RU2000102639A - SUBSTITUTED ALKANOHYDROXAMIC ACIDS AND METHOD TO REDUCE TNFα LEVELS - Google Patents

SUBSTITUTED ALKANOHYDROXAMIC ACIDS AND METHOD TO REDUCE TNFα LEVELS

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RU2000102639A
RU2000102639A RU2000102639/04A RU2000102639A RU2000102639A RU 2000102639 A RU2000102639 A RU 2000102639A RU 2000102639/04 A RU2000102639/04 A RU 2000102639/04A RU 2000102639 A RU2000102639 A RU 2000102639A RU 2000102639 A RU2000102639 A RU 2000102639A
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methoxyphenyl
ethoxy
hydroxy
carbon atoms
propionamide
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RU2000102639/04A
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RU2199530C2 (en
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Джордж В. Маллер
Хон-Во МАН
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Селджин Корпорейшн
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Claims (15)

1. Производное гидроксамовой кислоты, выбранное из группы, состоящей из (а) соединений формулы:
Figure 00000001

где каждый из R1 и R2 независимо друг от друга представляет собой водород, низший алкил, или R1 и R2 соединены друг с другом и вместе с изображенными атомами углерода, к которым каждый из них присоединен, представляют собой о-фенилен, о-нафтилен или циклогексен-1,2-диил, незамещенный или замещенный заместителями в количестве от 1 до 4, каждый из которых независимо выбран из группы, состоящей из нитро, циано, трифторметила, карбэтокси, карбометокси, карбопропокси, ацетила, карбамоила, ацетокси, карбокси, гидрокси, амино, алкиламино, диалкиламино, ациламино, алкила из 1-10 атомов углерода, алкокси из 1-10 атомов углерода, циклоалкокси из 3-6 атомов углерода, С4-С6циклоалкилиденметила, С3-С10алкилиденметила, инданилокси и галогено;
R3 представляет собой фенил, замещенный заместителями в количестве от одного до четырех, выбранными из группы, состоящей из нитро, циано, трифторметила, карбэтокси, карбометокси, карбопропокси, ацетила, карбамоила, ацетокси, карбокси, гидрокси, амино, алкила из 1-10 атомов углерода, алкокси из 1-10 атомов углерода, циклоалкокси из 3-6 атомов углерода и галогено;
R4 представляет собой водород, алкил из 1-10 атомов углерода, фенил или бензил;
R4' представляет собой водород или алкил из 1-6 атомов углерода;
R5 представляет собой -CH2-, -CH2-CO-, -СО-, -SO2-, -S- или -NHCO-; и n имеет значение 0, 1 или 2; и
(б) полученные присоединением кислоты соли указанных соединений, которые содержат атом азота, способный протонироваться.1. Derived hydroxamic acid selected from the group consisting of (a) compounds of the formula:
Figure 00000001

where each of R 1 and R 2 independently of each other represents hydrogen, lower alkyl, or R 1 and R 2 are connected to each other and together with the depicted carbon atoms to which each of them is attached, are o-phenylene, o naphthylene or cyclohexene-1,2-diyl, unsubstituted or substituted by substituents in an amount of from 1 to 4, each of which is independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, ac lamin, alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, cycloalkoxy of 3-6 carbon atoms, C 4 -C 6 tsikloalkilidenmetila, C 3 -C 10 alkilidenmetila, indanyloxy, and halo;
R 3 is phenyl substituted with one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl from 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, cycloalkoxy of 3-6 carbon atoms and halogeno;
R 4 is hydrogen, alkyl of 1-10 carbon atoms, phenyl or benzyl;
R 4 ' represents hydrogen or alkyl of 1-6 carbon atoms;
R 5 is —CH 2 -, —CH 2 —CO—, —CO—, —SO 2 -, —S—, or —NHCO—; and n is 0, 1 or 2; and
(b) salts of these compounds obtained by the addition of acid, which contain a nitrogen atom capable of protonation. 2. Производное гидроксамовой кислоты по п.1, где указанное соединение имеет формулу:
Figure 00000002

