发明名称 N-HYDROXY-2-(ALKYL, ARYL OR HETEROARYL, SULFANYL, SULFINYL OR SULFONYL)-3-SUBSTITUTED ALKYL, ARYL OR HETEROARYLAMIDES AS MATRIX METALLOPROTEINASE INHIBITORS
摘要 1. A compound of the formula wherein: A is -S-, -SO- or SO2-; R<1> is phenyl, naphthyl, heterocyclyl selected from the group: thienyl, triazolyl, pyridyl, pyrazinyl, imidazolyl, optionally benzocondensed and optionally substituted with C1-C6 alkyl, C1-C6 alkoxy or phenyl, aryloxy, benzyloxy and heteroaryloxy; or R<1> is R<11>-Y-Ph-Z where Y is O, S, NH or a simple bond, Z is A simple bond or C1-C4 alkylen; R<11> is H, C1-C4 alkyl, acyl, benzyl, pyridylpropyl, 5-hydroxypentyl, 1-methylpyrolidinyl, tetrahydropyran-4-yl, chlorothienyl, 3-morpholine-4-ylpropyl, biphenyl, pyridyl, C3-C7 cycloalkyl; R<2> is H, phenyl, carboxyphenyl, metoxycarbonylphenyl, benzyl, biphenylmethyl, C5-C10 alk(di)enyl and, C5-C10 alk(di)ynyl, cyclohexymethyl, heteroarylalkoxybenzyl, amino(C1-C6) alkyl, benzyloxymethyl, imidazolylmethyl, guanidinylbutyl; R<3> is H, C1-C4 alkyl, C5-C10 alk(di)enyl and, C5-C10 alk(di)ynyl, phenyl (C1-C4) alkyl, phenoxybutyl, hydroxyaminocarbonyl (C1-C4) alkyl; or R<2> and R<3>, taken together with the carbon atom to which they are attached, form a piperidine ring which is optionally substituted with N-group selected from phenyl-C1-C4 alkyl, which may be substituted by C1-C6 alkoxy, biphenyl- C1-C6 alkyl, C2-C10 alkenyl, C1-C8 alkyl, C4-C10 cycloalkyl or phenoxy- C1-C6 alkyl; R<4> is H, provided that a). when A is S, R<2> is H and R<3> is H, then R<1> is not thienyl, optionally mono or disubstituted C1-C6 alkyl or C1-C6 alkoxy, b). when A is SO2, R<2> is H and R<3> is 4-phenyl-n-butyl, then R<1> is not 3,4-dimethoxyphenyl, and provided that compounds are excluded, when: a. A is S, R<2> and R<3> are H and R<1> is phenyl comprising three carbon atoms and two bromine atoms as a ring substituents; b. A is S, R<2> and R<3> are H and R<1> is phenyl comprising three carbon atoms, one chlorine atom and one bromine atom as a ring substituents; c. A is S, R<2> and R<3> are H and R<1> is phenyl comprising two carbon atoms and three bromine atoms as a ring substituents d. A is S, R<2> and R<3> are H and R<1> is phenyl comprising two carbon atoms and three chlorine atoms as a ring substituents. 2. The compound according to claim 1, wherein: R<1> is phenyl, naphthyl, heterocyclyl such as pyridyl, thienyl or imidazolyl, optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryloxy or heteroaryloxy; R<2> is C5-C10 alk(di)enyl and, C5-C10 alk(di)ynyl; R<3> is C1-C4 alkyl, C5-C10 alk(di)enyl and, C5-C10 alk(di)ynyl, phenyl (C1-C4) alkyl or phenoxybutyl; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 selected from the group of compounds comprising of: 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide; 3-(biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamide; 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid hydroxyamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(N,N-diethyl amino-ethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(N,N-diethyl amino-ethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(N,N-diethyl amino-ethoxy)-phenyl]-propionamide; 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid hydroxyamide; 2R*-(4-methoxy-phenyl-S*-sulfinyl)-heptanoic acid hydroxyamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(N,N-diisopropyl amino-ethoxy)-phenyl]-propionamide; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 1 selected from the group of compounds comprising of: N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide, N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide, 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide, N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-2-methyl-3-phenyl-propionamide, 2-(4-methoxy-benzenesulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide, N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide, 2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide, 2-(4-methoxy-benzene sulfonyl)-tetradecanoic hydroxyamide, N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide, 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide, 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid hydroxyamide; 3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide, 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid hydroxyamide; 3-(4-(3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide; 