WO2000058280A1 - Derives de sulfonamide carbocyclique - Google Patents

Derives de sulfonamide carbocyclique Download PDF

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Publication number
WO2000058280A1
WO2000058280A1 PCT/JP2000/001710 JP0001710W WO0058280A1 WO 2000058280 A1 WO2000058280 A1 WO 2000058280A1 JP 0001710 W JP0001710 W JP 0001710W WO 0058280 A1 WO0058280 A1 WO 0058280A1
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Prior art keywords
optionally substituted
compound according
substituted
active ingredient
lower alkyl
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PCT/JP2000/001710
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English (en)
Japanese (ja)
Inventor
Fumihiko Watanabe
Yoshinori Tamura
Yasuhiko Kanda
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Shionogi & Co., Ltd.
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Priority to AU31963/00A priority Critical patent/AU3196300A/en
Publication of WO2000058280A1 publication Critical patent/WO2000058280A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a sulfonamide derivative having a carbon ring and a meta-protease inhibitor containing the same.
  • Extracellular matrix is composed of collagen, fibronectin, laminin, proteoglycan, etc., and plays a role in tissue support, cell proliferation, differentiation, adhesion and the like.
  • the degradation of extracellular matrix involves the meta-oral protease, which is a protease containing a metal ion in the active center, and particularly the matrix meta-oral protease (MMP).
  • MMP matrix meta-oral protease
  • MMMM inhibitors having a cyclic structure are described in WO98 / 07677, WO98 / 1655 ⁇ 6, WO98 / 337768, and the like.
  • MMP activity can be inhibited as described above, Therefore, development of MMP inhibitors has been desired.
  • the present invention provides a compound of the general formula (I):
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or a substituted A heteroarylalkyl;
  • R 2 is a single bond, optionally substituted arylene, or optionally substituted heteroarylene;
  • NH—,-SO z -NH-N CH
  • R A is hydrogen or lower alkyl, n is 1 or 2);
  • R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted Heteroaryl, or an optionally substituted non-aromatic complex ring;
  • M is NHOH, hydroxy, or lower alkyloxy; m is 0 or 1;
  • R 4 is not a substituted aryl, and when R 3 is —0—, M is not NHOH.] Or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 5 has the formula:
  • R 6 is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, Lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, optionally substituted heteroaryl, optionally substituted non-aromatic Heterocyclic, substituted Optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, or optionally substituted raid;
  • R 7 is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower anoalkylthio, norogen, nitro, cyano, carboxy, lower alkyl Oxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acryl, acryloxy, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted non-aromatic heterocyclic ring, optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, or optionally substituted ureido; q and r are each independently , 0, 1, 2, or 3;
  • X is an oxygen or sulfur atom
  • Y 1 is one C ⁇ C—or the formula:
  • optically active form thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 M and m are as defined above;
  • R 8 is of the formula: , Or
  • R 7 and r are as defined above.
  • ⁇ 2 is one C ⁇ C—or the formula:
  • R 8 is the formula:
  • VI I A pharmaceutical composition comprising the compound according to any one of I) to VI) as an active ingredient.
  • a female protease inhibitor comprising as an active ingredient the compound according to any one of I) to VI).
  • IX A matrix meta-oral protease inhibitor comprising as an active ingredient the compound according to any of I) to VI).
  • a therapeutic or prophylactic agent for cancer comprising the compound according to any one of I) to VI) as an active ingredient.
  • a therapeutic or prophylactic agent for nephritis comprising the compound according to any one of I) to VI) as an active ingredient.
  • XI I A therapeutic or prophylactic agent for osteoarthritis comprising the compound according to any one of I) to VI) as an active ingredient.
  • XI I An agent for treating or preventing heart failure, comprising the compound according to any one of I) to VI) as an active ingredient.
  • XI V An agent for treating or preventing rheumatoid arthritis, comprising as an active ingredient the compound according to any one of I) to VI).
  • lower alkyl used alone or in combination with other terms includes a straight-chain or branched monovalent hydrocarbon group having 1 to 8 carbon atoms.
