CA2282720A1 - Dolastatin-15 derivatives in combination with taxanes - Google Patents
Dolastatin-15 derivatives in combination with taxanes Download PDFInfo
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- CA2282720A1 CA2282720A1 CA002282720A CA2282720A CA2282720A1 CA 2282720 A1 CA2282720 A1 CA 2282720A1 CA 002282720 A CA002282720 A CA 002282720A CA 2282720 A CA2282720 A CA 2282720A CA 2282720 A1 CA2282720 A1 CA 2282720A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides compositions and methods for the treatment of cancer in a subject wherein compounds of Formula (I) as defined herein in combination with paclitaxel, taxotere or modified taxane or taxoid analogs provide enhanced anticancer effects over the effects achieved with the individual compounds.
Claims (32)
1. A pharmaceutical composition comprising:
an effective amount of a first compound selected from the group consisting of paclitaxel, taxotere and modified taxane or taxoid analogs; and an effective amount of a second compound, wherein the second compound is of Formula I
R 1 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, allo-isoleucyl, 2,2-dimethylglycyl,
an effective amount of a first compound selected from the group consisting of paclitaxel, taxotere and modified taxane or taxoid analogs; and an effective amount of a second compound, wherein the second compound is of Formula I
R 1 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, 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, tetrahydrosioquinolyl-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;
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X is hydrogen, alkyl, cycloalkyl, -CH2-cyclohexyl or arylalkyl;
s, t and a are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a substituted or unsubstituted amino moiety;
and the salts thereof with physiologically tolerated acids.
2. The pharmaceutical composition of Claim 1 further comprising a pharmaceutically acceptable carrier.
3. A composition of Claim 1 wherein for the compound of Formula I, K is a substituted amino moiety having 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, or 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 substituents 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 substituents 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; -NCH3-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, and C3-4-alkylene group forming a bicyclic system with the heterocycle; phenyl; or -CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono- or di-substituted wherein the substituents are independently 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; and R7 is hydrogen, linear or branched C1-5 alkyl , benzyl , or R7 and R5 together form a group - (CH2)3- or - (CH2) 4- .
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, .beta.-alanyl and 3-naphthylalanyl residues;
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X is hydrogen, alkyl, cycloalkyl, -CH2-cyclohexyl or arylalkyl;
s, t and a are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a substituted or unsubstituted amino moiety;
and the salts thereof with physiologically tolerated acids.
2. The pharmaceutical composition of Claim 1 further comprising a pharmaceutically acceptable carrier.
3. A composition of Claim 1 wherein for the compound of Formula I, K is a substituted amino moiety having 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, or 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 substituents 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 substituents 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; -NCH3-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, and C3-4-alkylene group forming a bicyclic system with the heterocycle; phenyl; or -CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono- or di-substituted wherein the substituents are independently 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; and R7 is hydrogen, linear or branched C1-5 alkyl , benzyl , or R7 and R5 together form a group - (CH2)3- or - (CH2) 4- .
4. A composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and a are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 2-ethylglycyl, 1-isoleucyl or 2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched alkyl group selected from the group of monovalent radicals consisting of:
-C(CH3)3;
-C(CH3)2-CH(CH2)2;
-CH(CH3)2;
-CH(CH3)CH2CH3; and -CH(CH3)CH(CH3)2.
-C(CH3)3;
-C(CH3)2-CH(CH2)2;
-CH(CH3)2;
-CH(CH3)CH2CH3; and -CH(CH3)CH(CH3)2.
5. A composition of Claim 4 wherein the monovalent radical is -C (CH3) 3.
6. A composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and a are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is selected from the group of monovalent radicals consisting of: (CH2)v-phenyl (wherein v is 1) and .alpha.,.alpha.-dimethylbenzyl.
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is selected from the group of monovalent radicals consisting of: (CH2)v-phenyl (wherein v is 1) and .alpha.,.alpha.-dimethylbenzyl.
7. A composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or 2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched hydroxyalkyl.
8. A composition of Claim 7 wherein R6 is 3-hydroxy-1,1-dimethylpropyl.
9. A composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C3-10 cycloalkyl selected from the group consisting of: (1)-adamantyl, (2)-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl and [3.3.0]octa-1-yl.
