WO2000066562A1 - Pyrazoles presentant une activite anti-inflammatoire - Google Patents

Pyrazoles presentant une activite anti-inflammatoire Download PDF

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Publication number
WO2000066562A1
WO2000066562A1 PCT/IB2000/000556 IB0000556W WO0066562A1 WO 2000066562 A1 WO2000066562 A1 WO 2000066562A1 IB 0000556 W IB0000556 W IB 0000556W WO 0066562 A1 WO0066562 A1 WO 0066562A1
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Prior art keywords
pyrazol
salts
hydroxymethyl
benzenesulfonamide
trifluoromethyl
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PCT/IB2000/000556
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English (en)
Inventor
Vidya Bhushan Lohray
Kumar Singh Sunil
Venkateswarlu Akella
Braj Bhushan Lohray
Ganapathi Reddy Pamulapati
Rajagopalan Ramanujam
Misra Parimal
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Dr. Reddy's Research Foundation
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Priority to AU43083/00A priority Critical patent/AU4308300A/en
Publication of WO2000066562A1 publication Critical patent/WO2000066562A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel antiinflammatory compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel heterocychc compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the present invention also relates to novel intermediates, process for their preparation and their use in the preparation of compounds of formula (I).
  • the compounds of general formula (I) are useful as antiinflammatory, analgesic, antipyretic, antiarthritic, antibacterial, anticancer agents or for treating Alzheimer diseases.
  • the compounds of the present invention are also useful for the treatment of
  • CONFIRMATION COPV diseases of human or animals such as pain, fever or inflammation.
  • Compounds of formula (I) also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
  • the compounds of the present invention are useful for treatment of pain, fever, and inflammation related to common cold, influenza, viral infections.
  • the compounds of the present invention can be used for the treatment of arthritis such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, spondylo arthritis; systemic lupus erythematosus, skin inflammation disorders such as eczema, burns, dermatitis, psoriasis; low back and neck pain, head ache, tooth ache, sprains, strains, myostis, neuralgia, synovitis, bursitis, tendinitis, injuries following surgical and dental procedures, post-operative inflammation including ophthalmic surgery such as cataract and refractive surgery.
  • arthritis such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, spondylo arthritis
  • systemic lupus erythematosus skin inflammation disorders such as eczema, burns, dermatitis, psoriasis
  • low back and neck pain head ache, tooth
  • the compounds of general formula (I) are also useful for the treatment of dysmenorrhoea, premature labour, asthma and bronchitis, gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, diverticulitis, regional enteritis, peptic ulcers.
  • These compounds may also be useful for treating inflammation in diseases such as vascular diseases, migraine head aches, periarteritis nodosa, thyroiditis, aplastic anemia, Behcat's syndrome, Hodgkin's diseases, scleroderma, myasthenia gravies, sarcoidosis, nephrotic syndrome, Type I diabetes, polymyositis, conjunctivitis, gingivitis, myocardial ischaemia, nephritis, swelling after injury, hypersensitivity and the like.
  • diseases such as vascular diseases, migraine head aches, periarteritis nodosa, thyroiditis, aplastic anemia, Behcat's syndrome, Hodgkin's diseases, scleroderma, myasthenia gravies, sarcoidosis, nephrotic syndrome, Type I diabetes, polymyositis, conjunctivitis, gingivitis, myocardial ischaemia, nephriti
  • the compounds of the present inventions are useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, and central nervous system damage resulting from stroke, ischaemia and trauma; pulmonary inflammation such as in the case of viral infections and cystic fibrosis; ophthalmic diseases such as retinitis, retinopathy, uveitis, ocular photophobia and acute injury to eye tissues.
  • the compounds of general formula (I) are also useful for treating central nervous system disorders such as cortical dementia (Alzheimer's diseases), useful for treatment of pain not limited to dental pain, muscular pain, pain from cancer, postoperative pain, and useful for the treatment of diseases where NSAIDS are used with the benefit of having significantly less side effects.
  • the compounds of general formula (I) are cyclooxygenase inhibitors and are therefore useful to treat the cyclooxygenase mediated diseases.
  • the compounds of formula (I) are also useful for the treatment of mammals not limited to human beings such as horses, dogs, cats, sheep, pigs etc., and also for treating rats, mice, rabbits etc.
  • the compounds of formula (I) may also be used in cotherapies for inflammation, Alzheimer's disease or cancer, in place of, or together with the conventional therapies.
  • the compounds of the general formula (I) are useful as partial or complete substitute for NSAIDS in compositions or preparations wherein they are presently coadministered with other agents or ingredients.
  • the present invention also comprises pharmaceutical compositions for treating cyclooxygenase mediated diseases as defined earlier, comprising a non-toxic therapeutically effective amount of the compound of formula (I) as defined above and pharmaceutically acceptable carrier optionally containing one or more ingredients such as another analgesic agent like acetaminophen of phenacetin, a potentiator like caffeine, a H 2 antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant such as phenylephrine, phenyl propanolamine, pseudophedrine, oxymetazoline, epinephrine, nephazoline, propylhexadrine or leavo- desoxyephedrine, xylomatezoline, a sedating or non sedating antihistamine
  • Nonsteroidal anti-inflammatory drugs are widely used in the treatments of arthritis and pain. These agents act by inhibiting the production of prostaglandin, which plays an important role in the inflammation process.
  • the prostaglandin synthesis is inhibited by blocking the enzyme cyclooxygenase (COX) (Vane J. R. Nature [New Biol.] 1971, 231-232).
  • COX cyclooxygenase
  • these NSAIDS while reducing the prostaglandin induced inflammation and associated symptoms, have also been found to affect prostaglandin regulated other beneficial processes causing side effects [Allison M. C, etal., J. Med. 1992, 327, 749].
  • the side effects showed by NSAIDS are gastrointestinal ulceration and intolerance, blockade of platelet aggregation, inhibition of uterine motility, inhibition of prostaglandin mediated renal function and hypersensitivity reactions.
  • COX-1 isoforms of cyclooxygenase enzyme
  • COX-2 is induced during inflammation. Therefore, selective inhibition of COX-2 enzyme would be useful in treating inflammation without causing side effects due to inhibition of COX-1.
  • Leukotriens also are mediators of inflammation and related disorders.
  • the leukotriens (LTB4, LTC4, LTD4 etc.,) are produced by the 5- lipoxygenase mediated oxidation of arachidonic acid.
  • 5- lipoxygenase (5-LO) enzyme would also be useful in treating inflammation and related disorders. It is therefore possible to treat inflammation with agents which can selectively inhibit COX-2 or 5-LO or both without causing the potential side effects caused by chronic treatment with common NSAIDS.
  • R 1 is an alkyl or NR 4 R 5 group, wherein R 4 and R 5 each independently is hydrogen or an alkyl or benzyl group;
  • R 2 is a naphthyl, tetrahydronaphthyl, unsubstituted phenyl or phenyl group, substituted by from 1 to 3 halogen atoms, alkyl, hydroxy, alkoxy or trifluoromethyl groups and
  • R 3 is hydrogen or an alkyl group.
