Methods of treating cancer using inhibitors of 5′-methylthioadenosine phosphorylase
View Patent ↗The invention relates to the treatment of cancer using an inhibitor of 5′-methylthioadenosine phosphorylase (MTAP). The invention particularly relates to the treatment of prostate cancer and head and neck cancer.
1. A method of treating a prostate cancer or a head and neck cancer or a lung cancer in a patient in need thereof comprising administering to the patient with a prostate cancer or a head and neck cancer or a lung cancer a compound of formula (I) in an amount effective to kill cancer cells in a patient, wherein formula (I) is:
where Z is selected from SQ and Q, where Q is alkyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, methoxy, amino, and carboxy,
or a pharmaceutically acceptable salt thereof, or an ester thereof.
2. A method as claimed in claim 1 where Z is SQ.
3. A method as claimed in claim 2 where Z is not methylthio.
4. A method as claimed in claim 2 where Q is an alkyl group, optionally substituted with one or more substituents selected from hydroxy, halogen, methoxy, amino, and carboxy.
5. A method as claimed in claim 4 where the alkyl group is a C 1 -C 6 alkyl group.
6. A method as claimed in claim 2 where Q is an aryl group, optionally substituted with one or more substituents selected from hydroxy, halogen, methoxy, amino, and carboxy.
7. A method as claimed in claim 6 where the aryl group is a phenyl or benzyl group.
8. A method as claimed in claim 1 where any halogen is chlorine or fluorine.
9. A method as claimed in claim 1 where Q is methyl, ethyl, n-propyl, i-propyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, or cycloheptyl.
10. A method as claimed in claim 1 where Q is phenyl, optionally substituted with one or more halogen substituents.
11. A method as claimed in claim 1 where Q is phenyl, p-chlorophenyl, p-fluorophenyl, or m-chlorophenyl.
12. A method as claimed in claim 1 where Q is heteroaryl, 4-pyridyl, aralkyl, benzylthio, or —CH 2 CH 2 (NH 2 )COOH.
13. A method as claimed in claim 1 where the compound of formula (I) is:
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(2-phenylethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(benzylthiomethyl) pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(4-chlorophenylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(4-fluorophenylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(n-propylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(cyclohexylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(3-chlorophenylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(ethylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(phenylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(4-pyridylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-n-propylpyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(homocysteinylmethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(i-propylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(cyclohexylmethylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(cycloheptylthiomethyl)pyrrolidine;
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(cyclopentylthiomethyl)pyrrolidine; or
(3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(cyclobutylthiomethyl)pyrrolidine.
14. A method as claimed in claim 1 where the cancer is prostate cancer.
15. A method as claimed in claim 1 where the cancer is head and neck cancer.
16. A method as claimed in claim 1 where the cancer is lung cancer.