  • a C1-C6 alkyl is mentioned. Even more preferred are C1-C3 alkyl.
  • lower alkenyl refers to a straight-chain or branched-chain monovalent hydrocarbon having 2 to 8 carbon atoms and having one or more double bonds. Include groups. For example, butyl, aryl, propenyl, crotonyl, isopentyl, various butyr isomers and the like can be mentioned. Preferably, C2-C6 alkenyl is mentioned. More preferably, a C2-C4 alkenyl is mentioned.
  • lower alkynyl refers to a linear or branched monovalent hydrocarbon group having 2 to 8 carbon atoms and having 1 or 2 or more triple bonds. Wrap It may have a double bond.
  • ethynyl, 2-propynyl, 3-prop, tininole, 4-pentinole, 5-hexynole, 6-heptinole, 7-octinole, and the like can be mentioned.
  • a C2-C6 alkynyl is mentioned.
  • C2-C4 alkynyl is mentioned.
  • cycloalkyl includes cycloalkyl having 3 to 8 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclootatyl are exemplified.
  • a C3-C6 cycloalkyl is mentioned.
  • aryl used alone or in combination with other terms includes a monocyclic or condensed cyclic aromatic hydrocarbon.
  • aryl used alone or in combination with other terms includes a monocyclic or condensed cyclic aromatic hydrocarbon.
  • phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.
  • the “aralkyl” is the same as the above “lower alkyl” substituted by the above “aryl”, and these may be substituted at all possible positions.
  • benzyl, phenylethyl for example, 2-phenylethyl
  • phenylpropyl for example, 3-phenylpropyl
  • naphthylmethyl for example, 1-naphthylmethyl, 2-naphthylmethyl
  • anthrylmethyl for example, 9) —Anthrylmethyl, etc.
  • benzyl and phenylethyl are exemplified.
  • heteroaryl J used alone or in combination with other terms is a 5- to 6-membered arbitrarily selected member containing one or more oxygen, sulfur or nitrogen atoms in a ring. Which may be fused to a cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions, eg, pyrrolyl (For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (for example, 2-furyl, 3-furyl), chenyl (for example, 2-phenyl, 3-phenyl), imidazolyl ( For example, 2-imidazolyl, 4-imidazolyl), virazolyl (for example, 1-virazolyl, 3-virazolyl), isothiazolyl (for example, 3-isothiazolyl), isoxazolyl ( example For example, 3-isoxazolyl), oxazolyl (eg, 2-xazolyl), oxazo
  • heteroarylalkyl is the same as the above “lower alkyl” substituted at any position with the above “heteroaryl”, and these may be substituted at all possible positions.
  • thiazolylmethyl for example, 4-thiazolylmethyl
  • thiazolylethyl for example, 5-thiazolyl-2-ethyl
  • benzothiazolylmethyl for example, (benzothiazoyl-2-yl) methyl
  • indolylmethyl for example, (indole-3) —Yl) methyl
  • imidazolylmethyl for example, 4-imidazolylmethyl
  • benzothiazolylmethyl for example, 2-benzothiazolylmethyl
  • indazolylmethyl for example, 1-indazolylmethyl
  • benzotriazolylmethyl Eg, 1-benzotriazolylmethyl
  • benzoquinolylmethyl eg, 2-benzoquinolylmethyl
  • benzimidazolylmethyl e
  • non-aromatic complex ring used alone or in combination with other terms refers to an arbitrarily selected non-aromatic complex ring containing one or more oxygen, sulfur or nitrogen atoms in the ring. Includes aromatic 5- to 7-membered rings or rings obtained by condensing two or more of them.
  • pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl
  • pyrrolidinyl eg, 3-pyrrolinyl
  • imidazolidinyl eg, 2-imidazolidinyl
  • imidazolinyl eg, imidazolinyl
  • pyrazolidinyl eg, 1 -Birazolidinyl, 2-birazolidinyl
  • pyrazolinyl for example, birazolinyl
  • piperidyl for example, piperidino, 2-piperidyl
  • piperazinyl for example, 1-piperazur
  • indolinyl for example, 1-indolinil
  • Soindolinyl for example, isoindolinyl
  • morpholinyl for example, mo ⁇ ⁇ holino, 3-morpholinyl
  • non-aromatic heterocycle examples include bilazolidinyl, piperidyl, Linyl, morpholinyl and the like are preferred.
