Prenylation inhibitors containing dimethylcyclobutane and methods of their synthesis and use
AssigneePPD Discovery, Inc.
InventorsBradley B. Brown, Kenneth S. Rehder, Jon-Paul Strachan, Jeron H. Eaves, Christopher T. Lowden
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Abstract
The present invention is directed to compounds useful in the treatment of diseases associated with prenylation of proteins and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising same, and to methods for inhibiting protein prenylation in an organism using the same.
Claims63
A compound of the following formula:
- wherein
- R is selected from the group consisting of:
A compound of the following formula:
- wherein R is selected from the group consisting of CONH2, H, CO2H, CO2Me, CH2OH, CH2OMe, CO2Bn, CONHMe, CONMe2, CONHcyclohexyl, CSNH2 and CONHOH.
A compound of the following formula:
- wherein
- R is selected from the group consisting of H, methyl, ethyl, CH2CH3, n-Pr, CH2CF2OH, CH2CH2CN, cyclohexyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-O-methyl phenyl, 4-O-methyl phenyl, 4-CF3-phenyl, 3,5-dichlorophenyl, 3,4-dimethyl phenyl, 3-Cl-4-F-phenyl, 4-CO2H-phenyl, 2-pyridyl,
A compound of the following formula:
- wherein R is selected from the group consisting of:
A compound of the following formula:
- wherein R is selected from the group consisting of 4-OH-benzyl, 3-indoyl-CH2, 4-imidazoyl-CH2, CH2OH, CH2CH2SCH3, phenyl, H, CH(CH3)2, 4-chloro-benzyl, 2-thienyl-CH2, CH2CH2Phenyl, 2-Chloro-benzyl, 4-O-methyl-benzyl, 4-O-t-butyl-benzyl, 4-CF3-benzyl, 4-NH2-benzyl, 3-chloro-benzyl, 3,4-dichloro-benzyl, 4-Fluoro-benzyl, 4-methyl-Benzyl, 4-CN-benzyl, 4-Ph—Ph—CH3, 3-pyr-CH2, 2-pyr-CH2, 2-naphthyl-CH2, CH2-cyclohexyl and 2-benzylimidazole-5-methyl.
A compound of the following formula:
- wherein R is NH2 or N(CH3)2.
A compound of the following formula:
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof, wherein
- R is selected from the group consisting of:
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof, wherein R is selected from the group consisting of CONH2, H, CO2H, CO2Me, CH2OH, CH2OMc, CO2Bn, CONHMe, CONMe2, CONHcyclohexyl, CSNH2 and CONHOH.
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof, wherein
- R is selected from the group consisting of H, methyl, ethyl, CH2CF3, n-Pr, CH2CH2OH, CH2CH2CN, cyclohexyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-O-methyl phenyl, 4-O-methyl phenyl, 4-CF3-phenyl, 3,5-dichlorophenyl, 3,4-dimethyl phenyl, 3-Cl-4-F-phenyl, 4-CO2H-Phenyl, 2-pyridyl,
The method of 29, wherein said compound inhibits geranylgeranyl-protein transferase Type II.
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof, wherein
- R is selected from the group consisting of:
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof, wherein R is selected from the group consisting of 4-OH-benzyl, 3-indoyl-CH2, 4-imidazoyl-CH2, CH2OH, CH2CH2SCH3, phenyl, H, CH(CH3)2, 4-chloro-benzyl, 2-thienyl-CH2, CH2CH2Phenyl, 2-Chloro-benzyl, 4-O-methyl-benzyl, 4-O-t-butyl-benzyl, 4-CF3-benzyl, 4-NH2-benzyl, 3-Chloro-benzyl, 3,4-dichloro-benzyl, 4-Fluoro-benzyl, 4-methyl-Benzyl, 4-CN-benzyl, 4Ph—Ph—CH3, 3-pyr-CH2, 2-pyr-CH2, 2-naphthyl-CH2, CH2-cyclohexyl and 2-benzylimidazole-5-methyl.
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof, wherein
- R is NH2 or N(CH3)2.
A method for inhibiting protein prenylation in an organism comprising contacting an isoprenoid transferase with a protein prenylation inhibitory effective amount of a compound of the formula:
- or a pharmaceutically-acceptable salt thereof.
Dependencies are inferred from the claim text.