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WO2000058304A1 - Derives sulfonamides heterocycliques - Google Patents

Derives sulfonamides heterocycliques Download PDF

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Publication number
WO2000058304A1
WO2000058304A1 PCT/JP2000/001708 JP0001708W WO0058304A1 WO 2000058304 A1 WO2000058304 A1 WO 2000058304A1 JP 0001708 W JP0001708 W JP 0001708W WO 0058304 A1 WO0058304 A1 WO 0058304A1
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WIPO (PCT)
Prior art keywords
optionally substituted
substituted
phenylene
compound according
formula
Prior art date
Application number
PCT/JP2000/001708
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English (en)
Japanese (ja)
Inventor
Fumihiko Watanabe
Yoshinori Tamura
Yasuhiko Fujii
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Priority to AU31961/00A priority Critical patent/AU3196100A/en
Publication of WO2000058304A1 publication Critical patent/WO2000058304A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a sulfonamide derivative having a heterocycle 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 meta-oral proteases, which are proteases containing a metal ion in the active center, particularly matrix protease (MMP).
  • MMP matrix protease
  • Many families of MMPs ranging from MMP-1 (type I collagenase) to MMP-23, have been reported to work on growth and tissue reform under the original physiological conditions.
  • MM ⁇ inhibitors having a cyclic structure are described in W097 / 18194, WO98 / 088814, WO98 / 088815, WO98 / 088222, WO98 / 16650, W098 / 1 6 5 14 4, WO 98/16 52 0, WO 98 3/30 56, WO 98/349 18, WO 98/50 348, EP-7 6 94 9 8, EP-8 0 35050, EP-8181442, EP878467 and the like.
  • a compound having a similar side chain and MMP inhibitory activity is 00 / 1708-. Disclosure of the invention
  • MMP activity can be inhibited, it is considered that it will greatly contribute to amelioration of the above-mentioned pathological conditions caused by or related to the activity or prevention of the progress thereof, and development of MMP inhibitors is desired. .
  • the present invention provides a compound of the general formula (I):
  • R 5 is a hydrogen atom, hydroxy, —Z—R 6 (where Z is —0—, —S—, or one N (R A ) —; R 6 may be substituted) Aryl; R A is a hydrogen atom, lower alkyl, aralkyl, or acyl);
  • R 1 is NH ⁇ H, hydroxy, or lower alkyloxy
  • R 2 is a single bond, optionally substituted arylene, or optionally substituted heteroarylene; -
  • One NH—N CH—, or the formula:
  • R B is hydrogen or lower alkyl, ⁇ is 1 or 2;
  • R 4 is cycloalkyl which may be substituted, aryl which may be substituted, or aryl which may be substituted Heteroaryl, or an optionally substituted non-aromatic compound;
  • R 4 may be substituted but not aryl.] An optically active form thereof, or a pharmaceutically acceptable salt thereof. , Or hydrates thereof.
  • the present invention relates to II) to XIV) shown below.
  • R 7 has the formula:
  • R 8 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 heterocycle An optionally substituted aralkyl, a lower alkylsulfonyl, a guanidino, an azo group, or an optionally substituted ureid;
  • R 9 is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxy.
  • X is an oxygen or sulfur atom
  • Y i is one C ⁇ C one or formula
  • X is an oxygen atom or a sulfur atom), an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 Q is the formula:
  • R 9 and r are as defined above.
  • Y 2 is one C ⁇ C one or formula: - —— OO——
  • R 1 ° is the formula:
  • Ring A has the formula: -
  • (VII) A pharmaceutical composition comprising the compound according to any one of (I) to (VI) as an active ingredient.
  • VI I A metastatic protease inhibitor comprising, as an active ingredient, the compound according to any one of I) to VI)).
  • IX A matrix protease inhibitor containing the compound according to any one of I) to VI) as an active ingredient.
  • An agent for treating or preventing cancer comprising the compound according to any one of I) to VI) as an active ingredient.
  • a therapeutic or prophylactic agent for astritis 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 J includes straight-chain or branched monovalent hydrocarbon groups having 1 to 8 carbon atoms.
  • C1-C6 alkyl More preferably, a C1-C3 alkyl is included.
  • 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, isopentenyl, various butenyl 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 one or more triple bonds. And may have a double bond.
  • ethynyl, 2-probyl, 3-butyninole, 4-pentinole, 5-hexyninole, 6-heptininole, 7-octininole and the like can be mentioned.
  • a C2-C6 alkynyl is mentioned. Even more preferred are C2-C4 alkynyl.
  • cycloalkyl includes cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably 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 eg, 2-phenylethyl
