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US 2004/0006042 A1Published application
Diaminopyrimidines and combination therapies effective for treatment of P-glycoprotein positive cancers
OwnerDavid Allen Berry, Ellen Myra Dobrusin +4inventors
InventorsDavid Allen Berry, Ellen Myra Dobrusin, Judith Lynne Johnson-Philipsen, Wayne Daniel Klohs, Dennis Joseph McNamara, Leslie Morton Werbel
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Abstract
The present invention provides compounds of Formula II: 1
Claims38
A method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
- 1) 5-fluorouracil;
- 2) leucovorin;
- and
- 3) a compound of Formula I
- 49
- wherein
- R1 is hydrogen or alkyl of from one to six carbon atoms;
- R2 and R3 are independently hydrogen or methyl;
- R4 and R5 are independently:
- hydrogen,
- halogen,
- nitro,
- cyano,
- trifluoromethyl,
- hydroxyl,
- alkyl of from one to six carbon atoms,
- alkoxyl of from one to six carbon atoms,
- alkanoyl of from one to six carbon atoms;
- —NR6R7, where R6 and R7 are independently
- hydrogen,
- alkyl of from one to six carbon atoms,
- alkanoyl of from one to six carbon atoms;
- —COOR8 where R8 is
- hydrogen,
- a pharmaceutically acceptable metal cation,
- a pharmaceutically acceptable amine cation,
- alkyl of from one to six carbon atoms;
- —CONR9 R10 where R9 and R10 are independently
- hydrogen,
- alkyl of from one to six carbon atoms,
- alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups,
- alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups and one —OH, —SH, or —NH2 group,
- alkyl of from one to six carbon atoms, substituted with one or two carboalkoxy groups of from one to six carbon atoms,
- alkyl of from one to six carbon atoms, substituted with one or two carboalkoxy groups of from one to six carbon atoms and one —OH, —SH, or —NH2 group;
- 50
- where R11 is hydrogen, or alkyl of from one to six carbon atoms;
- or
- —SO2R12 where R12 is
- hydroxyl,
- alkyl of from one to six carbon atoms,
- alkoxy of from one to six carbon atoms, or
- —NR13R14 where R13 and R14 are independently hydrogen or alkyl of from one to six carbon atoms;
- and the pharmaceutically acceptable salts thereof.
40 more elements
A method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
- 1) a thymidylate synthase inhibitor;
- and
- 2) a compound of Formula I
- 51
- wherein
- R1 is hydrogen or alkyl of from one to six carbon atoms;
- R2 and R3 are independently hydrogen or methyl;
- R4 and R5 are independently:
- hydrogen,
- halogen,
- nitro,
- cyano,
- trifluoromethyl,
- hydroxyl,
- alkyl of from one to six carbon atoms,
- alkoxyl of from one to six carbon atoms,
- alkanoyl of from one to six carbon atoms;
- —NR6R7, where R6 and R7 are independently
- hydrogen,
- alkyl of from one to six carbon atoms,
- alkanoyl of from one to six carbon atoms;
- —COOR8 where R8 is
- hydrogen,
- a pharmaceutically acceptable metal cation,
- a pharmaceutically acceptable anine cation,
- alkyl of from one to six carbon atoms;
- —CONR9 R10 where R9 and R10 are independently
- hydrogen,
- palkyl of from one to six carbon atoms,
- alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups,
- alkyl of from one to six carbon atoms, substituted with one or two carboxyl groups and one —OH, —SH, or —NH2 group,
- alkyl of from one to six carbon atoms, substituted with one or two carboalkoxy groups of from one to six carbon atoms,
- alkyl of from one to six carbon atoms, substituted with one or two carboalkoxy groups of from one to six carbon atoms and one —OH, —SH, or —NH2 group;
- 52
- where R11 is hydrogen, or alkyl of from one to six carbon atoms;
- or
- —SO2R12 where R12 is
- hydroxyl,
- alkyl of from one to six carbon atoms,
- alkoxy of from one to six carbon atoms, or
- —NR13R14 where R13 and R14 are independently hydrogen or alkyl of from one to six carbon atoms;
- and the pharmaceutically acceptable salts thereof.
39 more elements
A compound of Formula II:
- 53
- wherein
- each n is independently 0 to 6;
- Ra and Rb are independently hydrogen or C1-C6 alkyl;
- R1 is C1-C6 alkyl or
- 54
- R2 and R3 are independently hydrogen, —C1-C6 alkyl, —CH2OH, or —OH;
- R4 is hydrogen;
- R5 is —(CH2)nNH2,
- 55
- and the pharmaceutically acceptable salts thereof.
8 more elements
A compound of Formula II:
- 56
- wherein
- each n is independently 0 to 6;
- Ra and Rb are independently hydrogen or C1-C6 alkyl;
- R1 is C2-C6 alkyl or
- 57
- R2 and R3 are independently hydrogen, —C1-C6 alkyl, —CH2OH, or —OH;
- R4 is hydrogen;
- R5 is —(CH2)n—OH, —(CH2)nNH2,
- 58
- and the pharmaceutically acceptable salts thereof.
