WO2012038944A1 - Matrix metalloproteinase inhibitors - Google Patents

Matrix metalloproteinase inhibitors 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
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PCT/IB2011/054229
Other languages
French (fr)
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 SG2013021654A priority Critical patent/SG188641A1/en
Priority to AU2011306398A priority patent/AU2011306398A1/en
Priority to JP2013529763A priority patent/JP2013538821A/en
Priority to MX2013003362A priority patent/MX2013003362A/en
Priority to CA2812362A priority patent/CA2812362A1/en
Priority to KR1020137010369A priority patent/KR20140045287A/en
Priority to CN2011800564244A priority patent/CN103249719A/en
Priority to EP11776885.3A priority patent/EP2619179A1/en
Priority to BR112013008008A priority patent/BR112013008008A2/en
Publication of WO2012038944A1 publication Critical patent/WO2012038944A1/en
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.

Abstract

The present invention relates to methyl sulfonamides and N-formamides derivatives of formula (I) and to processes for their syntheses. The invention also relates to pharmacological compositions containing these derivatives and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatie 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 characterized by over expression and over activation of an matrix metalloproteinase using the compounds.

Description

MATRIX METALLOPROTEINASE INHIBITORS
Field of the Invention
The present invention relates to methyl sulfonamides and N-formamides derivatives and to processes for their syntheses. The invention also relates to
pharmacological compositions containing these derivatives 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
proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, tumor metastasis, and other inflammatory disorders characterized by over expression and over activation of a matrix metalloproteinase using the compounds.
Background of the Invention
Metalloproteinases (MMPs) are a naturally occurring superfamily of proteinases (enzymes) found in most mammals. The superfamily is composed of at least 26 members of zinc-containing enzymes produced by many cell types 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. 1 -6 (1994)), such as collagenases (MMP-1, -8 and -13), gelatinases (MMP-2, and -9), metalloelastases (MMP-12), the MT-MMPs (MMP-14, -15, -16, -17, - 24 and 25), matrilysins (MMP-7 and -26), stromelysins (MMP- 3, -10 and -1 1) and sheddases such as TNF -converting enzymes (TACE and ACE).
Metalloproteinases are believed to be important in physiological disease processes that involve remodeling, such as, 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. Apart from their role in degrading connective tissue, MMPs are involved in the activation of zymogen (pro) forms of other MMPs thereby inducing MMP activation. They are also involved in the biosynthesis of TNF-alpha which is implicated in many pathological conditions. MMP-9, 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). 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.
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) is one member of the MMP family that is released as a proenzyme and subsequently activated via a protease cascade in vivo.
Over-expression or over-activation of an MMP, or an imbalance between an MMP and a natural, (i.e., endogenous), tissue inhibitor of a matrix metalloproteinase (TIMP) has been linked to a pathogenesis of diseases characterized by the breakdown of connective tissue or extracellular matrix.
Inhibition of the activity of one or more MMPs may be of benefit in treatment of various inflammatory, 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.
The design and therapeutic application of 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 Zn2+ 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. U.S. 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.
Research has been carried out into the identification of inhibitors that are selective, e.g., for a few of the MMP subtypes. An MMP inhibitor of improved selectivity would avoid potential side effects associated with inhibition of MMPs that are not involved in the pathogenesis of the disease being treated.
Further, use of more selective MMP inhibitors would require administration of a lower amount of the inhibitor for treatment of disease than would otherwise be required, and after administration, partitioned in vivo among multiple MMPs. Still further, the administration of a lower amount of compound would improve the margin of safety between the dose of the inhibitor required for therapeutic activity and the dose of the inhibitor at which toxicity is observed.
Many drugs exist as asymmetric three-dimensional molecules, i.e., chiral, and will therefore have several stereoisomers depending upon the number of chiral centers present. The importance of evaluating new chemical entities having chiral centers as single isomers is to understand their effect on pharmacological and toxicological aspects. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between
enantiomers/diastereomers. Even if natural physiological mediators are achiral, based on their target environment, their receptors/enzymes may demonstrate a preference for only one optically pure enantiomer of agonists, antagonists or inhibitors. From a
pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. Pure single isomers may also offer advantages in terms of these pharmacokinetic parameters thus enabling better developability of such molecules as drug candidates. It is also known that chirality has a significant effect of the physicochemical properties and crystallinity of a chiral molecule which in turn have profound effects on the pharmacokinetics and developability of the molecule. Besides those mentioned above, regulatory principles guide one to preferably develop single isomers as drug candidates in order to avoid any pharmacological, pharmacokinetic and toxicological problems that may arise due to interactions of an unwanted isomer with undesirable molecular targets.
In this context, synthetic strategies to produce pure single isomers offer advantages over analytical techniques of separation of isomer not only in terms of cost and efficiency but larger amounts of compound can be prepared for elaborate pharmaceutical testing. Thus, compounds of the present invention, which are single chiral isomers, have improved potency, improved pharmacokinetics and/or improved physicochemical properties as compared to racemic compounds.
The present invention is directed to overcoming problems encountered in the art.
Summary of the Invention
The present invention provides 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.
Pharmaceutical compositions containing such compounds are provided together with the pharmaceutically acceptable carriers or diluents, which can be used for the treatment or prevention of inflammatory and autoimmune diseases. These pharmaceutical compositions may be administered or co administered by a wide variety of routes including, for example, oral, topical, rectal, intranasal or by parenteral route. The composition may also be administered or co-administered in slow-release dosage forms.
Although, specific enantiomers have been shown by way of examples, racemates, diastereomers, and pharmaceutically acceptable salts are also provided. Pharmaceutical compositions comprising the compounds, their enantiomers, racemates, diastereomers and pharmaceutically acceptable salts are also included.
The therapeutically effective amount of one or more compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, other anti-inflammatory agents, antihypertensive agents and immunosuppressive agents
Other objects will be set forth in accompanying description and in the part will be apparent from the description or may be by the practice of the invention.
Detailed Description of the Invention
In accordance with one aspect, there is provided compounds having structure of
Formula I:
Figure imgf000006_0001
Formula 1
including racemates, enantiomers, or diastereomers thereof; or a pharmaceutically acceptable salt thereof, wherein,
L1 can be selected from bond, O, S, CH2, NR4, NHCO(CH2)n, (CH2)nCONH, NHCONH, S02NH, NHSO2, NHCO(O), -0-(CH2)n, -(CH2)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;
R1 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 R5;
R2 can be CHO or S02Ci_6 alkyl;
R3 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 R5;
R4 can be H or Ci_6alkyl;
R5 can be selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno- Ci-C6 alkyl, halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0)-Rf, - COORf, -NRfRq,
Figure imgf000007_0001
(CH2)n NHC(=0)NRfRq„ -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)-Rf
or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rqare 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} .
In one aspect the invention encompasses compounds that include, for example,
2-[Formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 1);
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[formyl(4'-methylbiphenyl-4- yl)amino]butanoic acid (Compound no. 2);
2-[(4'-Ethylbiphenyl-4-yl)(formyl)amino]-4-(5-methyl-4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 3);
0-[(4-Fluorophenyl)carbamoyl]-N-formyl-N-(4'-methylbiphenyl-4-yl)homoserine (Compound no. 4);
N-Formyl-N-(4'-methylbiphenyl-4-yl)-0-[(4-methylphenyl)carbamoyl]homoserine (Compound no. 5);
O- [(3 ,4-Dichlorophenyl)carbamoyl] -N-formyl-N-(4'-methylbiphenyl-4- yl)homoserine (Compound no. 6);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0- {[4-(propan-2-yl)phenyl]carbamoyl} homoserine (Compound no. 7);
N-(4'-Ethylbiphenyl-4-yl)-0-[(3-fluorophenyl)carbamoyl]-N-formylhomoserine (Compound no. 8);
0-[(2,4-Difluorophenyl)carbamoyl]-N-(4'-ethylbiphenyl-4-yl)-N- formylhomoserine (Compound no. 9);
N-(4'-Ethylbiphenyl-4-yl)-0-[(2-fluorophenyl)carbamoyl]-N-formylhomoserine (Compound no. 10);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0- {[4-(trifluoromethyl)phenyl]carbamoyl} homoserine (Compound no. 1 1);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0-[(2-methylphenyl)carbamoyl]homoserine (Compound no. 12); N-(4'-Ethylbiphenyl-4-yl)-0-[(4-ethylphenyl)carbamoyl]-N-formylhomoserine (Compound no. 13);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0-[(4-methoxyphenyl)carbamoyl]homoserine (Compound no. 14);
0-[(2,6-Dichlorophenyl)carbamoyl]-N-(4'-ethylbiphenyl-4-yl)-N- formylhomoserine (Compound no. 15);
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)butanoic acid (Compound no. 16);
4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 17);
4-(l ,3-Dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2-[(4'-methoxybiphenyl-4- yl)(methylsulfonyl)amino]butanoic acid (Compound no. 18);
2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 19);
4-(7-Methoxy-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 20);
2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-[4-oxo-7- (trifluoromethyl)-l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 21);
4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 22);
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4- methylphenoxy)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 23);
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4-methylphenoxy) phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 24);
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-[4-oxo-7-
(trifluoromethyl)-l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 25);
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 26);
2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 27);
2-[(4'-Ethylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 28);
2- { [4-(2-Methoxypyrimidin-5-yl)phenyl] (methylsulfonyl)amino } -4-(4-oxo- 1 ,2,3 - benzotriazin-3(4H)-yl)butanoic acid (Compound no. 29);
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 30);
2-[(2',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 31); 2-[(4-Methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 32);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(4- methoxyphenyl)(methylsulfonyl)amino]butanoic acid (Compound no. 33);
4-(l ,3-Dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2-[(4-methoxyphenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 34);
2- [(4-Methoxyphenyl)(methylsulfonyl)amino] -4-(5 -methyl- 1 ,3 -dioxo- 1 ,3 -dihydro- 2H-isoindo-2-yl)butanoic acid (Compound no. 35);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4- methylphenoxy)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 36);
4-(5-Methyl- 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2- {[4-(4-methylphenoxy) phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 37);
2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 38);
2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 39);
2- {(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 40);
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 41);
2- {[4-(6-Methylpyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 42);
2- {(Methylsulfonyl)[4-(pyrimidin-5-yl)phenyl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 43);
2- {(Methylsulfonyl)[4-(pyridin-3-yl)phenyl]amino} -4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 44);
2- {(Methylsulfonyl)[4'-(trifluoromethyl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 45);
2- {(Methylsulfonyl)[4-(pyridin-4-yl)phenyl]amino} -4-(4-oxo- 1 ,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 46);
2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 47);
2-[(4'-ieri-Butylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 48);
2-[(2',3'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 49);
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 50); 4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- {(methylsulfonyl)[4-(propan-2- yl)phenyl] amino jbutanoic acid (Compound no. 51);
4-(6-Methoxy-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan- 2-yl)phenyl] amino jbutanoic acid (Compound no. 52);
4-(7-Methyl-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-2- yl)phenyl] amino jbutanoic acid (Compound no. 53);
4-(l ,3-Dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2-[(4-ethylphenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 54);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)butanoic acid (Compound no. 55);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 56);
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 57);
2-[(Methylsulfonyl)(phenyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 58);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methyl- 1 ,3-dioxo- 1,3- dihydro-2H-isoindol-2-yl)butanoic acid (Compound no. 59);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-chloro-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 60);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-chloro-4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 61);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 62);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-(trifluoromethyl)- l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 63);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methoxy-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 64);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-fluoro-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 65);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(l-methyl-2,4-dioxo-l,4- dihydroquinazolin-3(2H)-yl)butanoic acid (Compound no. 66);
4- {(Methylsulfonyl) [ 1 -oxo-4-(4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)- 1 -(prop-2-en- 1 - yloxy)butan-2-yl] amino} benzoic acid (Compound no. 67);
2-[ {4-[(4-Methylphenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 68);
2-[ {4-[(4-Chlorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 69); 2- {(Methylsulfonyl)[4-(phenylcarbamoyl)phenyl]amino} -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 70);
2-[ {4-[(3-Fluorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 71);
2-[(Methylsulfonyl)(4- {[4-(propan-2-yl)phenyl]carbamoyl} phenyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 72);
2-[ {4-[(4-Methoxyphenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 73);
2-[ {4-[(4-Fluorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 74);
2-[(Methylsulfonyl)(4- {[4-(trifluoromethyl)phenyl] carbamoyljphenyl) amino] -4- (4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 75);
(2R)-2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3 - benzotriazin-3(4H)-yl)butanoic acid (Compound no. 76);
(2R)-2- {(Methylsulfonyl) [4-(pyrimidin-5-yl)phenyl] amino } -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 77);
(2R)-2- {(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 78);
(2R)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 79);
(2R)-2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 80);
(2R)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 81);
(2R)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 82);
(2R)-2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 83);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 84);
(2R)-2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 85);
(2R)-2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 86);
(2S)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 87);
(2S)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 88); (2S)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzo triazin-3(4H)-yl)butanoic acid (Compound no. 89);
(2S)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 90);
(2R)-2-[(3',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 91);
(2R)-2- {[4-(2,3-Dihydro- l,4-benzodioxin-6-yl)phenyl](methylsulfonyl)amino} -4- (4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 92);
(2R)-2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 93);
(2R)-2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 94);
(2R)-2- {(Methylsulfonyl)[4'-(trifluoromethoxy)biphenyl-4-yl]amino}-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 95);
(2R)-2- {[4'-Chloro-3'-(trifluoromethyl)biphenyl-4-yl](methylsulfonyl)amino}-4- (4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 96);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7- (trifluoro methyl)- l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 97);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-methyl- 4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 98);
(2R)-4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(3'-fluoro-4'- methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid (Compound no. 99);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(7- methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 100); (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-methyl- 4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 101);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8- methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 102);
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-fluoro-4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 103);
4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(4-chlorophenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 104);
2-[(4-Bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 105);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 106);
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 107); 2-[(4-Chlorophenyl)(methylsulfonyl)amino] -4-(6-methoxy-4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 108).
In another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds, described herein, together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided herein, are methods for treating or 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.
In one embodiment, 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
In yet another aspect, the present invention relates to the therapeutically effective amount of compounds of Formula I in combination with one or more of other therapeutic agents used in treating various inflammatory and allergic diseases. Examples of such therapeutic agents includes, but are not limited to,
1) anti-inflammatory agents, experimental or commercial (i) such as
nonsteroidal anti-inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4 -Inhibitors, 5- lipoxygenase inhibitor and PAF -receptor antagonists, (iii) Cox-2 inhibitors, (iv) MMP inhibitors, and (v) interleukin-I inhibitors;
2) antihypertensive agents, (i) ACE inhibitors, e.g., enalapril, lisinopril,
valsartan, telmisartan and quinapril, (ii) angiotensin II receptor antagonists and agonists, e.g., losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) β-blockers, and (iv) calcium channel blockers.
3) immunosuppressive agents such as cyclosporine, azathioprine and
methotrexate, and anti inflammatory corticosteroids. The following definitions apply to terms, as used herein.
