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WO2000058278A1 - Derives d'acides amines $g(b) - Google Patents

Derives d'acides amines $g(b) Download PDF

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Publication number
WO2000058278A1
WO2000058278A1 PCT/JP2000/001709 JP0001709W WO0058278A1 WO 2000058278 A1 WO2000058278 A1 WO 2000058278A1 JP 0001709 W JP0001709 W JP 0001709W WO 0058278 A1 WO0058278 A1 WO 0058278A1
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Prior art keywords
optionally substituted
compound according
substituted
phenylene
formula
Prior art date
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Ceased
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PCT/JP2000/001709
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English (en)
Japanese (ja)
Inventor
Fumihiko Watanabe
Yoshitaka Araki
Shinichiro Hara
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Filing date
Publication date
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Priority to AU31962/00A priority Critical patent/AU3196200A/en
Publication of WO2000058278A1 publication Critical patent/WO2000058278A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07C311/16—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 hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—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 hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • the present invention relates to novel amino acid derivatives and meta-oral protease inhibitors containing them.
  • Extracellular matrix is composed of collagen, fibronectin, laminin, proteoglycan, etc., and plays a role in tissue support, cell proliferation, differentiation, adhesion and the like.
  • 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
  • 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 an optionally substituted May be heteroarylalkyl;
  • R 2 is a single bond, an optionally substituted arylene, or an optionally substituted heteroarylene;
  • R A is hydrogen or lower alkyl; m 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 optionally substituted non-aromatic compound
  • G 1 and G 2 are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; M is NH OH, hydroxy, or Lower alkyloxy], 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 A heterocyclic ring, an optionally substituted aralkyl, a lower alkylsulfonyl, a guanidino, an azo group, or an optionally substituted ureide;
  • R 7 is independently optionally substituted lower alkyl, cycloalkyl, Lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, no, logen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino An unsubstituted or substituted aminocarbonyl, an acyl, an acyloxy, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic heterocycle, an optionally substituted aralkyl, Lower alkylsulfonyl, guanidino, azo group, or an optionally substituted ureide;
  • X is an oxygen or sulfur atom
  • q and r are each independently 0, 1, 2, or 3;
  • optically active form thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • RGG 2 and M are as defined above;
  • R 8 is of the formula:
  • Z is one C ⁇ C—or the formula:
  • R 8 is the formula:
  • G 1 and G 2 are both hydrogen atoms I) compound according to any one of to VI), an optically active form thereof, or a pharmaceutically acceptable salt thereof or hydrates thereof.
  • a meta-oral protease inhibitor comprising as an active ingredient the compound according to any one of I) to VII).
  • a matrix meta-oral protease inhibitor comprising as an active ingredient the compound according to any one of I) to VII).
  • a therapeutic or prophylactic agent for cancer comprising the compound according to any one of I) to VII) as an active ingredient.
  • XI I A therapeutic or prophylactic agent for angitis comprising the compound according to any one of I) to VII) as an active ingredient.
  • XI I I An agent for treating or preventing osteoarthritis, which comprises the compound according to any one of I) to V I I) as an active ingredient.
  • XI V An agent for treating or preventing heart failure, comprising the compound according to any one of I) to VII) as an active ingredient.
  • An agent for treating or preventing rheumatoid arthritis comprising the compound according to any one of I) to -VII) as an active ingredient.
  • 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, vinyl, aryl, propenyl, crotonyl, isopentyl, various butyr isomers and the like can be mentioned.
  • C2-C6 alkenyl is I can do it. 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.
  • a C2-C6 alkynyl is mentioned.
  • C2-C4 alkynyl is mentioned.
  • cycloalkyl includes cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably c
  • 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, etc.
