Patent DE-19949208-A1 (DE)
Title: New 3-(amino-methylene)-2-indolinone derivatives are kinase inhibitors and cell proliferation inhibitors useful e.g. for treating tumors, metastasis, rheumatoid arthritis or psoriasis
Inventor: HECKEL ARMIN
IPC: A61P35/00
Filed: 1999-10-13
Abstract: 6-Carboxy-3-(anilino- or cycloalkylamino-methylene)-indolin-2-one or -thione derivatives (I) are new.  6-Carboxy-3-(anilino- or cycloalkylamino-methylene)-indolin-2-one or -thione derivatives of formula (I) and their tautomers, diastereomers, enantiomers (and mixtures) and salts are new. X = O or S; R1 = H or prodrug residue; R2 = COOH, (1-6C) alkoxycarbonyl (optionally substituted (os) terminally by Ph, heteroaryl, COOH, alkoxycarbonyl, CONH2, mono- or dialkylaminocarbonyl or (in the case of (2-6C) alkoxycarbonyl) Cl, OH, alkoxy, NH2 or mono- or dialkylamino), (5-7C) cycloalkoxycarbonyl, arylalkoxycarbonyl, CONH2, CONHMe or ethylaminocarbonyl (os in the 2-position by OH or alkoxy); or di-(1-2C alkyl)-aminocarbonyl if R4 is other than aminosulfonylphenyl or N-(1-5C alkyl)-alkylaminocarbonylphenyl; R3 = H, 1-6C alkyl, 3-7C cycloalkyl, CF3 or heteroaryl; or phenyl or naphthyl (both os by 1 or 2 of halo, CF3, alkyl or alkoxy, and further os by OH, hydroxyalkyl, alkoxyalkyl, CN, carboxyalkyl, alkoxycarbonyl, CONH2, mono- or dialkylaminocarbonyl, NO2, NH2, mono- or dialkylamino, aminoalkyl, alkylcarbonylamino, N-(alkyl)-alkylcarbonylamino, alkylcarbonylaminoalkyl, N-(alkyl)-alkylcarbonylaminoalkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, N-(alkyl)-alkylsulfonylamino, N-(alkyl)-alkylsulfonylaminoalkyl, arylalkylaminosulfonyl, 4-7C cycloalkylamino, Q, Q-CO-, Q-SO2-, Q-alkyl-, Q-CO-alkyl-, Q-SO2-alkyl-, heteroaryl or heteroarylalkyl); Q = 4-7 membered cycloalkyleneimino (CAI), where CH2 in the 4-position of 6- or 7-membered CAI is optionally replaced by O, S, SO, SO2, NH or N(alkyl); R4 = 3-7C cycloalkyl (in which the CH2 in the 4-position of 6-7 membered cycloalkyl is os by NH2 or mono- or dialkylamino or replaced by NH or N(alkyl)); or phenyl substituted by R6 and further os by 1 or 2 of halo, 1-5C alkyl, CF3, alkoxy, COOH, alkoxycarbonyl, NH2, NHCOMe, alkylsulfonylamino, CONH2, mono- or dialkylaminocarbonyl, SO2NH2, mono- or dialkylaminosulfonyl, NO2 or CN; R6 = e.g. (i) H, halo, CN, NO2, 1-5C alkyl, 3-7C cycloalkyl, CF3, heteroaryl, 2,4-dioxo-imidazolidin-5-ylidenemethyl (os by alkyl on either or both N), alkoxy, alkoxyalkoxy, phenylalkoxy, amino-(2-3C) alkoxy, mono- or dialkylamino-(2-3C) alkoxy, phenylalkylamino-(2-3C) alkoxy, N-(alkyl)-phenylalkylamino-(2-3C) alkoxy, 5-7 membered CAI-(2-3C) alkoxy, alkylthio, COOH, (1-4C) alkoxycarbonyl, CONH2, alkylaminocarbonyl, N-(1-5C alkyl)-alkylaminocarbonyl, phenylalkylaminocarbonyl, N-(alkyl)-phenylalkylaminocarbonyl, piperazinocarbonyl or N-(alkyl)-piperazinocarbonyl; (ii) alkylaminocarbonyl or N-(1-5C alkyl)-alkylaminocarbonyl, in which an alkyl group is substituted by COOH or alkoxycarbonyl or in the 2- or 3-position by di-(2-3C alkyl)-amino, piperazino, N-alkylpiperazino or 4-7 membered CAI; (iii) (3-7C) cycloalkylcarbonyl (in which the CH2 in the 4-position of 6-7 membered cycloalkyl is os by NH2 or mono- or dialkylamino or replaced by NH or N(alkyl)) or (iv) 4-7 membered CAI (in which (a) CH2 groups bonded to the imino can be replaced by CO or SO2, (b) the cycloalkylene part is optionally fused with phenyl, (c) 1 or 2 H can be replaced by alkyl and (d) CH2 in the 4-position of 6- or 7-membered CAI is os by COOH, alkoxycarbonyl, CONH2, mono- or dialkylaminocarbonyl, phenylalkylamino or N-(alkyl)-phenylalkylamino or replaced by O, S, SO, SO2, NH, N(alkyl), N(Ph), N(alkanoyl) or N(benzoyl)); R7 = e.g. (i) 3-7C cycloalkyl (in which the CH2 in the 4-position of 6-7 membered cycloalkyl is os by NH2 or mono- or dialkylamino or replaced by NH or N(alkyl); or in 5-7 membered cycloalkyl (CH2)2 is optionally replaced by CONH, (CH2)3 is optionally replaced by NHCONH or CONHCO or (CH2)4 is optionally replaced by NHCONHCO, where all N atoms are os by alkyl), or (ii) aryl, heteroaryl, OH, alkoxy, NH2, mono- or di-(1-7C alkyl)-amino, NHPh, N-(phenyl)-alkylamino, phenylalkylamino, N-(alkyl)-phenylalkylamino, di-(phenylalkyl)-amino, mono- or di-(w-hydroxy-(2-3C) alkyl)-amino, mono- or di-(w-hydroxy-(2-3C) alkyl)-amino, di-(w-alkoxy-(2-3C) alkyl)-amino, N-(dioxolan-2-yl)-alkylamino, alkylcarbonylamino-(2-3C) alkylamino, alkylcarbonylamino-(2-3C) alkyl-N-(alkyl)-amino, alkylsulfonylamino, N-(alkyl)-alkylsulfonylamino, alkylsulfonylamino-(2-3C) alkylamino, alkylsulfonylamino-(2-3C) alkyl-N-(alkyl)-amino, carboxyalkylamino, N-(alkyl)-carboxyalkylamino or guanidino (os by 1 or 2 alkyl) and R5 = H or alkyl. See DEFINITIONS for 'Full definitions'. An Independent claim is included for the preparation of (I).