The term "alkyl", unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term "alkenyl", unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
The term "alkynyl", unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
The term "cycloalkyl", unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, 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.
The term "aryl", unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring, and the like.
The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined above.
The term "heteroaryl", unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S and optionally are benzofused or fused heteroaryl having 5-6 ring members.
The term "heterocyclyl", unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members.
The terms "cycloalkylalkyl", "arylalkyl", "heteroarylalkyl", "heterocyclylalkyl" refers respectively to cycloalkyl, aryl, heteroaryl or heterocyclyl group linked to the remainder of the molecule via an alkyl group.
The term "amino" refers to— NH2
The term "halogen" refers to fluorine, chlorine, bromine or iodine;
The term "leaving group" refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (e.g., F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals, and the like.
The term "protecting groups" refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, New York, N.Y. 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. Although the specific compounds exemplified in this application may be depicted in a particular sterochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixture thereof are envisioned as part of the invention. The term "pharmaceutically acceptable salts" forming part of this invention includes the salts of carboxylic acids moiety, which can be prepared by reacting the compound with appropriate base to provide corresponding base addition salts. Examples of such base are alkali metal hydroxide including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide. Further, the salts of organic bases, such as lysine, arginine, guanidine, ethanolamine, choline and the like, inorganic bases, e.g., ammonium or substituted ammonium salts are also included. Wherever appropriate, compounds with
pharmaceutically acceptable organic and inorganic acids, e.g., hydro halides, such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts, such as sulphate, nitrate, phosphate, etc.; and alkyl and mono-arylsulphonates, such as ethane sulphonate, toluene sulphonate and benzene sulphonate; and other organic acids and their corresponding salts, such as acetate, tartaratae, maleate, succinate, citrate, etc.
In another aspect, the compounds, disclosed herein, may be prepared by following reaction sequences as depicted in Schemes I, II, III, IV, V and VI.
Scheme I
Figure imgf000017_0001
Formula 10 Formula 12 Formula 13 {Formula 1 when R3 is {Formula 1 when R3 is heteroaryl, L1 is bond} OCONHR, L1 is bond}
The compound of Formula 10 (Path A) and Formula 13 (Path B) can be prepared according to Scheme I. Thus, reacting 4-bromo-nitrobenzene with a compound of
Formula 2 (wherein is aryl or heteroaryl ring and R6 is hydrogen, alkyl, halogen,
alkoxy or halogeno-Ci-C6 alkyl) gives a compound of Formula 3 which on reduction
forms a compound of Formula 4. The reaction of a compound of Formula 4 with alpha - bromolactone gives a compound of Formula 5 which on upon formylation forms a
compound of Formula 6. The compound of Formula 6 on ring opening forms a compound of Formula 7 (wherein Rp is carboxy protecting group, such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC-anhydride) which on reaction with a compound of Formula 8 (wherein is a heteroaryl ring, R5 is same as defined earlier) gives a compound of Formula 9
which finally on deprotection gives a compound of Formula 10. The reaction of a compound of Formula 7 with a compound of Formula 1 1 (where R' is same as defined earlier) gives a compound of Formula 12 which on deprotection give a compound of Formula 13.
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.
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.
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) or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), activated formic ester, ammonium formate in the presence of a solvent selected from, for example, toluene, dimethoxymethane, xylene, or mixture(s) thereof.
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. 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
diisopropylazodicarboxylate (DIAD). 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.
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.
Or alternatively, 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.
Or alternatively, 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.
Or alternatively, 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 I¾, 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.
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.
The deprotection of a compound of Formula 12 to give a compound of Formula 13 can be carried out under similar conditions as described for the compound of Formula 9 to give a compound of Formula 10.
Scheme II
Figure imgf000020_0001
Formula 20 Formula 19 Formula 18
[Formula 1 when R3 is
heteroaryl and L1 is bond]
The compound of Formula 20 can be prepared according to Scheme II. Thus, the
(set Ν 5 alpha halogenation of a compound of Formula 14 (wherein is a heteroaryl ring, R is same as defined earlier) to give a compound of Formula 15 (wherein Hal is F, CI, Br, I) which upon protection gives a compound of Formula 16 (wherein Rp is the same as defined earlier). The reaction of a compound of Formula 16 with a compound of Formula 17 (wherein Ak is Ci-6alkyl and Rk is alkyl, halogen, aryl, heteroaryl) can take place in two ways.
Path C (when ¾ 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 R6 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 R6): 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/Br2, 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.
Or alternatively, 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. The reaction of a compound of Formula 16 with a compound of Formula 17 (Path
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.
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
(Pd(dppf)Cl2), tetrakis(triphenylphosphine) palladium (0) [Pd(Pli3P)4], palladium acetate or dichlorotriphenylphosphine palladium (II), with suitable base selected from, for example, potassium carbonate, sodium acetate, potassium acetate in the presence of solvent selected from, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, toluene, or mixture(s) thereof.
The deprotection of a compound of Formula 19 to give a compound of Formula 20 can be carried out under similar conditions as described for the compound of Formula 9 to give a compound of Formula 10.
The reaction of a compound of Formula 16 with a compound of Formula 17 (Path
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, Ν,Ν'- dimethylformamide, dimethylsulfoxide, or mixture(s) thereof.
Scheme III
Figure imgf000023_0001
Figure imgf000023_0002
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. Thus reacting a compound of Formula 17a (wherein ¾'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 Rp 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 Rp> is hydroxy protecting group). The coupling of a compound of Formula 24 with a compound of Formula 24a (wherein R6 is alkyl, aryl, heteroaryl) 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 Rp 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 COORp): 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.
The 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 carboxy-protection of a compound of Formula 22 to give a compound of Formula 23 can be carried out under similar conditions as described for the compound of Formula 15 to give a compound of Formula 16.
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.
The coupling of a compound of Formula 24 with a compound of Formula 24a to give a compound of Formula 25 can be carried out under similar conditions as for the reaction 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 25 to give a compound of Formula 26 can be carried out using deprotecting agent selected from, for example, boron trifluoride ethearte (BF3.0Et2), HF-pyridine, boron trichloride, boron tribromide, cesium fluoride (CsF), potassium fluoride (KF), «-tetrabutylammonium fluoride, Pd/C in !¾, potassium carbonate in presence of solvent, for example, dichloromethane, N, N-dimethylformamide, acetonitrile, methanol, ethanol, acetone, tetrahydrofuran, or mixture thereof.
The 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.
The 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.
The 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.
The 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 deprotection of a compound of Formula 32 to give a compound of Formula 33 can be carried out as described for the compound of Formula 9 to give a compound of Formula 10.
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 hexafluorophosphate or (benzotriazol-l-yloxy)Zrw-(dimethylamino)phosphonium hexafluorophosphate in the presence of a solvent selected from, for example, N,Ndimethylformamide,
dimethylsulfoxide, acetonitrile, or mixture(s) thereof.
The deprotection of a compound of Formula 35 to give a compound of Formula 36 can be carried out under similar condition as described for the compound of Formula 9 to give a compound of Formula 10.
Scheme IV
Figure imgf000027_0001
Formula 42
Formula 43
{Formula 1 when R3 is heteroaryl, L1 is
bond and R1 is aryl/heteroaryl}
The compound of Formula 43 can be prepared according to Scheme IV. Thus, protecting a compound of Formula 37 (wherein Rp is same as defined earlier) gives a compound of Formula 38 (wherein Rp> is same as defined earlier) which on reaction with a compound of Formula 39 (Wherein R6 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 R5 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.
The protection of a compound of Formula 37 to give a compound of Formula 38 can be carried out under similar conditions as described for the compound of Formula 23 to give a compound of Formula 24.
The 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.
The deprotection of a compound of Formula 40 to give a compound of Formula 41 can be carried out under similar conditions as described for the compound of Formula 25 to give a compound of Formula 26.
The 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.
The deprotection of a compound of Formula 42 to give a compound of Formula 43 can be carried as described for the compound of Formula 9 to give a compound of Formula 10.
Scheme V
Figure imgf000029_0001
gen Formula 49
Formula 45 Formula 46 Formula 47
Figure imgf000029_0002
Formula 52 Formula 51 Formula 50
Formula I
[when R3 is heteroaryl,
L1 is bond and R1 is aryl/heteroaryl]
The compound of Formula 52 can be prepared according to 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 Rp> 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 reaction of 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane with a compound of Formula 44 form a compound of Formula 45 can be carried out under similar condition as for the 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 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.
The protection of a compound of Formula 46 to give a compound of Formula 47 can be carried out under similar conditions as described for the compound of Formula 23 to give a compound of Formula 24.
The 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.
The 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
hypochlorite in presence of 2,2,6,6-tetramethylpiperidine-N-oxyl) (TEMPO), sodium periodate in presence of ruthenium trichloride, potassium dichromate, potassium permanganate, using a solvent selected from, acetonitrile, carbon tetrachloride, water, or mixture(s) thereof. Scheme VI
Figure imgf000031_0001
The compound of Formula 61 can be prepared according to Scheme VI. Thus, protecting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane gives a compound of Formula 53 (wherein Rp 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 reaction of a compound of Formula 58 with a compound of Formula 27 (wherein R5 is same as defined earlier) gives a compound of Formula 59. The compound of Formula 59 on deprotection gives a compound of Formula 60 which on oxidation forms a compound of Formula 61.
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.
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.
The 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 coupling of a compound of Formula 56 with a compound of Formula 2 to give a compound of Formula 57 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 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.
In the above schemes, where specific reagents, for example, bases, acids, solvents, condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, catalysts, etc., as mentioned, is to be understood that other reagents, e.g., other acids, bases, solvents, condensing agents, reducing agent, deprotecting agent, hydrolyzing agents, catalysts, etc., known to one of ordinary skill in the art may be used. Similarly, reaction temperatures and durations may be adjusted according to the desired needs without undue
experimentation and well within the abilities of one of ordinary skill in the art.
The compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally or by parenteral route. Pharmaceutical compositions disclosed herein comprise pharmaceutically effective amounts of compounds described herein formulated together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Solid form preparations for oral administration include capsules, tablets, pills, powder, granules, lozenges, troches, cachets and suppositories. For solid form preparations, active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carrier. Tablets and capsules for oral administration may contain conventional excipients, such as binding agents and/or dissolution enhancers, for example, polyvinyl pyrrolidine, cellulose, mucilage of starch, gelatin, sorbitol, syrup, acacia or tragacanth; fillers or bulking agents, for example, microcrystalline cellulose, sugar, maize -starch, calcium phosphate, sorbitol or lactose; lubricants, for example, talc, silica, polyethyleneglycol, magnesium stearate or stearic acid; disintegrating agents and binder, for example, croscarmellose sodium, pregelatinized starch, sodium starch gylcollate or potato starch; glidants, for example, colloidal silicon dioxide or talc; 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.
General Example
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:
Figure imgf000034_0001
Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In such liquid form preparations, active compounds can be mixed with water or one or more non-toxic solvents, solubilizing agents or emulsifiers, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil, glycerol, fatty acid esters of sorbitan, or mixtures thereof. Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, or mixtures thereof.
Injectable preparations, for example, sterile injections, and aqueous suspensions may be formulated according to methods known to one of ordinary skill in the art, and in particular, using one or more suitable dispersing or wetting and suspending agents.
Acceptable vehicles and solvents that may be employed include one or more of water, Ringer's solution, isotonic sodium chloride, or mixtures thereof. Suppositories for rectal administration of the compound of this invention can be prepared by mixing the drug with suitable nonirritating excipients, such as 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.
Pharmaceutical preparations may be in unit dosage form. In unit dosage form, the preparations can be subdivided into unit doses containing appropriate quantities of active components. Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, sachets, tablets, gels, creams or any combination and number of such packaged forms.
Table I
Figure imgf000035_0001
R2
Formula 1
c R1 L1 R2 R3
No.
1 H3CHO bond -CHO
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
The following examples are set forth to demonstrate general synthetic procedures for the preparation of representative compounds of the present invention. The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention. Experimental
Various solvents, for example, dimethylformamide, benzene, tetrahydrofuran, etc., were dried using various drying reagents according to procedure as described in the literature.
Synthesis of intermediate
Synthesis of 6-methyl-l,2,3-benzotriazin-4(3H)-one
The title compound was prepared following the procedure outlined in J. Med. Chem., 35(14), p. 2626-2630 (1992).
The following analogues of benzotriazin-4(3H)-one were prepared analogously:
7-Methoxy- 1 ,2,3-benzotriazin-4(3H)-one
7-(Trifluoromethyl)- 1 ,2,3-benzotriazin-4(3H)-one;
7-Methyl- 1 ,2,3-benzotriazin-4(3H)-one;
6- Methoxy- 1 ,2,3-benzotriazin-4(3H)-one;
5-Chloro- 1 ,2,3-benzotriazin-4(3H)-one;
7- Chloro- 1 ,2,3-benzotriazin-4(3H)-one;
5-Methoxy- 1 ,2,3-benzotriazin-4(3H)-one;
5- Fluoro- 1 ,2,3-benzotriazin-4(3H)-one;
8- Methoxy- 1 ,2,3-benzotriazin-4(3H)-one;
6- Fluoro- 1 ,2,3-benzotriazin-4(3H)-one.
Synthesis of 5-methyl-lH-isoindole-1.3(2H)-dione
The title compound was prepared following the procedure outline in Chem. Ber. 1877, 10, 1 163.
Synthesis of 4-(1.3-dioxo-1.3-dihvdro-2H-isoindol-2-yl)butanoic acid
To a solution of γ-aminobutyric acid (20.68 g, 0.199 moles) and phthalic anhydride (29.6 g, 0.199 moles) in toluene (300 mL) was added triethylamine (3 mL, 0.0215 moles) and heated at 110°C for aboutl 8 hours. After completion, the reaction mixture was allowed to cool to room temperature. The reaction mixture was washed with IN HC1 solution (20 mL) at 40°C and solid was crystallized out from organic layer. The residues was filtered, washed with water and dried under vacuum overnight to get desired product. Yield: 31.64 g
LCMS: 234.2 (M+l)
Synthesis of N-(4-bromophenyl)methane sulfonamide
To a solution of 4-bromoaniline (100 g, 581 mmoles) in dichloromethane (75 mL) and pyridine (75 mL) was slowly added methanesulphonyl chloride (99 g, 872 mmoles). The reaction mixture was allowed to stir for about one hour at the same temperature. After one hour, dilute hydrochloric acid was added to the reaction mixture to remove pyridine. The organic layer was collected, dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using 60% ethyl acetate: hexane as eluent to afford a desired compound.
Yield: 1 10 g
LCMS: 267.03, 268.97 (M+Na)
Synthesis of N-r4-(4-methylphenoxy)phenyl1methane sulfonamide
To a solution of 4-(4-methylphenoxy)aniline (3.5 g, 17.6 mmoles) in pyridine (20 mL) and dichloromethane (20 mL) at 0°C was added methanesulfonyl chloride (2.2 mL, 26.4 mmoles). The reaction mixture was allowed to stir at room temperature for about 2 hours. After completion of reaction, pyridine was evaporated and the reaction mixture was extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous sodium sulphate and evaporated to get a crude product. The crude product obtained was purified on silica gel column using 25% ethyl acetate: hexane as eluent to get desired compound.
