Preparation of methyl 2-[formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl- 4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoate
  • step e To a compound obtained from step e (0.3 g, 0.0009 moles) in tetrahydrofuran (5 mL) were added 6-methylbenzotriazinone (0.177 g, 0.001 1 moles) and triphenyl phosphine (0.353 g, 0.0013 moles) under argon atmosphere. The reaction mixture was allowed to cool to 0°C and to it was added diisopropylazodicarboxylate (0.272 g, 0.0013 moles) and stirred for about 30 minutes at room temperature. After completion, reaction mixture was quenched by addition of water and extracted with ethyl acetate.
  • Step g Preparation of 2-[formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid
  • Step a Preparation of methyl 0-[(4-fluorophenyl)carbamoyl]-A'-formyl-A'-(4 , -methyl biphenyl-4-yl)homoserinate
  • a solution of methyl N-formyl-N-(4'-methylbiphenyl-4-yl)homoserinate (0.3 g, 0.0009 moles) in tetrahydrofuran (5 mL) was added triethylamine (0.272 g, 0.0027 moles) and 1 -fluoro-4-isocyanatobenzene (0.147 g, 0.0010 moles) under argon atmosphere at room temperature.
  • reaction mixture was allowed to stir for about 2 hours at room temperature. After completion, the reaction mixture was quenched by addition of water and extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound. The crude compound was purified on silica gel column using 15% ethyl acetate: hexane as eluent to obtain desired product.
  • Step b Preparation of ⁇ M ⁇ -fluorophenylJcarbamoyll-A ⁇ -formyWV- ⁇ '- methylbiphenyl-4-yl)homoserine
  • Step a Preparation of 2-bromo-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoic acid
  • 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoic acid (1 1.7 g, 0.050 moles) in carbon tetrachloride (60 mL) was added red phosphorous (5.2 g, 0.167 mole) and heated at about 60°C.
  • bromine 40 mL, 0.792 mole
  • water 50 mL
  • the reaction mixture was solidified and extracted with ethyl acetate.
  • the organic layer was washed with aqueous solution of sodium bicarbonate.
  • the obtained aqueous layer was acidified (pH ⁇ 2) using aqueous solution of hydrochloric acid and extracted with ethyl acetate.
  • the combined organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated to get desired product.
  • Step b Preparation of tert-but ⁇ 2-bromo-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl) butanoate
  • Step c Preparation of tert-buty ⁇ 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoate
  • Step d Preparation of tert-but ⁇ 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-[(4'- methoxy biphenyl-4-yl)(methylsulfonyl)amino] butanoate
  • Step e Preparation of 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-[(4'- methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid
  • step d To a solution of compound obtained from step d (0.144 g, 0.00025 moles) in dichloromethane (5 mL) was added trifluoroacetic acid (1.2 mL) at 0°C. The reaction mixture was allowed to stir for about 3 hours at 0°C and then at room temperature for about 4 hours. After completion, the reaction mixture was extracted with dichloromethane, washed with water and brine. The organic layer was evaporated under reduced pressure to get a crude product which was purified on silica gel column using 50% ethyl acetate:
  • Step a Preparation of tert-but ⁇ 2-[biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoate
  • the combined organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude product.
  • the crude product was purified on silica gel column using 40% ethyl acetate: hexane as eluent to get desired product.