  • phenylpropyl eg, 3-phenylpropyl
  • naphthylmethyl eg, 1-naphthylmethyl, 2) -Naphthylmethyl, etc.
  • anthrylmethyl for example, 91-anthrylmethyl etc.
  • benzyl and phenylethyl are exemplified.
  • heteroaryl used alone or in combination with other terms refers to an arbitrarily selected 5- to 6-membered ring containing at least one oxygen, sulfur or nitrogen atom. Which may be fused to a cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions.
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • furyl eg, 2-furyl, 3-furyl
  • phenyl eg, 2-phenyl, 3-phenyl
  • Chenyl imidazolyl (eg, 2-imidazolyl, 4-imidazolyl), vilazolyl (eg, 1- virazolyl, 3-birazolyl), isothiazolyl (eg, 3-isothiazolyl), isoxazolyl (eg, 3-) Isoxazolyl), oxazolyl (eg, 2-xazolyl), thiazolyl (eg, 2-thiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), virazinyl (eg, 2-pyrazinyl), Pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl),
  • 2-pteridinyl carbazolyl (for example, 2-caprolyl, 3-carbazolyl), phenanthridinyl (for example, 2-phenanthridinyl, 3-phenanthridinyl), atalidinyl (for example, 1-ataridinyl, 2-ataridinyl) ), Dibenzofuranyl (eg, 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg, 2-benzoimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), Benzoxazolyl (for example, 2-benzoxazolyl), Benzoxadiazolyl (for example, 4-benzobenzodiazolyl), Benzoisothiazolyl (for example, 3-benzoisothiazolyl) , Benzothiazolyl (eg, 2-benzothiazolyl), benzofuryl ( Eg to three to base Nzofurir
  • heteroaryl for R 4 , phenyl, pyridyl, dibenzofurer, isoxazolyl, tetrazolyl and pyrrolyl are preferred.
  • 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-monothiazolylmethyl
  • thiazolylethyl for example, 5-thiazolyl-2-ethyl
  • benzothiazolylmethyl for example, (benzothiazoluyl-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
  • benzoto Lyazolylmethyl eg, 1-benzotriazolylmethyl
  • benzoquinolylmethyl eg, 2-benzoquinolylmethyl
  • non-aromatic compound used alone or in combination with other terms.
  • primary ring includes a non-aromatic 5- to 7-membered ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring, or a ring obtained by condensing two or more of these atoms. You.
  • pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl
  • pyrrolyl eg, 3-pyrrolidinyl
  • imidazolidinyl eg, 2-imidazolidinyl
  • imidazolinyl eg, Midazolinyl
  • birazolidinyl eg, 1-virazolidinyl, 2-birazolidinyl
  • birazolinyl eg, birazolinyl
  • piperidyl eg, piperidino, 2-piperidyl
  • piperazinyl eg, 1-piperazinyl
  • indolinyl eg, 1-indolinyl) Indolininole
  • isoindolinyl for example, isoindolinyl
  • morpholinyl for example, morpholino, 3-morpholininole
  • non-aromatic heterocyclic ring examples include birazolidinyl, piperidyl, pivalinyl, morpholinyl, 4 H— [1,2,4] oxaziazolyl 5-one, 1,2,3,4-tetrahi Draw [1, 8] naphthyridine 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. Preferred is 1,4-phenylene.
  • heteroarylene means the divalent group of the above “heteroaryl”.
  • thiofenzil, frangyl, pyridinezyl and the like can be mentioned.
  • 2,5-chofenzir, 2,5-furangyl 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 an arylcarbonyl wherein the aryl moiety is the above “aryl”. Is included. example -For example, acetyl, propionyl, benzoyl and the like. “Lower alkyl” and “aryl” may be substituted by the respective substituents described below.
  • halogen means fluorine, chlorine, bromine, and iodine, and preferably includes fluorine, chlorine, and bromine.
  • 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.
  • lower alkyloxycarbonyl includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like.
  • halo lower alkyl used alone or in combination with other terms includes the above “lower alkyl” substituted with 1 to 8, preferably 1 to 5 positions by the halogen. I do.
  • trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl and the like can be mentioned.
  • trifluoromethyl is used.
  • halo-lower alkyloxy includes 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.
  • methylamino, dimethylamino, ethylmethylamino, getylamino, 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 used.
  • examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, and lower alkyloxycarbonyl.
  • substituent in the “optionally substituted raido” is a lower alkyl which may be substituted, cyclo, -Alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, non-substituted or substituted Amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted
  • arylene and “optionally substituted heteroarylene” for R 2
  • substituents include nitrogen, nitro, cyano, lower alkyloxy and the like.
  • Optionally substituted cycloalkyl “optionally substituted aryl”, “optionally substituted heteroaryl”, and “optionally substituted non-aromatic heterocycle” for R 4