  • phenylpropyl eg, 3-phenylpropyl, etc.
  • naphthylmethyl eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.
  • anthrylmethyl eg, 9-anthrylmethyl, etc.
  • benzyl and phenylethyl are mentioned.
  • heteroaryl used alone or in combination with other terms refers to an arbitrarily selected 5- to 6-membered ring containing at least one oxygen atom, sulfur atom 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
  • chenyl eg.
  • heteroaryl for R 4 , chenyl, pyridyl, dibenzofuranyl, 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-thiazolylmethyl
  • thiazolylethyl for example, 5-thiazolyl-2-ethyl
  • benzothiazolylmethyl for example, (benzothiazoyl-2-yl) methyl
  • indolylmethyl for example, 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 eg, 2-benzimidazolylmethyl
  • 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-pyrrolidinyl
  • imidazolidinyl eg, 2-imidazolidinyl
  • imidazolinyl eg, imidazolinyl
  • pyrazolidinyl eg, 1-birazolidinyl, 2-birazolidinyl
  • birazolinyl eg, birazolinyl
  • piperidyl eg, piperidino, 2-piperidyl
  • piperazinyl eg, 1-piperazur
  • indolinyl eg, 1-indolini
  • Isoindolinyl eg, isoindolinyl
  • morpholinyl eg, morpholino, 3-morpholinyl
  • non-aromatic heterocycle for R 4 , birazolidinyl, piperidyl, piperylyl, morpholinyl and the like are preferable.
  • 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, flangyl, pyridingil and the like can be mentioned.
  • 2,5—chofenzir, 2,5—furanfur, 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.
  • the “lower alkylthio” includes methylthio, ethylthio and the like.
  • the “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.
  • examples of the “halo lower alkyloxy” include trifluoromethyloxy and the like.
  • examples of the “lower alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like. Preferably, methylsulfonyl is used.
  • acetyloxy J includes acetyloxy, propionoxy, benzoyloxy and the like.
  • substituted amino used alone or in combination with other terms includes 1 or 2 in the “lower alkyl”, the “aralkyl”, the “heteroarylalkyl”, or the “acyl”. Includes partially substituted amino.
  • 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, ethylmethylaminopropyl, ethylaminopropyl, and the like. Preferably, dimethylaminocarbonyl is used.
  • examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl, hydroxy, lower alkyloxy, mercapto, and lower alkyl.
  • an aminocarbonyl or an optionally substituted non-aromatic heterocyclic ring is preferable.
  • optionally substituted arylene In the present specification, “optionally substituted arylene”, “optionally substituted heteroarylene”, “optionally substituted cycloalkyl”, “optionally substituted aryl” , “Optionally substituted heteroaryl”, “optionally substituted non-aromatic heterocycle”, “optionally substituted aralkyl”, “optionally substituted heteroarylalkyl”, and Examples of the substituent in the “optionally substituted raido” include optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, and nitro.
  • Cyano carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyl Xy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic Examples include a heterocyclic ring, an optionally substituted aralkyl, a lower alkylsulfonyl, a guanidino, an azo group, and an optionally substituted ureido. These may be substituted one or more times in all possible positions.
  • substituents include halogen, nitro, cyano, lower alkyloxy and the like.
  • Optionally substituted cycloalkyl in R 4, "optionally substituted ⁇ Li Ichiru”, “heteroaryl which may be substituted”, and “optionally substituted non-aromatic heterocyclic
  • substituent for the ring include lower alkyl, hydroxy lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, halogen, nitro, carboxy, halo lower alkyl, halo lower alkyloxy, unsubstituted or substituted amino, unsubstituted
  • a substituted aminocarbonyl, a heteroaryl, a non-aromatic heterocycle and the like are preferable.
  • substitution of “optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted heteroaryl”, and “optionally substituted heteroarylalkyl” in R 1 The group includes optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, logen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl Preferred are halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, aryl, heteroaryl, non-aromatic heterocycle, aralkyl 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 alkyloxycarbonyl, and lower halo.
  • Examples include alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, and acyloxy.
  • Optionally substituted heteroaryl “optionally substituted non-aromatic heterocycle”, “optionally substituted aralkyl”, and R 6 and R 7
  • the “optionally substituted urea” an unsubstituted one is preferable.
