Methods of modulating protein tyrosine kinase function with substituted indolinone compounds
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/404
C07D-403/06
출원번호
US-0013944
(2001-12-13)
발명자
/ 주소
Tang, Peng Cho
출원인 / 주소
Sugen, Inc.
대리인 / 주소
Burrous, Beth A.Foley & Lardner
인용정보
피인용 횟수 :
10인용 특허 :
10
초록▼
The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds and methods of treating diseases by mod
The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.
대표청구항▼
The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds and methods of treating diseases by mod
The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways. s 4-methoxyphenyl, 2,4,6-trimethylphenyl, phenyl, 3,4-methylenedioxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-hydroxyphenyl, 4-methylphenyl, 4-dimethylaminophenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 4-nitrophenyl, 5-methoxy-3,4-methylenedioxyphenyl, 3,4-difluoromethylenedioxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 2-naphthyl, or 3-chlorophenyl. 11. The composition according to claim 2, wherein R4is 4-pyridyl. 12. The composition according to claim 2, wherein R1and R2are independently hydrogen or C1-10alkyl. 13. The composition according to claim 2, wherein R1and R2are both methyl. 14. The composition according to claim 2, wherein R3is hydrogen. 15. The composition according to claim 2, wherein said compound is one of: 2-amino-3-cyano-7,7-dimethyl-4-(4-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(2,4,6-trimethylphenyl)-5-oxo-6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-phenyl-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(3,4-methylenedioxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-4-(4-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(3-hydroxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-methylphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-dimethylaminophenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-hydroxyphenyl)-5-oxo-5,6,7,8-tetrabydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(3-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-pyridyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(5-methoxy-3,4-methylenedioxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(3,4-difluoromethylenedioxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-4-cyanophenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(4-fluorophenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; 2-amino-3-cyano-7,7-dimethyl-4-(2-naphthyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; or 2-amino-3-cyano-7,7-dimethyl-4-(3-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; or a pharmaceutically acceptable salt or prodrug thereof. 16. A pharmaceutical composition for treating a disorder responsive to the positive modulation of AMPA receptors in an animal suffering thereof, comprising a pharmaceutically acceptable carrier or diluent; and an amount effective to positively modulate AMPA receptors in said animal of a compound of Formula IV: or a pharmaceutically acceptable salt or prodrug thereof wherein R1and R2are independently hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, C1-6thioalkyl C6-10aryl, C4-7cycloalkyl, C2-6alkenyl, C6-10alkynyl, C6-10aryl(C1-6)alkyl, C6-10aryl(C2-6)alkenyl, C6-10aryl(C2-6)alkynyl, or C4-7cycloalkyl(C1-6)alkyl; or R1and R2are taken together with the carbon atom to which they are attached to form a C3-7cycloalkyl; R3is hydrogen, or C1-6alkyl; R5-R9are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a carbocyclic group, C1-10alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, car bonylamido or alkylthiol; provided that either R5and R6,or R6and R7are taken together to form --OCH2O--, --OCF2O--, --(CH2)3--, --(CH2)4--, --OCH2CH2O--, --CH2N(R)CH2--, --CH2CH2--, --CH2N(R)CH2CH2--, --N(Me)--C(O)--O--, --CH=CH--CH=CH--, or --N=CH--CH=N--. 17. The composition according to claim 16, wherein R6and R7taken together are --OCH2O--, --OCF2O--, --(CH2)3--, --(CH2)4--, --OCH2CH2O--, --CH2N(R)CH2--, --CH2CH2N(R)CH2--, --CH2N(R)CH2CH2--, --N(Me)--C(O)--O--, --CH=CH--CH=CH-- or --N=CH--CH=N--. 18. The composition according to claim 16, wherein R1and R2are both methyl. 19. The composition according to claim 16, wherein R3is hydrogen. 20. A semiconductor device producing method according to claim 18, wherein the dust particle detecting apparatus is provided proximate to a handling mechanism arranged between a work feed station for loading and unloading the semiconductor work and the processing apparatus so that the handling mechanism transports the semiconductor work to and from the dust particle detecting apparatus. 21. A method of treating or ameliorating schizophrenia; treating or ameliorating the adverse consequences of hypostimulation of the excitatory amino acids; enhancing cognition; treating or ameliorating malnutrition or neural maldevelopment; treating or ameliorating neurodegenerative diseases, or treating or ameliorating myoclonus in an animal in need thereof; said method comprising: administering to the animal an effective amount of a compound having the Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1and R2are independently hydrogen, C1-10alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, hydroxyalkyl, aminoalkyl and thioalkyl; or R1and R2are taken together to form a carbocycle; R3is hydrogen, or C1-10alkyl; R4is substituted or unsubstituted aryl, heteroaryl, carbocycle or heterocycle; X is hydrogen, NO2,CN, C1-10alkyl, haloalkyl, aryl, COR, CO2R or CONRxRy,wherein R, Rxand Ryare independently hydrogen, C1-10alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, carbocycloalkyl, hydroxyalkyl or aminoalkyl; Y is NH2,NHR, or NHCOR; and Z is O or S. 22. The method of claim 21, wherein a neurodegenerative disease selected from the group consisting of AIDS associated dementia, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Down's syndrome is treated or ameliorated. 23. The method according to claim 21, wherein X is CN. 24. The method according to claim 21, wherein Z is O. 25. The method according to claim 21, wherein Y is NH2. 26. The method according to claim 21, wherein X is CN, Y is NH2,and Z is O. 27. The method according to claim 26, wherein R1and R2are independently hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, or C1-6thioalkyl. 28. The method according to claim 26, wherein R4is optionally substituted phenyl, naphthyl or pyridyl. 29. The method according to claim 28, wherein R4is optionally substituted phenyl. 30. The method according to claim 29, wherein R4is 4-methoxyphenyl, 2,4,6-trimethylphenyl, phenyl
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