Patent ID: 6693119
Filing Date: 2004-02-17
Classification: A61K,A61P

Abstract:
A method of treating antitumor agent resistant tumors, metastasizing carcinoma including development and spread of metastases, tumors sensitive to angiogenesis inhibitors or tumors that are both antitumor agent resistant and sensitive to angiogenesis inhibitors, comprising administration to a patient suffering from an antitumor agent resistant tumor, a metastasizing carcinoma including development and spread of metastases, a tumor sensitive to angiogenesis inhibitors or a tumor that is both antitumor agent resistant and sensitive to angiogenesis inhibitors of an effective amount of one or more N-substituted indole-3-glyoxylamides of formula I wherein each of R, R1, R2, R3, R4 and Z have the following meanings:R is hydrogen, a benzyloxycarbonyl group, a tertiary-butoxycarbonyl radical, an acetyl group or a (C1-C6)-alkyl, wherein the alkyl group is monosubstituted or polysubstituted by a phenyl ring, the phenyl ring is monosubstituted or polysubstituted by a member selected from the group consisting of halogens, (C1-C6)-alkyl groups, (C3-C7)-cycloalkyl groups, carboxyl groups, carboxyl groups esterified with (C1-C6)-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and a benzyl group which is monosubstituted or polysubstituted with a member selected from the group consisting of (C1-C6)-alkyl groups, halogen atoms and trifluoromethyl groups; R1 is a phenyl ring, which is monosubstituted or polysubstituted with a member of the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino, carboxyl group, carboxyl group esterified with (C1-C6)-alkanols, and pyridine moiety of formula 2 or an N-oxide of a pyridine moiety of formula 2; â€ƒwherein the pyridine moiety is alternatively bonded to ring carbon atoms 2, 3 and 4 and can be substituted by substituents R5 and R6, and wherein radicals R5 and R6 can be identical or different and may be (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, an ethoxycarbonylamino radical or a carboxyalkyloxy group in which the alkyl group can have 1-4 C atoms; or R1 is a 2-pyrimidinyl heterocycle or 4-pyrimidinyl heterocycle, having a 2-pyrimidinyl ring that is monosubstituted or polysubstituted with a methyl group, a 2-, 3-, 4- or 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, a nitro group, an amino group or a (C1-C6)-alkylamino radical, or a 2-, 3- or 4-quinolylmethyl group, wherein ring carbons of the pyridylmethyl radical of the quinolyl group and of the quinolylmethyl radical can be substituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino or (C1-C6) -alkoxycarbonylamino; wherein when R is hydrogen, a methyl benzyl group, a benzyloxycarbonyl radical, a tert-butoxycarbonyl radical or an acetyl group, R1, may be the following radicals: â€”CH2COOH; â€”CH(CH3)&boxH;COOH; â€”(CH3)2â€”CHâ€”(CH2)2â€”CHâ€”COOâ€”; H3Câ€”H2Câ€”CH(CH3)â€”CH(COOH)â€”; HOâ€”H2Câ€”CH(COOH)â€”; phenyl-CH2â€”CH(COOH)â€”; (4-imidazolyl)-CH2â€”CHâ€”(COOH)â€”; HN&boxH;C(NH2)â€”NHâ€”(CH2)3â€”CH(COOH)â€”; H2Nâ€”(CH2)4â€”CH(COOH)â€”; H2Nâ€”COâ€”CH2â€”CHâ€”(COOH)â€”; HOOCâ€”(CH2)2â€”CH(COOH)â€”; wherein when R is hydrogen, the Z radical, the tertiary-butoxycarbonyl radical, an acetyl group or a benzyl group, R1, is an acid radical of a natural amino acid or unnatural amino acid selected from the group consisting of &agr;-glycyl, &agr;-sarcosyl, &agr;-alanyl, &agr;-leucyl, &agr;-isoleucyl, &agr;-seryl, &agr;-phenylalanyl, &agr;-histidyl, &agr;-prolyl, &agr;-arginyl, &agr;-lysyl, &agr;-asparagyl and &agr;-glutamyl radical, wherein an amino group of the amino acid is unprotected or protected by a member of the group consisting of a carbobenzoxyl radical, a tert-butoxycarbonyl radical and an acetyl group, wherein when R1 is an asparagyl or glutamyl radical, a second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with (C1-C6)-alkanol as a methyl, ethyl or as a tert-butyl ester, or R1 is an allylamino-carbonyl-2-methylprop-1-yl group; wherein R and R1 optionally form, together with the nitrogen atom to which they are bonded, a piperazine ring of formula 3 or a homopiperazine ring, provided R1 is an aminoalkylene group, in which â€ƒR7 is an alkyl radical, a phenyl ring which can be monosubstituted or polysubstituted by a (C1-C6)-alkyl, a (C1-C6)-alkoxy, a halogen, a nitro group, an amino functions, or a (C1-C6)-alkylamino group, or R7 is a benzhydryl group or a bis-p-fluorobenzylhydryl group; R2 is hydrogen or a (C1-C6)-alkyl group, wherein the alkyl group is monosubstituted or polysubstituted by halogen and phenyl group that is monosubstituted or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl groups, carboxyl groups esterified with (C1-C6)-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups, wherein when R2 is a (C1-C6)-alkyl group, the (C1-C6)-alkyl group is substituted by a 2-quinolyl group and a 2-, 3- and -pyridyl structure, each of which may be monosubstituted or polysubstituted by one or more halogens, (C1-C6)-alkyl groups or (C1-C4)-alkoxy groups, wherein R2 may be an aroyl radical having an aryl moiety comprising a phenyl ring, that is monosubstituted or -polysubstituted by one or more of halogens, (C1-C6)-alkyls, (C3-C7)-cycloalkyls, carboxyl groups, carboxy groups esterified with (C1-C6)-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups; R3 and R4 are identical or different and are selected from the group consisting of hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy, a nitro group, an amino group, a (C1-C4)-mono or dialkyl-substituted amino group, a (C1-C6)-alkoxycarbonylamino function and a (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function; and Z is O or S.