в которой каждый из R4 и R4' независимо представляет собой водород или алкил из 1-4 атомов углерода;
R5 представляет собой -СН2-, -СН2-СО- или -СО-;
каждый из R6 и R7 независимо от другого представляет собой нитро, циано, трифторметил, карбэтокси, карбометокси, карбопропокси, ацетил, карбамоил, ацетокси, карбокси, гидрокси, амино, алкил из 1-4 атомов углерода, алкокси из 1-4 атомов углерода, циклоалкокси из 3-6 атомов углерода или галогено;
каждый из R8, R9, R10 и R11 независимо от других представляет собой водород, нитро, циано, трифторметил, карбэтокси, карбометокси, карбопропокси, ацетил, карбамоил, ацетокси, карбокси, гидрокси, амино, алкиламино, диалкиламино, ациламино, алкил из 1-10 атомов углерода, алкокси из 1-10 атомов углерода и галогено; и
n имеет значение 1.2. The hydroxamic acid derivative of claim 1, wherein said compound has the formula:
Figure 00000002

in which each of R 4 and R 4 ' independently represents hydrogen or alkyl of 1-4 carbon atoms;
R 5 is —CH 2 -, —CH 2 —CO — or —CO—;
each of R 6 and R 7 independently of the other is nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1-4 carbon atoms, alkoxy of 1-4 atoms carbon, cycloalkoxy of 3-6 carbon atoms or halo;
each of R 8 , R 9 , R 10 and R 11 independently of the others represents hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms and halo; and
n is 1. 3. Производное гидроксамовой кислоты по п.2, где каждый из R8, R9, R10 и R11 представляет собой галогено, алкил из 1-4 атомов углерода или алкокси из 1-4 атомов углерода.3. The hydroxamic acid derivative of claim 2, wherein each of R 8 , R 9 , R 10, and R 11 is halo, alkyl of 1-4 carbon atoms, or alkoxy of 1-4 carbon atoms. 4. Производное гидроксамовой кислоты по п.2, где один из R8, R9, R10 и R11 представляет собой амино, а остальные из R8, R9, R10 и R11 представляют собой водород.4. The hydroxamic acid derivative of claim 2, wherein one of R 8 , R 9 , R 10 and R 11 is amino, and the remaining of R 8 , R 9 , R 10 and R 11 are hydrogen. 5. Производное гидроксамовой кислоты по п.2, где один из R8, R9, R10 и R11 представляет собой алкил, а остальные из R8, R9, R10 и R11 представляют собой водород.5. The hydroxamic acid derivative of claim 2, wherein one of R 8 , R 9 , R 10 and R 11 is alkyl, and the remaining of R 8 , R 9 , R 10 and R 11 are hydrogen. 6. Производное гидроксамовой кислоты по п.2, где R8, R9, R10 и R11 представляют собой водород.6. The hydroxamic acid derivative of claim 2, wherein R 8 , R 9 , R 10 and R 11 are hydrogen. 7. Производное гидроксамовой кислоты по п.1, где указанное соединение имеет формулу:
Figure 00000003

в которой R4' представляет собой водород или алкил из 1-4 атомов углерода;
R5 представляет собой С=O или СН2;
каждый из R12 и R13 независимо от другого представляет собой алкокси из 1-4 атомов углерода, циклоалкокси из 3-6 атомов углерода, С4-С6циклоалкилиденметил, C2-С10алкилиденметил, С6-С10бициклоалкокси или инданилокси; и
каждый из R8, R9, R10 и R11 независимо от других представляет собой водород, нитро, циано, трифторметил, карбэтокси, карбометокси, карбопропокси, ацетил, карбамоил, ацетокси, карбокси, гидрокси, амино, алкиламино, диалкиламино, ациламино, алкил из 1-10 атомов углерода, алкокси из 1-10 атомов углерода и галогено.7. Derived hydroxamic acid according to claim 1, where the specified compound has the formula:
Figure 00000003