Yield: 3.1 g
The following compound can be prepared accordingly: N-(4-Methoxyphenyl) methanesulfonamide. Synthesis of benzyl 2.4-dihydroxybutanoate
To a solution of oc-hydroxylactone (10 g, 0.098 moles) in methanol (50 mL) was added sodium hydroxide (5.88 g, 0.147 moles) in water (10 mL) and allowed to stir at room temperature for about one hour. The reaction mixture was concentrated and taken in N, N'-dimethylformamide (40 mL) and benzyl bromide (14 mL, 0. 1 17 moles) was added drop wise. The reaction mixture was again allowed to stir for overnight at room temperature. After completion of reaction, solvent was evaporated under vacuum and the reaction mixture was extracted with ethyl acetate. 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.
Yield: 10.4 g
LCMS: 21 1.47 (M+l), 233.5 (M+Na)
Synthesis of N-(biphenyl-4-yl)methanesulfonamide
To the solution of 4-biphenyl amine (1 g, 0.0059 moles) in dimethylformamide (10 mL) was added potassium carbonate (1.63 g, 0.01 18 moles) and stirred for about 10 minutes and then methanesulfonyl chloride (3.64 mL, 0.0472 moles) was added slowly. The reaction mixture was allowed to stir at room temperature for about 30 minutes. After completion, the reaction mixture was extracted with ethyl acetate while washing with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product which was purified on silica gel column to get desired product.
Yield: 0.75 g Synthesis of tert-butyl 4- (r4-hvdroxy-l-oxo-l-rprop-2-en-l -yloxy butan-2-yl1 (methyl sulfonyDamino } benzoate
Step a: Preparation of tert-but \ 4-nitrobenzoate
To a solution of / nitrophenol (10 g, 59.88 mmoles) in ZerZ-butanol (100 mL) and tetrahydrofuran (100 mL) were added N,N-dimethylaminopyridine (1.4 g, 1 1.97 mmoles) and Boc anhydride (38.4 mL, 179.64 mmoles) at room temperature. The reaction mixture was allowed to stir for about 10 hours at room temperature. The temperature was increased slowly to 35°C and reaction mixture was stirred for about 6 hours. After completion, solvent was evaporated under reduced pressure and reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and evaporated under vacuum to get a crude product. The crude product was purified on silica gel column using 20% ethyl acetate: hexane as eluent to get desired compound.
Yield 12 g
Step b: Preparation of tert-but \ 4-aminobenzoate
To a solution of compound obtained from Step a (1 1 g) in tetrahydrofuran (50 mL) and methanol (50 mL) was added 10% Pd/C (3 g) and ¾ was supplied at 60 psi in Pan- apparatus for about 2 hours. After completion, reaction mixture was filtered through celite pad and residue was washed with ethyl acetate. The filtrate obtained was concentrated under vacuum to get the desired compound.
Yield: 10 g.
LCMS: 194.47 (M+l)
Step c: Preparation of tert-but \ 4- [(methylsulfonyl)amino] benzoate
To an ice cooled solution of compound obtained from Step b (10 g, 51.81 mmoles) in pyridine (50 mL) and dichloromethane (50 mL) was added methanesulphonyl chloride (8.86 g, 77.72 mmoles). The reaction mixture was allowed to stir for about one hour at same temperature. After one hour, HC1 (1 1 N) solution was added to bring the pH of the reaction mixture to neutral and then extracted with ethyl acetate. 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 50% ethyl acetate: hexane as eluent to get desired product.
Yield: 10 g
LCMS: 293.76 (M+Na)
Step d: Preparation of tert-but \ 4-[(methylsulfonyl)(2-oxotetrahydrofuran-3- yl)amino] benzoate
To an ice cooled solution alpha-hydroxy lactone (1 g, 9.80 mmoles) in tetrahydrofuran (30 mL) were added compound obtained from Step c (2.6 g, 9.80 mmoles) and triphenylphosphine (13.6 g, 14.70 mmoles). The reaction mixture was stirred for about 15 minutes and diisopropylazodicarboxylate (DIAD) (2.9 g, 14.70 mmoles) was added at same temperature. The reaction mixture was allowed to stir for about 2 hours at room temperature. After complete conversion of starting material, solvent was evaporated under vacuum to obtain a crude compound. The crude compound was purified on silica gel column using 30% ethyl acetate: hexane as elutent to get the desired product.
Yield: 6 g
LCMS: 354.82 (M).
Step e: Preparation of A,-[4-(teri-butoxycarbonyl)phenyl]-A'-(methylsulfonyl) homoserine
To an ice-cooled solution of compound obtained from Step d (4 g, 1 1.26 mmoles) in ethanol (30 mL) and methanol (10 mL) was added sodium hydroxide (0.495 g, 12.39 mmoles) in water (5 mL). The reaction mixture was allowed to stir at same temperature for about 30 minutes. After 30 minutes, solvent was evaporated and reaction mixture was extracted with ethyl acetate while washing with water. The aqueous layer was acidified with aqueous solution of sodium bisulfate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and evaporated to get desired compound.
Yield: 3g Step f: Preparation of tert-buty\ 4-{[4-hydroxy-l-oxo-l-(prop-2-en-l-yloxy)butan-2- yl](methylsulfonyl)amino}benzoate
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.
Yield: 1.4 g.
LCMS: 413.87 (M+l).
Synthesis of prop-2-en-l-yl N-(4'-chlorobiphenyl-4-yl)-N-(methylsulfonyl)homoserinate Step a: Preparation of A'-(4,-chlorobiphenyl-4-yl)methanesulfonamide
To a solution of N-(4-bromophenyl)methanesulfonamide (2 g, 0.008 moles) in N,
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.
Yield: 1.8 g
Step b: Preparation of A'-(4,-chlorobiphenyl-4-yl)-A'-(2-oxotetrahydrofuran-3- yl)methane sulfonamide
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.
Yield: 10 g
LCMS: 365.71 (M+l)
Step c: Preparation of A'-(4,-chlorobiphenyl-4-yl)-A'-(methylsulfonyl)homoserine
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.
Yield: lOg
Step d: Preparation of prop-2-en-l-yl A'-(4,-chlorobiphenyl-4-yl)-A'-(methylsulfonyl) homoserinate
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. The organic layer was collected, washed with water, brine, dried over anhydrous sodium sulphate solution 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 title compound. Yield: 5.2 g
Example 1 : Synthesis of 2-[formyir4'-methylbiphenyl-4-yl aminol-4-r6-methyl-4-oxo- 1.2.3-benzo triazin-3(4H)-yl)butanoic acid (Compound no. 1) (Scheme I. Path A)
Step a: Preparation of 4-methyl-4'-nitrobiphenyl
To a solution of 4-bromo-nitrobenzene (5 g, 0.0247 moles) in N,N- dimethylformamide (25 mL) were added potassium carbonate (10.2 g, 0.0741 moles) and 4-methylboronic acid (4 g, 0.0297 moles) under argon atmosphere and heated at 100°C for about 3 hours. After completion, reaction mixture was quenched by addition of water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under vacuum to get a crude product which was purified on silica gel column using 15% ethyl acetate: hexane as eluent to obtain desired compound. Yield: 5.3 g
LCMS: 236.07 (M+23)
Step b: Preparation of 4'-methylbiphenyl-4-amine
To a solution of compound obtained from Step a (5.2 g, 0.0244 moles) in tetrahydrofuran (25 mL) and methanol (25 mL) was added 10% Pd/C (5.2 g) under vacuum and then hydrogen gas was supplied by balloon. The reaction mixture was allowed to stir for about 2 hours at room temperature. After completion, reaction mixture was filtered through celite pad and filtrate was concentrated under vacuum to obtained title compound. Yield: 5 g
LCMS: 184.01 (M+l)
Step c: Preparation of 3-[(4'-methylbiphenyl-4-yl)amino]dihydrofuran-2(3 )-one
To alpha-bromo lactone (3 g, 0.018 moles) was added compound obtained from Step b (4.9 g, 0.027 moles) and heated to 100°C to 1 10°C for about 3 hours. After completion consumption of starting material, reaction mixture was evaporated under reduced pressure and purified on silica gel column using 20% ethyl acetate: hexane as eluent to get desired compound.
Yield: 4 g
LCMS: 268.1 1 (M+l) Step d: Preparation of A'-(4,-methylbiphenyl-4-yl)-A'-(2-oxotetrahydrofuran-3- yl)formamide
To a solution of compound obtained from Step c (2 g, 0.00749 moles) in toluene (30 mL) was added formic acid (0.4 g, 0.0089 moles) and reflux for about 9 hours. After complete, reaction mixture was evaporated under reduced pressure to get a crude product which was purified over silica gel column using 15% ethyl acetate: hexane as eluent to obtain title compound.
Yield: 1.9 g
LCMS: 295.94 (M+l)
Step e: Preparation of methyl A'-formyl-7V-(4,-methylbiphenyl-4-yl)homoserinate
To a solution of compound obtained from Step d (1.9 g, 0.0064 moles) in N,N- dimethylformamide (4 mL) and water (1 mL) was added sodium hydroxide (0.309 g, 0.0077 moles) and stirred for about 30 minutes at room temperature. After 30 minutes sodium bicarbonate (0.624 g, 0.0074 moles), 18-crown-6 (0.168 g, 0.00064 moles) amd methyl iodide (1.3 g, 0.0914 moles) was added to the reaction mixture and again stirred for overnight at room temperature. After completion, reaction mixture was quenched by addition of water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product which was purified on silica gel column using 8% ethyl acetate: hexane as eluent. Yield: 2.1 g
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
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. The organic layer was separated, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude compound which was purified on silica gel column using 7% ethyl acetate: hexane as eluent to get desired product.
Yield: 0. 15 g
LCMS: 470 (M+l)
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
To a compound obtained from Step f (0.15 g, 0.0003 moles) in tetrahydrofuran (5 mL) and methanol (5 mL) was added solution of lithium hydroxide (0.018 g, 0.0004 moles) in water (1 mL). The reaction mixture was allowed to stir for about one hour at room temperature. After completion, the reaction mixture was acidified with sodium bisulphate solution (pH~2) and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to get crude compound which was purified by preparative TLC using 10% methanol: dichloromethane as mobile phase. Yield: 0.030 g
LCMS-455.35 (M-l)
¾ NM (400 MHz) δ 8.40 (1H, s), 8.03-8.05 (1H, m), 7.87 (2H, m), 7.61 -7.63 (2H, m), 7.52-7.54 (2H, m), 7.40-7.42 (2H, m), 7.24-7.26 (2H, m), 4.84 (1H, m), 4.39 (2H, m), 2.51 (2H, m), 2.28-2.33 (6H, m).
The following compounds can be prepared by following the above synthetic route.
4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[formyl(4'-methylbiphenyl-4- yl)amino]butanoic acid (Compound no. 2);
LCMS-447.23 (M-28)
2-[(4'-Ethylbiphenyl-4-yl)(formyl)amino]-4-(5-methyl-4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 3).
LCMS-469.34 (M-1)
Example 2: Synthesis of 0-[(4-fluorophenyl)carbamoyll-N-formyl-N-(4'-methylbiphenyl- 4-yl)homoserine (Compound no. 4) (Scheme L Path B)
Step a: Preparation of methyl 0-[(4-fluorophenyl)carbamoyl]-A'-formyl-A'-(4,-methyl biphenyl-4-yl)homoserinate To 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. The 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.
Yield: 0.15 g
LCMS: 464.93 (M+l)
Step b: Preparation of^M^-fluorophenylJcarbamoyll-A^-formyWV-^'- methylbiphenyl-4-yl)homoserine
To a compound obtained from Step a (0.15 g, 0.0003 moles) in tetrahydrofuran (5 mL) and methanol (5 mL) was added solution of lithium hydroxide (0.018 g, 0.0004 moles) in water and stirred for about one hour at room temperature. After completion, the reaction mixture was acidified with sodium bisulfite (pH~2) and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated under vacuum to get crude compound which was purified by preparative TLC using 10% methanol: dichloromethane as mobile phase to obtain a desired product. Yield: 0.03 g
LCMS-449.28 (M-l)
¾ NMR (400 ΜΗζ)-δ 9.63 (1H, s), 8.45(1H, s), 7.67-7.69 (2H, m), 7.53-7.55 (4H, m), 7.26-7.28 (2H, m), 7.12-7.14 (4H, m), 4.89-4.93 (1H, m), 4.06-4.10 (2H, s), 2.45 (2H, m), 2.41-2.43 (3H, m).
The following compounds can be prepared by following the above synthetic route.
N-Formyl-N-(4'-methylbiphenyl-4-yl)-0-[(4-methylphenyl)carbamoyl]homoserine (Compound no. 5);
LCMS-417.27 (M-28) O- [(3 ,4-Dichlorophenyl)carbamoyl] -N-formyl-N-(4'-methylbiphenyl-4- yl)homoserine (Compound no. 6);
LCMS-501.15 (M)
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0- { [4-(propan-2- yl)phenyl]carbamoyl}homoserine (Compound no. 7);
LCMS-487.35 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-0-[(3-fluorophenyl)carbamoyl]-N-formylhomoserine (Compound no. 8);
LCMS-463.33 (M-l)
0-[(2,4-Difluorophenyl)carbamoyl]-N-(4'-ethylbiphenyl-4-yl)-N- formylhomoserine (Compound no. 9);
LCMS-481.32 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-0-[(2-fluorophenyl)carbamoyl]-N-formylhomoserine Compound no. 10);
LCMS-463.33 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-<9- { [4-
(trifluoromethyl)phenyl]carbamoyl}homoserine (Compound no. 1 1);
LCMS-513.32 (M-1)
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0-[(2-methylphenyl)carbamoyl]homoserine (Compound no. 12);
LCMS-459.33 (M-l)
N-(4'-Ethylbiphenyl-4-yl)-0-[(4-ethylphenyl)carbamoyl]-N-formylhomoserine (Compound no. 13);
LCMS-473.30 (M-1)
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0-[(4-methoxyphenyl)carbamoyl]homoserine (Compound no. 14);
LCMS-475.35 (M-l)
0-[(2,6-Dichlorophenyl)carbamoyl]-N-(4'-ethylbiphenyl-4-yl)-N- formylhomoserine (Compound no. 15);
LCMS-515.29 (M-1)
Example 3: Synthesis of 4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-r(4'- methoxybiphenyl-4-yl) (methyl) amino "Ibutanoic acid (Compound no. 18); (Scheme II,
Path C)
Step a: Preparation of 2-bromo-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoic acid To a solution of 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. To this reaction mixture, bromine (40 mL, 0.792 mole) was added slowly over a period of about one hour and again heated up to 60°C for about 8 hours then cooled to 0°C. After that, water (50 mL) was added to the reaction mixture. 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.
