Dolastatin-15 derivatives in combination with taxanes

A method for treating cancer in a mammal, selected from the group consisting of:

• lung, breast, colon, prostate, bladder, rectal, endometrial and hematological cancers, comprising:
• administering to said mammal an effective amount of a first compound selected from the group consisting of paclitaxel, taxotere, modified taxane and taxoid analogs;
• and
• administering to said mammal an enhanced effective amount of a second compound of Formula I:
• R1 R2 N—CHX—CO—A—B—D—(E)s—(F)t—(G)u—K (I)
• wherein:
• R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl, or aminosulfonyl;
• R2 is hydrogen, alkyl, fluoroalkyl or cycloalkyl;
• R1—N—R2 together may be a pyrrolidino or piperidino residue;
• A is a valyl, isoleucyl, leucyl, alloisoleucyl, 2,2-dimethylglycyl, 2-cyclopropylglycyl, 2-cyclopentylglycyl, 3-tert-butylalanyl, 2-tert-butylglycyl, 3-cyclohexylalanyl, 2-ethylglycyl, 2-cyclohexylglycyl, norleucyl or norvalyl residue;
• B is a N-alkyl-valyl, -norvalyl, -leucyl, -isoleucyl, -2-tert-butylglycyl, -3-tert-butylalanyl, -2-ethylglycyl, -2-cyclopropylglycyl, -2-cyclopentylglycyl, -norleucyl or -2-cyclohexylglycyl residue;
• D is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methylprolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;
• E is a prolyl, homoprolyl, hydroxyprolyl, 3,4-dehydroprolyl, 4-fluoroprolyl, 3-methylprolyl, 4-methyl prolyl, 5-methylprolyl, azetidine-2-carbonyl, 3,3-dimethylprolyl, 4,4-difluoroprolyl, oxazolidine-4-carbonyl or thiazolidine-4-carbonyl residue;
• F and G are independently selected from the group consisting of prolyl, homoprolyl, hydroxyprolyl, thiazolidinyl-4-carbonyl, 1-aminopentyl-1-carbonyl, valyl, 2-tert-butylglycyl, isoleucyl, leucyl, 3-cyclohexylalanyl, phenylalanyl, N-methylphenylalanyl, tetrahydrosioquinolyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, trytophanyl, glycyl, 2,2-dimethylglycyl, alanyl, β-alanyl and 3-naphthylalanyl residues;
• X is hydrogen, alkyl, cycloalkyl, —CH2-cyclohexyl or arylalkyl;
• s, t and u are independently 0 or 1;
• and
• K is hydroxy, alkoxy, phenoxy, benzyloxy or an amino moiety of the formula R5—N—R6 wherein:
• R5 is hydrogen;
• hydroxy;
• C1-7 alkoxy;
• benzyloxy;
• phenyloxy;
• fluorine substituted or unsubstituted C1-7-linear or branched alkyl;
• C1-12 linear or branched hydroxyalkyl;
• C3-10-cycloalkyl;
• unsubstituted benzyl;
• or mono-, di- or tri-substituted benzyl, wherein the substituents are independently selected from the group consisting of:
• CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, and COONH2;
• R6 is hydrogen;
• fluorine substituted or unsubstituted C1-12 linear or branched alkyl;
• C1-12 linear or branched hydroxyalkyl;
• C3-10-cycloalkyl;
• —(CH2)v—C3-7-cycloalkyl (v=0,1,2, or 3);
• norephedryl;
• norpseudoephedryl;
• quinolyl;
• pyrazyl;
• —CH2-benzimidazolyl;
• (1)-adamantyl;
• (2)-adamantyl;
• —CH2-adamantyl;
• alpha-methyl-benzyl;
• alpha-dimethylbenzyl;
• —(CH2)v-phenyl (v=0,1,2, or 3) wherein the phenyl group is unsubstituted or mono- or di-substituted and the substitutents are independently selected from the group consisting of:
• CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, phenoxy, benzoxy, halogen, C1-4-alkyl or fused alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, and COONH2;
• —(CH2)m-naphthyl (m=0 or 1);
• —(CH2)w-benzhydryl (w=0,1, or 2);
• biphenyl;
• picolyl;
• benzothiazolyl benzoisothiazolyl;
• benzopyrazolyl;
• benzoxazolyl;
• —(CH2)m-fluorenyl (m=0 or 1);
• pyrimidyl;
• —(CH2)m-indanyl (m=0 or 1);
• —(CH2CH2O)y—CH3 (y=0,1,2,3,4, or 5);
• —(CH2CH2O)y—CH2CH3 (y=0,1,2,3,4, or 5) NH-phenyl wherein the phenyl group is unsubstituted or mono- or di-substituted and the substitutents are independently selected from the group consisting of:
• CF3, nitro, C1-7 alkylsulfonyl, C1-4 alkoxy, halogen, C1-4 alkyl or fused alkyl, cyano, hydroxy, COOMe, COOEt, COOiPr, and COONH2;
• —NCH3—C6H5;
• —NH—CH2—C6H5;
• —CH3—CH2—C6H5;
• 5-membered unsubstituted or mono- or di-substituted heteroaryl wherein the substituents are selected from the group consisting of:
• CF3, nitro, thiomethyl, thioethyl, C3-6-cycloalkyl, —CH2—COOEt, C3-4-alkylene group forming a bicyclic system with the heterocycle;
• phenyl;
• —CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono- or di-substituted and the substituents are selected from the group consisting of:
• CF3, nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH2, C1-4-alkyl, C1-4-alkoxy, phenyl, benzyl, naphthyl, and C1-7-alkylsulfonyl;
• R7 is hydrogen, linear or branched C1-5 alkyl, and benzyl;
• or
• R7 and R5 together form a group —(CH2)3— or —(CH2)4—;
• and the salts thereof with physiologically tolerated acids.