in which R 4 ' represents hydrogen or alkyl of 1-4 carbon atoms;
R 5 is C = O or CH 2 ;
each of R 12 and R 13 independently of the other is alkoxy of 1-4 carbon atoms, cycloalkoxy of 3-6 carbon atoms, C 4 -C 6 cycloalkylidenemethyl, C 2 -C 10 alkylidenemethyl, C 6 -C 10 bicycloalkoxy or indanyloxy ; and
each of R 8 , R 9 , R 10 and R 11 independently of the others represents hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms and halogen. 8. Производное гидроксамовой кислоты по п.7, где R4 представляет собой водород.8. The hydroxamic acid derivative according to claim 7, wherein R 4 is hydrogen. 9. Производное гидроксамовой кислоты по п.7, где каждый из R8, R9, R10 и R11 представляет собой водород, галогено, алкил из 1-4 атомов углерода или алкокси из 1-4 атомов углерода.9. The hydroxamic acid derivative of claim 7, wherein each of R 8 , R 9 , R 10, and R 11 is hydrogen, halo, alkyl of 1-4 carbon atoms or alkoxy of 1-4 carbon atoms. 10. Производное гидроксамовой кислоты по п.7, где один из R8, R9, R10 и R11 представляет собой амино, гидрокси или алкил, а остальные из R8, R9, R10 и R11 представляют собой водород.10. The hydroxamic acid derivative of claim 7, wherein one of R 8 , R 9 , R 10, and R 11 is amino, hydroxy, or alkyl, and the remaining of R 8 , R 9 , R 10, and R 11 are hydrogen. 11. Производное гидроксамовой кислоты по п.1, где указанное соединение выбирают из группы, состоящей из 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(1-оксоизоиндолинил)пропионамида, 3-(3-этокси-4-метоксифенил)-N-метокси-3-(1-оксоизоиндолинил)пропионамида, N-бензилокси-3-(3-этокси-4-метоксифенил)-3-фталимидопропионамида, N-бензилокси-3-(3-этокси-4-метоксифенил)-3-(3-нитрофталимидо)пропионамида, N-бензилокси-3-(3-этокси-4-метоксифенил)-3-(1-оксоизоиндолинил)пропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-фталимидопропионамида, N-гидрокси-3-(3,4-диметоксифенил)-3-фталимидопропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(3-нитрофталимидо)пропионамида, N-гидрокси-3-(3,4-диметоксифенил)-3-(1-оксоизоиндолинил)пропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(4-метилфталимидо)пропионамида, 3-(3-циклопентилокси-4-метоксифенил)-N-гидрокси-3-фталимидопропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(1,3-диоксо-2,3-дигидро-1Н-бензо[f] изоиндол-2-ил)пропионамида, N-гидрокси-3-{3-(2-пропокси)-4-метоксифенил} -3-фталимидопропионамида, 3-(3-этокси-4-метоксифенил)-3-(3,6-дифторфталимидо)-N-гидроксипропионамида, 3-(4-аминофталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-аминофталимидо)-3-(3-метокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-аминофталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-аминофталимидо)-3-(3-циклопентокси-4-метоксифенил)-N-гидроксипропионамида, N-гидрокси-3-(3,4-диметоксифенил)-3-(1-оксоизоиндолинил)пропионамида, N-бензилокси-3-(3-этокси-4-метоксифенил)-3-(3-нитрофталимидо)пропионамида, 3-(3-циклопентилокси-4-метоксифенил)-N-гидрокси-3-(1-оксоизоиндолинил)пропионамида, 3-(3-метилфталимидо)-3-(3-циклопентокси-4-метоксифенил)-N-гидроксипропионамида, 3-(4-метилфталимидо)-3-(3-циклопентокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-гидроксифталимидо)-3-(3-циклопентокси-4-метоксифенил)-N-гидроксипропионамида, 3-(4-гидроксифталимидо)-3-(3-циклопентокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-метилфталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(4-метилфталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-гидроксифталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(4-гидроксифталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, N-гидрокси-N-метил-3-(3-этокси-4-метоксифенил)-3-(1-оксоизоиндолинил)пропионамида, 3-(3-циклопентилокси-4-метоксифенил)-N-гидрокси-3-(4-этилфталимидо)пропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(3-гидроксифталимидо)пропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(4-гидроксифталимидо)пропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(3-метилфталимидо)пропионамида, 3-(3-ацетоамидо-фталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(4-ацето-амидофталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(1,3-диоксо-2,3-дигидро-1Н-бензо[е] изо-индол-2'-ил)пропионамида, 3-(4-трет-бутилфталимидо)-3-(3-этокси-4-метокси-фенил)-N-гидроксипропионамида, 3-(3,4-диметоксифенил)-N-гидрокси-3-(1,3-диоксо-2,3-дигидро-1Н-бензо[е]изоиндол-2'-ил)пропионамида, 3-(3,4-диметоксифталимидо)-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида, 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(3-диметиламинофталимидо)пропионамида, 3-(6,8-диоксо(2Н-1,3-диоксолано[4,5-е] изоиндолин-7-ил))-3-(3-этокси-4-метоксифенил)-N-гидроксипропионамида и 3-(3-этокси-4-метоксифенил)-N-гидрокси-3-(3,4-диметил-фталимидо)пропионамида. 