  • R represents hydrogen, alkoxycarbonyl, carboxy, halo, alkyl, phenyl or alkanoyl; R , R and R represents hydrogen, alkyl, alkoxy or halo; X represents alkyl or
  • R 2 is selected from the group consisting of (C,- C 6 )alkyl; (C -C )cycloalkyl; mono, di or tri substituted phenyl wherem the substituent is selected from the group consisting of hydrogen, halo, (C ⁇ -C 6 )alkoxy, (C,--C 6 )alkylthio, CN, CF 3 , (C,-C 6 )alkyl, N 3 , -CO 2 H, -CO 2 -(C,-C 4 )alkyl, -C(R 5 )(R°)-OH, -C(R 5 )(R 6 )-O- (C ⁇ -C 4 )alkyl and -(C ⁇ -C 6 )alkyl-CO 2 -R 5 ; mono, di or tri substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of
  • An example of these compounds is shown in formula (Ilf)
  • A is a 5 or 6 membered ring substituent selected from partially unsaturated or unsaturated heterocycle and carbocyclic rings, A may be optionally substituted with a radical selected from acyl, halo, alkyl, haloalkyl, cyano, nitro, carboxyl, alkoxy, oxo, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl and hydroxyalkyl; Y is a radical selected from oxy, thio, sulfinyl, sulfonyl, alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxyalkyl, hydroxyalkylthio, hydroxyalkylthioalkyl, oximinoalkoxy, oximinoal
  • alkyl oximinoalkylthioalkyl, carbonylalkyloxy, carbonylalkyloxyalkyl, carbonylalkylthio, carbonylalkylthioalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocycloalkyl, acyl, alkylthioalkyl, alkyloxyalkyl, alkenylthio, alkynylthio, alkenyloxy, alkynyloxy, alkenylthioalkyl, alkenyloxyalkyl, alkynyloxyalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkylarylalkynyloxy, alkylarylalkenyloxy, alkylarylalkynylthio, alkylarylalkenylthio, haloalkylcarbonyl, alkoxyalkyl, alkylaminocarbonylalkyl
  • N-alkyl-N- arylaminoalkyl, aminoalkoxy, aminoalkoxyalkyl, aminoalkylthio, aminoalkylthioalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylthio, cycloalkylalkylthio, aryloxy, aralkoxy, arylthio, aralkylthio, aralkylsulfinyl, alkylsulfonyl aminosulfonyl, N- alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminosulfonyl, N- alkyl-N-arylaminosulfonyl, or Y represents following groups
  • Ar is selected from aryl and heteroaryl, Ar may be optionally substituted with one or two substituents selected from halo, hydroxyl, mercapto, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfmyl, alkylamino, dialkylamino, haloalkyl, alkoxycarbonyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy, carbamoylalkoxy, alkoxycarbonylalkoxy, and where R 1 is one or more substituents selected from heterocycle, cycloalkyl, cycloalkenyl, and aryl, R 1 may be optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano,
  • R 3 , R 4 R 5 , R 8 and n are as defined above
  • German patent DE 19533643 discloses compounds of formula (Ilk)
  • A is O, S or NH;
  • R 1 is optionally substituted cycloalkyl, aryl or heteroaryl;
  • R is hydrogen, optionally substituted alkyl, aralkyl, aryl, heteroaryl, or (CH 2 ) n -X;
  • m is 0-2;
  • n is 0-8;
  • X is halo, NO 2 , optionally substituted OH, COH, COOH, OCOOH, CONHOH, CONH 2 , SH, S(O)H, SO 2 H, NH 2 , NHCOH or NHSO 2 H or CN;
  • R 6 is optionally substituted (C,
  • R 2 is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxy, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonyl, cyanoalkenyl and hydroxyalkyl; wherein R 3 is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl, and halo; R 4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocychc, R is optionally substituted at a substitutable position with one or more radicals selected from halo, alkyl,
  • R is methylsulfonylphenyl, aminosulfonylphenyl or alkylaminosulfonylphenyl and the other is 5-7carbon cycloalkyl optionally substituted by alkyl, thienyl or furyl optionally substituted by alkyl or halo; R 2 is lower alkyl.
  • R is methylsulfonylphenyl, aminosulfonylphenyl or alkylaminosulfonylphenyl and the other is 5-7carbon cycloalkyl optionally substituted by alkyl, thienyl or furyl optionally substituted by alkyl or halo;
  • R 2 is lower alkyl.
  • the main objective of the present invention is therefore, to provide novel compounds and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
  • Another objective of the present invention is to provide novel compounds and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
  • Yet another objective of the present invention is to produce a process for the preparation of novel compounds and their derivatives of the formula (I) as defined above, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
  • Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their regioisomers, their polymo ⁇ hs, their salts, solvates or their mixtures in combination with pharmaceutically acceptable carriers, solvents, diluents and other media normally employed in preparing such compositions, optionally containing one or more ingredients such as another analgesic agent like acetaminophen of phenacetin, a potentiator like caffeine, a H 2 antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant such as phenylephrine, phenyl propanolamine, pseudophedrine, oxymetazoline, epinephrine, nephazoline, propylhexadrine or leavo-desoxyephedrine, xylomatazoline, a sedating or non sedating antihist
  • the present invention also provides a method for the treatment of cyclooxygenase mediated diseases consisting of administering a patient in need thereof, a nontoxic therapeutically effective amount of compound of formula (I) or pharmaceutical composition described above.
  • the present invention relates to compounds having the general formula (I)
  • Suitable groups represented by R 1 may be selected from amino, hydrazino, which may be substituted; hydrazido, which may be substituted; aminoacid residue, wherein the aminoacid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; substituted or unsubstituted linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; alkylamino group such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino and the like, which may be substituted; acylamino groups such as NHCOCH 3 , NHCOC 2
  • the substituents may be selected from halogen atom such as chlorine, fluorine, bromine or iodine; hydroxy, nitro, amino, cyano, alkyl, alkoxy, acyl, aryl, aralkyl or heteroaryl groups.
  • Suitable groups represented by R 2 may be selected formyl, cyano, nitro, azido, thio, oximealkyl groups such as oximemethyl, oximeethyl, oximepropyl and the like; halo(C ⁇ -C 6 )alkyl, which may be substituted; (C ⁇ -C 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; halo( - C 6 )alkoxy, which may be substituted; hydroxy(C ⁇ -C6)alkyl, which may be substituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; amino(G-C6)alkyl, which may be substituted; thio( -C 6 )alkyl, which may be substituted; hydra
  • the substituents may be selected from halogen atom such as chlorine, fluorine, bromine or iodine; hydroxy, nitro, amino, thio, cyano, alkyl, haloalkyl, haloalkoxy, acyl, acyloxy, aryl, alkoxy, aralkyl, aralkoxy or carboxy groups.