Yield: 10.8 g
LCMS: 313.4 (M+l)
Step b: Preparation of tert-but \ 2-bromo-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl) butanoate
To a solution of compound obtained from Step a (180 mg, 0.576 mmoles) in tetrahydrofuran (5 mL) was added Boc anhydride (1 mL, 0.461 mmoles) and N,N- dimethylaminopyridine (7 mg, 0.057 mmoles). The reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of reaction, solvent was azeotropically distilled using toluene and ethyl acetate to obtain a crude product. The crude product was purified on silica gel column using 20% ethyl acetate: hexane as eluent to get the desired product.
Yield: 180 mg
Step c: Preparation of tert-buty\ 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoate
To a solution of N-(4-bromophenyl)methanesulfonamide (1 g, 0.04 moles) in acetonitrile (20 mL) was added potassium carbonate (0.276 g, 0.002 moles) at room temperature. The reaction mixture was allowed to stir for about 15 minutes and then compound obtained from Step b (1.472 g, 0.004 moles) was added. The reaction mixture was heated at about 80°C for about 56 hours. After completion, the reaction mixture was concentrated and residue obtained was taken in ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified by preparative TLC using 30% ethyl acetate: hexane as mobile phase to get the desired product.
Yield: 1.7 g
LCMS: 555.9 (M+NH4 +)
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
To a solution of a compound obtained from Step c (0.205 g, 0.381 moles) in dry NN-dimethylformamide (5 mL) were added tetrakistriphenylphosphine (8 mg, 0.007 moles), potassium carbonate (0.21g, 1.527 moles) and 4-methoxyphenylboronic acid (0.191 g, 1.259 moles) at room temperature. The reaction mixture was heated to 105°C for about 4.5 hours. After 4.5 hours, it was allowed to cool to room temperature and N, N-dimethylformamide was evaporated and residues obtained were taken in ethyl acetate. The organic layer was washed with water, brine and evaporated under vacuum to get crude product which was purifiedby preparative TLC using 30% ethyl acetate: hexane as mobile phase to get desired product.
Yield: 0.161 g
LCMS: 587.1 (M+Na)
Step e: Preparation of 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-[(4'- methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid
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:
hexane as eluent to get desired product.
Yield: 0.1 13 g
LCMS: 509.1 (M+l) *H NMR (CDCI3, 400 MHz) δ: 7.84 (2H, m), 7.71 (2H, m), 7.62 (4H, m), 7.51 (2H, d, J = 8 Hz), 6.97 (2H, d, J= 8 Hz), 5.04 (1H, m), 4.12 (2H, m), 3.85 (3H, s), 3.13 (3H, s), 2.36 (lH, m), 1.95 (lH, m).
Example 4: Synthesis of 2-rbiphenyl-4-yl(methylsulfonyl)amino1-4-(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)butanoic acid (Compound no. 16) (Scheme II. Path D)
Step a: Preparation of tert-but \ 2-[biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3- dioxo-l,3-dihydro-2H-isoindol-2-yl)butanoate
To a solution of tert-butyl 2-bromo-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl) butanoate (300 mg, 0.815 mmoles) in N, N-dimethylformamide (5 mL) were added N- (biphenyl-4-yl)methanesulfonamide (161 mg, 0.652 mmoles) and potassium carbonate (1 12 mg, 0.815 mmoles). The reaction mixture was heated at 80°C for about 7.5 hours. After completion, reaction mixture was allowed to cool to room temperature and water was added to it. The reaction mixture was extracted with ethyl acetate. 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.
Yield: 152 mg
LCMS: 552.1 (Μ+ΝΗ4 +)
Step b: Preparation of 2-[biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)butanoic acid
To an ice-cooled solution of compound obtained from Step a (152 mg, 0.0002 moles) in dichloromethane (10 mL) was added trifluoroacetic acid (0.7 mL) and stirred for about 2.5 hrs at room temperature. After completion of reaction, the solvent was evaporated and the reaction mixture was taken in dichloromethane and washed with water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to get crude product. The crude product was purified on silica gel column using 40% ethyl acetate: hexane as eluent to get desired product.
Yield: 41.6 mg LCMS: 479.0 (M+l)
*H NMR (MeOH-d6, 400 MHz): δ 7.85 (4H, m), 7.78 (4H, m), 7.63 (2H, m), 7.45 (2H, m), 7.36 (1H, m), 4.88 (1H, m), 3.86 (2H, m), 3.15 (3H, s), 2.36 (1H, m), 1.89 (1H, m).
The following compounds can be prepared by following the above synthetic route. 4-(l ,3-Dioxo- l ,3-dihydro-2H-isoindol-2-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 17);
LCMS: 510.1 (M+1)
Example 5: Synthesis of 2- {r4-(6-methoxypyridin-3-yl)phenyl1(methylsulfonyl)amino} - 4-(4-oxo- l ,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 19) (when Ry is halogen) (Scheme III, Path E)
Step a: Preparation of A'-(4-bromophenyl)-A'-(2-oxotetrahydrofuran-3- yl)methanesulfonamide
To a solution of oc-hydroxy lactone (673 mg, 0.0072 moles) at 0°C were added N- (4-bromophenyl)methanesulfonamide (1.5 g, 0.006 moles) and triphenylphosphine (2.35 g, 0.009 moles). The reaction mixture was allowed to stir for aboutl 5 minutes at 0°C and diisopropylazodicarboxylate (1.8 g, 0.0009 moles) was added. The reaction mixture was again stirred for about 30 minutes at 0°C. After completion, the reaction mixture was concentrated to get a crude product which was purified on silica gel column using 40% ethyl acetate: hexane as eluent to get the desired compound.
Yield: 920 mg
LCMS: 351.18 and 353.12 (Μ+ΝΗ4 +)
Step b: Preparation of sodium 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-hydroxy butanoate
To a solution of compound obtained from Step a (1.5g, 0.0044 moles) in methanol (10 mL) was added sodium hydroxide (79 mg, 0.0044 moles) and stirred for about one hour at room temperature. After completion, the reaction mixture was concentrated and ethyl acetate was added and decanted to get the desired product.
Yield: 850 mg. Step c: Preparation of benzyl A'-(4-bromophenyl)-A'-(methylsulfonyl)homoserinate
To a solution of compound obtained from Step b (800 mg, 0.0022 moles) in N, N- dimethylformamide (5 mL) at 0°C was added benzyl bromide (388 mg, 0.0022 moles). The reaction mixture was allowed to stir for overnight at room temperature. After completion, reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulphate and concentrated to get crude product. The crude product so obtain was purified on silica gel column using 70% ethyl acetate: hexane to get desired product.
Yield: 850 mg.
Step d: Preparation of benzyl N-(4-b romophenyl)-6>- [to*f-butyl(dimethyl)silyl]-A'- (methylsulfonyl)homoserinate
To a solution of compound obtained from Step c (800 mg, 0.0018 moles) in N,N- dimethylformamide (8 mL) were added Ze^butyldimethylsilylchloride (325 mg, 0.0021 moles) and imidazole (369 mg, 0.0054 moles). The reaction mixture was allowed to stir for about one hour at room temperature. After completion, reaction mixture was quenched by addition of water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford the desired product.
Yield: 1.2 g
LCMS: 556.77 and 558.78 (M+l)
Step e: Preparation of benzyl 0-[teri-butyl(dimethyl)silyl]-A'-[4-(6-methoxypyridin-3- ylJphenyll-A^methylsulfonyr^homoserinate
To a solution of compound obtained from Step d (1.7 g, 0.0045 moles) in N, N- dimethylformamide (20 mL) were added 5-methoxypyridineboronic acid (929 mg, 0.0061 moles), tetrakis triphenylphosphine palladium (0) (176 mg, 0.0008 moles) and potassium carbonate (1.26 g, 0.0091 moles). After completion of addition, reaction mixture was heated up to 1 10°C for about 3 hours. After 3 hours, solvent was evaporated and reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was collected, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product obtained was purified on silica gel column using 40% ethyl acetate to get desired product.
Yield: 1.3 g
Step f: Preparation of benzyl iV-[4-(6-methoxypyridin-3-yl)phenyl]-iV- (methylsulfonyl) homo serinate
To a solution of compound obtained from Step e (1.1 g, 0.0019 moles) in dichloromethane (20 mL) was added boron trifluoride etherate BF3.0Et (1.1 g, 0.0095 moles) slowly at room temperature. The reaction mixture was allowed to stir at room temperature for about one hour. After completion, reaction mixture was quenched with saturated solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to get crude product. The crude product was purified on silica gel column using 40% ethyl acetate: hexane as eluent to get desired product.
Yield: 750 mg
LCMS: 471.30 (M+l)
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
To a solution of compound obtained from Step f (250 mg, 0.531 mmoles) in tetrahydrofuran (15 mL) at 0°C were added benzotriazinone (78 mg, 0.531 mmoles) and triphenylphosphine (278 mg, 1.063 mmoles). The reaction mixture was allowed to stir for about 15 minutes at 0°C and diisopropylazodicarboxylate (161 mg, 0.797 mmoles) was added at same temperature. The reaction mixture was again stirred for about one hour at same temperature. After completion of reaction, solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified on silica gel column using 40% ethyl acetate: hexane to get desired product.
Yield: 200 mg.
LCMS: 600.88 (M+l) Step h: Preparation of 2-{[4-(6-methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}- 4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid
To a solution compound obtained from Step g (200 mg) in tetrahydrofuran (10 mL) was added 10% Pd/C (200 mg) and hydrogen was supplied at 55 psi in Parr apparatus for about 8 hours at room temperature. After completion, reaction mixture was filtered through celite pad and residue was washed with 20% methanol: dichloromethane. The filtrate was concentrated to get solid material which was treated with ethyl acetate. The ethyl acetate layer was decanted to get desired product.
Yield: 18 mg
LCMS: 510.70 (M+l)
*H NMR (DMSO-d6, 400 MHz) δ: 8.52 (1H, s), 8.25 (1H, d, J= 8 Hz), 8.18 (1H, d, J= 8 Hz), 8.05 (2H, m), 7.92 (1H, m), 7.76 (2H, d, J= 8 Hz), 7.66 (2H, d, J= 8Hz), 6.92 (1H, d, J= 8 Hz), 4.48 (3H, m), 3.90 (3H, s), 3.29 (3H, s), 2.3 (1H, m), 1.90 (1H, m).
The following compounds can be prepared by following the above synthetic route. 4-(7-Methoxy-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 20);
LCMS: 540.71 (M+l)
2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-[4-oxo-7- (trifluoro methyl)-l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 21); LCMS: 578.74 (M+l)
Example 6: Synthesis of 2-r(4-methoxyphenyl)(methylsulfonyl)aminol-4-(4-oxo- 1.2.3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 32) (Scheme III. Path F)
Step a: Preparation of benzyl 2-[(4-methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoate
To a solution of benzyl N-(4-methoxyphenyl)-N-(methylsulfonyl)homoserinate
(200 mg, 0.508 moles) in tetrahydrofuran (15 mL) were added triphenylphosphine (200 mg, 0.763 moles) and benzotriazinone (82 mg, 0.550 moles) at 0°C. The reaction mixture was stirred for about 15 minutes and diisopropylazodicarboxylate (154 mg, 0.763 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 get a crude product which was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired compound.
Yield: 180 mg
Step b: Preparation of 2-[(4-methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid
To a compound obtained from Step a (180 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) was added 10% Pd/C (60 mg) and hydrogen gas was supplied on Pan- apparatus at 50 psi for about one hour at room temperature. After one hour, the reaction mixture was filtered through celite pad and residue obtained was washed with 10% methanol: dichloromethane. The filtrated was concentrated under reduced pressure to get desired compound.
Yield: 24 mg
LCMS: 433. 69 (M+l)
1H NMR (MeOD, 400 MHz): δ 8.31 (1H, d, J= 8 Hz), 8.14 (1H, d, J= 8 Hz), 8.03 (1H, m), 7.88 (1H, m), 7.58 (2H, d, J = 8 Hz), 6.92 (2H, d, J= 8 Hz), 4.92 (1H, m), 4.57-4.67 (2H, m), 3.79 (3H, s), 3.14 (3H, s), 2.48 (1H, m), 2.02 (1H, m).
The following compounds can be prepared by following the above synthetic route.
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4-methylphenoxy) phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 23);
LCMS: 539.84 (M+l)
4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4-methylphenoxy) phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 24);
LCMS: 523.78 (M+l)
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-[4-oxo-7- (trifluoromethyl)-l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 25);
LCMS: 572.86 (M+l)
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 26);
LCMS: 509.74 (M+l)
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(4-methoxyphenyl) (methylsulfonyl)amino]butanoic acid (Compound no. 33);
LCMS: 463.79 (M+l) 4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-[(4- methoxyphenyl)(methylsulfonyl)amino]butanoic acid (Compound no. 34);
LCMS: 433.63 (M+l)
2- [(4-Methoxyphenyl)(methylsulfonyl)amino] -4-(5 -methyl- 1 ,3 -dioxo- 1 ,3 -dihydro- 2H-isoindol-2-yl)butanoic acid(Compound no. 35);
LCMS: 469.70 (M+l)
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4-methylphenoxy) phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 36);
LCMS: 539.84 (M+l)
4-(5-Methyl- 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2- { [4-(4- methylphenoxy)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 37);
LCMS: 523.85 (M+l)
2-[(Methylsulfonyl)(phenyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 58);
LCMS: 402.85 (M+l)
4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(4- chlorophenyl)(methylsulfonyl)amino]butanoic acid (Compound no. 104);
LCMS: 473.67 (M+l)
2-[(4-Bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 105);
LCMS: 481.54 and 483.51 (M+l)
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 106);
LCMS: 437.33 (M+l)
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 107);
LCMS: 451.70 (M+l)
2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 108);
LCMS: 467.75 (M+l)
Example 7: Synthesis of 2-r(4'-chlorobiphenyl-4-yl)(methylsulfonyl)amino1-4-(5-methyl- 1,3 -dioxo- L3-dihydro-2H-isoindol-2-yl)butanoic acid (Compound no. 59) (Scheme III, Path G)
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 To a solution of hydroxyl derivative (0.250 g, 0.591 moles) in tetrahydrofuran (10 mL) were added triphenylphosphine (0.232 g, 0.88 moles) and 4-methyl phthalimide (0.104 g, 0.65 moles) at 0°C. The 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.
Yield: 0.25 g.
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
To a compound obtained from Step a (250 mg, 0.441 moles) in acetonitrile (10 mL) at 0°C was added tetrakis triphenylphosphine (51 mg, 0.044 moles) and morpholine (384 mg, 4.4 moles). The reaction mixture was allowed to stir for about 3 hours at 0°C. After 3 hours, the reaction mixture was diluted by addition of water and extracted with ethyl acetate. The aqueous layer obtained was acidified with sodium bisulphite 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 get a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as mobile phase to get desired product.