  • substituents include an optionally substituted lower alkyl, lower alkenyl, lower alkynylene, hydroxy, lower alkyloxy, mercapto, lower alkylthio, nodogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, Examples include 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 produced from compound (IV) as a starting material according to the method described in W097 / 27177.
  • Compounds (IV) include 3-aminopropanoic acid, 3-amino-13-phenylpropanoic acid, 3-amino-2-hydroxypropanoic acid, 3-aminoadipic acid, 3-aminoisobutanoic acid, and 2 , 3-Diaminopropanoic acid, 3-Aminobutanoic acid, 3-Amino-1,4,4,1-Trifluorobutanoic acid, 3-Amino-12-hydroxy-5-methylhexanoic acid, 3-Amino-3- ( 4-—Mouth-phenyl) propanoic acid, hysulfo-1-alanine, 3-amino-2-hydroxy 4-butyric acid, 3-amino-2-hydroxy-1- (1-) Imidazole-4-yl) -1-methylhexanoic acid, glutamic acid, 2-fluoro
  • G 1 G 2 R 2 R 3 and R 4 are as defined above, R 10 is lower alkyl, and Hal is halogen
  • the compound (IV) having an amino group is converted to a sulfonamide derivative (V). It can be carried out in the same manner as described in W097227174 (Method A-1st step).
  • 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.)
  • salts with organic acids acetic acid, citric 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 compound of the present invention is not limited to a specific isomer, but includes all possible isomers. It contains sexual and racemic forms.
  • 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, hemangiofibromas, hemangiomas, febrile bleeding, coagulation, Use as a treatment for cachexia, anorexia, acute infection, shock,
  • 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 or weight of patient, but for oral administration to adults: typically 0.1 to 100 mg / kg / day, preferably 1 to 100 mg / kg / day. ⁇ 20 mg / kg / day.
  • ⁇ -rylanethyl hydrochloride (1) (338 mg, 2.2 mmol) was suspended in THF (6 mL). Butler, RN; Lambe, TM; Tobin, J.C; Scott, FLJ Chem. Soc. Perkin Trans. 1 1973, 1357. and Hoffman, RV Org. Synth. 1981, 60, 121.
  • Sulfonyl chloride compound (2) (641 mg, 2 mmol) and N-methylmorpholine (0.55 mL, 5 mmol) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice-2N hydrochloric acid and extracted twice with ethyl acetate / 2-butanone.
  • Compound (A-6) was synthesized by a method similar to the method described in the second step of Example 1.
  • compound (A-9) was synthesized using compound (9) as a starting material.
  • (R 2 , R 3 , R 4 ) (1,4-phenylene, -CH2-, Ph), (1,4-phenylene, -CH 2- , 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-P), (1,4-phenylene, -CH2-, 4-tBu-Ph), (1, 4-phenylene, -CH 2- , 4-OMe- Ph), (1,4-phenylene, -CH 2- , 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,
  • yQ p, BreeCFhnlne4--.- o y3 ⁇ 4 (p ,, Th5cedl2thoedl. M; liollnlvihni 4NHl ⁇ - ----
  • MMP-2 was purchased from Calbiochem-Novabiochem International, Inc.
  • Test Example 2 Method for measuring enzyme inhibitory activity of MM P-2
  • IC50 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 cornstarch through a sieve of 120 mesh. 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 combed through a vibrating sieve (12 to 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)
  • 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 No. 5 hard gelatin capsule.
  • a capsule-filling granule containing the following ingredients is produced.
  • Lactose a compound represented by the formula (I)
  • 150 mg Lactose a compound represented by the formula (I)
  • 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 sizing the obtained dried granules, 150 mg thereof 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 150 mg tablets.
  • the beta-amino acid derivative according to the present invention has an inhibitory action on female protease and can effectively function as an agent for treating or preventing cancer, nephritis, osteoarthritis, heart failure, rheumatoid arthritis, and the like. I found it.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des dérivés d'acides aminés β ayant des effets inhibiteurs de la métalloprotéase 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 une liaison simple, un arylène éventuellement substitué ou un hétéroarylène éventuellement substitué ; R3 est une liaison simple, -CH=CH, -C C- ou analogue ; R4 représente aryle éventuellement substitué ou analogue ; G1 et G2 sont chacun indépendamment hydrogène ou analogue ; et M est hydroxyle ou analogue.
PCT/JP2000/001709 1999-03-26 2000-03-21 Derives d'acides amines $g(b) Ceased WO2000058278A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31962/00A AU3196200A (en) 1999-03-26 2000-03-21 Beta-amino acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8452799 1999-03-26
JP11/84527 1999-03-26

