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US 5,792,783 AGranted
3-heteroaryl-2-indolinone compounds for the treatment of disease
AssigneeSugen, Inc.
InventorsPeng Cho Tang, Li Sun, Gerald McMahon
Life of this patent
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Abstract
The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
Claims28
A compound having the formula:
- ##STR11## or a pharmaceutically acceptable salt thereof, wherein:
- R.sub.1 is H;
- R.sub.2 is O or S;
- R.sub.3 is hydrogen;
- R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
- A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R or CONRR';
- n is 0-3;
- R is H, alkyl or aryl;
- and
- R' is H, alkyl or aryl;
- wherein said compound regulates, inhibits or modulates tyrosine kinase signal transduction;
- with the proviso that the following compounds are excluded:
- 3-(pyrrol-2-yl)methylene!-2-indolinone;
- 3-(5-chloro-3,4-dimethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene!-2-indolinone;
- Benzoic acid, 2-1-ethyl-2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene-1H-indol-5-yl!)o xy!methyl!-;
- 3-(1-methyl-5-nitro-imidazol-2-yl)methylene!-2-indolinone;
- 3-(thien-2ylmethylene)-2-indolinone;
- 1H-Indole-7-acetic acid, 3-(2-butyl-1H-imidazol-4-yl)methylene!-2,3-dihydro-2-oxo-, ethyl ester;
- and
- 1H-Indole-7-acetic acid, 3-(2-butyl-1-(1,1-dimethylethoxy)carbonyl!-1H-imidazoI-4-yl)methylene!-2 ,3-dihydro-2-oxo-, ethyl ester.
19 more elements
A compound having the formula:
- ##STR12## or a pharmaceutically acceptable salt thereof, wherein:
- R.sub.1 is H;
- R.sub.2 is O or S;
- R.sub.3 is hydrogen;
- R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR',
- A is a five membered heteroaryl ring selected from the group consisting of pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R or CONRR';
- n is 0-3;
- R is H, alkyl or aryl;
- and
- R' is H, alkyl or aryl.
7 more elements
A compound selected from the group consisting of 3-(3-Methylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(3,4-Dimethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(2-Methylthien-5-yl)methylene!-2-indolinone;
- 3-(3-Methylthien-2-yl)methylene!-2-indolinone;
- 3-{4-(2-methoxycarbonylethyl)-3-methylpyrrol-5-yl)!methylene}-2-indolinon e;
- 3-(4,5-Dimethyl-3-ethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(5-Methylimidazol-2-yl)methylene!-2-indolinone;
- 5-Chloro-3-(5-methylthien-2-yl)methylene!-2-indolinone;
- 3-(3,5-Dimethylpyrrol-2-yl)methylene!-5-nitro-2-indolinone;
- 3-(3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene!-2-indolinone;
- 5-Chloro-3-(3,5-dimethylpyrrol-2-yl)methylene!-2-indolinone;
- and 3-(2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.
8 more elements
A method for treating diseases related to tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:
- ##STR13## and pharmaceutically acceptable salts thereof, wherein:
- R.sub.1 is H or alkyl;
- R.sub.2 is O or S;
- R.sub.3 is hydrogen,
- R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.3).sub.n CO.sub.2 R, and CONRR';
- A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, akaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
- n is 0-3;
- R is H, alkyl or aryl;
- and
- R' is H, alkyl or aryl.
7 more elements
A method for regulating, modulating or inhibiting tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound having the formula:
- ##STR14## and pharmaceutically acceptable salts thereof, wherein:
- R.sub.1 is H or alkyl;
- R.sub.1 is O or S;
- R.sub.3 is hydrogen;
- R.sub.4, R.sub.5, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
- A is a five membered heteroaryl ring selected from the group consisting of thiopene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2 3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazoke, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO.sub.2 NRR', SO.sub.3 R, SR, NO.sub.2, NRR', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH.sub.2).sub.n CO.sub.2 R, and CONRR';
- n is 0-3;
- R is H, alkyl or aryl;
- and
- R' is H, alkyl or aryl.
7 more elements
A method for treating diseases related to tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of 3-(3-Methylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(3,4-Dimethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(2-Methylthien-5-yl)methylene!-2-indolinone;
- 3-(3-Methylthien-2-yl)methylene!-2-indolinone;
- 3-{4-(2-methoxycarbonylethyl)-3-methylpyrrol-5-yl!methylene}-2-indolinone ;
- 3-(4,5-Dimethyl-3-ethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(5-Methylimidazol-2-yl)methylene!-2-indolinone;
- 5-Chloro-3-(5-methylthien-2-yl)methylene!-2-indolinone;
- 3-(3,5-Dimethylpyrrol-2-yl)methylene!-5-nitro-2-indolinone;
- 3-(3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene!-2-indolinone;
- 5-Chloro-3-(3,5-dimethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(Thien-2-yl)methylene!-2-indolinone;
- 3-(Pyrrol-2-yl)methylene!-2-indolinone and 3-(2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.
9 more elements
A method for regulating, modulating or inhibiting tyrosine kinase signal transduction comprising administering to a subject a tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of 3-(3-Methylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(3,4-Dimethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(2-Methylthien-5-yl)methylene!-2-indolinone;
- 3-(3-Methylthien-2-yl)methylene!-2-indolinone;
- 3-{4-(2-methoxycarbonylethyl)-3-methylpyrrol-5-yl!methylene}-2-indolinone ;
- 3-(4,5-Dimethyl-3-ethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(5-Methylimidazol-2-yl)methylene!-2-indolinone;
- 5-Chloro-3-(5-methylthien-2-yl)methylene!-2-indolinone;
- 3-(3,5-Dimethylpyrrol-2-yl)methylene!-5-nitro-2-indolinone;
- 3-(3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene!-2-indolinone;
- 5-Chloro-3-(3,5-dimethylpyrrol-2-yl)methylene!-2-indolinone;
- 3-(Thien-2-yl)methylene!-2-indolinone;
- 3-(Pyrrol-2-yl)methylene!-2-indolinone and 3-(2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.
9 more elements
Dependencies are inferred from the claim text.