Yield: 35 mg
LCMS: 526.84 (M+l)
*H NMR (MeOH-d6, 400 MHz) δ: 7.78 (2H, d, J= 8 Hz), 7.70 (1H, d, J= 4Hz), 7.61 (6H, m), 7.43 (2H, m), 4.73 (1H, m), 3.72-3.90 (2H, m), 3.20 (3H, s), 2.48 (3H, s), 2.31 (1H, m), 1.77 (1H, m).
The following compounds can be prepared by following the above synthetic route.
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-chloro-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 60);
LCMS: 546.66 (M)
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-chloro-4-oxo-l,2,3- benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 61); LCMS: 546.73 and 548.68 (M+l
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 62);
LCMS: 526.70 and 528.72 (M+l)
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-(trifluoromethyl)- 1,2,3-benzo triazin-3(4H)-yl]butanoic acid (Compound no. 63);
LCMS: 580.74 (M+l)
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methoxy-4-oxo- 1,2,3- benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 64);
LCMS: 542.76 (M+l)
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-fluoro-4-oxo- 1,2,3- benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 65);
LCMS: 530.73 (M+l)
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(l-methyl-2,4-dioxo-l,4- dihydro quinazolin-3(2H)-yl)butanoic acid (Compound no. 66);
LCMS: 543.6 (M+l)
Example 8: Synthesis of 2-r i4-r(4-methylphenyl)carbamoyl1phenyl}(methylsulfonyl) aminol-4-(4-oxo-1.2.3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 68) Scheme III, Path Η)
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
To a solution of hydroxyl derivative (1.4 g, 3.389 mmoles) in tetrahyrofuran (20 mL) at 0°C were added triphenylphosphine (1.77g, 6.779 mmole) and 1,2,3-benzotriazin- 4(3H)-one (0.498 g, 3.389 mmole) after 5 minutes at the same temperature
diisopropylazodicarboxylate (1.027 g, 5.084 mmole) was added. Then, the reaction mixture was stirred for 30 minutes at the same temperature. Solvent was evaporated and purification was performed on silica gel 60- 120 mesh column using 40% EtOAc:Hexane as eluent to get 3 gm of product.
LCMS: 542.83 (M+l)
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
To a solution of compound obtained from Step a (3 g, 5.535 mmoles) in dichloromethane (30 mL) was added trifluoroacetic acid (6 mL, 28.782 mmol) at room temperature. The reaction mixture was allowed to stir for about 2 hours at the same temperature. After 2 hours, the solvent was evaporated and the reaction mixture was neutralized by aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over anhydrous sodium sulphate and evaporated under vacuum to get desired product.
Yield: 1 g
LCMS: 486.78 (M+l)
The following compounds can be prepared by following the above synthetic route.
4- {(Methylsulfonyl) [ 1 -oxo-4-(4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)- 1 -(prop-2-en- 1 - yloxy)butan-2-yl]amino}benzoic acid (Compound no. 67);
LCMS: 486.78 (M+l)
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
To an ice-cooled solution of compound obtained from Step b (400 mg, 0.823 mmoles) in N, N'-dimethylformamide (20 mL) were added / toludine (88 mg, 0.823 mmoles), l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.234 mmoles), N, N'-dimethylaminopyridine (20 mg, 0.164 mmoles) and hydroxybenzotriazole (1 1 1 mg, 0.823 mmoles). The reaction mixture was allowed to stir at room temperature for 12 hours. After completion, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate. 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.
Yield: 520 mg
Step d: Preparation of 2-[{4-[(4-methylphenylkarbamoyllphenylKmethylsulfonyl) amino I -4-(4-oxo-l ,2,3-benzotriazin-3(4 )-yl)butanoic acid
To an ice-cooled solution of compound obtained from Step c (520 mg, 0.904 mmoles) in acetonitrile (25 mL) were added tetrakis triphenylphosphine palladium (0) (208 mg, 0.180 mmoles) and morpholine (786 mg, 9.043 mmoles). The reaction mixture was allowed to stir at same temperature for about 30 minutes. After 30 minutes, the solvent was evaporated and the reaction mixture was acidified using aqueous solution of sodium bisulphate and 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 preparative TLC using 10% methanol: dichloromethane as mobile phase to get desired compound.
Yield: 250 mg.
LCMS: 535.84 (M+l), 557.82 (M+Na)
¾ NMR (DMSO-d6, 400 MHz): δ 10.3 (1H, s), 8.25 (2H, m), 8.20 (1H, m), 8.06-8.10 (3H, m), 7.96 (4H, m), 7.15 (2H, d, J = 8 Hz), 4.78 (1H, m). 4.51 (2H, m), 3.16 (3H, s), 2.42 (1H, m), 2.20 (3H, s), 1.95 (lH, m).
The following compounds can be prepared by following the above synthetic route.
2-[ {4-[(4-Chlorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- 1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound no. 69);
LCMS: 555.74 and 557.72 (M+l)
2- {(Methylsulfonyl)[4-(phenylcarbamoyl)phenyl]amino} -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 70);
LCMS: 521.80 (M+l)
2-[ {4-[(3-Fluorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound no. 71);
LCMS: 539.74 (M+l)
2-[(Methylsulfonyl)(4- {[4-(propan-2-yl)phenyl]carbamoyl}phenyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 72);
LCMS: 563.80 (M+l)
2-[ {4-[(4-Methoxyphenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- 1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound no. 73);
LCMS: 551.77 (M+l)
2-[ {4-[(4-Fluorophenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- 1,2,3-benzo triazin-3(4H)-yl)butanoic acid (Compound no. 74);
LCMS: 539.74 (M+l)
2-[(Methylsulfonyl)(4- {[4-(trifluoromethyl)phenyl]carbamoyl}phenyl)amino]-4- (4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 75).
LCMS: 589.75 (M+l) Example 9: Synthesis of 4-n.3-dioxo-1.3-dihvdro-2H-isoindol-2-yl -2- (rmethylsulfonyl r4-rpropan-2-yl phenyllamino}butanoic acid (Compound no. 51) (Scheme IV)
Step a: Preparation of benzyl 4-{[teri-butyl(dimethyl)silyl]oxy}-2-hydroxybutanoate To an ice-cooled solution of benzyl 2,4-dihydroxybutanoate (10.4 g, 49.52 mmoles) in dichloromethane (100 mL) were added triethylamine (8.3 mL, 59.42 mmoles) followed by Ze^butyldimethylsilyl chloride (8.20 g, 54.47 mmoles) and N, N- dimethylaminopyridine (241 mg, 1.98 mmoles). The reaction mixture was allowed to stir at room temperature for about one hour. After completion, 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
LCMS: 325.67 (M+l), 347.64 (M+Na)
Step b: Preparation of benzyl 0-[terf-butyl(dimethyl)silyl]-AL(methylsulfonyl)-A'-[4- (propan-2-yl)phenyl]homoserinate
To an ice-cooled solution of compound obtained from Step a (1 g, 3.08 mmoles) in tetrahydrofuran (5 mL) were added N-[4-(propan-2-yl)phenyl]methanesulfonamide (722 mg, 3.39 mmoles) and triphenylphosphine (1.21 g, 4.62 mmoles) under argon atmosphere. Diisopropylazodicarboxylate (0.67 mL, 3.39 mmoles) was added dropwise and the reaction mixture was allowed to stir at the same temperature for about 30 minutes. After completion, solvent was evaporated under vacuum and crude compound obtained was purified on silica gel using 20% ethyl acetate: hexane as eluent to get desired compound. Yield: 1.7 g.
Step c: Preparation of benzyl A'-(methylsulfonyl)-A'-[4-(propan-2-yl)phenyl] homoserinate
To a solution of compound obtained from Step b (1.7 g, 3.27 mmoles) in dichloromethane (10 mL) was added borane trifluoride ethearte BF3.0Et2 (2 mL, 16.35 mmoles) slowly at room temperature. The reaction mixture was allowed to stir at room temperature for about one hour. After completion, reaction mixture was quenched with saturated solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous sodium sulphate and concentrated under vacuum to get a crude compound. The crude compound obtained was purified on silica gel column and eluting with 40% ethyl acetate: hexane as eluent to get the desired product.
Yield: 510 mg
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
To an ice-cooled solution of compound obtained from Step c (170 mg, 0.41 mmoles) in tetrahydrofuran (10 mL) were added phthalimide (67 mg, 0.46 mmoles) and triphenylphosphine (161 mg, 0.61 mmoles). Diisopropylazodicarboxylate (0.09 mL, 0.46 mmoles) was added to the reaction mixture and stirred for about 30 minutes at the same temperature. After completion, solvent was evaporated and crude product obtained was purified on silica gel column chromatography using 50% ethyl acetate: hexane as eluent to get desired product.
Yield: 150 mg
Step e: Preparation of 4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-{(methylsulfonyl)
[4-(propan-2-yl)phenyl] amino} butanoic acid
To a solution of compound obtained from Step d (150 mg, 0.280 mmoles) in tetrahydrofuran (10 mL) at room temperature was added 10% Pd/C (100 mg) and hydrogen gas was supplied by balloon. The reaction mixture was allowed to stir for about 30 minutes at the same temperature. After completion, the reaction mixture was filtered using celite pad and residue obtained was washed with 10% methanol: dichloromethane solution. The filtrate was concentrated and purification was performed on preparative TLC using 10% methanol: dichloromethane as mobile phase to afford desired product. Yield: 30 mg.
LCMS: 445.79 (M+l), 467.75 (M+Na) *H NMR (MeOO-d6, 400 MHz) δ: 7.78-7.85 (2H, m), 7.52 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 8 Hz), 4.90 (1H, m), 3.74-3.91 (2H, m), 3.29 (3H, s), 2.93 (1H, m), 2.20 (1H, m), 1.79 (1H, m), 1.25 (6H, dd, J = 8 Hz).
The following compounds can be prepared by following the above synthetic route. 4-(6-Methoxy-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-
2-yl) phenyl] amino} butanoic acid (Compound no. 52);
LCMS: 475.82 (M+l)
4-(7-Methyl-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-2- yl) phenyl] amino} butanoic acid (Compound no. 53);
LCMS: 459.83 (M+l)
4-( 1 , 3-Dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2- [(4- ethylphenyl)(methylsulfonyl)amino] butanoic acid (Compound no. 54);
LCMS: 431.75 (M+l)
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(5-methyl- l,3-dioxo- l,3-dihydro-2H- isoindol-2-yl)butanoic acid (Compound no. 55);
LCMS: 445.79 (M+l)
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- l,2,3-benzotriazin- 3(4H)-yl) butanoic acid (Compound no. 56);
LCMS: 445.79 (M+l)
2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl) butanoic acid (Compound no. 57);
LCMS: 461.79 (M+l)
Example 10: Synthesis of 2-r(3'.4'-difluorobiphenyl-4-yl)(methylsulfonyl)amino1-4-(4- oxo- L2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 27) (Scheme V)
Step a: Preparation of 3-[2-(2,2-dimethyl-l,3-dioxolan-4-yl)ethyl]-l,2,3-benzotriazin- 4(3H)-one
To an ice-cooled solution of 4-(2-hydroxyethyl)-2,2-dimethyl 1 ,3-dioxolane (3.8 g, 0.025 moles) in tetrahydrofuran (50 mL) were added benzotriazinone (4.2 g, 0.028 moles) and triphenylphosphine (13.6 g, 0.051 moles). The reaction mixture was allowed to stir for about 15 minutes at 0°C and diisopropylazodicarboxylate (7.3 mL, 0.038 moles) was added to it. The reaction mixture was again stirred for about 2 hours at room temperature. After completion of reaction, solvent was evaporated under vacuum to obtain a crude product which was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired product.
Yield: l lg
LCMS: 294.99 (M+Na)
Step b: Preparation of 3-(3,4-dihydroxybutyl)-l,2,3-benzotriazin-4(3H)-one
To a solution of compound obtained from Step a (1 1 g, 39.954 mmoles) in acetone (60 mL) was added concentrated HC1 (12 mL) and reaction mixture was allowed to stir at room temperature for about one hour. After one hour, the solvent was evaporated under reduced pressure and reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum to get crude compound. The crude compound obtained was purified on silica gel column using 70% ethyl acetate: hexane as eluent to get desired product.
Yield: 4.5 g
LCMS: 236.49 (M+l)
Step c: Preparation of 2-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4 )-yl)butyl benzoate
To an ice-cooled solution of compound obtained from Step b (1 g, 0.0042 moles) in dichloromethane (150 mL) were added triethylamine (1.1 mL, 0.0085 moles) and benzoyl chloride (0.5 mL, 0.0042 moles) and stirred at same temperature for about 2 hours and at room temperarure for about 3 hours. After completion, reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulphate and evaporated under vacuum to get crude product. The crude product was purified on silica gel column using 70% ethyl acetate: hexane as eluent to get desired product.
Yield: 1.8 g
LCMS: 340.59 (M+l) Step d: Preparation of 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butyl benzoate
To an ice-cooled solution of compound obtained from Step c (1.8 g, 0.0053 moles) in tetrahydrofuran (20 mL) were added triphenylphosphine (2.78 g, 0.0161 moles) and N- (4-bromophenyl)methanesulfonamide (1.46 g, 0.00584 moles). The reaction mixture was allowed to stir for about 15 minutes and then diisopropylazodicarboxylate (1.5 mL, 0.00796 moles) was added at same temperature. The reaction mixture was again stirred at room temperature for about one hour. After one hour, solvent was evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired product.
Yield: 1.3 g.
Step e: Preparation of 2-[(3',4'-difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butyl benzoate
To a solution of compound obtained from Step d (400 mg, 0.0007 moles) in N, N- dimethylformamide (15 mL) were added tetrakis triphenylphosphine palladium (0) (40 mg, 0.000035 moles), potassium carbonate (290 mg, 0.0021 moles) and 3, 4-difluorobenzene boronic acid (221 mg, 0.0014 moles). The reaction was heated upto 1 10°C for about 3 hours. After 3 hours, solvent was evaporated and reaction mixture was taken in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on silica gel column using 50% ethyl acetate: hexane to get desired product. Yield: 300 mg
LCMS: 606.27 (M+2).
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
To a solution of compound obtained from Step e (300 mg, 0.496 moles) in methanol (10 mL) and tetrahydrofuran (10 mL) was added potassium carbonate (102 mg, 0.745 moles) and stirred for about one hour at room temperature. After one hour, solvent was evaporated and reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on silica gel column using 60% ethyl acetate: hexane as eluent to get the desired product.
Yield: 200 mg
LCMS: 501.81 (M+l)
Step g: Preparation of 2-[(3',4'-difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid
To a solution of compound obtained from Step f (200 mg, 0.4 moles) in
acetonitrile (10 mL) were added 2,2,6,6-tetramethylpiperidine-N-oxyl (6 mg, 0.04 moles), sodium chlorite (72 mg, 0.8 moles) and 5% aqueous solution of sodium hypochlorite (59 mg, 0.8 moles). The reaction was heated up to 35°C for about 6 hours. After 6 hrs, the solvent was evaporated and reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as mobile phase to get desired product.