11. The hydroxamic acid derivative of claim 1, wherein said compound is selected from the group consisting of 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxo-isoindolinyl) propionamide, 3- (3-ethoxy) -4-methoxyphenyl) -N-methoxy-3- (1-oxoisoindolinyl) propionamide, N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3-phthalimidopropionamide, N-benzyloxy-3- (3-ethoxy) 4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide, N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (1-oxoisoindolinyl) propionamide, 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide, N-hydroxy-3- (3,4-dimethoxyphenyl) -3-phthal idopropionamide, 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-nitrophthalimido) propionamide, N-hydroxy-3- (3,4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide, 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-methylphthalimido) propionamide, 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopionamide, 3- (3- ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-1H-benzo [f] isoindol-2-yl) propionamide, N-hydroxy-3- {3- ( 2-propoxy) -4-methoxyphenyl} -3-phthalimidopropionamide, 3- (3-ethoxy-4-methoxyphenyl) -3- (3,6-difluorophthalimido) -N-hydroxypropionamide, 3- (4-aminophthalimido) -3- (3 is Si-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-aminophthalimido) -3- (3-methoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-aminophthalimido) -3- (3-ethoxy- 4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-aminophthalimido) -3- (3-cyclopentoxy-4-methoxyphenyl) -N-hydroxypropionamide, N-hydroxy-3- (3,4-dimethoxyphenyl) -3- ( 1-oxoisoindolinyl) propionamide, N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide, 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3- ( 1-oxoisoindolinyl) propionamide, 3- (3-methylphthalimido) -3- (3-cyclopentoxy-4-methoxyphenyl) -N-hydroxypropionamide a, 3- (4-methylphthalimido) -3- (3-cyclopentoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-hydroxyphthalimido) -3- (3-cyclopentoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (4-hydroxyphthalimido) -3- (3-cyclopentoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-methylphthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (4-methylphthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-hydroxyphthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (4 -hydroxyphthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, N-hydroxy-N-methyl-3- (3-ethoxy-4-m toxphenyl) -3- (1-oxoisoindolinyl) propionamide, 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3- (4-ethylphthalimido) propionamide, 3- (3-ethoxy-4-methoxyphenyl) -N -hydroxy-3- (3-hydroxyphthalimido) propionamide, 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-hydroxyphthalimido) propionamide, 3- (3-ethoxy-4-methoxyphenyl) -N -hydroxy-3- (3-methylphthalimido) propionamide, 3- (3-acetoamido-phthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (4-aceto-amidophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-1H-b zo [e] iso-indole-2'-yl) propionamide, 3- (4-tert-butylphthalimido) -3- (3-ethoxy-4-methoxy-phenyl) -N-hydroxypropionamide, 3- (3,4- dimethoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-1H-benzo [e] isoindol-2'-yl) propionamide, 3- (3,4-dimethoxyphthalimido) -3- ( 3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide, 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-dimethylaminophthalimido) propionamide, 3- (6,8-dioxo (2H-1 , 3-dioxolano [4,5-e] isoindolin-7-yl)) - 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide and 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy -3- (3,4-dimethyl-phthalimido) propionamide. 12. Способ снижения нежелательных уровней TNFα у млекопитающего, при котором ему вводят эффективное количество производного гидроксамовой кислоты по п.1. 12. The way to reduce unwanted levels of TNFα in a mammal, in which he was administered an effective amount of a derivative of hydroxamic acid according to claim 1. 13. Фармацевтическая композиция, содержащая количество производного гидроксамовой кислоты по п.1, достаточное для снижения уровней TNFα у млекопитающего при введении по схеме, включающей в себя однократный или многократный прием дозы, в комбинации с носителем. 13. A pharmaceutical composition comprising an amount of hydroxamic acid derivative according to claim 1, sufficient to reduce the levels of TNFα in a mammal when administered according to a regimen including single or multiple doses of the dose, in combination with a carrier. 14. Фармацевтическая композиция, содержащая количество производного гидроксамовой кислоты по п.1, достаточное для ингибирования нежелательных уровней матриксных металлопротеиназ у млекопитающего при введении по схеме, включающей в себя однократный или многократный прием дозы, в комбинации с носителем. 14. A pharmaceutical composition comprising a quantity of hydroxamic acid derivative according to claim 1, sufficient to inhibit undesirable levels of matrix metalloproteinases in a mammal when administered according to a regimen involving single or multiple doses, in combination with a carrier. 15. Способ ингибирования нежелательных уровней матриксных металлопротеиназ у млекопитающего, при котором ему вводят эффективное количество производного гидроксамовой кислоты по п.1. 15. A method of inhibiting undesirable levels of matrix metalloproteinases in a mammal in which it is administered an effective amount of a hydroxamic acid derivative according to claim 1.
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