Patent DE-19940829-A1 (DE)
Title: New 3-(anilino-methylidene)-2-indolinone derivatives, are kinase inhibitors and cell proliferation inhibitors, useful e.g. for treating tumors, metastasis, rheumatoid arthritis or psoriasis
Inventor: ROTH GERALD JUERGEN
IPC: C07D209/34
Filed: 1999-08-27
Abstract: 6-Substituted 3-(anilino-methylidene)-indolin-2-one or -thione derivatives (I) are new.  Indolinone derivatives of formula (I) and their isomers and salts are new.  X  = O or S;  R1  = alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, CF3, CN, OH, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, heteroaryloxy, SH, alkylsulfenyl, SPh, SCH2Ph, alkylsulfinyl, SOPh, SOCH2Ph, alkylsulfonyl, SO2Ph, SO2CH2Ph, SO3H, alkoxysulfonyl, SO2OPh, SO2OCH2Ph, NH2, mono- or dialkylamino, carboxyalkylamino, N-(alkyl)-carboxyalkylamino, alkoxycarbonyl-alkylamino, N-(alkyl)-alkoxycarbonyl-alkylamino, NHPh, N-phenyl-alkylamino, NPh2, NHCH2Ph, N-benzyl-alkylamino, N(CH2Ph)2, alkylcarbonylamino, NHCOPh or NHCOCH2Ph; N-(alkyl)-alkylcarbonylamino or N-(alkyl)-alkylsulfonylamino, in which both alkyl groups can be replaced by 2-5C n-alkylene or one or both alkyl groups can be replaced by Ph or CH2Ph; or alkylsulfonylamino, NHSO2Ph, NHSO2CH2Ph, SO2NH2, mono- or dialkylaminosulfonyl, SO2NHPh, SO2NHCH2Ph, SO2NPh2, phosphono, (alkoxy)PO(H)-, (alkoxy)PO(alkyl)-, (alkoxy)PO(OH)-, (dialkoxy)PO-, (2-4C n-alkylenedioxy)PO-, ureido (optionally substituted by 1-3 alkyl), -Q or -SO2-Q;  Q  = 4-7 membered cycloalkyleneimino, where CH2 in the 4-position of 6- or 7-membered cycloalkyleneimino is optionally replaced by O, S, SO, SO2, NH or N(alkyl);  R2  = H, halo, 1-6C alkyl, CF3, OH, alkoxy, SH, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, SO3H, alkoxysulfonyl, SO2NH2, mono- or dialkylaminosulfonyl, NO2, NH2, mono- or dialkylamino, alkylcarbonyl, CN, COOH, alkoxycarbonyl, phosphono, (alkoxy)PO(H)-, (alkoxy)PO(alkyl)-, (alkoxy)PO(OH)-, (dialkoxy)PO-, Q, -COQ or -SO2Q;  or R1 + R2  = OCH2O, OCH2CH2O, (CH2)3, (CH2)4 or CH=CHCH=CH;  R3  = H, 1-6C alkyl, 3-7C cycloalkyl, CF3 or heteroaryl; or phenyl or naphthyl (both optionally substituted by 1 or 2 of halo, CF3, alkyl or alkoxy; and optionally further substituted by OH, hydroxyalkyl, alkoxyalkyl, CN, cyanoalkyl, cyanoalkenyl, cyanoalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, CONH2, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, mono- or dialkylaminocarbonylalkyl, mono- or dialkylaminocarbonylalkenyl, mono- or dialkylaminocarbonylalkynyl, NO2, nitroalkyl, nitroalkenyl, nitroalkynyl, NH2, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, N-(alkyl)-alkylcarbonylamino, N-(alkyl)-alkylcarbonylaminoalkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, N-(alkyl)-alkylsulfonylamino, N-(alkyl)-alkylsulfonylaminoalkyl, Q, Q-CO-, Q-SO2-, Q-alkyl-, Q-CO-alkyl-, Q-SO2-alkyl-, heteroaryl or heteroarylalkyl);  R4  = H, alkyl or prodrug residue;  R5  = H or alkyl;  R6  = (i) H, halo, CF3, heteroaryl, alkoxy (optionally substituted by 1-3 F), aminoalkoxy, mono- or dialkylamino-(2-3C) alkoxy, benzylamino-(2-3C) alkoxy, 4-7 membered cycloalkyleneimino-(2-3C) alkoxy, alkylthio, NO2, CN, COOH, alkoxycarbonyl, alkylcarbonylamino or N-(alkyl)-alkylcarbonylamino; (ii) 1-4C alkyl (optionally terminally substituted by OH, alkoxy, NH2, mono- or di-(1-4C alkyl)-amino, NHPh, N-phenyl-alkylamino, phenyl-n-alkylamino, N-(alkyl)-phenyl-n-alkylamino, di-(phenyl-n-alkyl)-amino, 4-7 membered cycloalkyleneimino (in which (a) CH2 groups bonded to the imino can be replaced by CO or SO2, (b) 1 or 2 H can be replaced by alkyl and (c) CH2 in the 4-position of 6- or 7-membered cycloalkyleneimino is optionally substituted by COOH, alkoxycarbonyl, CONH2, mono- or dialkylaminocarbonyl, phenyl-n-alkylamino or N-(alkyl)-phenyl-n-alkylamino or replaced by O, S, SO, SO2, NH or N(alkyl)), 5-7 membered cycloalkenyleneimino (in which the double bond is separated from N), 4-7C cycloalkylamino, N-(alkyl)-(4-7C) cycloalkylamino, 5-7C cycloalkenylamino (in which the double bond is not in the 1-position and N is optionally substituted by alkyl), alkylcarbonylamino, N-(alkyl)-alkylcarbonylamino, CONH2 or mono- or dialkylaminocarbonyl); (iii) -N(Ra)-CO-(CH2)n-Rb; or (iv) -N(Rc)-(CH2)m-(CO)o-Rd;  Ra  = alkyl;  n  = 0-2;  Rb  = NH2, mono- or di-(1-4C alkyl)-amino, NHPh, N-(1-4C alkyl)-phenylamino, NHCH2Ph, N-(1-4C alkyl)-benzylamino or Q;  Rc  = alkylcarbonyl , arylcarbonyl, COCH2Ph, alkylsulfonyl, arylsulfonyl or SO2CH2Ph;  m  = 1-4;  o = 0 or 1; and Rd  = as Rb; or di-(1-4C alkyl)-aminoalkylamino (optionally substituted by alkyl in the 1-position. COOH, NH2 or NH groups are optionally substituted by in vivo cleavable groups; alkyl moieties have 1-3C and alkenyl or alkynyl moieties 2-3C unless specified otherwise.  An Independent claim is included for the preparation of (I).