Yield: 30 mg.
LCMS: 515.72 (M+l)
¾ NMR (DMSO-d6, 400 MHz): δ 8.28 (2H, d, J = 4 Hz), 8.22 (1H, d, J= 8 Hz), 8.12 (1H, dd, J= 8 and 4 Hz), 7.96 (1H, m), 7.85 (4H, m), 7.58 (2H, m), 4.74 (1H, d, J = 8 HZ), 4.56 (2H, m, -NCH2), 3.21 (3H, s), 2.48 (2H, m).
The following compounds can be prepared by following the above synthetic route.
4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 22);
LCMS: 510.69 (M+l)
2-[(4'-Ethylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 28);
LCMS: 507.79 (M+l)
2- {[4-(2-Methoxypyrimidin-5-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 29);
LCMS: 51 1.76(M+1)
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 30); LCMS: 51 1.76 (M+l)
2-[(2',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 31);
LCMS: 539.84 (M+l)
2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 38);
LCMS: 509.81 (M+l)
2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 39);
LCMS: 497.78 (M+l)
2- {(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 40);
LCMS: 521.82 (M+l)
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 41);
LCMS: 479.78 (M+l)
2- {[4-(6-Methylpyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 42);
LCMS: 494.83 (M+l)
2- {(Methylsulfonyl)[4-(pyrimidin-5-yl)phenyl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 43);
LCMS: 481.79 (M+l)
2- {(Methylsulfonyl)[4-(pyridin-3-yl)phenyl]amino} -4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 44);
LCMS: 480.79 (M+l)
2- {(Methylsulfonyl)[4'-(trifluoromethyl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3- benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 45);
LCMS: 547.83 (M+l)
2- {(Methylsulfonyl)[4-(pyridin-4-yl)phenyl]amino} -4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 46);
LCMS: 480.7969 (M+l)
2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 47);
LCMS: 547.76 and 549.71 (M+l)
2-[(4'-Zert-Butylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 48);
LCMS: 535.87 (M+l) 2-[(2',3'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 49);
LCMS: 515.79 (M+l)
2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 50).
LCMS: 527.81 (M+l)
Example 1 1 : Svnthersis of (2R)-2-r(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino1- 4-(4-oxo-1.2.3-benzotriazin-3 (4H)-yl)butanoic acid (Compound no. 79): Scheme V
Step a: Preparation of 3-[2-(2,2-dimethyl-l,3-dioxolan-4-yl)ethyl]-l,2,3-benzotriazin- 4(3H)-one
To an ice-cooled solution of 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane (20 g, 0.136 mole) in tetrahydrofuran (200 mL) were added benzotriazinone (22 g, 0.150 mole) and triphenylphosphine (71 g, 0.273 mole). The reaction mixture was allowed to stir for about 15 minutes at 0°C and diisopropylazodicarboxylate (41.5 g, 0.205 mole) was added to it. The reaction mixture was again stirred for 2 hours at room temperature. After completion of reaction, solvent was evaporated under vacuum to obtain a crude product which was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired product.
Yield: 69 g
Step b: Preparation of 3-(3,4-dihydroxybutyl)-l,2,3-benzotriazin-4(3H)-one
To a solution of compound obtained from Step a (69 g, 0.250 moles) in acetone (200 mL) was added concentrated HQ (70 mL) and reaction mixture was allowed to stir at room temperature for about one hour. After one hour, the solvent was evaporated under reduced pressure and reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum to get crude compound. The crude compound obtained was purified on silica gel column using 70% ethyl acetate: hexane as eluent to get desired product.
Yield: 21 g Step c: Preparation of 2-hydroxy-4-(4-oxo-l,2,3-benzotriazin-3(4H)-yl)butyl benzoate
To an ice-cooled solution of compound obtained from Step b (21 g, 0.089 mole) in dichloromethane (100 mL) were added triethylamine (27 g, 0.268 mole) and benzoyl chloride (15.5 mL, 0.134 mole) and stirred at same temperature for about 3 hours. After completion, the reaction mixture was diluted with water and extracted with
dichloromethane. The organic layer was collected, dried over anhydrous sodium sulphate and evaporated under vacuum to get crude product. The crude product was purified on silica gel column using 70% ethyl acetate: hexane as eluent to get desired product.
Yield: 16 g
Step d: Preparation of 2-[(4-bromophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzo triazin-3(4H)-yl)butyl benzoate
To an ice-cooled solution of compound obtained from Step c (1 1 g, 0.032 mole) in tetrahydrofuran (100 mL) were added triphenylphosphine (17 g, 0.064 mole) and N-(4- bromophenyl)methane sulfonamide (8.95 g, 0.035 mole). The reaction mixture was allowed to stir for about 15 minutes and then diisopropylazodicarboxylate (9.8 g, 0.048 mole) was added at the same temperature. The reaction mixture was again stirred at room temperature for about one hour. After one hour, solvent was evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on silica gel column using 30% ethyl acetate: hexane as eluent to get desired product.
Yield: 1.3 g.
Step e: Preparation of 2-[(3',4'-dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butyl benzoate
To a solution of compound obtained from Step d (0.8g, 0.0014 mole) in N, N- dimethylformamide (20 mL) were added tetrakis triphenylphosphine palladium (0) (0.08 g, 0.00007 mole), potassium carbonate (.58 g, 0.0042 mole) and 3,4-chlorobenzene boronic acid (0.535 g, 0.0028 mole). The reaction was heated up to 1 10°C for about 3 hours.
After 3 hours, the solvent was evaporated and the reaction mixture was taken in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on silica gel column using 50% ethyl acetate: hexane to get desired product. Yield: 850 mg
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
To a solution of compound obtained from Step e (0.85 g, 0.00133 mole) in methanol (15 mL) was added potassium carbonate (0.276 g, 0.0020 mole) and stirred for about one hour at room temperature. After one hour, the solvent was evaporated and the reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude product. The crude product obtained was purified on silica gel column using 60% ethyl acetate: hexane as eluent to get the desired product.
Yield: 0.430 g.
LCMS: 533.13 (M+)
Step g: Preparation of 2-[(3',4'-dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid
To a solution of compound obtained from Step f (0.43 g 0.0008 mole) in acetonitrile (15 mL) were added 2,2,6,6-tetramethylpiperidine-N-oxyl (0.012 g, 0.000007 mole), sodium chlorite (0.145 g, 0.0016 mole) and 5% aqueous solution of sodium hypochlorite (0.12 g, 0.0016 moles). The reaction was heated up to 35°C for about 6 hours. After 6 hours, the solvent was evaporated and the reaction mixture was taken in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as mobile phase to get desired product.
Yield: 0.15 g.
1H MR (DMSO-i¾, 400 MHz): 8.22 (2H, m), 8.16 (1H, m), 8.03 - 8.05 (2H, m), 7.67 - 7.71 (6H, m), 4.63 (1H, m), 4.55 (2H, m), 3.15 (3H,s), 2.14 (1H, m), 1.99 (1H, m)
LCMS: 547.1 1 (M+l)
The following compounds can be prepared by following the above synthetic route. (2R)-2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3 - benzotriazin-3(4H)-yl)butanoic acid (Compound no. 76);
LCMS: 497.19 (M+l)
(2R)-2- {(Methylsulfonyl) [4-(pyrimidin-5-yl)phenyl] amino } -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 77);
LCMS: 481.21 (M+l)
(2R)-2- {(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 78);
LCMS: 521.29 (M+l)
(2R)-2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 80);
LCMS: 515.22 (M+l)
(2R)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 81);
LCMS: 51 1.32 (M+l)
(2R)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 82);
LCMS: 513.71 (M+l)
(2R)-2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 83);
LCMS: 509.25 (M+l)
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 84);
LCMS: 527.22 (M+l)
(2R)-2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 85);
LCMS: 479.25 (M+l)
(2R)-2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 86);
LCMS: 510.169 (M+l)
(2S)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 87);
LCMS: 513.23 (M+l)
(2S)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 88);
LCMS: 547.22 and 549.1 1 (M+l) (2S)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 89);
LCMS: 51 1.27 (M+l)
(2S)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 90);
LCMS: 527.28 (M+l)
(2R)-2-[(3',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 91);
LCMS: 537.5 (M- l)
(2R)-2- {[4-(2,3-Dihydro- l,4-benzodioxin-6-yl)phenyl](methylsulfonyl)amino} -4- (4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 92);
LCMS: 537.30 (M+l)
(2R)-2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 93);
LCMS: 545.22 (M+l)
(2R)-2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 94);
LCMS: 533.27 (M+l)
(2R)-2- {(Methylsulfonyl)[4'-(trifluoromethoxy)biphenyl-4-yl]amino}-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 95);
LCMS: 563.16 (M+l)
(2R)-2- {[4'-Chloro-3'-(trifluoromethyl)biphenyl-4-yl](methylsulfonyl)amino}-4- (4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 96);
LCMS: 581.9 (M+l)
Example 12: Synthesis of (2R)-2-r(3'-fluoro-4'-methoxybiphenyl-4- yl)(methylsulfonyl)amino"|-4-r4-oxo -7-(trifluoromethyl)-L2,3-benzotriazin-3(4H)- yllbutanoic acid (Compound no. 97) (Scheme VI)
Step a: Preparation of (45)-4-[2-(benzyloxy)ethyl]-2,2-dimethyl-l,3-dioxolane
To an ice-cooled solution of 2-[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]ethanol (5 g, 34.24 mmoles) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.06 g,
44.52 mmoles) and stirred for about 15 minutes. After 15 minutes, benzyl bromide (7.02 g, 41.09 mmole) was added and again stirred for about one hour at the same temperature. After completion of reaction, aqueous solution of ammonium chloride was added and the solvent was evaporated under vacuum. The reaction mixture was taken in ethyl acetate and washed with water. The organic layer was collected, 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 20% ethyl acetate: hexane as eluent to get the desired product.
Yield: 8 g
LCMS: 237.30 (M+l)
Step b: Preparation of (25)-4-(benzyloxy)butane-l,2-diol
To a solution of compound obtained from Step a (8 g) in acetone (50 mL) was added hydrochloric acid (12 mL, 1 1 N) at room temperature and stirred for about 3 hours at room temperature. After completion of reaction, the solvent was evaporated under reduced pressure and pH was adjusted to neutral by addition of aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on silica gel column using 20% ethyl acetate: hexane as eluent to get desired compound. Yield: 5g
LCMS: 197.24 (M+l)
Step c: Preparation of (25)-4-(benzyloxy)-2-hydroxybutyl benzoate
To an ice-cooled solution of compound obtained from Step b (5 g, 31.05 mmoles) in dichloromethane (100 mL) were added triethylamine (9.4 g, 93.16 mmoles) and benzoyl chloride (3.9 g, 27.95 mmoles). The reaction mixture was allowed to stir for about 45 minutes at the same temperature. After 45 minutes, the reaction mixture was extracted with dichloromethane while washing with water. The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on silica gel column using 60% ethyl acetate: hexane as eluent to get desired compound.
Yield: 5g
LCMS: 301.25 (M+l) Step d: Preparation of (2i?)-4-(benzyloxy)-2-[(4-bromophenyl)(methylsulfonyl) amino] butyl benzoate
To a solution of compound obtained from Step c (5 g, 16.66 mmole) in tetrahydrofuran (100 mL) at 0°C were added triphenyl phosphine (8.7 g, 33.33 moles), N- (4-bromophenyl)methanesulfonamide (4.58 g, 18.33 mmoles) and
diisopropylazodicarboxylate (5 g, 25 mmoles). The reaction mixture was allowed to stir for about one hour at same temperature. After that the reaction mixture was concentrated to obtain a crude product which was purified on column chromatography on silica gel column using 60% ethyl acetate: hexane as eluent to get desired product.
Yield: 14 g
LCMS: 534.04 (M+2)
Step e: Preparation of (2J?)-4-(benzyloxy)-2-[(3'-fluoro-4'-methoxybiphenyl-4-yl) (methyl sulfonyl)amino] butyl benzoate
To a solution of compound obtained from Step d (5 g, 9.398 mmoles) in N, N- dimethylformamide (50 mL) were added 3 -fluoro-4-methoxyphenylboronic acid (3.19 g, 18.796 mmoles), potassium carbonate (3.89 g, 28.195 mmoles) and tetrakistriphenyl phosphine palladium (0) (542 mg, 0.469 mmoles). The reaction mixture was heated upto 1 10°C for about 3 hours. After 3 hours, the solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. 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.
Yield: 4.3 g
Step f: Preparation of (2J?)-2-[(3'-fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl) amino] -4-hydroxybutyl benzoate
To a solution of compound obtained from Step e (4.39 g, 0.008 moles) in tetrahydrofuran (60 mL) and methanol (40 mL) was added Pd/C (2.5 g) in the presence of hydrogen gas supplied using balloon. The reaction mixture was allowed to stir for overnight at room temperature. After completion, reaction mixture was filtered through celite and residue so obtained was washed with 10% methanol: dichloromethane (200 mL). The filtrate was collected and dried to get desired compound.
Yield: 2.5 g
LCMS: 488.16
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
To a solution of compound obtained from Step f (2.5 g, 0.0051 moles) in tetrahydrofuran (30 mL) were added 7-trifluoromethoxy benzotriazinone (1.21 g, 0.00564 moles) and triphenyl phosphine (2.68 g, 0.010 moles) at room temperature under nitrogen atmosphere. After 5 minutes, diisopropylazodicarboxylate (1.55 g, 0.0077 moles) was added under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for about one hour. After completion, the reaction mixture was extracted with ethyl acetate and washed with water. 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.
Yield: 4.2 g
LCMS: 685.15 (M+l)
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
To a solution of compound obtained from Step g (4.2 g, 0.00614 moles) in methanol (40 mL) at room temperature was added potassium carbonate (1.27 g, 0.00921 moles) under argon atmosphere. The reaction mixture was allowed to stir for about one hour at same temperature. After completion, solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. 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 40% ethyl acetate: hexane as eluent to obtain a desired compound. Yield: 3.1 g
LCMS: 581.04
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
To a solution of compound obtained from Step h (900 mg, 1.552 mmoles) in acetonitrile:carbon tetrachloride:water (12ml: 12ml: 16ml) at room temperature were added ruthenium trichloride (13 mg, 0.062 mmoles) and sodium periodate (996 mg, 4.66 mmoles). The reaction mixture was allowed to stir for about 30 minutes at same the temperature. After completion, solvent was evaporated and the reaction mixture was extracted with ethyl acetate while washing with water. The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get a crude product. The crude product was purified on preparative TLC using 10% methanol: dichloromethane as mobile phase to get the desired product.
Yield: 107 mg.
