Patent ID: 6632795
Filing Date: 2003-10-14
Classification: A61K,A61P

Abstract:
A pharmaceutical composition comprising:an effective amount of a first compound selected from the group consisting of paclitaxel, taxotere, modified taxane and taxoid analogs; and an enhanced effective amount of a second compound, wherein the second compound is of Formula I R1R2Nâ€”CHXâ€”COâ€”Aâ€”Bâ€”Dâ€”(E)sâ€”(F)tâ€”(G)uâ€”Kâ€ƒâ€ƒ(I) wherein:R1 is alkyl, cycloalkyl, alkylsulfonyl, fluoroalkyl, or aminosulfonyl; R2 is hydrogen, alkyl, fluoroalkyl or cycloalkyl; R1â€”Nâ€”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, &bgr;-alanyl and 3-naphthylalanyl residues; X is hydrogen, alkyl, cycloalkyl, â€”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 R5â€”Nâ€”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; â€”(CH2)vâ€”C3-7-cycloalkyl (v=0,1,2, or 3); norephedryl; norpseudoephedryl; quinolyl; pyrazyl; â€”CH2-benzimidazolyl; (1)-adamantyl; (2)-adamantyl; â€”CH2-adamantyl; alpha-methyl-benzyl; alpha-dimethylbenzyl; â€”(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; â€”(CH2)m-naphthyl (m=0 or 1); â€”(CH2)w-benzhydryl (w=0,1, or 2); biphenyl; picolyl; benzothiazolyl; benzoisothiazolyl; benzopyrazolyl; benzoxazolyl; â€”(CH2)m-fluorenyl (m=0 or 1); pyrimidyl; â€”(CH2)m-indanyl (m=0 or 1); â€”(CH2CH2O)yâ€”CH3 (y=0,1,2,3,4, or 5); â€”(CH2CH2O)yâ€”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; â€”NCH3â€”C6H5; â€”NHâ€”CH2â€”C6H5; â€”NCH3â€”CH2â€”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, â€”CH2â€”COOEt, C3-4-alkylene group forming a bicyclic system with the heterocycle; phenyl; â€”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 â€”(CH2)3â€” or â€”(CH2)4â€”; and the salts thereof with physiologically tolerated acids.