  • the lower alkyl, hydroxy lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, halogen, nitro, carboxy, halo lower alkyl, halo lower alkyloxy, unsubstituted or substituted amino, unsubstituted or Preferred are substituted aminocarbonyl, heteroaryl, non-aromatic heterocycle, and the like.
  • an unsubstituted aryl is preferable.
  • the substituent include an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkynoleoxycarbonyl, and lower halo.
  • Examples include alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, and acyloxy.
  • an unsubstituted one is preferable.
  • substituents include optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogeno, nitro, cyano, carboxy, lower alkyloxycarbonyl, and lower halo.
  • the compound (I) of the present invention can be prepared by using the following starting materials by the methods described in WO97 / 27174 (methods A to F) and methods similar to known methods. Can be done. This will be described in detail below.
  • Examples of commercially available starting materials include a proline derivative, a 2-carboxyindolin derivative, a 2-carboxyindoline derivative, a 3-carboxy-1,3,4-dihydroisoquinoline derivative, and a 3-carboxypiperidine derivative.
  • the starting material (IV) is converted to a sulfonamide derivative (V).
  • the method can be carried out in the same manner as described in W09 7/2 7174 (Method A-1st step).
  • the protecting group for the carboxyl group of the compound (V) is deprotected to obtain a compound (VI) in which R 1 is —COOH.
  • R 1 is —COOH.
  • a pharmaceutically acceptable salt or a hydrate thereof is also conjugated.
  • alkali metal lithium, sodium, potassium, etc.
  • alkaline earth metal magnesium, calcium, etc.
  • ammonium salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid) , Phosphoric acid, sulfuric acid, etc.) and salts with organic acids (acetic acid, cunic acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).
  • These 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 Experimental Examples described later.
  • osteoarthritis rheumatoid arthritis, corneal ulcer, periodontitis, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, atherosclerotic aneurysms, atherosclerosis Disease, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, Scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, bullous epidermis, psoriasis, diabetes, nephritis, neurological disease, inflammation, osteoporosis, Bone resorption, gingivitis, tumor growth, tumor angiogenesis, ocular tumors, angiofibromas, hemangiomas, fever, bleeding, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, It can be used as
  • 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.
  • excipients binders, wetting agents, disintegrating agents, lubricants and other pharmaceutical additives suitable for the dosage form, if necessary. it can.
  • they should be sterilized with a suitable carrier to produce the preparation.
  • Dosages will vary depending on disease state, route of administration, age of patient, or body weight, but for oral administration to adults, usually 0.1 to 100 mg / kg / day, preferably 1 ⁇ 20 mg / kg / day.
  • dl-2-Methoxycarbonylindoline hydrochloride (1) (1.45 g, 6.79 mmol) was suspended in dichloromethane (20 mL), and N-methylmorpholine (2.2 mL, 20.0 mmol) was added at room temperature under a nitrogen atmosphere. And 4-nitrobenzenesulfonino rechloride (2) (lg, 4.51 mmol) were added, and the mixture was stirred at room temperature for 24 hours.
  • Compound (A-9) was obtained in the same manner as in the method described in the fourth step of Example 1.
  • Tables 1 to 3 show physical constants of the compounds obtained above.
  • R 2 R 3 R 4 (1,4-phenylene, -CH 2- , Ph), (1,4-phenylene, -CH 2- , 4-Me-Ph), (1,4-phenylene, -CH2-, 4-Et-Ph), (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, -CH2-, 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-Cl-Ph), (1, 4-phenylene,
  • MMP-2 was purchased from Calbiochem-Novabiochem International, Inc.
  • Test Example 2 Method for measuring the enzyme inhibitory activity of various MMPs
  • Inhibition (%) ⁇ 1 (A—B) Z (C-D) ⁇ ⁇ 100 -
  • ICso indicates the concentration at which the inhibition (%) becomes 50%.
  • Table 4 shows the inhibitory activities measured by the above method.
  • a granule containing the following ingredients is produced.
  • a powder for capsule filling containing the following ingredients is produced.
  • Lactose a compound represented by the formula (I)
  • Cornstarch is passed 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.
  • 150 mg Lactose a compound represented by the formula (I)
  • 150 mg Lactose is passed through a 60-mesh sieve. Pass the filter through a 120-mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder, and the mixture is kneaded, granulated, and dried. 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 CM C—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.