LCMS: 595 (M+l)
¾ NMR (DMSO-de, 400 MHz): δ 8.59 (1H, s), 8.44 (1H, d, J= 8 Hz), 8.22 (1H, d, J= 8 Hz), 7.71 (2H, d, J = 8 Hz), 7.59 ( 3H, m), 7.50 (1H, d, J= 8 Hz), 7.25 (1H, t, J= 8 Hz), 4.82 (1H, m), 4.55 (2H, m), 3.88 (3H, s, -OCH3), 3.17 (3H, s, S-CH3), 2.4 (1H, m), 1.90 (lH, m).
The following compounds can be prepared by following the above synthetic route.
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-methyl- 4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 98);
LCMS: 541.1 1 (M+l)
(2R)-4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(3'-fluoro-4'- methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid (Compound no. 99);
LCMS: 561.00 (M+l)
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(7- methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 100);
LCMS: 557.10 (M+l)
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-methyl- 4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 101); LCMS: 541.05 (M+l)
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8- methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 102);
LCMS: 557.10 (M+l)
(2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-fluoro-4- oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 103).
Assay for Matrix Metallo Proteinases (MMPs)
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 CaCl2, 150 mM NaCl, 0.05% Brij-35, pH 7.5). 1 μΐ of the compound and 88 μΐ of TCNB was added to wells of 96 well plate to achieve the desired final concentration of NCE (final DMSO concentration should not exceed 0.5%). 1 μΐ of activated, recombinant MMPs was added to each well (20-100 ng/100 μΐ reaction mixture) except the "negative well".
(MMP-1, 9 &14 enzymes require prior activation. For this, supplied enzyme was incubated with either APMA, final concentration 1 mM, for a time period of 1 hour at 37°C). Incubation was done at room temperature (~ 25°C) for 4 minutes to 5 minutes. The Reaction was initiated with 10 μΐ of 100 μΜ 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 IC50 values below 10 micromolar. Activities for MMP12 provided IC50 values 35 nanomolar to 10 micromolar.

Claims

We Claim:
1. A compound of Formula I:
Figure imgf000088_0001
Formula 1
including racemates, enantiomers or diastereomers thereof; or a pharmaceutically acceptable salt thereof, wherein,
L1 is selected from bond, O, S, CH2, NR4, NHCO(CH2)n, (CH2)nCONH, NHCONH, S02NH, NHS02, NHCO(O), -0-(CH2)n, -(CH2)n-0-, -OC(0)NH-, C(S)NH, NHC(S), NHC(S)NH or -COO- wherein n is zero or an integer between 1 and 2; R1 is selected from hydrogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, cyano, nitro, halogen, halogeno Ci-Cealkyl, C5-Ci2 aryl, C6-Ci2 heteroaryl, C3-C6cycloalkyl wherein aryl, heteroaryl, cycloalkyl is optionally substituted by one or more substitutents independently selected from R5;
R2 is CHO or S02Ci_6 alkyl;
R3 is unsubstituted or substituted heteroaryl or -OCONHR' where R' is C6-Ci2 aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more substitutents independently selected from R5;
R4 is H or Ci_6alkyl;
R5 is selected from alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-OR¾ -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NR^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH-C(=0)- Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl, n is as define earlier and m is an integer 0-2} . ompound of Formula I, which is:
2-[Formyl(4'-methylbiphenyl-4-yl)amino]-4-(6-methyl-4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 1);
4-(7-Chloro-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2-[formyl(4'-methylbiphenyl-4- yl)amino]butanoic acid (Compound no. 2);
2-[(4'-Ethylbiphenyl-4-yl)(formyl)amino]-4-(5-methyl-4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 3);
0-[(4-Fluorophenyl)carbamoyl]-N-formyl-N-(4'-methylbiphenyl-4-yl)homoserine (Compound no. 4);
N-Formyl-N-(4'-methylbiphenyl-4-yl)-0-[(4-methylphenyl)carbamoyl]homoserine (Compound no. 5);
0-[(3,4-Dichlorophenyl)carbamoyl]-N-formyl-N-(4'-methylbiphenyl-4- yl)homoserine (Compound no. 6);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0- { [4-(propan-2-yl)phenyl]carbamoyl} homoserine (Compound no. 7);
N-(4'-Ethylbiphenyl-4-yl)-0-[(3-fluorophenyl)carbamoyl]-N-formylhomoserine (Compound no. 8);
0-[(2,4-Difluorophenyl)carbamoyl]-N-(4'-ethylbiphenyl-4-yl)-N- formylhomoserine (Compound no. 9);
N-(4'-Ethylbiphenyl-4-yl)-0-[(2-fluorophenyl)carbamoyl]-N- formylhomoserine (Compound no. 10);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0- { [4-trifluoromethyl)phenyl]carbamoyl} homoserine (Compound no. 1 1);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0-[(2-methylphenyl)carbamoyl]homoserine (Compound no. 12);
N-(4'-Ethylbiphenyl-4-yl)-0-[(4-ethylphenyl)carbamoyl]-N- formylhomoserine (Compound no. 13);
N-(4'-Ethylbiphenyl-4-yl)-N-formyl-0-[(4-methoxyphenyl)carbamoyl]homoserine (Compound no. 14);
0-[(2,6-Dichlorophenyl)carbamoyl]-N-(4'-ethylbiphenyl-4-yl)-N- formylhomoserine (Compound no. 15);
2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)butanoic acid (Compound no. 16);
4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- {[4-(6-methoxypyridin-3-yl)phenyl] (methyl sulfonyl)amino}butanoic acid (Compound no. 17);
4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-[(4'-methoxybiphenyl-4yl)
(methylsulfonyl) amino]butanoic acid (Compound no. 18); 2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 19);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl](methylsulfonyl)amino}butanoic acid (Compound no. 20);
2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino}-4-[4-oxo-7- (trifluoromethyl)-l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 21); 4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2- {[4-(6-methoxypyridin-3- yl)phenyl] (methyl sulfonyl)amino}butanoic acid (Compound no. 22);
4-(6-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4- methylphenoxy)phenyl](methyl sulfonyl) amino jbutanoic acid (Compound no. 23); 4-(7-Methyl-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4-methylphenoxy) phenyl] (methyl sulfonyl) amino jbutanoic acid (Compound no. 24);
2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino}-4-[4-oxo-7- (trifluoromethyl)- 1 ,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 25); 2- {[4-(4-Methylphenoxy)phenyl](methylsulfonyl)amino} -4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 26);
2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 27);
2-[(4'-Ethylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin- 3(4H)-yl)butanoic acid (Compound no. 28);
2- {[4-(2-Methoxypyrimidin-5-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo-l,2,3- benzotriazin -3(4H)-yl)butanoic acid (Compound no. 29);
2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1 ,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 30);
2-[(2',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 31);
2-[(4-Methoxyphenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)- yl)butanoic acid (Compound no. 32);
4-(7-Methoxy-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2-[(4-methoxyphenyl)
(methylsulfonyl)amino]butanoic acid (Compound no. 33);
4-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-2-[(4- methoxyphenyl)methylsulfonyl)amino]butanoic acid (Compound no. 34);
2- [(4-Methoxyphenyl)(methylsulfonyl)amino] -4-(5 -methyl- 1 ,3 -dioxo- 1 ,3 -dihydro- 2H-isoindo-2-yl)butanoic acid (Compound no. 35);
4-(7-Methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2- {[4-(4- methylphenoxy)phenyl] (methyl sulfonyl) amino jbutanoic acid (Compound no. 36); 4-(5-Methyl- 1 ,3-dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2- {[4-(4-methylphenoxy) phenyl] (methylsulfonyl)amino}butanoic acid (Compound no. 37); 76 2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
77 3(4H)-yl)butanoic acid (Compound no. 38);
78 2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-
79 3(4H)-yl)butanoic acid (Compound no. 39);
80 2- {(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-
81 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 40);
82 2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)-
83 yl)butanoic acid (Compound no. 41);
84 2- {[4-(6-Methylpyridin-3-yl)phenyl](methylsulfonyl)amino}-4-(4-oxo-l,2,3-
85 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 42);
86 2- {(Methylsulfonyl)[4-(pyrimidin-5-yl)phenyl]amino}-4-(4-oxo-l,2,3-
87 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 43);
88 2- {(Methylsulfonyl)[4-(pyridin-3-yl)phenyl]amino} -4-(4-oxo-l,2,3-benzotriazin-
89 3(4H)-yl)butanoic acid (Compound no. 44);
90 2- {(Methylsulfonyl)[4'-(trifluoromethyl)biphenyl-4-yl]amino}-4-(4-oxo-l,2,3-
91 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 45);
92 2- {(Methylsulfonyl)[4-(pyridin-4-yl)phenyl]amino} -4-(4-oxo-l,2,3-benzotriazin-
93 3(4H)-yl)butanoic acid (Compound no. 46);
94 2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
95 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 47);
96 2-[(4'-?ert-Butylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
97 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 48);
98 2-[(2',3'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
99 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 49);
100 2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3-
101 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 50);
102 4-(l ,3-Dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2- {(methylsulfonyl)[4-(propan-2-
103 yl)phenyl] amino jbutanoic acid (Compound no. 51);
104 4-(6-Methoxy-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-
105 2-yl)phenyl] amino jbutanoic acid (Compound no. 52);
106 4-(7-Methyl-4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)-2- {(methylsulfonyl)[4-(propan-2-
107 yl)phenyl] amino jbutanoic acid (Compound no. 53);
108 4-( 1 ,3-Dioxo- 1 ,3-dihydro-2H-isoindol-2-yl)-2-[(4-
109 ethylphenyl)(methylsulfonyl)amino]butanoic acid (Compound no. 54);
1 10 2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(5-methyl-l,3-dioxo-l,3-dihydro-2H-
1 1 1 isoindol-2-yl)butanoic acid (Compound no. 55);
1 12 2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3-benzotriazin-
1 13 3(4H)-yl)butanoic acid (Compound no. 56); 2-[(4-Ethylphenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 57);
2-[(Methylsulfonyl)(phenyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 58);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methyl- 1 ,3-dioxo- 1,3- dihydro-2H-isoindol-2-yl)butanoic acid (Compound no. 59);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-chloro-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 60);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-chloro-4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 61);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 62);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-(trifluoromethyl)- l,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 63);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-methoxy-4-oxo- 1,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 64);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(5-fluoro-4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 65);
2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(l -methyl-2,4-dioxo- 1 ,4- dihydroquinazolin-3(2H)-yl)butanoic acid (Compound no. 66);
4- {(Methylsulfonyl) [ 1 -oxo-4-(4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)- 1 -(prop-2-en- 1 - yloxy)butan-2-yl] aminojbenzoic acid (Compound no. 67);
2-[ {4-[(4-Methylphenyl)carbamoyl]phenyl} (methylsulfonyl)amino] -4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 68);
2-[ {4-[(4-Chlorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 69);
2- {(Methylsulfonyl)[4-(phenylcarbamoyl)phenyl]amino}-4-(4-oxo-l,2,3- benzotriazin-3(4H)-yl)butanoic acid (Compound no. 70);
2-[ {4-[(3-Fluorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 71);
2-[(Methylsulfonyl)(4- {[4-(propan-2-yl)phenyl]carbamoyl}phenyl)amino]-4-(4- oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 72);
2-[ {4-[(4-Methoxyphenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 73);
2-[ {4-[(4-Fluorophenyl)carbamoyl]phenyl}(methylsulfonyl)amino]-4-(4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 74);
2-[(Methylsulfonyl)(4- {[4-(trifluoromethyl)phenyl]carbamoyl}phenyl)amino]-4- (4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 75); 152 (2R)-2-[(4'-Fluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1,2,3 -
153 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 76);
154 (2R)-2- {(Methylsulfonyl)[4-(pyrimidin-5-yl)phenyl]amino} -4-(4-oxo-l,2,3-
155 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 77);
156 (2R)-2- {(Methylsulfonyl)[4'-(propan-2-yl)biphenyl-4-yl]amino} -4-(4-oxo- 1 ,2,3-
157 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 78);
158 (2R)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
159 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 79);
160 (2R)-2-[(3',4'-Difluorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1 ,2,3-
161 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 80);
162 (2R)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
163 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 81);
164 (2R)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
165 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 82);
166 (2R)-2-[(3'-Methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
167 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 83);
168 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-
169 l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 84);
170 (2R)-2-[Biphenyl-4-yl(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)-
171 yl)butanoic acid (Compound no. 85);
172 (2R)-2- {[4-(6-Methoxypyridin-3-yl)phenyl](methylsulfonyl)amino} -4-(4-oxo-
173 l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 86);
174 (2S)-2-[(4'-Chlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- l,2,3-
175 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 87);
176 (2S)-2-[(3',4'-Dichlorobiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo- 1 ,2,3-
177 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 88);
178 (2S)-2-[(3'-Fluoro-4'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
179 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 89);
180 (2S)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-
181 l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 90);
182 (2R)-2-[(3',4'-Dimethoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
183 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 91);
184 (2R)-2- {[4-(2,3-Dihydro- l,4-benzodioxin-6-yl)phenyl](methylsulfonyl)amino} -4-
185 (4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 92);
186 (2R)-2-[(4'-Methoxy-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-
187 l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 93);
188 (2R)-2-[(4'-Fluoro-3'-methylbiphenyl-4-yl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-
189 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 94); 190 (2R)-2- {(Methylsulfonyl)[4'-(trifluoromethoxy)biphenyl-4-yl]amino}-4-(4-oxo-
191 l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 95);
192 (2R)-2- {[4'-Chloro-3'-(trifluoromethyl)biphenyl-4-yl](methylsulfonyl)amino}-4-
193 (4-oxo- 1 ,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 96);
194 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-[4-oxo-7-
195 (trifluoro methyl)- 1 ,2,3-benzotriazin-3(4H)-yl]butanoic acid (Compound no. 97);
196 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-methyl-
197 4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 98);
198 (2R)-4-(7-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(3'-fluoro-4'-
199 methoxybiphenyl-4-yl)(methylsulfonyl)amino]butanoic acid (Compound no. 99);
200 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(7-
201 methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 100);
202 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-methyl-
203 4-oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 101);
204 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(8-
205 methoxy-4-oxo-l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 102);
206 (2R)-2-[(3'-Fluoro-4'-methoxybiphenyl-4-yl)(methylsulfonyl)amino]-4-(6-fluoro-4-
207 oxo- l,2,3-benzotriazin-3(4H)-yl)butanoic acid (Compound no. 103);
208 4-(5-Chloro-4-oxo-l,2,3-benzotriazin-3(4H)-yl)-2-[(4-
209 chlorophenyl)(methylsulfonyl)amino]butanoic acid (Compound no. 104);
210 2-[(4-Bromophenyl)(methylsulfonyl)amino]-4-(4-oxo- 1 ,2,3-benzotriazin-3(4H)-
21 1 yl)butanoic acid (Compound no. 105);
212 2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(4-oxo-l,2,3-benzotriazin-3(4H)-
213 yl)butanoic acid (Compound no. 106);
214 2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(7-methyl-4-oxo- 1,2,3-
215 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 107);
216 2-[(4-Chlorophenyl)(methylsulfonyl)amino]-4-(6-methoxy-4-oxo- 1 ,2,3-
217 benzotriazin-3(4H)-yl)butanoic acid (Compound no. 108)
218 including racemates or diastereomers thereof; or a pharmaceutically acceptable salt thereof.