8 more elements
The compounds:
- 4-[4-(2,4-Diamino-methyl-pyrimidin-5-yl)-piperazin-1-yl)-benzaldehyde;
- 1-{4-[4-(2,4-Diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]-phenyl}-4-(diethyl-amino)-1-butanone;
- 4-[4-(2,4-Diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid, hydrazide;
- 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-benzaldehyde O-(2-amino-ethyl)-oxime, dihydrochloride;
- 4-[4-(2,4-Diamino-6-methyl-5-pryimidinyl)-1-piperazinyl]benzoic acid, 1-methylhydrazide;
- 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yI)- piperazin-1-yl]-benzoic acid pentylidenehydrazide, hemiacetate;
- 4-[4-(2,4-Diamino-6-methyl-pryimidin-5-yl)-piperazin-1-yl]-benzoic acid, N′-pentyl-hydrazide;
- 4-[4-(2,4-Diamino-6-methyl-5-pryimidinyl)-1-piperazinyl]benzoic acid, 2-acetylhydrazide, hydrochloride;
- 6-Methyl-5-(4-{4-[1-(phenyl-hydrazono)-ethyl]-phenyl}-piperazin-1-yl)-pyrimidine-2,4-diamine;
- Benzaldehyde, 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]-, [2-[(2-hydroxyethyl)amino]ethyl]hydrazone, methanesulfonate;
- 1-{4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-phenyl}-ethanone O-(2-amino-ethyl)-oxime, hydrochloride;
- 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-benzaldehyde O-(2-methylamino-ethyl)-oxime, dihydrochloride;
- 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-benzoic acid, 2-cyclohexylhydrazide;
- 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-benzaldehyde O-(2-morpholin-4-yl-ethyl)-oxime;
- 4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-benzaldehyde O-(2-diethylamino-ethyl)-oxime, dihydrochloride;
- 1-{4-[4-(2,4-Diamino-6-methyl-pyrimidin-5-yl)-piperazin-1-yl]-phenyl}-ethanone O-(2-diethylamino-ethyl)-oxime, dihydrochloride;
- 5-{4-[4-(3-Dimethylamino-propane-1-sulfonyl)-phenyl]-piperazin-1-yl}-6-methyl-pyrimidine-2,4-diamine;
- and
- 1-{4-[4-(2,4-Diamino-6-methyl-5-pyrimidinyl)-piperazin-1-yl]-phenyl}-ethanone O-(2-methylamino-ethyl)-oxime, trihydrochloride.
16 more elements
A compound of Formula II:
- 59
- wherein
- each n is independently 0 to 6;
- Ra and Rb are independently hydrogen or C1-C6 alkyl;
- R1 is C1-C6 alkyl or
- 60
- R2 and R3 are independently hydrogen, —C1-C6 alkyl, —CH2OH, or —OH;
- R4 is hydrogen;
- R5 is —(CH2)n—OH,
- and the pharmaceutically acceptable salts thereof.
7 more elements
A compound of Formula III:
- 61
- wherein
- each n is independently 0 to 6;
- Ra and Rb are independently hydrogen or C1-C6 alkyl;
- R1 is C1-C6 alkyl or
- 62
- R2 and R3 are independently hydrogen, —C1-C6 alkyl, —CH2OH, or —OH;
- R4 is hydrogen;
- R5 is —(CH2)n—OH, —(CH2)nNH2,
- 63
- and the pharmaceutically acceptable salts thereof.
8 more elements
A method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
- 1) 5-fluorouracil;
- 2) leucovorin;
- and
- 3) a compound of Formula II
- 64
- wherein
- each Ra and Rb are independently hydrogen, C1-C6 alkyl,
- 65
- or C1-C6 cycloalkyl;
- each n is hydrogen independently 0 to 5;
- R1 is hydrogen, C1-C6 alkyl, or —NRaRb;
- R2 and R3 are independently hydrogen, C1-C6 alkyl, —CH2OH, or —OH;
- R4 is hydrogen, halogen, C1-C6 alkyl, —NO2, —CN, CF3, —OH, —OC1-C6
- alkyl, —NRaRb, —CO2Ra, or
- 66
- R5 is hydrogen, —CO2Ra,
- 67 68
- and the pharmaceutically acceptable salts thereof.
15 more elements
A method of treating cancer, the method comprising administering to a patient having cancer, a therapeutically effective amount of a combination of:
- 1) a thymidylate synthase inhibitor;
- and
- 2) a compound of Formula II
- 69
- wherein
- each Ra and Rb are independently hydrogen, C1-C6 alkyl,
- 70
- or C1-C6 cycloalkyl;
- each n is independently 0 to 5;
- R1 is hydrogen, C1-C6 alkyl, or —NRaRb;
- R2 and R3 are independently hydrogen, C1-C6 alkyl, —CH2OH, or —OH;
- R4 is hydrogen, halogen, C1-C6 alkyl, —NO2, —CN, CF3, —OH, —OC1-C6 alkyl, —NRaRb, —CO2Ra, or
- 71
- R5 is hydrogen, —CO2Ra,
- 72 73
- and the pharmaceutically acceptable salts thereof.
13 more elements
Dependencies are inferred from the claim text.