Publications (1)

Publication Number Publication Date
WO2000058278A1 true WO2000058278A1 (fr) 2000-10-05

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PCT/JP2000/001709 Ceased WO2000058278A1 (fr) 1999-03-26 2000-03-21 Derives d'acides amines $g(b)

Country Status (2)

Country Link
AU (1) AU3196200A (fr)
WO (1) WO2000058278A1 (fr)

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WO2002079200A1 (fr) * 2001-03-30 2002-10-10 Pfizer Limited Acide 3-heterocyclylpropanohydroxamique en tant qu'inhibiteur de procollagene c-proteinase
US6821972B2 (en) 2001-03-30 2004-11-23 Pfizer Inc. 3-heterocyclylpropanohydroxamic acid PCP inhibitors
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
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
EP1880719A3 (fr) * 2006-06-08 2008-02-20 Lin Chih-Hsiung Composition pour la prophylaxie ou le traitement des infections du système urinaire et son procédé associé
US7504431B2 (en) 2004-04-16 2009-03-17 Bristol-Myers Squibb Company Sulfonyl amide inhibitors of calcium channel function
JP2015148621A (ja) * 2005-12-22 2015-08-20 アボツト・モレキユラー・インコーポレイテツド 肺がんへの傾向についてのスクリーニングのための方法およびマーカー組合せ
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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WO1999007675A1 (fr) * 1997-08-08 1999-02-18 Pfizer Products Inc. Derives de l'acide aryloxyarylsulfonylamino hydroxamique
EP0935963A2 (fr) * 1997-10-24 1999-08-18 Pfizer Products Inc. Utilisation des inhibiteurs selectifs de MMP-13 pour le traitement de l'osteoarthrite et autres maladies mediées par le matrix metalloproteinase
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EP0877018A1 (fr) * 1997-05-09 1998-11-11 Hoechst Aktiengesellschaft Acides sulfonylaminocarboxyliques
WO1999007675A1 (fr) * 1997-08-08 1999-02-18 Pfizer Products Inc. Derives de l'acide aryloxyarylsulfonylamino hydroxamique
EP0935963A2 (fr) * 1997-10-24 1999-08-18 Pfizer Products Inc. Utilisation des inhibiteurs selectifs de MMP-13 pour le traitement de l'osteoarthrite et autres maladies mediées par le matrix metalloproteinase
JPH11246527A (ja) * 1998-03-02 1999-09-14 Shionogi & Co Ltd Ｍｍｐ−８阻害剤

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US6821972B2 (en) 2001-03-30 2004-11-23 Pfizer Inc. 3-heterocyclylpropanohydroxamic acid PCP inhibitors
WO2002079200A1 (fr) * 2001-03-30 2002-10-10 Pfizer Limited Acide 3-heterocyclylpropanohydroxamique en tant qu'inhibiteur de procollagene c-proteinase
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
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
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
US8129540B2 (en) 2003-04-11 2012-03-06 Ptc Therapeutics, Inc. Methods for the synthesis of 1,2,4-oxadiazole benzoic acid compounds
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
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
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
US7683082B2 (en) 2003-04-11 2010-03-23 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
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
US8017636B2 (en) 2003-04-11 2011-09-13 Ptc Therapeutics, Inc. 1,2,4-Oxadiazole benzoic acid compositions and their use in bioassays
US7304080B2 (en) 2003-04-11 2007-12-04 Ptc Therapeutics, Inc. Substituted 1,2,4-oxadiazoles, compositions and methods of use
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
US8299105B2 (en) 2003-04-11 2012-10-30 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays
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
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
US7504431B2 (en) 2004-04-16 2009-03-17 Bristol-Myers Squibb Company Sulfonyl amide inhibitors of calcium channel function
JP2015148621A (ja) * 2005-12-22 2015-08-20 アボツト・モレキユラー・インコーポレイテツド 肺がんへの傾向についてのスクリーニングのための方法およびマーカー組合せ
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
EP1880719A3 (fr) * 2006-06-08 2008-02-20 Lin Chih-Hsiung Composition pour la prophylaxie ou le traitement des infections du système urinaire et son procédé associé
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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