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C3-10 cycloalkyl selected from the group consisting of: (1)-adamantyl, (2)-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl and [3.3.0]octa-1-yl.
10. A composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valyl;
B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.
B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.
11. 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 and modified taxane or taxoid analogs; and administering to said mammal an 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, 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-methylphenyl-alanyl, tetrahydrosioquinolyl-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 a are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a substituted or unsubstituted amino moiety;
and the salts thereof with physiologically tolerated acids.
administering to said mammal an effective amount of a first compound selected from the group consisting of paclitaxel, taxotere and modified taxane or taxoid analogs; and administering to said mammal an 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, 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-methylphenyl-alanyl, tetrahydrosioquinolyl-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 a are independently 0 or 1; and K is hydroxy, alkoxy, phenoxy, benzyloxy or a substituted or unsubstituted amino moiety;
and the salts thereof with physiologically tolerated acids.
12. A method of Claim 11 wherein the compound of Formula I is administered first followed by administration of the first compound.
13. A method of Claim 11 wherein the first compound is administered first followed by administration of the compound of Formula I.
14. A method of Claim 11 wherein the first compound and the compound of Formula I are administered simultaneously.
15. A method of Claim 11 wherein said mammal is human.
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16. A method of Claim 15 wherein for the compound of Formula I K is a substituted amino moiety having the formula R~-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, or COONH2;
R6 is hydrogen; fluorine-substituted or unsubstituted C1-12 linear or branched alkyl;
C1-12 linear or branched hydroxyalkyl; C3-10-cycloalkyl; -(CH2)~-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 substituents 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 substituents 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; -NCH3-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, and C3-4-alkylene group forming a bicyclic system with the heterocycle; phenyl; or -CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono- or di-substituted wherein the substituents are independently 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; and R7 is hydrogen, linear or branched C1-5 alkyl, benzyl, or R7 and R5 together form a group -(CH2)3- or -(CH2)4-.
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, or COONH2;
R6 is hydrogen; fluorine-substituted or unsubstituted C1-12 linear or branched alkyl;
C1-12 linear or branched hydroxyalkyl; C3-10-cycloalkyl; -(CH2)~-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 substituents 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 substituents 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; -NCH3-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, and C3-4-alkylene group forming a bicyclic system with the heterocycle; phenyl; or -CHR7-5-membered heteroaryl wherein the heteroaryl group is unsubstituted or mono- or di-substituted wherein the substituents are independently 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; and R7 is hydrogen, linear or branched C1-5 alkyl, benzyl, or R7 and R5 together form a group -(CH2)3- or -(CH2)4-.
17. A method of Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and a are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -isoleucyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched alkyl group selected from the group of monovalent radicals consisting of:
-C(CH3)3;
-C(CH3)2-CH(CH3)2;
-CH(CH3)2;
-CH(CH3)CH2CH3; and -CH(CH3)CH(CH3)2.
-C(CH3)3;
-C(CH3)2-CH(CH3)2;
-CH(CH3)2;
-CH(CH3)CH2CH3; and -CH(CH3)CH(CH3)2.
18. A method of Claim 17 wherein said monovalent radical is -(CH3)3.
19. A method of Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and a are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is selected from the group of monovalent radicals consisting of: (CH2)v-phenyl (wherein v is 1), and .alpha.,.alpha.-dimethylbenzyl.
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is selected from the group of monovalent radicals consisting of: (CH2)v-phenyl (wherein v is 1), and .alpha.,.alpha.-dimethylbenzyl.
20. A method of Claim 16 wherein for the compound of Formula I R1- and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and a are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -1-isoleucyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched hydroxyalkyl.
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C1-C12 linear or branched hydroxyalkyl.
21. A method of Claim 20 wherein R6 is 3-hydroxy-1,1-dimethylpropyl.
22. A method of Claim to wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, 2-ethylglycyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, -2-ethylglycyl, -isoleucyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; E is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl; and K is a substituted amino moiety having the formula R5-N-R6 wherein R5 is hydrogen or C1-C4 alkoxy and R6 is a C3-10 cycloalkyl selected from the group consisting of:
(1)-adamantyl, (2)-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl and [3.3.0]octa-1-yl.
(1)-adamantyl, (2)-adamantyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1-methylcyclohexyl and [3.3.0]octa-1-yl.