  • halogen atom such as chlorine, fluorine, bromine or iodine
  • Suitable groups represented by R 3 may be selected from hydrogen, halogen atom such as chlorine, fluorine, bromine or iodine; hydroxy, nitro, cyano, azido, hydrazino, which may be substituted; hydrazinoalkyl groups such as hydrazinomethyl, hydrazinoethyl, hydrazinopropyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazidoalkyl such as hydrazidomethyl, hydrazidoethyl, hydrazidopropyl and the like, which may be substituted; aminoacid residue, wherein the aminoacid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n- propyl, isopropyl
  • Suitable groups represented by R 4 , R 5 and R 6 are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, thio, oxo, hydroxylamino, substituted or unsubstituted linear or branched (C ⁇ -C 6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; (C ⁇ -C 6 )alkoxy such as methoxy, ethoxy, propoxy, butoxy and the like, the alkoxy groups may be substituted; acyl group such as formyl, acetyl, propanoyl, benzoyl and the like; the acyl group may be substituted; acyloxy group such as OCOMe,
  • Suitable substituents on the groups represented by R 4 , R 5 and R 6 are selected from halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, optionally halogenated (C ⁇ -C 6 )alkyl, optionally halogenated (G-C 3 )alkoxy, acyl, amino, acylamino, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonylamino, heteroaralkoxycarbonylamino, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, monoalkylamino, dialkylamino, arylamino, aralkylamino, amino
  • Suitable ring structures formed by pyrazole fused with R 4 may be selected from benzothiopyranopyrazolyl, benzopyranopyrazolyl, benzindazolyl, naphthopyrazolyl, dihydrobenzindazolyl, dihydronapthopyrazolyl, dihydroindenopyrazolyl, dihydroindanopyrazolyl, benzopiperidinopyrazolyl, benzopiperidinopyrazolyl, pyranopyrazolyl and the like.
  • salts derived from inorganic bases such as Li, Na, K, Ca, M, Fe, Cu, Zn, Mn
  • salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2- diethylaminoethanol, 2-dimethylaminoethanol, N-ethymo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, mo ⁇ holine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'- diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline,
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Representative compounds according to the present invention are selected from : 4-[5-(4-Methoxy-3-methylphenyl)-3-trifluoromethyl- 1 H-pyrazol- l-yl]-2- hydroxymethyl-1 -benzene sulfonamide ;
  • solvents such as toluene, DMF, dioxane, THF, isopropanol, ethanol, DMSO, DCM
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as He, N 2 , Ar and the like.
  • the reaction may be carried out in the presence of a catalyst such as bis(triphenyl phosphine)palladium(II)chloride, 1 ,4-bis(diphenyl phosphine butane)palladium (I ⁇ )chloride, bis(dibenzylideneacetone)palladium(o), palladium acetate, palladium acetate-tri(o-tolyl)phosphine, bis(acetonitrile)palladium(II)chloride, palladium on carbon + triphenyl phosphine, tetrakis(triphenylphosphine)palladium(o) and the like.
  • a catalyst such as bis(triphenyl phosphine)palladium(II)chloride, 1 ,4-bis(diphenyl
  • the amount of catalyst used may range from 0.1 mol% to 50 mol%, preferably from 1 to 10 mol%.
  • the reaction may be effected in the presence of a base such as alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal bicarbonates like sodium bicarbonate or potassium bicarbonate; organic bases like triethylamine, pyridine, DMAP or di- isopropylethylamine and the like.
  • the amount of base may range from 1 to 20 equivalents, preferably the amount of base ranges from 1 to 5 equivalents.
  • Phase transfer catalysts such as tetraalkylammonium halide, benzyl triethylammonium halide, benzyl tributylammonium halide, tetraalkylammonium bisulfate, benzyl triethylammonium bisulfate or benzyl tributylammonium bisulfate may be employed.
  • the amount of phase transfer catalyst used may range from 0.01 equivalents to 1 equivalent, preferably from 0.05 to 0.5 equivalents.
  • the reaction temperature may range from 0 °C to reflux temperature of the solvent, preferably from 30 °C to reflux temperature of the solvent.
  • the duration of the reaction may range from 0.5 to 76 hours, preferably from 6 hours to 24 hours.
  • the compounds of general formula (I) where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m are as defined earlier can be prepared by any of the following routes shown in Scheme 2 below :
  • reaction of a compound of general formula (II- 1) where L 3 represents halogen atom such as fluorine, chlorine, bromine or iodine, and all other symbols are as defined earlier with a compound of formula (II-2) where R 4 , R 5 and R 6 are as defined earlier or the reaction of a compound of formula (II-3) where all symbols are as defined earlier with a compound of formula (II-4) where L 3 represents halogen atom such as fluorine, chlorine, bromine or iodine and R 4 is as defined earlier may be carried out in the presence of solvents such as DMSO, DMF, DMA, DME, THF, dioxane, alcohols such as (C ⁇ -C 4 ) linear or branched alcohols like methanol, ethanol, propanol, isopropanol and the like DCM, acetonitrile, water and the like or mixtures thereof.
  • solvents such as DMSO, DMF, DMA, DME, THF, dio
  • the reaction may be effected in the presence of a base such as metal hydrides like NaH or KH; organolithiums like CH 3 Li or BuLi; alkoxides such as NaOMe, NaOEt, NaOiBu, t-BuOK or sodium amyloxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal bicarbonate like sodium bicarbonate or potassium bicarbonate; organic bases like TEA, pyridine, DMAP, DIPEA or DBU; hydroxides like NaOH or KOH and the like.
  • the amount of base may range from 1 to 10 equivalents, preferably the amount of base ranges from 1 to 5 equivalents.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as He, N 2 , Ar and the like.
  • Phase transfer catalysts such as tetraethylammonium halide, benzyl triethylammonium halide, tetraethylammonium bisulfate, benzyl triethylammonium bisulfate and the like, may be employed and they may be used in the range of 0.01 to 1.5 equivalents, preferably 0.05 to 0.50 equivalents.
  • the reaction may be more effective under anhydrous conditions.
  • the reaction temperature may be in the range of -78 °C to reflux temperature of the solvent used, preferably at a temperature in the range of 0 °C to reflux temperature of the solvent.
  • the duration of the reaction may range from 1 to 80 hours, preferably from 2 to 50 hours.
  • the compounds of general formula (I) where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and m are as defined earlier can be prepared by following the routes shown in Scheme 3 below :
  • the compound of formula (III-l) may be used as the salts of mineral acids such as HCl, H SO 4 , and the like or organic acids such as p-toluene, sulfonic acid, acetic acid, trifluoroacetic acid and the like.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as He, N 2 , Ar and the like.
  • the amount of compound of formula (III-2) or (III-3) may range from 1 to 3 equivalents, preferably 1 to 1.5 equivalents.
  • the reaction may be facilitated by azeotropic removal of water using a Dean Stark water separator.
  • the reaction temperature may be in the range of 0 °C to reflux temperature of the solvent used, preferably at a temperature in the range of 20 °C to reflux temperature of the solvent.
  • the duration of the reaction may range from 2 to 20 hours.
  • the compound of formula (I) where R 1 represents amino group, m represents 2 and all other symbols are as defined above may be prepared by transforming a compound of formula (I) where R 1 represents lower alkyl group, m represents 2 and all other symbols are as defined earlier in the presence of a Grignard reagent like MeMgCl, MeMgBr, EtMgCl or a base such as nBuLi, LiNH 2 or LDA.
  • a Grignard reagent like MeMgCl, MeMgBr, EtMgCl or a base such as nBuLi, LiNH 2 or LDA.
  • the reaction may be carried out in the presence of trialkyl borane such as triethyl borane or tributyl borane in the presence of a solvent such as dioxane, diethylether, diisobutylether, diphenylether, THF and the like or mixtures thereof.
  • the reaction may be carried out in inert atmosphere which may be maintained by using Ar, N or He.
  • the reaction may be carried out in the temperature range of -78 °C to the reflux temperature of solvent used, preferably at 0 °C to reflux temperature of the solvent used
  • the reaction may be more effective under anhydrous condition.