  • arylene means the divalent group of the above “aryl”.
  • phenylene, naphthylene and the like can be mentioned. More specifically, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and the like can be mentioned. Preferably, 1,4-phenylene is used.
  • heteroarylene means the divalent group of the above “heteroaryl”.
  • thiofenzil, flangyl, pyridingil and the like can be mentioned.
  • 2,5-chofenzir, 2,5 frangyl and the like can be mentioned.
  • acyl used alone or in combination with other terms refers to an alkylcarbonyl wherein the alkyl moiety is the above “lower alkyl” or the aryl moiety is the above “aryl”.
  • Arylcarbonyl For example, acetyl, propionyl, benzoyl and the like can be mentioned.
  • “Lower alkyl” and “aryl” may be substituted by the respective substituents described below.
  • halogen means fluorine, chlorine, bromine, and iodine. Preferably, fluorine, chlorine, and bromine are used.
  • examples of the “lower alkyloxy” include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like.
  • methyloxy, ethyloxy, n-propyloxy, isopropyloxy, and n-butyloxy are exemplified.
  • lower alkylthio includes methylthio, ethylthio and the like.
  • the “quaternary alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like.
  • the term ⁇ halo lower alkyl '' used alone or in combination with other terms refers to the above ⁇ lower alkyl '' substituted at 1 to 8, preferably 1 to 5 positions with the halogen. Include. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluorethyl, dichloroethyl, trichloroethyl and the like can be mentioned. Preferably, trifluoromethyl is used.
  • examples of the “halo lower alkyloxy” include trifluoromethyloxy and the like.
  • lower alkylsulfonyl J includes methylsulfonyl, ethylsulfonyl, and the like. Methylsulfonyl is preferable.
  • examples of "asyloxy” include acetyloxy, propionoxy, benzoyloxy and the like.
  • substituted amino used alone or in combination with other terms refers to 1 or 2 in the above “lower alkyl”, the above “aralkyl”, the above “heteroarylalkyl”, or the above “acyl”.
  • 2-substituted amino For example, methylamino, dimethylamino, ethylmethylamino, acetylamino, benzylamino, acetylamino, benzoylamino and the like can be mentioned.
  • methylamino, dimethylamino, ethylmethylamino, getylamino, and acetylamino are exemplified.
  • examples of the “substituted aminocarbonyl” include methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, getylaminocarbonyl, and the like. Preferably, dimethylaminocarbonyl is exemplified.
  • examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, and nitrogen.
  • Cyano carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acysiloxy, may be substituted And non-aromatic heterocycles, aryloxy (eg, phenyloxy), aralkyloxy (eg, benzyloxy), lower alkylsulfonyl, guanidino, azo group, and optionally substituted ureido. These may be substituted one or more times in all possible positions.
  • an aminocarbonyl or an optionally substituted non-aromatic heterocyclic ring is preferable.
  • substituents in the raid j include an optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, and di.
  • Toro cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyl Xy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocycle And optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, or optionally substituted ureide, etc. These may be substituted one or more times in all possible positions.
  • R 4 "optionally substituted cycloalkyl", “optionally substituted O 1
  • substituents of the “good aryl”, the “optionally substituted heteroaryl”, and the “optionally substituted non-aromatic heterocycle” include lower alkyl, hydroxy lower alkyl, hydroxy, lower alkyloxy, Preferred are lower alkylthio, halogen, nitro, carboxy, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, heteroaryl, non-aromatic heterocycle, and the like.
  • substitution of “optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted heteroaryl”, and “optionally substituted heteroarylalkyl” in R 1 examples include an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, nodogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo.
  • an unsubstituted aryl is preferable.
