3-methylidenyl-2-indolinone modulators of protein kinase
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/40
A61K-031/44
A61K-031/535
C07D-209/34
C07D-413/00
출원번호
US-0383690
(2003-03-10)
발명자
/ 주소
Tang, Pen Cho
Sun, Li
Miller, Todd Anthony
Liang, Congxin
Tran, Ngoc My
Nguyen, Anh Thi
Nematalla, Asaad
출원인 / 주소
Sugen, Inc.
대리인 / 주소
Foley &
인용정보
피인용 횟수 :
1인용 특허 :
29
초록▼
The present invention relates to novel 3-methylidenyl-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders s
The present invention relates to novel 3-methylidenyl-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
대표청구항▼
1. A compound having the chemical structure: wherein:A is carbon; Q is R0 is selected from the group consisting of hydrogen, alkyl, ?C(O)R19 and ?C(O)OR19 R1 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, aryl, ?(CH2)nOC(O)R19; ?C(O)NR19; ?C(O)OR19 and ?(CH2)nR20, wherein: R
1. A compound having the chemical structure: wherein:A is carbon; Q is R0 is selected from the group consisting of hydrogen, alkyl, ?C(O)R19 and ?C(O)OR19 R1 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, aryl, ?(CH2)nOC(O)R19; ?C(O)NR19; ?C(O)OR19 and ?(CH2)nR20, wherein: R19 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and aryl; n is 1, 2, 3 or 4; R20 is selected from the group consisting of hydroxy, halo, ?C(O)OR19, ?OC(O)NR21R22; ?OC(S)NR21R22, ?OC(O)NHS2R21R22; ?NR21R22 and a heteroalicylic group containing at least one nitrogen atom in the ring, the ring being bonded to the adjacent CH2 group through the nitrogen atom; R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, trihalomethyl, alkoxy, halo, ?(CH2)nR20, ?SO2NR21R22, ?C(O)OR19, ?C(O)R19, ?NHC(O)OR19, ?NR21R22 and ?N?CR23 wherein R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic; R23 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl; R3 is selected from the group consisting of hydrogen, alkyl, trihalomethyl, alkoxy, aryl, aryloxy, heteraryl, heteroalicyclic, hydroxy, halo, ?SO2NR21R22, ?NHSO2R19, ?C(O)OR19, ?NR21R22 and ?NHC(O)R24, wherein R24 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic; R4 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo; R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, aryl and heteroaryl; R6 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, cycloalkyl, aryl and, combined with R18, a heteroalicyclic group having the structure whereiny and y′ are independently selected from the group consisting of hydrogen, alkyl and aryl; R7 is OR18, wherein R18 is selected from the group consisting of alkyl, ?(CH)nR20 and, combined with R6 or R8, a heteroalicyclic group having the structure R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl and, combined with R18, a heteroalicyclic ring having the structure R9 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo and ?NR21R22; R10 is selected from the group consisting of alkyl and ?C(O)OR19; R11 is selected from the group consisting of hydrogen, alkyl and ?C(O)OR19; R12 is ?(CH2)nR20; and, physiologically acceptable salts thereof. 2. The compound or salt of claim 1, wherein:R1 is selected from the group consisting of hydrogen, lower alkyl and ?C(O)OH; R2 is selected from the group consisting of hydrogen, lower alkyl, halo, ?C(O)R19, ?C(O)OR19, lower alkoxy, ?NR21R22, ?(CH2)nR20 and ?NHC(O)OR19; R3 is selected from the group consisting of hydrogen, hydroxy, halo, ?NHC(O)O (lower alkyl), ?NHSO2R19, ?NHC(O)R24, trihalomethyl, and aryl optionally substituted with one or more lower alkoxy groups; R4 is hydrogen; R19 is selected from the group consisting of hydrogen and lower alkyl; n is 2 or 3; R20 is selected from the group consisting of hydroxy, ?C(O)OH, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl and ?NR21R22; R21 and R22 are independently selected from the group consisting of hydrogen and lower alkyl; and, R24 is selected from the group consisting of hydrogen and lower alkyl. 3. The compound or salt of claim 2, wherein,R5 is selected from the group consisting of hydrogen, lower alkyl, halo, five-member ring heteroaryl and aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, halo, hydroxy, ?NR21R22 and lower alkoxy; R6 is selected from the group consisting of hydrogen, lower alkyl, 3 to 7-member cycloalkyl, lower alkoxy, halo, aryl optionally substituted with one or more groups independently selected from the group consisting of lower alkyl, halo, hydroxy, ?NR21R22 and lower alkoxy and, combined with R18, a group having the structure wherein y and y′ are either both hydrogen or both lower alkyl; R7 is ?OR18 wherein R18 is selected from the group consisting of lower alkyl, ?(CH2)nR20 and, combined with R6 or R8, a group having the structure R8 is selected from the group consisting of hydrogen, lower alkyl, 3 to 6-member ring cycloalkyl, lower alkoxy, halo, aryl optionally substituted with one or more groups selected from the group consisting of lower alkyl, lower alkoxy, halo, ?NR21R22 and ?NHC(O) (lower alkyl), five member heteroaryl having from 1 to 3 heteroatoms in the ring and 6-member heteroaryl having from 1 to 3 heteroatoms in the ring and, combined with R18 a group having the structure R9 is selected from the group consisting of hydrogen, lower alkyl; hydroxy, lower alkoxy, halo and ?NR21R22. 