  • the duration of the reaction may be in the range of 12 to 72 hours, preferably in the range of 15 to 24 hours.
  • the oxidative amination reaction may be carried out in the presence of hydroxylamine-O sulfonic acid and NaOAc.
  • the temperature range of 0 °C to reflux temperature of the solvent, preferably 0 °C to 50 °C may be used.
  • the duration of the reaction may be 2 to 20 hours, preferably 2 to 10 hours.
  • the compound of formula (I) where all symbols are as defined earlier and m represents 0 may be prepared by reducing a compound of formula (I) where all symbols are as defined earlier and m represents 1 or 2.
  • the reduction may be carried out using reagents such as LAH, HI, Bu 3 SnH, TiCl 2 , MeSiCl 3 , Nal, PC1 3 , H 2 -Pd-C, acetyl chloride, PPh 3 , t-BuBr and tris(dimethylamino)phosphine-I .
  • the reduction may also be carried out using diisobutyl aluminium hydride[(iBu) 2 AlH], LAH according to the procedure described in J.O.C.48,1617(1983).
  • the compound of formula (I) where all symbols are as defined earlier and m represents 1 (sulfoxide) or m represents 2 (sulfone) may be prepared by oxidising a compound of formula (I) where all symbols are as defined earlier and m represents 0 with a suitable oxidising agent.
  • the oxidation of a compound of formula (I) where m is 0 may be carried out in the presence of an oxidising agent such as 30 % H O 2 , m-CPBA, oxone, NaIO 4 , KMnO , sodium perborate.
  • the quantity of the reagent varies from 2 mol to 20 mol preferably 4 to 10 mol.
  • the reaction may be effective in presence of a solvent such as CHC1 3 , t-Butanol, CH 2 C1 2 , CH 3 COOH, acetone, water and the like or mixtures thereof. Water may be used as cosolvent.
  • the reaction may be carried out in inert atmosphere which may be maintained by using He, N 2 or Ar.
  • the reaction may be carried out at temperature in the range of 0 °C to 150 °C, preferably in the range of 30 °C to 120 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • the compound of formula (III- la) where R is hydrogen, L represents halogen atom such as fluorine or chlorine and R 3 is as defined earlier may be converted to a compound of formula (III- lb) where R 2 is hydrogen, L 3 represents halogen atom such as fluorine or chlorine and R 3 is as defined earlier using chlorosulfonic acid either neat or mixed with chlorinated solvents such as chloroform, DCM and the like or mixtures thereof.
  • the amount of chlorosulfonic acid varies from 2 equivalents to 10 equivalents, preferably 3 equivalents to 5 equivalents.
  • the temperature of the reaction may vary from - 20 °C to the reflux temperature of the solvent used, preferably from -10 °C to 30 °C.
  • the duration of the reaction may vary from 0.5 h to 10 h, preferably from 2 h to 5 h. The reaction may be more effective under anhydrous conditions.
  • reaction of compound of formula (III- lb) defined above with t-butylamine to produce a compound of formula (III-lc) where R is hydrogen or lower alkyl, L represents halogen atom such as fluorine or chlorine and R 3 is as defined earlier may be carried out neat or in the presence of solvents such as dichloromethane, chloroform, ethyl acetate, toluene benzene, DMF, DME, DMAc, THF, dioxane, DMSO and the like or mixtures thereof.
  • the quantity of t-butylamine may vary from 1 equivalents to 20 equivalents, preferably from 2 - 5 equivalents.
  • the reaction may be carried out in an inert atmosphere which is maintained using inert gases such as N , He or Ar.
  • the temperature of the reaction may vary from -10 °C to reflux temperature of the solvent used, preferably from -5 °C to 35 °C.
  • the duration of reaction may range from 1 h to 10 h, preferably from 1 h to 5 h.
  • the reaction may also be carried out using phase transfer catalyst in the quantity ranging from 0.05 to 1.5 equivalent preferably 0.05 equivalent to 1.0 equivalent.
  • the reaction may be more effective under anhydrous conditions.
  • the conversion of compound of formula (III-lc) where R ⁇ is hydrogen and other symbols are as defined above to a compound of formula (III- Id) where R represents hydrogen or alkyl group, L 3 represents halogen atom such as fluorine or chlorine and R 3 is as defined earlier may be carried out using organolithium base such as n-butyl lithium, sec-butyl lithium or t-butyl lithium and electrophilic equivalent reagent such as DMF, acid anhydride, DMAc, esters or orthoesters.
  • the quantity of the organo lithium base and the electrophilic equivalent reagent may vary from 1 equivalents to 10 equivalents, preferably from 1.5 equivalents to 3.5 equivalents.
  • the reaction may be carried out in the presence of solvents like diethylether, THF and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained using inert gases such as He, N or Ar.
  • the temperature of the reaction may vary from -78 °C to the reflux temperature of solvent used, preferably from -78 °C to 40 °C.
  • the duration of the reaction varies from 1 h to 50 h, preferably from 2 h to 24 h.
  • the reaction may be more effective under anhydrous conditions.
  • halogenating agent such as thionyl chloride, phosphorousoxy chloride, phosphoruspenta chloride, carbon tetra chloride-TPP mixture, N-chlorosuccinimide, N-bromosuccinimide and the like.
  • the quantity of halogenating agent may vary from 0.5 to 2.5 equivalents, preferably, from 0.75 to 1.5 equivalents.
  • the reaction may be carried out in the presence of dry CC-U, benzene and the like.
  • the reaction may be carried out in an inert atmosphere which may be maintained using inert gases such as He, N or Ar.
  • the reaction may be carried out using radical initiators selected form benzoyl peroxide, light, or 2,2-azobis-isobutyronitrile in the quantity ranging from 0.05 to 1.5 equivalents.
  • the temperature of the reaction may vary from 25 °C to reflux temperature of the solvent used.
  • the duration of the reaction varies from 1 h to 50 h, preferably from 2 h to 24 h.
  • the reaction may be more effective under anhydrous conditions.
  • the reduction of compound of formula (III- Id) defined above to a compound of formula (III- If) where R represents hydrogen or alkyl group, L 3 represents halogen atom such as fluorine or chlorine and R 3 is as defined earlier may be carried out using reducing agents such as sodium borohydride, lithium borohydride, Na-Ethanol and the like.
  • the quantity of the reducing agent may vary from 0.25 equivalents to 2.5 equivalents, preferably from 0.25 equivalents to 1 equivalents.
  • the reaction may be carried out in the presence of solvents such as THF, dioxane, alcohol (C ⁇ -C , linear or branched) like methanol, ethanol or IP A, water or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such N 2 , Ar or He.
  • the temperature of the reaction may range from -20 °C to the reflux temperature of the solvent used, preferably from -10 °C to 50 °C.
  • the duration of the reaction may vary from 0.5 h to 50 h, preferably from 1 h to 20 h.
  • the reaction may be more effective under anhydrous conditions.
  • the reduction may also be carried out in situ after neutralizing the reaction mass (1 g) with 1N-HC1 solution at -20 °C to 50 °C.
  • the compound of formula (III- If) may be prepared directly from (III-lc).
  • the reaction may be carried out using organo lithium base such as n-butyl lithium, sec-butyl lithium or t-butyl lithium and aldehydes such as paraformaldehyde, acetaldehyde, methoxyacetaldehyde and the like.