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Abstract

La présente invention concerne des derivés sulfonamides présentant des effets inhibiteurs des métalloprotéases matrices, en l'occurrence des composés représentés par la formule générale (I), certains de leurs isomères optiques, certains de leurs sels pharmaceutiquement admis, ou les deux, ou certains de leurs hydrates ou analogues. Dans la formule générale (Ia), A est un groupe représenté par la formule spécifique suivante, dans laquelle R5 est hydrogène ou analogue. R1 est hydroxyle ou analogue; R2 est liaison unique, arylène éventuellement substitué, ou hétéroarylène éventuellement substitué; R3 est liaison unique, -C C-, ou analogue; R4 est aryle éventuellement substitué, hétéroaryle éventuellement substitué, ou analogue; et m vaut 0 ou 1.
PCT/JP2000/001708 1999-03-26 2000-03-21 Derives sulfonamides heterocycliques WO2000058304A1 (fr)

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AU31961/00A AU3196100A (en) 1999-03-26 2000-03-21 Heterocyclic sulfonamide derivatives

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JP11/84526 1999-03-26
JP8452699 1999-03-26

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Cited By (14)

* Cited by examiner, † Cited by third party
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KR100372757B1 (ko) * 2000-04-07 2003-02-17 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
WO2003015762A1 (fr) * 2001-08-20 2003-02-27 Ono Pharmaceutical Co., Ltd. Agent therapeutique pour insuffisance cardiaque
KR100384693B1 (ko) * 2000-04-07 2003-05-22 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
KR100405912B1 (ko) * 2000-04-08 2003-11-14 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
KR20040041418A (ko) * 2002-11-11 2004-05-17 재단법인 목암생명공학연구소 설폰아미드계 유도체를 함유하는 혈관신생 억제제
WO2004060874A1 (fr) * 2003-01-03 2004-07-22 Aventis Pharma Deutschland Gmbh Derives d'aminoacides utilises en tant qu'inhibiteurs de metalloproteinases matricielles
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US6992096B2 (en) 2003-04-11 2006-01-31 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
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US7576222B2 (en) 2004-12-28 2009-08-18 Wyeth Alkynyl-containing tryptophan derivative inhibitors of TACE/matrix metalloproteinase
US9289398B2 (en) 2006-03-30 2016-03-22 Ptc Therapeutics, Inc. Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith
US9873677B2 (en) 2014-03-06 2018-01-23 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10517853B2 (en) 2015-10-30 2019-12-31 Ptc Therapeutics, Inc. Methods for treating epilepsy

