Antitumor agents and angiogenesis inhibitors having low neurotoxicity, comprise indole-3-glyoxylamide derivatives, are effective against resistant and metastasis-forming carcinomas

摘要

Use of indole-3-glyoxylamide derivatives (I) as antitumor agents and angiogenesis inhibitors is new. The use of indole derivatives of formula (I) as antitumor agents and angiogenesis inhibitors is new. R = H, alkyl (optionally substituted (os) by one or more phenyl, itself os by one or more of halo, alkyl, cycloalkyl, COOH, alkoxycarbonyl, CF3, OH, OMe, OEt, benzyloxy or benzyl ring-substituted by one or more of alkyl, halo and CF3), benzyloxycarbonyl, tert. butoxycarbonyl or acetyl; R1 = (i) phenyl, substituted by one or more of alkyl, alkoxy, CN, halo, CF3, OH, benzyloxy, NO2, NH2, alkylamino, alkoxycarbonylamino, COOH and alkoxycarbonyl; (ii) pyridyl (optionally as the N-oxide) os by 1 or 2 of alkyl, cycloalkyl, alkoxy, NO2, NH2, OH, halo, CF3, NHCOOEt and carboxy-(1-4C) alkoxy; (iii) 2-pyrimidinyl (os by one or more Me); (iv) 4-pyrimidinyl; (v) 2-, 3-, 4- or 8-quinolyl substituted by alkyl, halo, NO2, NH2 or alkylamino; 2-, 3- or 4-quinolylmethyl (os in the ring bonded to methyl by alkyl, alkoxy, NO2, NH2 or alkoxycarbonyl); (vi) (if R = H, Me, benzyl, benzyloxycarbonyl, tert. butoxycarbonyl or acetyl) CH2COOH, CHMeCOOH, -(CH3)2-CH-(CH2)2-CH-COO- (sic), MeCH2CH(Me)CH(COOH)-, HOCH2CH(COOH), PhCH2CH(COOH)-, (4-imidazolyl)-CH2CH(COOH)-, HN=C(NH2)NH-(CH2)3CH(COOH)-, H2N-(CH2)4-CH(COOH)-, H2NCOCH2CH(COOH)- or HOOC-(CH2)2-CH(COOH)-; (vii) (if R = H, benzyl, benzyloxycarbonyl, tert. butoxycarbonyl or acetyl) the acid residue of a natural or non-natural aminoacid, e.g. alpha -glycyl, alpha -sarcosyl, alpha -alanyl, alpha -leucyl, alpha -seryl, alpha -phenylalanyl, alpha -histidyl, alpha -prolyl, alpha -arginyl, alpha -lysyl, alpha -asparagyl or alpha -glutamyl (where amino functions are optionally protected by benzyloxycarbonyl, tert. butoxycarbonyl or acetyl; and the second COOH group of asparagyl or glutamyl is optionally in alkyl ester form); or (viii) allylaminocarbonyl-2-methyl-prop-1-yl; or NRR1 = 4-(R7)-piperazino or homopiperazino; R7 = alkyl, phenyl (os by one or more of alkyl, alkoxy, halo, NO2, NH2 or alkylamino), benzhydryl or bis-p-fluorobenzhydryl; R2 = H; alkyl (os by (i) one or more of halo and phenyl, itself os by one or more of halo, alkyl, cycloalkyl, COOH, alkoxycarbonyl, CF3, OH, OMe, OEt or benzyloxy or (ii) 2-quinolyl or 2-, 3- or 4-pyridyl, all os by one or more of halo, 1-4C alkyl and 1-4C alkoxy); or benzoyl (os by one or more of halo, alkyl, cycloalkyl, COOH, alkoxycarbonyl, CF3, OH, OMe, OEt and benzyloxy); R3, R4 = H, alkyl, cycloalkyl, 1-6C alkanoyl, alkoxy, halo, benzyloxy, NO2, NH2, mono- or di-(1-4C alkyl)-amino, alkoxycarbonylamino or alkoxycarbonylaminoalkyl; Z' = O or S; unless specified otherwise, alkyl moieties have 1-6C and cycloalkyl moieties 3-7C. An Independent claim is also included for an antitumor agent composition containing (I) or its acid addition salt.