  • the quantity of the organo lithium base and the electrophillic equivalent reagent may vary from 1 equivalents to 10 equivalents, preferably from 1.5 equivalents to 3.5 equivalents.
  • the reaction may be carried out in the presence of solvents like diethylether, THF and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as He, N 2 or Ar.
  • the temperature of the reaction may vary from -78 °C to the reflux temperature of solvent used, preferably from -78 °C to 40 °C.
  • the duration of the reaction varies from 1 h to 50 h, preferably from 2 h to 24 h.
  • the reaction may be more effective under anhydrous conditions.
  • the compound of formula (Ill-le) defined above may be converted to a compound of formula (III- If) using solvents such as acetone, methanol, ethanol and the like or mixtures thereof.
  • the reaction may be effected in the presence of reagents like sodium formate or potassium formate.
  • the quantity of the reagent may vary from 1 equivalent to 20 equivalent, preferably from 2 - 10 equivalents.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such N 2 , Ar or He.
  • the reaction temperature may range from 25 °C to the reflux temperature of solvent used.
  • the duration of the reaction may vary from 1 h to 50 h, preferably from 5 - 20 h and the reaction may be more effective under anhydrous conditions.
  • the conversion of compound of the formula (III- If) to a compound of formula (Ill-lg) may be carried out in the presence of solvents such as benzene, toluene, xylene and the like or mixtures thereof.
  • the reaction may be effected in the presence of an acid catalyst such as p-TSA, TFA, acetic acid, H 2 SO 4 , HCl and the like.
  • the quantity of the acid catalyst used may vary from 0.05 equivalent to 2.5 equivalent, preferably 0.1 to 1.0 equivalent.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such N 2 , Ar or He.
  • the temperature of reaction may range from 30 °C to the reflux temperature of the solvent used and the duration of the reaction may vary from 1 h to 30 h, preferably from 2 h to 20 h.
  • the reaction may be more effective under anhydrous conditions.
  • the compound of formula (III-l) where all symbols are as defined above may be prepared by reacting a compound of formula (Ill-lg) with hydrazine.
  • the reaction may be carried out in neat or in the presence of solvents such as DMSO, DMF, acetonitrile, linear or branched (C ⁇ -C 4 )alcohol such as methanol, ethanol, isopropanol and the like; DCM, CHCI 3 , aromatic hydrocarbons such as benzene, toluene or xylene and the like or mixtures thereof.
  • solvents such as DMSO, DMF, acetonitrile, linear or branched (C ⁇ -C 4 )alcohol such as methanol, ethanol, isopropanol and the like; DCM, CHCI 3 , aromatic hydrocarbons such as benzene, toluene or xylene and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as He, N 2 or Ar.
  • the reaction temperature may range from 20 °C to the reflux temperature of the solvent used.
  • the duration of reaction
  • the reaction of a compound of formula (Ill-lh) where L 3 represents fluorine or chlorine and R 3 is as defined earlier to produce a compound of formula (Ill-li) may be carried out using elcetrophilic equivalent reagents such as dry CO 2 in presence of organo lithium base such as n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like, preferably n-butyl lithium.
  • organo lithium base such as n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like, preferably n-butyl lithium.
  • the reaction may be carried out in the presence of solvents such as dry diethyl ether, THF and the like or mixtures thereof.
  • the quantity of organolithium base may vary from 1 to 5 equivalents, preferably from 1.2 equivalent to 2.5 equivalents.
  • the dry CO 2 slurry may be used in any quantity.
  • the reaction may be carried out in an inert atmosphere which is maintained using inert gases such as He, N 2 or Ar.
  • the reaction temperature may range from range of -78 °C to 40 °C for the period in the range of 1 h to 24 h.
  • the reaction may be more effective under anhydrous conditions. Neutralization with cone, or dilute mineral acids like HCl, H 2 SO 4 may be necessary, but it is not essential.
  • the conversion of compound of the formula (Ill-li) defined above to a compound of formula (III-lj) where L 3 represents fluorine or chlorine and R 3 is as defined earlier may be carried out in the presence of solvents such as benzene, toluene, xylene and the like or mixtures thereof.
  • the reaction may be effected in the presence of acid catalysts such as p-TSA, TFA, acetic acid, H 2 SO 4 , HCl and the like.
  • the quantity of the acid catalyst used may vary from 0.05 equivalent to 2.5 equivalent, preferably 0.1 to 1.0 equivalent.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such N 2 , Ar or He.
  • the temperature of reaction may range from 30 °C to the reflux temperature of the solvent used and the duration of the reaction may vary from 1 h to 30 h, preferably from 2 h to 20 h.
  • the reaction may be more effective under anhydrous conditions.
  • the conversion of compound of formula (III-lj) defined above to an ester of formula (III- Ik) where R' represents alkyl group, L 3 represents fluorine or chlorine and R 3 is as defined earlier may be carried out in the presence of alcohol such as (C ⁇ -C 4 linear or branched) alcohol like methanol, ethanol, isopropanol and the like, using metal catalyst such as Zn, Sn and the like or an acid catalyst such as p-TSA, H SO 4 , HCl, TFA, acetic acid and the like or mixtures thereof.
  • the amount of acid catalyst may vary from 0.05 to 10 equivalents, preferably from 0.05 to 5.0 equivalents.
  • the amount of metal catalyst may vary from 0.01 to 20 equivalents, preferably from 0.01 - 0.50 equivalents.
  • the temperature of the reaction may range from 0 °C to the reflux temperature of the solvent used, preferably from 20 °C to reflux temperature of the solvent.
  • the duration of the reaction may vary from 1 h to 50 h, preferably from 1 h to 24 h. The reaction may be more effective under anhydrous conditions.
  • the conversion of compound of formula (III- Ik) defined above to a compound of formula (II- 1) where R 2 represents hydroxyalkyl, L 3 and R 3 are as defined above may be carried out in the presence of solvents such as THF, dioxane, (C ⁇ -C 4 linear or branched) alcohol like methanol, ethanol, isopropanol and the like or mixtures thereof.
  • solvents such as THF, dioxane, (C ⁇ -C 4 linear or branched) alcohol like methanol, ethanol, isopropanol and the like or mixtures thereof.
  • the reaction may be carried out in the presence of reagents such as lithium borohydride, sodium borohydride and the like or mixtures thereof.
  • the amount of the reagent may range from 0.1 to 5 equivalents, preferably from 0.1 - 2.0 equivalents.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such N 2 , Ar or He.
  • the temperature of the reaction may vary from 0 °C to the reflux temperature of the solvent used and the duration from 1 h to 80 h, preferably from 5 h to 50 h.
  • the reaction may be more effective under anhydrous conditions.
  • the conversion of compound of formula (II- 1) defined above to a compound of formula (III-l) where all symbols are as defined above may be carried out with hydrazine.
  • the reaction may carried out using solvents such as DMSO, DMF, acetonitrile, (C ⁇ -C 4 linear or branched)alcohol such as methanol, ethanol, isopropanol and the like; DCM, CHC1 3 , aromatic hydrocarbons such as benzene, toluene or xylene and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained using inert gases such as He, N or Ar.
  • the reaction temperature may range from 20 °C to the reflux temperature of the solvent used.