  • Step b Preparation of 2-[biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)butanoic acid
  • Step a Preparation of A'-(4-bromophenyl)-A'-(2-oxotetrahydrofuran-3- yl)methanesulfonamide
  • Step b Preparation of sodium 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-hydroxy butanoate
  • Step c Preparation of benzyl A'-(4-bromophenyl)-A'-(methylsulfonyl)homoserinate
  • Step d Preparation of benzyl N-(4-b romophenyl)-6>- [to*f-butyl(dimethyl)silyl]-A'- (methylsulfonyl)homoserinate
  • Step e Preparation of benzyl 0-[teri-butyl(dimethyl)silyl]-A'-[4-(6-methoxypyridin-3- ylJphenyll-A ⁇ methylsulfonyr ⁇ homoserinate
  • Step f Preparation of benzyl iV-[4-(6-methoxypyridin-3-yl)phenyl]-iV- (methylsulfonyl) homo serinate
  • Step g Preparation of benzyl 2- ⁇ [4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino ⁇ -4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoate
  • Step a Preparation of benzyl 2-[(4-methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoate
  • Step b Preparation of 2-[(4-methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid
  • Step a Preparation of prop-2-en-l-yl 2-[(4'-chlorobiphenyl-4- yl)(methylsulfonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)butanoate
  • triphenylphosphine (0.232 g, 0.88 moles)
  • 4-methyl phthalimide (0.104 g, 0.65 moles
  • reaction mixture was stirred for about 15 minutes and diisopropylazodicarboxylate (0.179 g, 0.0.88moles) was added to it at 0°C.
  • the reaction mixture was again stirred for about 2 hours at room temperature. After completion, solvent was evaporated to get a crude product which was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired compound.
  • Step b Preparation of 2-[(4'-chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5- methyl-l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoic acid
  • Step a Preparation of tert-but ⁇ 4- ⁇ (methylsulfonyl)[l-oxo-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)-l-(prop-2-en-l-yloxy)butan-2-yl]amino ⁇ benzoate
  • Step b Preparation of 4- ⁇ (methylsulfonyl)[l-oxo-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)-l-(prop-2-en-l-yloxy)butan-2-yl]amino ⁇ benzoic acid
  • Step c Preparation of prop-2-en-l-yl 2-[ ⁇ 4-[(4-methylphenyl)carbamoyl] phenyl ⁇ (methyl sulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoate
  • the organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum to get crude product.
  • the crude product obtained was purified on silica gel column using 80% ethyl acetate: hexane as eluent to get the desired compound.
  • Step d Preparation of 2-[ ⁇ 4-[(4-methylphenylkarbamoyllphenylKmethylsulfonyl) amino I -4-(4-oxo-l ,2,3-benzotriazin-3(4 )-yl)butanoic acid
  • Step a Preparation of benzyl 4- ⁇ [teri-butyl(dimethyl)silyl]oxy ⁇ -2-hydroxybutanoate
  • dichloromethane 100 mL
  • triethylamine 8.3 mL, 59.42 mmoles
  • Ze ⁇ butyldimethylsilyl chloride 8.20 g, 54.47 mmoles
  • N, N- dimethylaminopyridine 241 mg, 1.98 mmoles
  • reaction mixture was quenched by addition of water and extracted with ethyl acetate.
  • the organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum to afford the crude compound.
  • the crude compound obtained was purified on column chromatography using silica gel and eluting with 10% ethyl acetate: hexane as eluent to get the desired compound. Yield: 9.6 g
  • Step b Preparation of benzyl 0-[terf-butyl(dimethyl)silyl]-A L (methylsulfonyl)-A'-[4- (propan-2-yl)phenyl]homoserinate
  • Step c Preparation of benzyl A'-(methylsulfonyl)-A'-[4-(propan-2-yl)phenyl] homoserinate
  • Step d Preparation of benzyl 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- ⁇ (methyl sulfonyl) [4-(propan-2-yl)phenyl] amino ⁇ butanoate
  • Step e Preparation of 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- ⁇ (methylsulfonyl)
  • Step a Preparation of 3-[2-(2,2-dimethyl-l,3-dioxolan-4-yl)ethyl]-l,2,3-benzotriazin- 4(3H)-one
  • Step b Preparation of 3-(3,4-dihydroxybutyl)-l,2,3-benzotriazin-4(3H)-one
  • Step c Preparation of 2-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4 )-yl)butyl benzoate
  • Step e Preparation of 2-[(3',4'-difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butyl benzoate
  • Step f Preparation of A'-(3 , ,4 , -difluorobiphenyl-4-yl)-A'-[l-hydroxy-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butan-2-yl]methanesulfonamide
  • Step g Preparation of 2-[(3',4'-difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid
  • Step a Preparation of 3-[2-(2,2-dimethyl-l,3-dioxolan-4-yl)ethyl]-l,2,3-benzotriazin- 4(3H)-one
  • Step b Preparation of 3-(3,4-dihydroxybutyl)-l,2,3-benzotriazin-4(3H)-one
  • Step d Preparation of 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzo triazin-3(4H)-yl)butyl benzoate
  • Step e Preparation of 2-[(3',4'-dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butyl benzoate
  • Step f Preparation of A , -(3',4'-dichlorobiphenyl-4-yl)-A'-[l-hydroxy-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butan-2-yl] methanesulfonamide
  • Step g Preparation of 2-[(3',4'-dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid
  • Step a Preparation of (45)-4-[2-(benzyloxy)ethyl]-2,2-dimethyl-l,3-dioxolane
  • the combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude product.
