Indolyl-3-glyoxylic acid derivatives having therapeutically valuable properties

Use of N-substituted indole-3-gloxylamides [sic] of the general formula 1 as antitumor agents according to Main Patent Application 19 814 838.0 for tumor treatment in particular in the case of pharmaceutical resistance and metastasizing carcinoma, and also as angiogenesis inhibitors, with markedly lower side effects in particular markedly lower neurotoxicity

• 5
• where the radicals R, R1, R2, R3, R4 and Z have the following meaning:
• R is hydrogen, (C1-C6)-alkyl, where the alkyl group can be mono- or polysubstituted by the phenyl ring and this phenyl ring for its part can be mono- or polysubstituted by halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C1-C6-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups, benzyloxy groups and by a benzyl group which is mono- or polysubstituted in the phenyl moiety by (C1-C6)-alkyl groups, halogen atoms or trifluoromethyl groups,
• R is further the benzyloxycarbonyl group (z group) and the tertiary-butoxycarbonyl radical (BOC radical), furthermore the acetyl group.
• R1 can be the phenyl ring, which is mono- or polysubstituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C1-C6-alkanols, or can be a pyridine structure of the formula 2 and its N-oxide [sic]
• 6
• and its N-oxide, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substituents R5 and R6. The radicals R5 and R6 can be identical or different and have the meaning (C1-C6)-alkyl and the meaning (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and further are the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
• R1 can further be a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore are [sic] the 2-, 3-, and 4- and 8-quinolyl structure substituted by (C1-C6)-alkyl, halogen, the nitro group, the amino group and the (C1-C6)-alkylamino radical, are [sic] a 2-, 3- and [sic] 4-quinolylmethyl group, where the 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 and (C1-C6)-alkoxycarbonylamino.
• R1, in the case in which R=hydrogen, the methyl or benzyl group and the benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl radical (BOC radical) and the acetyl group, can furthermore be the following radicals:
• —CH2COOH;
• —CH(CH3)—COOH;
• —(CH3)2—CH—(CH2)2—CH—COO—;
• H3C—H2C—CH(CH3)—CH(COOH)—[sic];
• HO—H2C—CH(COOH)—;
• phenyl-CH2—CH(COOH)—;
• (4-imidazolyl)-CH2—CH—(COOH)—;
• HN═C(NH2)—NH—(CH2)3—CH(COOH)—;
• H2N—(CH2)4—CH(COOH)—;
• H2N—CO—CH2—CH—(COOH)—;
• HOOC—(CH2)2—CH(COOH)—;
• R1, in the case in which R is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl group, can furthermore be the acid radical of a natural or unnatural amino acid, e.g. the α-glycyl, the α-sarcosyl, the α-alanyl, the α-leucyl, the α-isoleucyl, the α-seryl, the α-phenylalanyl, the α-histidyl, the α-prolyl, the α-arginyl, the α-lysyl, the α-asparagyl and the α-glutamyl radical, where the amino groups of the respective amino acids can be present unprotected or can be protected. A possible protective group of the amino function is the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) as well as the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R1, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C1-C6-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.
• Furthermore, R1 can be the allylamino-carbonyl-2-methylprop-1-yl group.
• R and R1 can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the formula 3 or a homopiperazine ring, provided R1 is an aminoalkylene group, in which
• 7
• R7 is an alkyl radical, is a phenyl ring which can be mono- or polysubstituted by (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, the nitro group, the amino function and by the (C1-C6)-alkylamino group. R7 is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl group [sic].
• R2 can be hydrogen and the (C1-C6)-alkyl group, where the alkyl group is mono- or polysubstituted by halogen and phenyl, which for its part can be mono- 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. The (C1-C6)-alkyl group counting as R2 can further be substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl structure, which can both in each case be mono- or polysubstituted by halogen, (C1-C4)-alkyl groups or (C1-C4)-alkoxy groups. R2 is further the aroyl radical, where the aryl moiety on which this radical is based is the phenyl ring, which can be mono- 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.
• R3 and R4 can be identical or different and are hydrogen, (C16)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen and benzyloxy. R3 and R4 can furthermore be the nitro group, the amino group, the (C1-C4)-mono or dialkyl-substituted amino group, and the (C1-C6)-alkoxycarbonylamino function or (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl function.
• Z is O and S.