  • the duration of reaction may vary from 5 h to 100 h, preferably from 20 h to 75 h.
  • the quantity of hydrazine may vary from 1 equivalent to 50 equivalent, preferably 5 - 20 equivalents.
  • the reaction may be more effective under anhydrous conditions.
  • the compound of formula (Ill-lm) where all symbols are as defined earlier may be prepared from p-fluoro sulfonylamide of formula (III- 11) using alkyl lithium base such as n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like.
  • alkyl lithium base such as n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like.
  • the reaction may be carried out in the presence of solvents such as diethylether, THF, and the like or mixtures thereof.
  • the amount of base may vary from 1-10 equivalents, preferably from 1.5 to 3 equivalents.
  • the reaction may carried out in an inert atmosphere which may be maintained using inert gases such as He, Ar, N 2 and the like.
  • the reaction temperature may range from -78 °C to reflux temperature of the solvent used, preferably from -78 °C to 30 °C.
  • the reaction may be quenched with halogen such as iodine or bromine.
  • the quantity of the halogen may vary from 1 to 10 equivalents, preferably from 1.5 to 3 equivalents. Quenching may be carried out in an inert atmosphere at a temperature ranging from -78 °C to reflux temperature of the solvent used, preferably from -78 °C to 30 °C.
  • the compound of formula (III- In) where L is a ligand such as triarylphosphine and the like may be prepared by reacting the compound of formula (Ill-lm) using palladium catalyst such as tetrakis triphenyl phosphine palladium or palladium acetate in the presence of triphenyl phosphine.
  • palladium catalyst such as tetrakis triphenyl phosphine palladium or palladium acetate
  • the amount of catalyst varies from 2 to 20 mol %, preferably from 4-8 mol %.
  • the reaction may be carried out in the presence of a solvent such as DMF, DMSO and the like.
  • the compound of formula (III- In) may be coupled with a terminal alkyne to produce a compound of formula (III-lo) where R" represents alkyl, aryl, hydroxyalkyl, alkoxy or alkoxycarbonyl groups and all other symbols are as defined above.
  • the quantity of terminal alkyne may range from 1 to 10 equivalents, preferably from 2 to 5 equivalents.
  • the reaction may be carried out in the presence of a base such as ethylamine, diethylamine, triethylamine and the like.
  • the amount of base may range from 1 to 10 equivalents, preferably from 1.5 to 3 equivalents.
  • the reaction may be carried out in an inert atmosphere which may be maintained using inert gases such as He, Ar, N 2 and the like.
  • the temperature of the reaction may range from 40-150 °C, preferably from 80-120 °C.
  • the reaction may be more effective in the presence of 2-20 mol % copper halide such as CuBr, C
  • reaction of compound of formula (III- In) may be carried out under carbon monoxide atmosphere to afford compound of formula (Ill-lq) where R" represents alkyl, aryl, hydroxyalkyl, alkoxy or alkoxycarbonyl groups and all other symbols are as defined above.
  • the reaction may be carried out in the presence of solvents such as methanol, ethanol, propanol, butanol, and the like.
  • the temperature of the reaction may range from 40-150 °C, preferably from 80-120 °C.
  • the reaction may be more effective under anhydrous conditions.
  • the compound of formula (III-lp) may be produced by reducing the compounds of formula (III-lo) or (Ill-lq) using suitable reducing agent.
  • the reduction may be carried out in the presence of catalyst such as Raney nickel, palladium/charcoal, platinum or its oxide and the like.
  • the quantity of the catalyst may vary from 5 to 50 % of the amount of the substrate, preferably from 8-20 %.
  • the reaction may effective in the presence of solvents such as ethyl acetate, methanol, ethanol. isopropanol, butanol, acetic acid, water and the like or mixture thereof.
  • the reduction is carried out under hydrogen atmosphere, the pressure vary from normal atmosphere to 25 psi.
  • the reaction may be more effective in the presence of inert atmosphere which may be maintained by using inert gases such as He, Ar, N 2 and the like.
  • the reaction temperature may range from -78 °C to reflux temperature of the solvent used, preferably from -78 °C to 30 °C.
  • the reduction of compound of formula (Ill-lq) to produce compound of formula (III-lp) where n represents 1, and all other symbols are as defined earlier may be carried out using LiAlH 4 , LiBEL, NaBH , and the like, in the quantity vary from 2-20 equivalents, preferably from 4-8 equivalents.
  • the reaction may effective in the presence of solvents such as THF, diethylether and the like.
  • the conversion of compound of formula (III-lp) defined above to a compound of formula (III-l) where all symbols are as defined above may be carried out with hydrazine.
  • the reaction may carried out using solvents such as DMSO, DMF, acetonitrile, (C ⁇ -C 4 linear or branched)alcohol such as methanol, ethanol, isopropanol and the like; DCM, CHC1 3 , aromatic hydrocarbons such as benzene, toluene or xylene and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as He, N or Ar.
  • the reaction temperature may range from 20 °C to the reflux temperature of the solvent used.
  • the duration of reaction may vary from 5 h to 100 h, preferably from 20 h to 75 h.
  • the quantity of hydrazine may vary from 1 equivalent to 50 equivalent, preferably 5 - 20 equivalents.
  • the reaction may be more effective under anhydrous conditions.
  • the compounds of formula (III-l) where R represents alkyl group, R represents hydroxyalkyl, R represents a group inert to the bases like organolithium and m is an integer 1 or 2 may be prepared by a process shown in the Scheme - 7 below :
  • the conversion of compound of formula (Ill-lr) where R z is hydrogen, ⁇ represents halogen atom such as fluorine, chlorine, bromine or iodine and R 3 is as defined above to a compound of formula (III- Is) where R 1 represents alkyl, R 2 represents hydrogen, R 3 is as defined earlier, may be carried out in neat using alkyl halides or alkyl sulfate.
  • the reaction may be carried out in the presence of solvents such as DMF, DMAc, DMSO, acetone, methanol, ethanol, isopropanol, DME, and the like or mixtures thereof.
  • the reaction may be effective in heterophase using water as a cosolvent.
  • the amount of alkyl halides or alkyl sulfates may vary form 1 to 20, preferably, from 1.5 to 5 equivalents.
  • the reaction may be carried out in the presence of base such as alkyl metal carbonates, bicarbonates, hydroxides and the like, in the quantity ranging form 1 to 10, preferably, from 1.5 to 5 equivalents.
  • the reaction may be carried out at a temperature in the range of 0 to reflux temperature of the solvent used.
  • the duration of the reaction may vary from 1 h to 50 h, preferably from 2 h to 20 h.
  • the reaction may be more effective under anhydrous conditions.
  • organolithium base such as n-butyl lithium, sec-butyl lithium or t-butyl lithium
  • electrophilic equivalent reagent such as DMF, acid anhydride, DMAc, esters or orthoesters.
  • the quantity of the organo lithium base and the electrophilic equivalent reagent may vary from 1 equivalents to 10 equivalents, preferably from 1.5 equivalents to 3.5 equivalents.
  • the reaction may be carried out in the presence of solvents like diethylether, THF and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as He, N 2 or Ar.
  • the temperature of the reaction may vary from -78 °C to the reflux temperature of solvent used, preferably from -78 °C to 40 °C.
  • the duration of the reaction varies from 1 h to 50 h, preferably from 2 h to 24 h.
