Patent NZ-337416-A (NZ)
Title: Dolastatin-15 derivatives in combination with taxanes
Inventor: BARLOZZARI TERESA
IPC: A61K38/08
Filed: 1998-03-09
Abstract: A pharmaceutical composition comprising: a compound selected from the group consisting of paclitaxel, taxotere and modified taxane or taxoid analogs; and an compound of the formula R1R2N-CHX-CO-A-B-D-(E)s-(F)t-(G)u-K  wherein: R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl, or aminosulfonyl; R2 is hydrogen, alkyl, fluoroalkyl or cycloalkyl; R1 --N--R together may be a pyrrolidino or piperidino residue; A is a valyl, isoleucyl, leucyl, allo-isoleucyl, 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, tetrahydrosioquinclyl-2-histidyl, 1-aminoindyl-1-carbonyl, 3-pyridylalanyl, 2-cyclohexylglycyl, norleucyl, norvalyl, neopentylglycyl, trytophanyl, glycyl, 2,2-dimethylglycyl, alanyl, beta.-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; alkoxy; benzyloxy; phenyloxy; fluorine substituted or unsubstituted linear or branched alkyl, linear or branched hydroxyalkyl, cycloalkyl, unsubstituted benzyl or mono-, di- or tri-substituted benzyl, wherein the substituents are independently selected from the group consisting of: CF3, nitro, alkylsulfonyl, alkoxy, phenoxy, benzoxy, halogen, alkyl, cyano, hydroxy, N(CH3)2, COOMe, COOEt, COOiPr, and COONH2; R6 is hydrogen, fluorine substituted unsubstituted linear or branched alkyl, linear or branched hydroxyalkyl, cycloalkyl, (CH2)v-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 substituents are independently selected from the group consisting of: CF3, nitro, alkylsulfonyl, alkoxy, phenoxy, benzoxy, halogen, 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),-(CH2 CH2 O)y --CH3 (y = 0,1,2,3,4, or 5), -(CH2 CH2 O)y -CH2 CH3 (y = 0,1,2,3,4, or 5) NH-phenyl wherein the phenyl group is unsubstituted or mono- or di-substituted and the substituents are independently selected from the group consisting of: CF3, nitro, alkylsulfonyl, alkoxy, halogen, alkyl or fused alkyl, cyano, hydroxy, COOMe, COOEt, COOiPr, and COONH2 , -NCH3 -C6 H5 , -NH--CH2 -C6 H5 , -NCH3 -CH2-C6H5 , 5-membered unsubstituted or mono- or di-substituted heteroaryl wherein the substituted selected from the group consisting of: CF3, nitro, thiomethyl, thioethyl, cycloalkyl, -CH2-COOEt, alkylene group forming a bicyclic system with the heterocycle, phenyl, -CHR7-5-membered heteroaryl selected from the group consisting of: CF3, nitro, cyano, halogen, COOMe, COOEt, COOiPr, CONH2, alkyl, alkoxy, phenyl, benzyl, naphthyl, and alkylsulfonyl; R7 is hydrogen, linear or branched alkyl, and benzyl, or R7 and R5 together form a group --(CH2)3- or -(CH2)4-, and the salts thereof with physiologically tolerated acids. The compounds are useful for treating lung, breast, colon, prostate, bladder, rectal, endometrial and hematological cancers in a mammal.