  • the crude product was purified on silica gel column using 30% ethyl acetate hexane as eluent to get desired product.
  • Step f Preparation of (2J?)-2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl) amino] -4-hydroxybutyl benzoate
  • Step g Preparation of (2J?)-2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl) amino] -4- [4-oxo-7-(trifluoromethyl)-l ,2,3-benzotriazin-3(4H)-yl] butyl benzoate
  • the combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude product.
  • the crude product was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired product.
  • Step h Preparation of A'-(3 , -fluoro-4 , -methoxybiphenyl-4-yl)-A'- ⁇ (2i?)-l-hydroxy-4- [4-oxo-7-(trifluoromethyl)-l,2,3-benzotriazin-3(4H)-yl]butan-2- yl ⁇ methanesulfonamide
  • Step i Preparation of (2J?)-2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl) amino] -4- [4-oxo-7-(trifluoromethyl)-l ,2,3-benzotriazin-3(4H)-yl] butanoic acid
  • MMPs Matrix Metallo Proteinases
  • New chemical entities (NCEs) 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 50% DMSO-50% TCNB (50 mM Tris, 10 mM CaCl 2 , 150 mM NaCl, 0.05% Brij-35, pH 7.5). 1 ⁇ of the compound and 88 ⁇ 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 ⁇ of activated, recombinant MMPs was added to each well (20-100 ng/100 ⁇ reaction mixture) except the "negative well".
  • 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.
  • the Reaction was initiated with 10 ⁇ of 100 ⁇ substrate (ESOO 1 : Aliquots were freshly diluted in TCNB; stock: 2 mM) and increase in florescence was monitored at excitation wave length 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 MMP9 provided IC 50 values below 10 micromolar. Activities for MMP12 provided IC 50 values 35 nanomolar to 10 micromolar.

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Abstract

La présente invention concerne des dérivés méthylsulfonamides et N-formamides de formule (I) et des procédés pour leur synthèse. L'invention concerne aussi des compositions pharmacologiques contenant ces dérivés et des méthodes de traitement de l'asthme, de l'arthrite rhumatoïde, les maladies pulmonaires obstructives chroniques, la rhinite, l'ostéoarthrite, l'arthrite psoriasique, le psoriasis, la fibrose pulmonaire, l'inflammation pulmonaire, le syndrome de détresse respiratoire aiguë, la parodontite, la sclérose multiple, la gingivite, l'athérosclérose, la sécheresse oculaire, la prolifération néointimale qui entraîne la resténose et l'ischémie myocardique, l'accident vasculaire cérébral, des maladies rénales, des métastases tumorales, et d'autres troubles inflammatoires caractérisés par la sur-expression et la sur-activation de métalloprotéinase matricielle, utilisant lesdits composés.
PCT/IB2011/054229 2010-09-24 2011-09-26 Inhibiteurs de métalloprotéinase matricielle WO2012038944A1 (fr)

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SG2013021654A SG188641A1 (en) 2010-09-24 2011-09-26 Matrix metalloproteinase inhibitors
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AU2011306398A AU2011306398A1 (en) 2010-09-24 2011-09-26 Matrix metalloproteinase inhibitors
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CA2812362A CA2812362A1 (fr) 2010-09-24 2011-09-26 Inhibiteurs de metalloproteinase matricielle
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