  • the reaction may be more effective under anhydrous conditions.
  • the reduction of compound of formula (III- It) defined above to a compound of formula (III-lu) where R represents hydrogen or alkyl group, L 3 represents halogen atom such as fluorine, chlorine, bromine or iodine and all other symbols are as defined earlier may be carried out using reducing agents such as sodium borohydride, lithium borohydride, Na-ethanol and the like.
  • the quantity of the reducing agent may vary from 0.25 equivalents to 2.5 equivalents, preferably from 0.25 equivalents to 1 equivalents.
  • the reaction may be carried out in the presence of solvents such as THF, dioxane, alcohol (C ⁇ -C , linear or branched) like methanol, ethanol or IP A, water or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere, which is maintained by using inert gases such N 2 , Ar or He.
  • the temperature of the reaction may range from -20 °C to the reflux temperature of the solvent used, preferably from -10 °C to 50 °C.
  • the duration of the reaction may vary from 0.5 h to 50 h, preferably from 1 h to 20 h.
  • the reaction may be more effective under anhydrous conditions.
  • oxidation of compound of formula (III-lu) defined above to produce a compound of formula (III-lv) where L 3 represents fluorine, chlorine, iodine or bromine and all other symbols are as defined above may be carried out using oxidising agents such as hydrogen peroxide, potassium permanganate, m-CPBA, NaIO 4 , t-BuOCl, sodium perborate, potassium hydrogen persulfate, oxone, KHSO 5 and the like.
  • the quantity of oxidising agent used may vary from 1 to 20 equivalents, preferably 2 - 10 equivalents.
  • the reaction may be carried out in the presence of solvents such as glacial acetic acid, propionic acid, acetone, t-butanol, water and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained using inert gases such as He, N 2 or Ar.
  • the reaction temperature may range from 20 °C to the reflux temperature of the solvent used, preferably from 50 °C to the reflux temperature of the solvent used.
  • the duration may vary from 15 min to 15 h, preferably from 15 min to 3 h.
  • the compound of formula (III-l) where all symbols are as defined above may be prepared by reacting a compound of formula (III-lv) with hydrazine.
  • the reaction may be carried out in neat or in the presence of solvents such as DMSO, DMF, acetonitrile, linear or branched (C ⁇ -C 4 )alcohol such as methanol, ethanol, isopropanol and the like; DCM, CHCI 3 , aromatic hydrocarbons such as benzene, toluene or xylene and the like or mixtures thereof.
  • solvents such as DMSO, DMF, acetonitrile, linear or branched (C ⁇ -C 4 )alcohol such as methanol, ethanol, isopropanol and the like; DCM, CHCI 3 , aromatic hydrocarbons such as benzene, toluene or xylene and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which is maintained using inert gases such as He, N 2 or Ar.
  • the reaction temperature may range from 20 °C to the reflux temperature of the solvent used.
  • the duration of reaction may
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the compounds of formula (I) having CONH 2 groups may be transformed to CN by following a procedure disclosed in International publication WO No. 99/15505
  • the compound of formula (I) where R 1 represents SO 2 NH 2 may be transformed to 2,5,dimethyl-lH-pyrazolyl sulfone by following a procedure disclosed in International publication No. WO 96/25405.
  • the compound of formula (I) having CO 2 Et group may be transformed to CH 2 OH by following a procedure disclosed in International publication No. WO 95/15316.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) or its derivatives with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
  • the regioiosmers of compound of formula (I) may be prepared by modifying the reaction conditions, use of reagents like acid to base or base to acid or by reaction with free base hydrazine instead of its salt with diketone.
  • the molar proportion also can change the regiosiomer formation.
  • polymo ⁇ hs of compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymo ⁇ hs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymo ⁇ hs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the compounds of the general formula (I) are useful as partial or complete substitute for NSAIDS in compositions or preparations wherein they are presently coadministered with other agents or ingredients.
  • the present invention also comprises pharmaceutical compositions for treating cyclooxygenase mediated diseases as defined earlier, comprising a non-toxic therapeutically effective amount of the compound of formula (I) as defined above and pharmaceutically acceptable earner and optionally containing one or more other therapeutic ingredients such as another analgesic agent like acetaminophen of phenacetin, a potentiator like caffeine, a H 2 antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant such as phenylephrine, phenyl propanolamine, pseudophedrine, oxymetazoline, epinephrine, nephazoline, propylhexadrine or leavo-desoxyephedrine, xylomatazoline, a sedating or non sedating
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatine or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin or as soft gelatine capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl or n-propyl, p-hydroxybenzoate
  • flavouring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or di glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (I) are employed.
  • topical application shall include mouth washes and gargles).
  • Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc.
  • the compound of the invention is effective in the treatment of humans.
  • reaction mixture was quenched with saturated N ⁇ t O solution (100 ml), pH adjusted to 6-7 by IN HCl and extracted with ethyl acetate (3 x 50 ml), dried, evaporated and chromatographed over silica gel column using mixture of ethyl acetate : pet. ether (10 : 90) to yield the title compound as viscous liquid (2.00 g, 85 %).
  • the reaction mixture was re-cooled to 0 - 5 °C and neutralized to pH 7.0 - 8.0 with IN HCl and sodium borohydride (120 mg, 3.2 mmol) was slowly added and stirred for further 1 hr.
  • the solvent was evaporated and the residue was suspended in water and extracted with ethyl acetate (25 ml). The combined ethyl acetate extracts were dried (Na 2 SO 4 ), filtered and the solvent was evaporated to yield the crude compound.
  • the crude compound was triturated with ether to yield the title compound (508 mg, 90 %), mp 148 °C.
  • the compounds of the present invention are tested in vitro for their COX-1 and COX-2 inhibitory activity using literature assay methods.
  • the efficacy of the compound in vivo have been tested in male Sprague-Dawley rats using rat carrageenan foot paw edema test (Proc. Soc. Exp. Biol. Med., 111, 544 (1962); Laboratory models for testing NSAIDS in non steroidal antiinflammatory drugs (J. Lombardino ed., 1985).
  • Microsomal fraction of ram seminal vesicles used as a source of cox-1 enzyme Hemler et al, 1976
  • microsomes from sf-9 cells infected with baculo virus containing human cox-2 c-DNA used as a source of cox-2 enzyme (Wanda et al., 1994).
  • Enzyme activity was measured using a chromogenic assay based on oxidation of N, N, N', N' - tetramethyl -p- phenylenediamine (TMPD) during the reduction of PGG 2 to PGH 2 as per the procedure described by Copeland et al., 1994 with following modifications.
  • TMPD chromogenic assay based on oxidation of N, N, N', N' - tetramethyl -p- phenylenediamine
  • the assay mixture (lOOO ⁇ l) contains 100 ⁇ M Tris pH 8.0, 3 ⁇ M EDTA, 15 ⁇ M hematin, 150 units enzyme and 8% DMSO. The mixture was pre-incubated at 25°C for 15 minutes before initiation of enzyme reaction in presence of compound/ vehicle. The reaction was initiated by the addition of lOO ⁇ M arachidonic acid and 120 ⁇ M TMPD. The enzyme activity is measured by estimation of the initial velocity of TMPD oxidation over the first 25 seconds of the reaction followed by increase in absorbency at 603 nM. The IC 50 values were calculated using non- linear regression analysis of percent inhibitions.