23. A method of Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl; X is isopropyl;
s is 1; t and u are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.
s is 1; t and u are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.
24. A method of Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl; X is isopropyl;
s is 1; t and a are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen and the first compound is paclitaxel.
s is 1; t and a are each 0; A is valyl; B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen and the first compound is paclitaxel.
25. A composition of Claim 3 wherein the first compound is paclitaxel and wherein for the second compound of Formula I, R1 and R2 are each methyl; X is isopropyl; s is 1; t and u are each 0; A is valyl;
B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.
B is N-methylvalyl; D is prolyl; E is prolyl; R5 is benzyl and R6 is hydrogen.
26. A composition of Claim 3 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X
is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl, 2-ethylglycyl, or 2-tertbutylglycyl; B is N-methylvalyl, -1-isoleucyl, -2-ethylglycyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; and E is prolyl, 3-methylprolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl.
is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl, 2-ethylglycyl, or 2-tertbutylglycyl; B is N-methylvalyl, -1-isoleucyl, -2-ethylglycyl or -2-tertbutylglycyl; D is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; and E is prolyl, 3-methylprolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl.
27. A method of Claim 16 wherein for the compound of Formula I R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl, 2-ethylglycyl, or 2-tertbutylglycyl; B is N-methylvalyl, -1-isoleucyl, -2-ethylglycyl or -2-tertbutylglycyl; D
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; and E is prolyl, 3-methylprolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl.
is prolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, or 3,4-dehydroprolyl; and E is prolyl, 3-methylprolyl, 4-fluoroprolyl, thiazolidinyl-4-carbonyl, homoprolyl, 3,4-dehydroprolyl or hydroxyprolyl.
28. The use of a first compound selected from paclitaxel, taxotere and modified taxane or taxoid analogs and a second compound which is a compound of the Formula I as defined in any one of Claims 1 to 27 for the manufacture of a medicament for the treatment of cancer in a mammal, the cancer for example being selected from lung, breast, colon, prostate, bladder, rectal, endometrial, and haematological cancers.
29. The use of a first compound selected from paclitaxel, taxotere and modified taxane or taxoid analogs for the manufacture of a medicament for combination therapy in conjunction with a second compound, the second compound being a compound of the Formula I as defined in any one of Claims 1 to 27 in the treatment of cancer in a mammal, the cancer for example being selected from lung, breast, colon, prostate, bladder, rectal, endometrial and haematological cancers.
30. The use according to Claim 29 wherein the treatment of combination therapy involves administration of a first compound selected from paclitaxel, taxotere, and modified taxane or taxoid analogs, first followed by administration of the compound of the Formula I.
31. The use according to Claim 29 wherein the treatment or combination therapy involves administration of the compound of the Formula I, first followed by administration of a first compound selected from paclitaxel, taxotere, and modified taxane or taxoid analogs.
32. The use according to any one of Claims 28 to 29 wherein the treatment or combination therapy involves administration of the compound of the Formula I and a first compound selected from paclitaxel, taxotere, and modified taxane or taxoid analogs, simultaneously.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/819,101 US6103698A (en) | 1997-03-13 | 1997-03-13 | Dolastatin-15 derivatives in combination with taxanes |
| US08/819,101 | 1997-03-13 | ||