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US7459473B2 (en) 1998-06-03 2008-12-02 Glia Med, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
US7078424B2 (en) 1998-06-03 2006-07-18 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or carboxylic acid isosteres
KR100384693B1 (ko) * 2000-04-07 2003-05-22 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
KR100372757B1 (ko) * 2000-04-07 2003-02-17 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
KR100405912B1 (ko) * 2000-04-08 2003-11-14 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
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US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7034057B2 (en) 2001-12-20 2006-04-25 Schering Corporation Compounds for the treatment of inflammatory disorders
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
US7022708B2 (en) 2002-10-18 2006-04-04 Roche Palo Alto Llc 4-piperazinyl benzenesulfonyl indoles and uses thereof
KR20040041418A (ko) * 2002-11-11 2004-05-17 재단법인 목암생명공학연구소 설폰아미드계 유도체를 함유하는 혈관신생 억제제
JP4764009B2 (ja) * 2003-01-03 2011-08-31 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング マトリックスメタロプロテイナーゼ阻害剤として使用するためのイミノ酸誘導体
WO2004060874A1 (fr) * 2003-01-03 2004-07-22 Aventis Pharma Deutschland Gmbh Derives d'aminoacides utilises en tant qu'inhibiteurs de metalloproteinases matricielles
JP2006517912A (ja) * 2003-01-03 2006-08-03 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング マトリックスメタロプロテイナーゼ阻害剤として使用するためのイミノ酸誘導体
US7772270B2 (en) 2003-01-03 2010-08-10 Sanofi-Aventis Deutschland Gmbh Imino acid derivatives as inhibitors of matrix metalloproteinases
US7683082B2 (en) 2003-04-11 2010-03-23 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
US8299105B2 (en) 2003-04-11 2012-10-30 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
US7419991B2 (en) 2003-04-11 2008-09-02 Ptc Therapeutics, Inc. 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, compositions, and methods for the use thereof
US7304080B2 (en) 2003-04-11 2007-12-04 Ptc Therapeutics, Inc. Substituted 1,2,4-oxadiazoles, compositions and methods of use
US7772259B2 (en) 2003-04-11 2010-08-10 Ptc Therapeutics, Inc. 1,2,4-Oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US7202262B2 (en) 2003-04-11 2007-04-10 Ptc Therapeutics, Inc. Benzoic acid or benzoate substituted 1,2,4-oxadiazole compounds and their use for the treatment of disease
US6992096B2 (en) 2003-04-11 2006-01-31 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US8017636B2 (en) 2003-04-11 2011-09-13 Ptc Therapeutics, Inc. 1,2,4-Oxadiazole benzoic acid compositions and their use in bioassays
US8129540B2 (en) 2003-04-11 2012-03-06 Ptc Therapeutics, Inc. Methods for the synthesis of 1,2,4-oxadiazole benzoic acid compounds
US8163782B2 (en) 2003-04-11 2012-04-24 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions
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
US10071081B2 (en) 2003-04-11 2018-09-11 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use
US8486982B2 (en) 2003-04-11 2013-07-16 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acids
US8796322B2 (en) 2003-04-11 2014-08-05 Ptc Therapeutics, Inc. Methods for using 1,2,4-oxadiazole benzoic acid compounds
US8975287B2 (en) 2003-04-11 2015-03-10 Ptc Therapeutics, Inc. Methods for using 1,2,4-Oxadiazole benzoic acid compounds
US9205088B2 (en) 2003-04-11 2015-12-08 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazol benzoic acid compounds and methods for their use
US9861617B2 (en) 2003-04-11 2018-01-09 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use
US7576222B2 (en) 2004-12-28 2009-08-18 Wyeth Alkynyl-containing tryptophan derivative inhibitors of TACE/matrix metalloproteinase
US9289398B2 (en) 2006-03-30 2016-03-22 Ptc Therapeutics, Inc. Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith
US9873677B2 (en) 2014-03-06 2018-01-23 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10233161B2 (en) 2014-03-06 2019-03-19 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10618877B2 (en) 2014-03-06 2020-04-14 Ptc Therapeutics, Inc. Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid
US10517853B2 (en) 2015-10-30 2019-12-31 Ptc Therapeutics, Inc. Methods for treating epilepsy

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