  • LPS lipopolysaccharide
  • DMSO 2.5 ⁇ l vehicle
  • test compound for 24 hours at 37°C.
  • PG ⁇ 2 levels in the plasma were measured using EIA kit (Cayman chemicals, USA) after deproteinization.
  • Hyperalgesia to mechanical compression of the hind paw of male Wistar rats was induced by intraplantar injection of carrageenan (2 mg per paw) 3 h before the study. Test compounds were given two hours after carrageenan injection. The vocalization response to compression of the carrageenan-injected paw was measured one hour later by analgesiometer (Ugo-Basile, Italy). For normal response one group was given intraplantar injection of saline. The percent hyperalgesia was calculated with difference in threshold in treated group versus control group compared to saline controls.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention concerne de nouveaux composés anti-inflammatoires, ainsi que leurs dérivés, analogues, formes tautomères, stéréo-isomères, régioisomères, polymorphes, sels pharmaceutiquement acceptables, solvats pharmaceutiquement acceptables et les compositions pharmaceutiquement acceptables les contenant. Plus précisément, l'invention concerne de nouveaux composés hétérocycliques de formule générale (I), ainsi que leurs dérivés, analogues, formes tautomères, stéréo-isomères, régioisomères, polymorphes, sels pharmaceutiquement acceptables, solvats pharmaceutiquement acceptables et les compositions pharmaceutiquement acceptables les contenant.
PCT/IB2000/000556 1999-05-03 2000-05-02 Pyrazoles presentant une activite anti-inflammatoire WO2000066562A1 (fr)

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AU43083/00A AU4308300A (en) 1999-05-03 2000-05-02 Pyrazoles having antiinflammatory activity

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WO2001042221A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Forme solide de celecoxib, presentant une biodisponibilite accrue
WO2001042222A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Formes polymorphes cristallines du celecoxibe
WO2001083475A1 (fr) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nouveaux composes heterocycliques a activite anti-inflammatoire
WO2003011316A1 (fr) * 2001-08-01 2003-02-13 Altana Pharma Ag Combinaison d'inhibiteur cox-2 selectif et tensioactif pulmonaire pour syndrome respiratoire
WO2003024935A2 (fr) * 2001-09-19 2003-03-27 Pharmacia Corporation Composes de pyrazolyle substitues destines au traitement de l'inflammation
EP1308158A1 (fr) * 2001-11-02 2003-05-07 Pfizer Productors Inc. Derives de sulfonylarylpyrazole et sulfonylheteroarylpyrazole possedant un substituant d'hydrazine ou d'oxyde d'azote en position-5 en tant qu'inhibiteurs de cyclooxygenase
EP1308445A1 (fr) * 2001-11-02 2003-05-07 Pfizer Products Inc. Derives de pyrazoles contenant d heteroatom en position 5
WO2004050632A1 (fr) * 2002-12-02 2004-06-17 Fujisawa Pharmaceutical Co., Ltd. Derives de pyrazole utiles comme inhibiteurs de cox-i
WO2004089911A1 (fr) * 2003-04-10 2004-10-21 Merck Sharp & Dohme Limited Derives de pyrazole utilises comme inhibiteurs de gamma-secretase dans le traitement de la maladie d'alzheimer
WO2004094411A1 (fr) * 2003-04-18 2004-11-04 Memory Pharmaceuticals Corporation Derives du pyrazole inhibiteurs de la phosphodiesterase 4
EP1507766A1 (fr) * 2002-05-24 2005-02-23 Pharmacia Corporation Synthese de diarylpyrazoles
WO2006044528A1 (fr) * 2004-10-15 2006-04-27 Memory Pharmaceuticals Corporation Derives de pyrazole utilises en tant qu'inhibiteurs de phosphodiesterase 4
US7211598B2 (en) * 2002-06-28 2007-05-01 Nitromed, Inc. Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2010050577A1 (fr) 2008-10-31 2010-05-06 東レ株式会社 Dérivé du cyclohexane et son utilisation pharmaceutique
EP2228369A1 (fr) 2003-12-23 2010-09-15 Astex Therapeutics Ltd. Derives de pyrazole comme modulateurs de proteine kinase
WO2011125836A1 (fr) 2010-03-31 2011-10-13 東レ株式会社 Agent thérapeutique ou agent prophylactique pour la fibromyalgie
WO2011125838A1 (fr) 2010-03-31 2011-10-13 東レ株式会社 Agent thérapeutique ou agent préventif pour les troubles de collecte de l'urine
WO2011136318A1 (fr) 2010-04-28 2011-11-03 東レ株式会社 Agent thérapeutique et agent conservateur contre la maladie d'alzheimer
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical compounds
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
US10653673B2 (en) 2013-08-16 2020-05-19 Janssen Pharmaceutica Nv Substituted imidazoles as N-type calcium channel blockers
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WO2001042222A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Formes polymorphes cristallines du celecoxibe
EP1528058A1 (fr) * 1999-12-08 2005-05-04 Pharmacia Corporation Formes cristallines polymorphes du célécoxibe
US6964978B2 (en) 1999-12-08 2005-11-15 Pharmacia Corporation Solid-state form of celecoxib having enhanced bioavailability
WO2001083475A1 (fr) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nouveaux composes heterocycliques a activite anti-inflammatoire
WO2003011316A1 (fr) * 2001-08-01 2003-02-13 Altana Pharma Ag Combinaison d'inhibiteur cox-2 selectif et tensioactif pulmonaire pour syndrome respiratoire
WO2003024935A3 (fr) * 2001-09-19 2003-08-21 Pharmacia Corp Composes de pyrazolyle substitues destines au traitement de l'inflammation
WO2003024935A2 (fr) * 2001-09-19 2003-03-27 Pharmacia Corporation Composes de pyrazolyle substitues destines au traitement de l'inflammation
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EP1308158A1 (fr) * 2001-11-02 2003-05-07 Pfizer Productors Inc. Derives de sulfonylarylpyrazole et sulfonylheteroarylpyrazole possedant un substituant d'hydrazine ou d'oxyde d'azote en position-5 en tant qu'inhibiteurs de cyclooxygenase
US6864252B2 (en) 2001-11-02 2005-03-08 Pfizer, Inc. Hydrazinyl and nitrogen oxide pyrazoles
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CN102858748B (zh) * 2010-04-28 2015-06-17 东丽株式会社 阿尔茨海默病的治疗剂或预防剂
CN102858748A (zh) * 2010-04-28 2013-01-02 东丽株式会社 阿尔茨海默病的治疗剂或预防剂
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EP2565184A4 (fr) * 2010-04-28 2013-09-11 Toray Industries Agent thérapeutique et agent conservateur contre la maladie d'alzheimer
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CN114555555A (zh) * 2019-10-16 2022-05-27 拜耳公司 制备1，1’-二硫烷二基双(4-氟-2-甲基-5-硝基苯)的方法
US20220348538A1 (en) * 2019-10-16 2022-11-03 Bayer Aktiengesellschaft Process of preparing 1,1'-disulfandiylbis(4-fluoro-2-methyl-5-nitrobenzol)
CN114555555B (zh) * 2019-10-16 2024-03-01 拜耳公司 制备1，1’-二硫烷二基双(4-氟-2-甲基-5-硝基苯)的方法

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