Indibulin therapy

A method for treating cancer, comprising administering an indolyl-3-glyoxylic acid derivative of Formula (I) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone

• wherein
• R is selected from hydrogen;
• (C1-C6)-alkyl, where the alkyl group is optionally mono- or polysubstituted with a phenyl ring which is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with (C1-C6)-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy or a benzyl group which is mono- or polysubstituted on the phenyl moiety with (C1-C6)-alkyl groups, halogen or trifluoromethyl;
• benzyloxycarbonyl;
• tertiary-butoxycarbonyl;
• and acetyl;
• R1 is selected from a phenyl ring, which is optionally mono- or polysubstituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C1-C6)-alkylamino, (C1-C6)-alkoxycarbonylamino, carboxyl, or by carboxyl esterified with C1-C6-alkanol;
• a pyridine structure of the Formula (II)
• or an N-oxide thereof, where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 or 4 and is optionally substituted with the substituents R5 and R6, wherein R5 and R6 are identical or different and are selected from (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)—alkoxy, nitro, amino, hydroxyl, halogen, trifluoromethyl, ethoxycarbonylamino, and carboxyalkyloxy in which the alkyl group comprises 1-4 C atoms;
• 2- or 4-pyrimidinyl, wherein the 2-pyrimidinyl ring is optionally mono- or polysubstituted with a methyl group;
• 2-, 3-, 4- or 8-quinolyl structure which is optionally substituted with (C1-C6)-alkyl, halogen, nitro, amino or (C1-C6)-alkylamino;
• 2-, 3-, or 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl, the quinolyl, and the quinolylmethyl are optionally substituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, nitro, amino or (C1-C6)-alkoxycarbonylamino;
• and allylaminocarbonyl-2-methylprop-1-yl;
• R1 in the case in which R is hydrogen, methyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl, is further selected from —CH2COOH;
• —CH(CH3)—COOH;
• —(CH3)2—CH—(CH2)2—CH—COO—;
• H3C—H2C—CH(CH3)—CH(COOH)—;
• HO—H2C—CH(COOH)—;
• phenyl-CH2—CH(COOH)—;
• (4-imidazolyl)-CH2—CH—(COOH)—;
• HN═(NH2)—NH—(CH2)3—CH(COOH)—;
• H2N—(CH2)4—CH(COOH)—;
• H2N—CO—CH2—CH—(COOH)—;
• and HOOC—(CH2)2—CH(COOH)—;
• R1, in the case in which R is hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or benzyl, may be the acid radical of a natural or unnatural amino acid (e.g. α-glycyl, α-sarcosyl, α-seryl, α-phenylalanyl, α-histidyl, α-prolyl, α-arginyl, α-lysyl, α-asparagyl or α-glutamyl), where the amino groups of the respective amino acids may be protected or unprotected, wherein suitable protecting groups include, but are not limited to, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl, and in the case where R1 is asparagyl or glutamyl, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester of a C1-C6-alkanol (e.g. as a methyl, ethyl or as a tert-butyl ester);
• R and R1 can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the Formula (III) or a homopiperazine ring, provided R1 is an aminoalkylene group, in which
• R7 is selected from alkyl;
• phenyl which is optionally mono- or polysubstituted with (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, nitro, amino or by (C1-C6)-alkylamino;
• benzhydryl and bis-p-fluorobenzhydryl;
• R2 is selected from hydrogen;
• (C1-C6)-alkyl, wherein the alkyl group is optionally mono- or polysubstituted with halogen, phenyl (wherein the phenyl is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with C1-C6-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy), 2-quinolyl (optionally mono- or polysubstituted with halogen, (C1-C4-alkyl or (C1-C4)-alkoxy), or 2-, 3- or 4-pyridyl (optionally mono- or polysubstituted with halogen, (C1-C4)-alkyl or (C1-C4)-alkoxy);
• aroyl (where the aryl moiety is optionally mono- or polysubstituted with halogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, carboxyl, carboxyl esterified with C1-C6-alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy);
• R3 and R4 are identical or different and are selected from hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C1-C6)-alkanoyl, (C1-C6)-alkoxy, halogen, benzyloxy, nitro, amino, (C1-C4)-mono or dialkyl-substituted amino, (C1-C6)-alkoxycarbonylamino and (C1-C6)-alkoxycarbonylamino-(C1-C6)-alkyl;
• Z is O or S.