Patent EP-2157081-A1 (EP)
Inventor: HECKEL ARMIN
IPC: C07D209/30
Filed: 2000-10-09
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. [Image] X : O or S; R 1H or prodrug residue; R 2COOH, (1-6C) alkoxycarbonyl (optionally substituted (os) terminally by Ph, heteroaryl, COOH, alkoxycarbonyl, CONH 2, mono- or dialkylaminocarbonyl or (in the case of (2-6C) alkoxycarbonyl) Cl, OH, alkoxy, NH 2 or mono- or dialkylamino), (5-7C) cycloalkoxycarbonyl, arylalkoxycarbonyl, CONH 2, CONHMe or ethylaminocarbonyl (os in the 2-position by OH or alkoxy); or di-(1-2C alkyl)-aminocarbonyl if R 4 is other than aminosulfonylphenyl or N-(1-5C alkyl)-alkylaminocarbonylphenyl; R 3H, 1-6C alkyl, 3-7C cycloalkyl, CF 3 or heteroaryl; or phenyl or naphthyl (both os by 1 or 2 of halo, CF 3, alkyl or alkoxy, and further os by OH, hydroxyalkyl, alkoxyalkyl, CN, carboxyalkyl, alkoxycarbonyl, CONH 2, mono- or dialkylaminocarbonyl, NO 2, NH 2, 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-SO 2-, Q-alkyl-, Q-CO-alkyl-, Q-SO 2-alkyl-, heteroaryl or heteroarylalkyl); Q : 4-7 membered cycloalkyleneimino (CAI), where CH 2 in the 4-position of 6- or 7-membered CAI is optionally replaced by O, S, SO, SO 2, NH or N(alkyl); R 43-7C cycloalkyl (in which the CH 2 in the 4-position of 6-7 membered cycloalkyl is os by NH 2 or mono- or dialkylamino or replaced by NH or N(alkyl)); or phenyl substituted by R 6 and further os by 1 or 2 of halo, 1-5C alkyl, CF 3, alkoxy, COOH, alkoxycarbonyl, NH 2, NHCOMe, alkylsulfonylamino, CONH 2, mono- or dialkylaminocarbonyl, SO 2NH 2, mono- or dialkylaminosulfonyl, NO 2 or CN; R 6e.g. (i) H, halo, CN, NO 2, 1-5C alkyl, 3-7C cycloalkyl, CF 3, 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, CONH 2, 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 CH 2 in the 4-position of 6-7 membered cycloalkyl is os by NH 2 or mono- or dialkylamino or replaced by NH or N(alkyl)) or (iv) 4-7 membered CAI (in which (a) CH 2 groups bonded to the imino can be replaced by CO or SO 2, (b) the cycloalkylene part is optionally fused with phenyl, (c) 1 or 2 H can be replaced by alkyl and (d) CH 2 in the 4-position of 6- or 7-membered CAI is os by COOH, alkoxycarbonyl, CONH 2, mono- or dialkylaminocarbonyl, phenylalkylamino or N-(alkyl)-phenylalkylamino or replaced by O, S, SO, SO 2, NH, N(alkyl), N(Ph), N(alkanoyl) or N(benzoyl)); R 7e.g. (i) 3-7C cycloalkyl (in which the CH 2 in the 4-position of 6-7 membered cycloalkyl is os by NH 2 or mono- or dialkylamino or replaced by NH or N(alkyl); or in 5-7 membered cycloalkyl (CH 2) 2 is optionally replaced by CONH, (CH 2) 3 is optionally replaced by NHCONH or CONHCO or (CH 2) 4 is optionally replaced by NHCONHCO, where all N atoms are os by alkyl), or (ii) aryl, heteroaryl, OH, alkoxy, NH 2, mono- or di-(1-7C alkyl)-amino, NHPh, N-(phenyl)-alkylamino, phenylalkylamino, N-(alkyl)-phenylalkylamino, di-(phenylalkyl)-amino, mono- or di-(omega -hydroxy-(2-3C) alkyl)-amino, mono- or di-(omega -hydroxy-(2-3C) alkyl)-amino, di-(omega -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 R 5H or alkyl. See DEFINITIONS for 'Full definitions'. An independent claim is included for the preparation of (I). ACTIVITY : Cytostatic; antirheumatic; antiarthritic; antipsoriatic; ophthalmological; antidiabetic; anti-HIV; nephrotropic; hepatotropic; neuroprotective; antiinflammatory; immunosuppressive; vasotropic; antiarteriosclerotic. MECHANISM OF ACTION : Kinase inhibitor; receptor tyrosine kinase inhibitor; cyclin dependent kinase complex inhibitor; viral cyclin inhibitor. 3-(Z)-(1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)-anilino)-1-phenyl-methylene)-6-ethoxycarbonyl-2-indolinone (Ia) exhibited an IC 50 value of 0.003 mu M for inhibition of proliferation of human umbilical endothelial cells.