| PCT/US1998/004594 WO1998040092A1 (en) | 1997-03-13 | 1998-03-09 | Dolastatin-15 derivatives in combination with taxanes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2282720A1 true CA2282720A1 (en) | 1998-09-17 |
| CA2282720C CA2282720C (en) | 2009-12-29 |
Family
ID=25227196
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002282720A Expired - Fee Related CA2282720C (en) | 1997-03-13 | 1998-03-09 | Dolastatin-15 derivatives in combination with taxanes |
Country Status (30)
| Country | Link |
|---|---|
| US (2) | US6103698A (en) |
| EP (1) | EP0981358B1 (en) |
| JP (1) | JP2001514659A (en) |
| KR (1) | KR100555604B1 (en) |
| CN (1) | CN1157223C (en) |
| AT (1) | ATE241376T1 (en) |
| AU (1) | AU728027B2 (en) |
| BG (1) | BG64338B1 (en) |
| BR (1) | BR9808249A (en) |
| CA (1) | CA2282720C (en) |
| CO (1) | CO4940498A1 (en) |
| CZ (1) | CZ293905B6 (en) |
| DE (1) | DE69815100T2 (en) |
| DK (1) | DK0981358T3 (en) |
| ES (1) | ES2200317T3 (en) |
| HK (1) | HK1026851A1 (en) |
| HR (1) | HRP980125A2 (en) |
| HU (1) | HU228860B1 (en) |
| ID (1) | ID23900A (en) |
| IL (2) | IL131597A0 (en) |
| NO (1) | NO323894B1 (en) |
| NZ (1) | NZ337416A (en) |
| PL (1) | PL197834B1 (en) |
| PT (1) | PT981358E (en) |
| RU (1) | RU2218174C2 (en) |
| SK (1) | SK285133B6 (en) |
| TR (1) | TR199902244T2 (en) |
| TW (1) | TWI277426B (en) |
| WO (1) | WO1998040092A1 (en) |
| ZA (1) | ZA982093B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20010009901A1 (en) | 1996-12-11 | 2001-07-26 | Basf Aktiengesellschaft Germany | Antineoplastic peptides |
| EP1229934B1 (en) | 1999-10-01 | 2014-03-05 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US20050192443A1 (en) * | 2000-11-08 | 2005-09-01 | Lorus Therapeutics Inc. | Biological response modifier for the treatment of cancer |
| US20040101511A1 (en) * | 2000-11-08 | 2004-05-27 | Young Aiping H | Combination preparation of a biological response modifier and an anticancer agent and uses thereof |
| US7772177B2 (en) | 2005-05-18 | 2010-08-10 | Aegera Therapeutics, Inc. | BIR domain binding compounds |
| JP5419685B2 (en) | 2006-05-16 | 2014-02-19 | ファーマサイエンス・インコーポレイテッド | IAPBIR domain binding protein |
| CA2789629A1 (en) | 2010-02-10 | 2011-08-18 | Immunogen, Inc. | Cd20 antibodies and uses thereof |
| BR112012020113A2 (en) | 2010-02-12 | 2016-06-07 | Pharmascience Inc | iap bir domain binding compounds |
| JPWO2021246471A1 (en) * | 2020-06-03 | 2021-12-09 | ||
| CA3230737A1 (en) | 2021-09-03 | 2023-03-09 | Toray Industries, Inc. | Pharmaceutical composition for cancer treatment and/or prevention |
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| US4816444A (en) * | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
| US5676978A (en) | 1989-02-14 | 1997-10-14 | Amira, Inc. | Methods of inhibiting undesirable cell growth using a combination of a cyclocreatine compound and a hyperplastic inhibitory agent |
| US4879278A (en) * | 1989-05-16 | 1989-11-07 | Arizona Board Of Regents | Isolation and structural elucidation of the cytostatic linear depsipeptide dolastatin 15 |
| US5278324A (en) * | 1990-08-28 | 1994-01-11 | Virginia Tech Intellectual Properties, Inc. | Water soluble derivatives of taxol |
| MX9102128A (en) | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | DERIVATIVES OF TAXANE, PROCEDURE FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM |
| JP2618597B2 (en) | 1991-08-09 | 1997-06-11 | 帝国臓器製薬株式会社 | New tetrapeptide derivatives |
| US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
| US5250683A (en) * | 1991-09-23 | 1993-10-05 | Florida State University | Certain substituted taxanes and pharmaceutical compositions containing them |
| US5272171A (en) * | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
| FR2688518B1 (en) * | 1992-03-13 | 1994-05-06 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF TAXANE DERIVATIVES. |
| US5831002A (en) * | 1992-05-20 | 1998-11-03 | Basf Aktiengesellschaft | Antitumor peptides |
| US5248796A (en) * | 1992-06-18 | 1993-09-28 | Bristol-Myers Squibb Company | Taxol derivatives |
| US5254580A (en) * | 1993-01-19 | 1993-10-19 | Bristol-Myers Squibb Company | 7,8-cyclopropataxanes |