1 3. A pharmaceutical composition comprising a therapeutically effective amount of a
2 compound according to claims 1 and 2, together with one or more pharmaceutically
3 acceptable carriers, excipients or diluents.
1 4. A compound according to claims 1 and 2, for use in the treatment or prophylaxis of
2 an animal or a human suffering from an inflammatory or allergic disease.
1 5. A compound according to claim 4, wherein the inflammatory or allergic disease is
2 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, tumor metastasis.
6. A pharmaceutical composition according to claim 3, further comprising one or more of additional active ingredients selected from:
a) Anti-inflammatory agents, selected from (i) the nonsteroidal anti- inflammatory agents piroxicam, diclofenac, propionic acids, fenamates, pyrazolones, salicylates, PDE-4 inhibitors, p38 MAP Kinase/Cathepsin inhibitors, (ii) leukotrienes LTC4/LTD4/LTE4/LTB4 -Inhibitors, 5- lipoxygenase inhibitor and PAF -receptor antagonists, (iii) Cox-2 inhibitors, (iv) other MMP inhibitors, and (v) interleukin-I inhibitors;
b) antihypertensive agents, selected from (i) the ACE inhibitors, like enalapril, lisinopril, valsartan, telmisartan and quinapril (ii) the angiotensin II receptor antagonists and agonists-, losartan, candesartan, irbesartan, valsartan, and eprosartan, (iii) β-blockers, and (iv) calcium channel blockers. c) immunosuppressive agents selected from cyclosporine, azathioprine and methotrexate, and anti inflammatory corticosteroids.
7. A process for preparing a compound of Formula 10 (Formula 1 when R3 is
1 2 1
heteroaryl, L is bond, R is CHO and R is substituted aryl or heteroaryl) and Formula 13 (Formula 1 when R3 is -OCONHR', L1 is bond R2 is CHO and R1 is substituted aryl or heteroaryl) comprising:
a) reacting 4-bromo-4-nitrobenzene with a compound of Formula 2
Figure imgf000095_0001
Formula 2
to give a compound of Formula 3;
Figure imgf000096_0001
9 Formula 3
10 b) reducing a compound of Formula 3 to give a compound of Formula 4
Figure imgf000096_0002
j j Formula 4
12 c) reacting a compound of Formula 4 with alpha -bromolactone, to give a
13 compound of Formula 5
Figure imgf000096_0003
Formula 5
formylating a compound of Formula 5 to give a compound of Formula 6
Figure imgf000096_0004
Formula 6
ring opening of a compound of Formula 6 to give a compound of Formula 7
Figure imgf000096_0005
Formula 7
reacting a compound of Formula 7 with a compound of Formula 8 H
Figure imgf000097_0001
Formula !
to give a compound of Formula 9
Figure imgf000097_0002
deprotecting a compound of Formula 9 to give a compound of Formula 10
Figure imgf000097_0003
Formula 10
or
reacting a compound of Formula 7 with a compound of Formula 1 1
Figure imgf000097_0004
RTSTCO
Formula 7 Formula 1 1 to give a compound of Formula 12
Figure imgf000098_0001
Formula 12
deprotecting a compound of Formula 12 to give a compound of Formula 13
Figure imgf000098_0002
Formula 13
wherein, is aryl or heteroaryl ring;
R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl;
Rp is carboxy protecting group, such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride;
(Het N
is a heteroaryl ring;
R' is C6-C12 aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl each of which is optionally substituted by one or more substitutents independently selected from R5;
R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NRfRq, -(CH2)n-NHC(=0)-Rf, -(CH2)n-0- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq,, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH- C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer 0-2}.
8. A process for preparing a compound of Formula 20 (Formula 1 when R is heteroaryl, L1 is bond, R2 is S02-Ci_6-alkyl and R1 is substituted aryl or heteroaryl) comprising:
a) halogenating a compound of Formula 14 at alpha position
Figure imgf000099_0001
Formula 14
to give a compound of Formula 15
Figure imgf000099_0002
Formula 15
protecting a compound of Formula 15 to give a compound of Formula 16
Figure imgf000099_0003
Formula 16
reacting a compound of Formula 16 with a compound of Formula 17 (where Rk is halogen) to give a compound of Formula 18
Ak
Figure imgf000099_0004
R5 Formula 17 Formula 18
d) coupling of a compound of Formula 18 with a compound of Formula 2 to give a compound of Formula 19
Ak
Figure imgf000100_0001
Formula 2 Formula 19
deprotecting a compound of Formula 19 to give a compound of Formula 20
Ak
Figure imgf000100_0002
Formula 20
or
f) reacting a compound of Formula 16, with a compound of Formula 17 (where Rk is aryl/heteroaryl substituted with R6)
Figure imgf000100_0003
Formula 16 Formula 17 to give a compound of Formula 19 Ak
Figure imgf000101_0001
Formula 19
deprotecting a compound of Formula 19 to give a compound of Formula 20
Figure imgf000101_0002
Figure imgf000101_0003
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride;
R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf; -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NR^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq;, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH- C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer 0-2};
Hal is F, CI, Br, I; Ak is Ci_6alkyl; is aryl or heteroaryl ring;
R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl.
9. A process for preparing a compound of Formula 26b (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci_6-alkyl and R1 is aryl/heteroaryl substituted with OR6 ) and Formula 29 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci-6-alkyl and R1 is halogen/hydrogen, alkoxy/aryloxy) comprising:
a) reacting a compound of Formula 17a with alpha hydroxy lactone, to give a compound of Formula 21
Ak
Figure imgf000102_0001
Formula 17a Formula 21
ring opening of a compound of Formula 21 to give a compound of Formula 22
Figure imgf000102_0002
c) protecting a compound of Formula 22 at carboxyl group to give a compound of Formula 23
Figure imgf000103_0001
Formula 23
d) protecting a compound of Formula 23 (when R is halogen) at hydroxyl group to give a compound of Formula 24
Ak
Figure imgf000103_0002
Formula 24
e) coupling of a compound of Formula 24 with a compound of Formula 24a , to give a compound of Formula 25
Figure imgf000103_0003
Formula 24a Formula 25
f) deprotecting a compound of Formula 25 to give a compound of Formula 26
Figure imgf000103_0004
Formula 26 g) reacting a compound of Formula 26 with a compound of Formula 27, to give a compound of Formula 26a
Ak
Figure imgf000104_0001
Formula 27 Formula 26a
h) deprotecting a compound of Formula 26a to give a compound of Formula 26b
Figure imgf000104_0002
Formula 26b
or
i) reacting a compound of Formula 23 (when is
alkoxy/aryloxy/halogen/hydrogen) with a compound of Formula 27
Figure imgf000104_0003
Formula 23 Formula 27
to give a compound of Formula 28 Ak
Figure imgf000105_0001
Formula 28
deprotecting a compound of Formula 28 to give a compound of Formula 29;
Ak
Figure imgf000105_0002
Formula 29
wherein,
Ak is Ci_6alkyl:
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride;
RP' is hydroxyl protecting group such as benzoyl , silyl groups tert- butyldimethylsilyl, trimethylsilyl, ZerZ-butyldimethylsilyloxymethyl, triisopropylsilyl; f
v—' is a heteroaryl ring;
Rk' is hydrogen, halogen, alkoxy, aryloxy, aryl, carboxy;
R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(α¾)η-01¾ -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NR^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq;, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH- C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer 0-2} . is aryl or heteroaryl ring;
OR6 wherein R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl.
10. A process for preparing a compound of Formula 31 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci_6-alkyl and R1 is aryl/heteroaryl substituted with
3 1 2 halogen) and Formula 36 (Formula 1 when R is heteroaryl, L is -CONH-, R is S02-Ak and R1 is aryl/heteroaryl) comprising:
a) reacting a compound of Formula 23 (when R is aryl/heteroaryl substituted with halogen and Rp is allyl) with a compound of Formula 27
Figure imgf000106_0001
Formula 23 Formula 27
to give a compound of Formula 30
Ak
I
Figure imgf000106_0002
Formula 30
deprotecting a compound of Formula 30 to give a compound of Formula 31 ;
Ak
Figure imgf000107_0001
Formula 31
or
c) reacting a compound of Formula 23 (when is -COORp) with a compound of Formula 27
Ak
Figure imgf000107_0002
Formula 23 Formula 27
to give a compound of Formula 32;
Ak
Figure imgf000107_0003
Formula 32 deprotecting a compound of Formula 32 to give a compound of Formula 33 ;
Ak
Figure imgf000108_0001
Formula 33
coupling of a compound of Formula 33 with a compound of Formula 34
Figure imgf000108_0002
Formula 34
to give a compound of Formula 35
Ak
Figure imgf000108_0003
Formula 35 deprotecting a compound of Formula 35 to give a compound of Formula 36;
Ak
Figure imgf000109_0001
Formula 36
wherein,
Ak is Ci-6alkyl;
Hal is F, CI, Br, I;
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride; is aryl or heteroaryl ring; (net
— is a heteroaryl ring;
R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NRfRq, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq,, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH- C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer 0-2} ;
R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl.
1 1. A process for preparing a compound of Formula 43 (Formula 1 when R3 is heteroaryl, L1 is bond, R2 is S02-Ci_6-alkyl and R1 is aryl/heteroaryl) comprising: a) protecting a compound of Formula 37, to give compound of Formula 38
Figure imgf000110_0001
Formula 37 Formula 38
c) reacting a compound of Formula 38 with a compound of Formula 39 to give a compound of Formula 40
Ak
Figure imgf000110_0002
Formula 39 Formula 40 d) deprotecting a compound of Formula 40 to give a compound of Formula 41
Ak
Figure imgf000110_0003
Formula 41
e) reacting a compound of Formula 41 with a compound of Formula 27 to give a compound of Formula 42
Ak
Figure imgf000110_0004
Formula 27 Formula 42 deprotecting a compound of Formula 42 to give a compound of Formula 43
Ak
Figure imgf000111_0001
Formula 43
wherein,
Ak is Ci_6 alkyl: is aryl or heteroaryl ring;
Rp is carboxy protecting group such as methyl, ethyl, allyl, benzyl, t-butyl, silyl, BOC anhydride;
RP' is hydroxyl protecting group such as benzoyl , silyl groups tert- butyldimethylsilyl, trimethylsilyl, ZerZ-butyldimethylsilyloxymethyl, triisopropylsilyl;
(Het N
— is a heteroaryl ring;
R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-Ce alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf, -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NR^, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq;, -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH- C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer 0-2} ;
R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl.
12. A process for preparing a compound of Fonnula 52 (Formula 1 when R" is heteroaryl, L1 is bond, R2 is SC>2-Ci-6-alkyl and R1 is substituted aryl/heteroaryl) comprising:
a) reacting a compound of Formula 44 with 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane to give a compound of Formula 45
Figure imgf000112_0001
Fonnula 44 Fonnula 45
b) ring opening of a compound of Fonnula 45 to give a compound of Formula 46
Figure imgf000112_0002
Formula 46
c) protecting a compound of Formula 46 to give a compound of Fonnula 47
Rp'O OH
7
©
Fonnula 47
d) reacting a compound of Fonnula 47 with a compound of Fonnula 48 to give a compound of Formula 49
Figure imgf000113_0001
Foi-mula 48 Formula 49
e) coupling of a compound of Formula 49 with a compound of Formula 2 to give a compound of Formula 50
S02-Ak
Η
Figure imgf000113_0002
Formula 2 Formula 50
deprotecting a compound of Formula 50 to give a compound of Formula 51
Figure imgf000113_0003
Formula 51
g) oxidizing a compound of Formula 51 to give a compound of Formula 52
S02-Ak
Figure imgf000113_0004
Formula 52
wherein,
Ak is Ci_6 alkyl: O is aryl or heteroaryl ring;
Rp> is hydroxyl protecting group such as benzoyl, silyl including tert- butyldimethylsilyl, trimethylsilyl, Ze^butyldimethylsilyloxymethyl, triisopropylsilyl;
(Het N
—' is a heteroaryl ring;
Hal is F, CI, Br, I; and
R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl.
13. A process for preparing a compound of Formula 61 (Formula 1 when R is heteroaryl, L1 is bond, R2 is S02-Ci_6-alkyl and R1 is substituted aryl/heteroaryl) comprising:
a) protecting 4-(2-hydroxyethyl)-2,2-dimethyl 1,3-dioxolane to give a
compound of Formula 53;
Figure imgf000114_0001
Formula 53
b) ring opening of a compound of Formula 53 to give a compound of Formula 54;
HC^^H 0Rp'
Formula 54
c) protecting a compound of Formula 54 to give a compound of Formula 55 ;
Figure imgf000114_0002
Formula 55 d) reacting a compound of Formula 55 with a compound of Formula 48 to give a compound of Formula 56;
Ak
Figure imgf000115_0001
Formula 48 Formula 56
e) coupling of a compound of Formula 56 with a compound of Formula 2 to give a compound of Formula 57
Ak
Figure imgf000115_0002
Formula 2 Formula 57
f) deprotecting a compound of Formula 57 to give a compound of Formula 58
Ak
so2
Figure imgf000115_0003
Formula 58
g) reacting a compound of Formula 58 with a compound of Formula 27 to give a compound of Formula 59 Ak
I
so2
Figure imgf000116_0001
Formula 27 Formula 59
deprotecting a compound of Formula 59 to give a compound of Formula 60
Ak
Figure imgf000116_0002
Formula 60
oxidizing a compound of Formula 60 to give a compound of Formula 61
Ak
Figure imgf000116_0003
Formula 61
wherein,
Ak is Ci-6 alkyl: is aryl or heteroaryl ring; RP' and RP" is hydroxyl protecting group such as benzoyl , silyl groups tert- butyldimethylsilyl, trimethylsilyl, Ze^butyldimethylsilyloxymethyl, triisopropylsilyl;
Figure imgf000117_0001
is a heteroaryl ring;
R5 is alkyl, alkenyl, alkynyl, cyano, nitro, halogen, halogeno-Ci-C6 alkyl, halogeno-Ci-C6 alkoxy, azido, thiol, alkylthiol, -(CH2)n-ORf; -C(=0)-Rf, - COORf, -NRfRq, -(CH2)n-C(=0)NR¾, -(CH2)n-NHC(=0)-Rf, -(CH2)n- O- C(=0)-NRfRq, (CH2)n NHC(=0)NRfRq„ -(CH2)n-0-C(=0)- Rf, -(CH2)n-NH- C(=0)-Rf or -(CH2)nS(=0)m-NRfRq {wherein Rf and Rq are independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and alkylheterocyclyl; n can be zero or an integer between 1 and 2 and m is an integer 0-2};
Hal is F, CI, Br, I; and
R6 is hydrogen, alkyl, halogen, alkoxy or halogeno-Ci-C6 alkyl.
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