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid hydroxyamide; (4E)-2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoic acid hydroxyamide; 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide; 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide; N-hydroxy-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethyl aminoethoxy)-phenyl]-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamide; 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid hydroxyamide; 3-[4-(2-diethylamino-ethoxy)-phenyl]-2-(4-furan-2-yl-benzenesulfonyl)-N-hydroxy-2-methyl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyramide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyramide; 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid hydroxyamide; 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-octanoic acid hydroxyamide; 2-(4-methoxy-benzenesulfanyl)-octanoic acid hydroxyamide; 2-(4-fluoro-phenylsulfanyl)-octanoic acid hydroxyamide; 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide' N-hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl propionic acid hydroxamide; 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid hydroxyamide; 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid hydroxamide; 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid hydroxamide; 2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide; 2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]propionic acid hydroxamide; 2-methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide; 2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid hydroxyamide; 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy)-phenyl]-propionic acid hydroxamide; 3-(4-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyramide; 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid hydroxyamide; 3-(2-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide; 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide; 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid hydroxyamide; 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide; 2-(4-methoxy-benzenesulfonyl)-2-propyl-pentanoic acid hydroxyamide; 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyramide; 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid hydroxyamide; 3-(2-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide; 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide; 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid hydroxyamide; 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide; 2-(4-methoxy-benzenesulfonyl)-2-propyl-pentanoic acid hydroxyamide; 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide; 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid hydroxyamide; 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide; 2-benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butyramide; 3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionamide; 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid hydroxyamide; N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide; 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylme
申请公布号 EA003836(B1) 申请公布日期 2003.10.30
申请号 EA19990000768 申请日期 1998.02.17
申请人 AMERICAN CYANAMID COMPANY 发明人 VENKATESAN, MUDUMBAI, ARANAPAKAM;GROSU, GEORGE, THEODORE;DAVIS, JAMIE, MARIE;HU, BAIHUA;O'DELL, MATHEW, JAMES;COLE, DEREK, CECIL;BAKER, JANNIE, LEA;JACOBSON, MARCY, PAMELA
分类号 C07D295/08;A61K31/16;A61K31/165;A61K31/341;A61K31/351;A61K31/381;A61K31/40;A61K31/4035;A61K31/41;A61K31/415;A61K31/4164;A61K31/4166;A61K31/4184;A61K31/423;A61K31/426;A61K31/428;A61K31/433;A61K31/4402;A61K31/4406;A61K31/4409;A61K31/4436;A61K31/445;A61K31/4453;A61K31/4535;A61K31/47;A61K31/495;A61K31/4965;A61K31/5375;A61K31/55;A61P1/02;A61P1/04;A61P1/14;A61P3/10;A61P9/02;A61P9/04;A61P17/02;A61P19/02;A61P19/08;A61P29/00;A61P31/18;A61P35/00;A61P35/04;A61P37/06;C07C317/40;C07C317/44;C07C317/46;C07C323/60;C07D207/12;C07D209/48;C07D211/54;C07D211/66;C07D213/30;C07D213/32;C07D213/54;C07D213/56;C07D213/70;C07D213/71;C07D213/74;C07D213/89;C07D215/12;C07D215/36;C07D215/38;C07D215/48;C07D231/18;C07D233/02;C07D233/54;C07D233/64;C07D233/76;C07D233/84;C07D235/28;C07D241/12;C07D257/04;C07D263/58;C07D277/20;C07D277/36;C07D277/70;C07D277/74;C07D277/76;C07D285/14;C07D295/092;C07D307/30;C07D307/38;C07D307/64;C07D309/12;C07D333/28;C07D333/34;C07D409/04;(IPC1-7):C07C323/60 主分类号 C07D295/08
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