| FR2697752B1 (en) * | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Antitumor compositions containing taxane derivatives. |
| PL178766B1 (en) * | 1992-12-16 | 2000-06-30 | Basf Ag | Novel peptides, method of obtaining them and their application |
| US5484612A (en) * | 1993-09-22 | 1996-01-16 | The Board Of Trustees Of The Leland Stanford Junior University | Method of treating a mammal having a solid tumor susceptible to treatment with cisplatin |
| CA2129282A1 (en) | 1993-09-29 | 1995-03-30 | George Weber | Method for the treatment of neoplastic disease utilizing taxol and tiazofurin |
| US5447936A (en) * | 1993-12-22 | 1995-09-05 | Bionumerik Pharmaceuticals, Inc. | Lactone stable formulation of 10-hydroxy 7-ethyl camptothecin and methods for uses thereof |
| US5565478A (en) * | 1994-03-14 | 1996-10-15 | The United States Of America As Represented By The Department Of Health & Human Services | Combination therapy using signal transduction inhibitors with paclitaxel and other taxane analogs |
| US5494930A (en) * | 1994-06-02 | 1996-02-27 | Shimizu; Yuzuru | Caribenolide I |
| US5525613A (en) * | 1994-06-16 | 1996-06-11 | Entropin, Inc. | Covalently coupled benzoylecgonine ecgonine and ecgonidine |
| US5504191A (en) * | 1994-08-01 | 1996-04-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide methyl esters |
| US5530097A (en) * | 1994-08-01 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory peptide amides |
| US5543423A (en) * | 1994-11-16 | 1996-08-06 | Vertex Pharmaceuticals, Incorporated | Amino acid derivatives with improved multi-drug resistance activity |
| AU699442B2 (en) | 1994-12-15 | 1998-12-03 | Baker Norton Pharmaceuticals, Inc. | Method and composition for reducing tumor development with a combination of a taxane compound and a tellurium and/or selenium compound |
-
1997
- 1997-03-13 US US08/819,101 patent/US6103698A/en not_active Expired - Lifetime
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1998
- 1998-03-09 NZ NZ337416A patent/NZ337416A/en not_active IP Right Cessation
- 1998-03-09 CZ CZ19993211A patent/CZ293905B6/en not_active IP Right Cessation
- 1998-03-09 AU AU66945/98A patent/AU728027B2/en not_active Ceased
- 1998-03-09 SK SK1251-99A patent/SK285133B6/en not_active IP Right Cessation
- 1998-03-09 CA CA002282720A patent/CA2282720C/en not_active Expired - Fee Related
- 1998-03-09 AT AT98909066T patent/ATE241376T1/en active
- 1998-03-09 ID IDW991020A patent/ID23900A/en unknown
- 1998-03-09 PL PL335579A patent/PL197834B1/en unknown
- 1998-03-09 RU RU99122032/14A patent/RU2218174C2/en not_active IP Right Cessation
- 1998-03-09 WO PCT/US1998/004594 patent/WO1998040092A1/en active IP Right Grant
- 1998-03-09 BR BR9808249-3A patent/BR9808249A/en not_active IP Right Cessation
- 1998-03-09 HU HU0001381A patent/HU228860B1/en not_active IP Right Cessation
- 1998-03-09 PT PT98909066T patent/PT981358E/en unknown
- 1998-03-09 KR KR1019997008305A patent/KR100555604B1/en not_active IP Right Cessation
- 1998-03-09 CN CNB988033089A patent/CN1157223C/en not_active Expired - Fee Related
- 1998-03-09 DK DK98909066T patent/DK0981358T3/en active
- 1998-03-09 DE DE69815100T patent/DE69815100T2/en not_active Expired - Lifetime
- 1998-03-09 EP EP98909066A patent/EP0981358B1/en not_active Expired - Lifetime
- 1998-03-09 TR TR1999/02244T patent/TR199902244T2/en unknown
- 1998-03-09 JP JP53967998A patent/JP2001514659A/en active Pending
- 1998-03-09 IL IL13159798A patent/IL131597A0/en active IP Right Grant
- 1998-03-09 ES ES98909066T patent/ES2200317T3/en not_active Expired - Lifetime
- 1998-03-10 HR HR08/819,101A patent/HRP980125A2/en not_active Application Discontinuation
- 1998-03-12 CO CO98013903A patent/CO4940498A1/en unknown
- 1998-03-12 ZA ZA9802093A patent/ZA982093B/en unknown
- 1998-03-13 TW TW087103777A patent/TWI277426B/en not_active IP Right Cessation
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1999
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2000
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