4. The compound or salt of claim 2, wherein:R5 is selected from the group consisting of hydrogen, lower alkyl, thien-2-yl, thien-3-yl and aryl optionally substituted with one or more lower alkoxy groups; R6 is selected from the group consisting of hydrogen, lower alkyl, 5 or 6-member cycloalkyl, aryl optionally substituted with one or more lower alkoxy groups and, combined with R18, a group having the structure wherein?y and y′ are either both hydrogen or both lower alkyl; R7 is ?OR18, wherein R18 is selected from the group consisting of lower alkyl, ?(CH2)nR20 and, combined with R6 or R8, a group having the structure ?n is 2 or 3; ?R20 is selected from the group consisting of hydroxy, ?C(O)OH, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl pyrrolidin-1-yl and ?NR21R22; R8 is selected from the group consisting of hydrogen, lower alkyl, 5 or 6-member ring cycloalkyl, lower alkoxy, aryl optionally substituted with a ?NHC(O) (lower alkyl) group, thien-2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl and, combined with R18, a group having the structure: R9 is selected from the group consisting of hydrogen and lower alkyl. 5. The compound or salt of claim 1, wherein:R1 is selected from the group consisting of hydrogen, lower alkyl and ?(CH2)n R20; n is 2 or 3; R20 is selected from the group consisting of hydroxy and ?C(O)OH; R2 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy, ?SO2NR21R22 and ?C(O)OH; R3 is selected from the group consisting of hydrogen, halo, lower alkyl, lower alkoxy and aryl optionally substituted with one or more lower alkoxy groups; and, R4 is hydrogen. 6. A pharmaceutical composition, comprising a compound or salt of claim 1; and,a pharmaceutically acceptable carrier or excipient. 7. A method for the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound or salt of claim 1.8. The method of claim 7 wherein said protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase and a serine-threonine kinase.9. A method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a compound or salt of claim 1 to said organism.10. The method of claim 9 wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase related disorder and a serine-threonine kinase related disorder.11. The method of claim 9 wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder and a flk related disorder.12. The method of claim 9 wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer.13. The method of claim 9 wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder.14. The method of claim 9 wherein said organism is a human.15. A compound of claim 1, or salt thereof, selected from the group consisting of:3-(3,5-Diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; N-[3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-hydroxy-1,3-dihydroindol-2-one; 5-Acetyl-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester; 3-(3-Isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one; 3-(3-Cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-(3-Cyclopentyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one; 3-(3-Cyclohexyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 5-Bromo-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one; 5-Chloro-3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one; 5-Chloro-3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one; N-{3-[3-Cyclohexyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-2-oxo-2,3-dihydro-1H-indol-6yl}-acetamide; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-5-methoxy-1,3-dihydroindol-2-one; N-[3-(4-Methoxy-3-thiophen-3-ylbenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-5-methyl-1,3-dihydroindol-2-one; 5-Amino-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(4-methoxy-3,5-dimethylbenzylidene)-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-fluoro-1,3-dihydroindol-2-one; 3-(2,2-Dimethylchroman-6-ylmethylene)-5-fluoro-1,3-dihydroindol-2-one; 5-Chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-7-fluoro-1,3-dihydroindol-2-one; 3-(4-Methoxy-3-thiophen-3-ylbenzylidene)-5-(2-morpholin-4-ylethyl)-1,3-dihydroindol-2-one; N-[3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-5-ethyl-1,3-dihydroindol-2-one; N-[2′-Methoxy-5′-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-biphenyl-3-yl]-acetamide; 5-Fluoro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one; N-[3-(4-Methoxy-3-thiophen-2-ylbenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide; 6-Amino-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; N-[3-(2,2-Dimethylchroman-6-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide; 5-Bromo-3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one; 3-(4-Methoxy-3-thiophen-3-ylbenzylidene)-1,3-dihydroindol-2-one; 5-Bromo-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one; 