  • the substituent include optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, and halo-lower alkyl.
  • halo-lower alkyloxy unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, and acyloxy.
  • the compound (I) of the present invention can be obtained from WO97 / 27 by starting from 1-amino-1-cyclopentanecarboxylic acid or 1-amino-cyclohexanecarboxylic acid, an ester thereof, or a salt thereof. It can be produced according to the method described in 174 (Methods A to F). An example is shown below.
  • R 2 , R 3 , R 4 and m are as defined above, R 1 () is lower alkyl, and Ha 1 is halogen
  • the compound (IV) having an amino group is converted to a sulfonamide derivative (V).
  • the method can be carried out in the same manner as described in W097 / 271774 (Method A-first step).
  • Deprotection of the carboxyl group of compound (V) to obtain compound (VI) can be carried out according to the method described in Protective uroups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. .
  • a pharmaceutically acceptable salt or a hydrate thereof is also conjugated.
  • alkali metals lithium, sodium, potassium, etc.
  • alkaline earth metals magnesium, calcium, etc.
  • ammonium salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, lithium Acid, sulfuric acid, etc.) and salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).
  • salts can be formed by a commonly used method. When forming a hydrate, it may be coordinated with any number of water molecules.
  • the compounds of the present invention are not limited to specific isomers, but include all possible isomers and racemates.
  • the compound of the present invention exhibits excellent MMP-2 inhibitory activity and inhibits matrix degradation, as described in the experimental examples described below.
  • osteoarthritis rheumatoid arthritis, corneal ulcer, periodontitis, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, atherosclerotic aneurysms, atherosclerosis , Restenosis, sepsis, septic shock, coronary thrombosis, abnormal neovascularization, scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, Vesicular epidermis, psoriasis, diabetes, nephritis, neurological disease, inflammation, osteoporosis, bone resorption, gingivitis, tumor growth, tumor angiogenesis, eye tumor, angiofibromas, hemangiomas, fever, bleeding, coagulation, bad Can be used as a therapeutic agent for fluid, anorexia, acute infection, shock
  • the compound of the present invention When the compound of the present invention is administered to humans for the treatment of the above-mentioned diseases, it is administered orally as powders, granules, tablets, capsules, pills, liquids, etc., or as injections, suppositories, transdermals It can be administered parenterally as an absorbent, inhalant or the like.
  • a pharmaceutical formulation can be prepared by mixing an effective amount of the compound with excipients, binders, wetting agents, disintegrating agents, lubricants and other pharmaceutical additives suitable for the dosage form, if necessary. it can.
  • injection Is sterilized with an appropriate carrier to give a preparation.
  • Dosage will vary depending on disease state, route of administration, age or weight of patient, but for oral administration to adults, is usually 0.1 to 100 mg / kg / day, and is preferred. Or 1 to 20 mg / kg / day.
  • the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
  • Compound (A-4) was obtained according to a method similar to the method described in the third step of Example 1.
  • Compounds (A-5) to (A-7) were synthesized by carrying out a reaction similar to the above.
  • Table 1 shows the physical constants.
  • N N jj—— ji N- -N
  • (R 2 , R 3 , R 4 ) (1, 4-phenylene, -CH2-, Ph), (1, 4-phenylene, -CH2-, 4-Me-Ph), (1,4-phenylene, -CH2-, 4-Et-P), (1, 4-phenylene, -CH2-, 4-nPr-Ph), (1,4-phenylene, -CH2-, 4-iPr-Ph), (1, 4-phenylene, -CH2-, 4-nBu-Ph), (1,4-phenylene, -CH2-, 4-tBu-Ph), (1,4-phenylene, -CHs-, 4-OMe-Ph) , (1, 4-phenylene, -CH2-, 4-OEt-Ph), (1,4-phenylene, -CH2-, 4-SMe-Ph), (1,4-phenylene, -CH2-, 4- F-Ph), (1,4-phenylene, -CH2-, 4-F-Ph), (1,4-phenylene,
  • MMP-2 was purchased from Calbiochem-Novabiochem International, Inc.
  • Test Example 2 Method for measuring enzyme inhibitory activity of MM P-2
  • MMP-2 enzyme activity measurement method is described in C. Graham Knight, Frances Willenbrock and Gillian Murphy: A novel co marin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases: FEBS LETT., 296, (1992), 263-266 Method.
  • Substrate: MOCAc-Pro-Leu-Gly-Leu-A 2 Pr (DNP) -Ala-Arg-NH 2 was from Peptide Institute, Inc. Osaka, Japan. The following four assays are performed for one inhibitory compound (inhibitor).
  • inhibition (%) ⁇ 1- (A-B) / (C-D) ⁇ ⁇ 100
  • ICso indicates the concentration at which the inhibition (%) becomes 50%.
  • a granule containing the following ingredients is produced.
  • 1000 mg of the compound represented by the formula (I) and lactose are passed through a 60-mesh sieve. Pass the cone through a 120 mesh sieve. These are mixed with a V-type mixer. An aqueous solution of HPC-L (low viscosity hydroxypropylcellulose) is added to the mixed powder, and the mixture is kneaded, granulated (extrusion granulated with a pore size of 0.5 to lmm), and dried. The obtained dried granules are passed through a vibrating sieve (12/60 mesh) to obtain granules.
  • HPC-L low viscosity hydroxypropylcellulose
  • a powder for capsule filling containing the following ingredients is produced.
  • Lactose a compound represented by the formula (I)
  • Cone Put it through a 120 mesh sieve.
  • These and magnesium stearate are mixed with a V-type mixer. Fill 100 mg of 100 mg into a No. 5 hard gelatin capsule.
  • a capsule-filling granule containing the following ingredients is produced.
  • Lactose a compound represented by the formula (I)
  • a compound represented by the formula (I) is passed through a 60-mesh sieve. Pass cornstarch through a sieve of 120 mesh. These are mixed, and an HP C-L solution is added to the mixed powder, followed by kneading, granulation, and drying. After the obtained dried granules are sized, 150 mg of the dried granules is filled into a No. 4 hard gelatin capsule.
  • a tablet is prepared containing the following ingredients:
  • 150 mg of the compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tablet making.
  • the mixed powder is directly hit to obtain tablets of 150 mg.
  • the sulfonamide derivative according to the present invention has a meta-oral protease inhibitory activity and can effectively function as a therapeutic or preventive agent for cancer, nephritis, osteoarthritis, heart failure, rheumatoid arthritis and the like.

Abstract

L'invention porte sur des dérivés de sulfonamide ayant des effets inhibiteurs de la métaloprotéase matricielle. Lesdits dérivés sont des composés représentés par la formule générale (I), des isomères optiques de ces composés, des sels pharmaceutiquement acceptables des composés et des isomères ou des hydrates de ces sels. Dans cette formule, R1 est hydrogène, alkyle inférieur éventuellement substitué ou analogue ; R2 est liaison simple, arylène éventuellement substitué ou analogue ; R3 est liaison simple, -C C- ou analogue ; R4 est aryle éventuellement substitué ou analogue ; M est hydroxyle ou analogue ; et m vaut 0 ou 1.
PCT/JP2000/001710 1999-03-26 2000-03-21 Derives de sulfonamide carbocyclique WO2000058280A1 (fr)

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AU31963/00A AU3196300A (en) 1999-03-26 2000-03-21 Carbocyclic sulfonamide derivatives

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JP11/84528 1999-03-26
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US7576222B2 (en) 2004-12-28 2009-08-18 Wyeth Alkynyl-containing tryptophan derivative inhibitors of TACE/matrix metalloproteinase
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EP0771565A2 (fr) * 1995-10-25 1997-05-07 Senju Pharmaceutical Co., Ltd. Inhibiteur d'angiogenèse
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Cited By (23)

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US8227494B2 (en) 2003-04-11 2012-07-24 Ptc Therapeutics, Inc. Pharmaceutical compositions of 1,2,4-oxadiazole benzoic acid and their use for the treatment of disease
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