5-Fluoro-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one; 3-(3-Isopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 3-(4,5-Dimethoxy-2-thiophen-2-ylbenzylidene)-1,3-dihydroindol-2-one; N-{3-[4-(2-Morpholin-4-ylethoxy)-3-thiophen-2-ylbenzylidene]-2-oxo-2,3-dihydro-1H-indol-6yl}-acetamide; 3-(2,2-Dimethylchroman-6-ylmethylene)-4-methyl-1,3-dihydroindol-2-one; 3-(2,3-Dihydrobenzofuran-5-ylmethylene)-5-fluoro-1,3-dihydroindol-2-one; 3-(3-Cyclohexyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one; 5-Fluoro-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one; 3-(3′-Ethoxy-6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one; 3-(3-Cyclopentyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3]pyridin-2-one; 3-(3-Cyclopentyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 3-(4,5,2′-Trimethoxybiphenyl-2-ylmethylene)-1,3-dihydroindol-2-one; {3-[4-(2-Morpholin-4-ylethoxy)-3-thiophen-3-ylbenzylidene]-2-oxo-2,3-dihydro-1H-indole-6yl}-acetamide; 5-Chloro-3-(3-cyclohexyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; [3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbamic acid tert-butyl ester; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 5-Bromo-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; N-{3-[3-tert-Butyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide; 3-(4-Methoxy-3,5-dimethylbenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one; 5-Bromo-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one; 3-(3′-Ethoxy-4,5-dimethoxybiphenyl-2-ylmethylene)-1,3-dihydroindol-2-one; 5-Chloro-3-(4-methoxy-3-thiophen-2-ylbenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(4-methoxy-3-pyridin-3-ylbenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(4,5,3′-trimethoxybiphenyl-2-ylmethylene)-1,3-dihydroindol-2-one; 3-(4,5-Dimethoxy-2-naphthalen-2-ylbenzylidene)-1,3-dihydroindol-2-one; N-[3-(3′-Acetylamino-6-methoxybiphenyl-3-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide; 6-Methoxy-3-(4-methoxy,-3-thiophen-3-ylbenzylidene)-1,3-dihydroindol-2-one; 3-(6-Methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one; 3-(2,3-Dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one; 5-Chloro-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one; 3-(3-Cyclohexyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 3-(2,3-dihydrobenzofuran-5-ylmethylene)-4-methyl-1,3-dihydroindol-2-one; 3-(3-Isopropyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one; 3-(6-Methoxybiphenyl-3-ylmethylene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one; 3-(3-Cyclohexyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one; 3-(2,3-Dihydrobenzofuran-5-ylmethylene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one; 3-[3,5-Diisopropyl-4-methoxybenzylidene)-1,3-dihydropyrrolo(2,3-b]pyridin-2-one; 5-Bromo-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 5-Bromo-3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(3-cyclopentyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 5-Chloro-3-(6-methoxybiphenyl-3-ylmethylene)-4-methyl-1,3-dihydroindol-2-one; 5-Chloro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-4-methyl-1,3-dihydroindol-2-one; 5-Chloro-3-(4-methoxy-3,5-dimethylbenzylidene)-4-methyl-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-trifluoromethyl-1,3-dihydroindol-2-one; 6-Chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-[3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-propionic acid; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-methoxy-1,3-dihydroindol-2-one; 5-Butyl-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-(3-methoxyphenyl)-1,3-dihydroindol-2-one; 7-Chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-5-methyl-1,3-dihydroindol-2-one; [3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-carbamic acid tert-butyl ester; 5-Chloro-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 5-Chloro-3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one; 3-(6-Methoxybiphenyl-3-ylmethylene)-4-methyl-1,3-dihydroindol-2-one; 3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-4-methyl-1,3-dihydroindol-2-one; 5-Bromo-3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one; 5-Chloro-3-(3-isopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 5-Chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one; 5-Chloro-3-(2,2-dimethylchroman-6-ylmethylene)-4-methyl-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-5,6-dimethoxy-1,3-dihydroindol-2-one; N-[3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-methanesulfonamide; N-[3-(3,5-Diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-benzamide; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-(3-ethoxyphenyl)-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one; 3-(3,5-Diisopropyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one; 5-Fluoro-3-(4-methoxy-3,5-dimethylbenzylidene)-1,3-dihydroindol-2-one; 3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one.
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