Diarylthiohydantoin compounds
The present invention relates to diarylthiohydantoin compounds and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.
1. A compound having the formula
and pharmaceutically acceptable salts thereof,
wherein R 1 and R 2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms,
wherein R 3 is selected from the group consisting of cyanoalkyl and dialkylcarbamoylalkyl, and
wherein R 4 is hydrogen or fluorine.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
3. The compound of claim 1 , having the formula
wherein R3 is dialkylcarbamoylalkyl and
wherein R3 is not dimethylcarbamoylalkyl.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
5. The pharmaceutical composition of claim 2 , having a form selected from the group consisting of a solution, dispersion, suspension, powder, capsule, tablet, pill, time release capsule, time release tablet, and time release pill.
6. A method for treating a cancer, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the cancer.
7. The method of claim 6 , wherein the composition is administered at a dosage of the compound in the range of from about 0.001 mg per kg body weight per day to about 100 mg per kg body weight per day.
8. The method of claim 6 , wherein the composition is administered at a dosage of the compound in the range of from about 0.01 mg per kg body weight per day to about 100 mg per kg body weight per day.
9. The method of claim 6 , wherein the composition is administered at a dosage of the compound in the range of from about 0.1 mg per kg body weight per day to about 10 mg per kg body weight per day.
10. The method of claim 6 , wherein the composition is administered at a dosage of the compound of about 1 mg per kg body weight per day.
11. A method comprising contacting a mammalian cell capable of expressing prostate specific antigen with a sufficient amount of a compound according to claim 1 to interfere with the transcription of prostate specific antigen mRNA.
12. A method, comprising contacting a mammalian cell with a sufficient amount of a compound according to claim 1 to prevent formation of a transcription complex on a prostate specific antigen gene.
13. A method, comprising contacting a mammalian cell with a sufficient amount of a compound according to claim 1 to prevent an androgen receptor protein from complexing with a prostate specific antigen gene.
14. A method, comprising contacting a mammalian cell with a sufficient amount of a compound according to claim 1 to prevent an RNA polymerase II from complexing with a prostate specific antigen gene.
15. A method, comprising contacting a mammalian cell with a sufficient amount of a compound according to claim 1 to prevent nuclear translocation of an androgen receptor protein and/or to destabilize an androgen receptor protein.
16. The method of claim 6 , wherein the compound is administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally.
17. The method of claim 6 , wherein the cancer is selected from the group consisting of a metastatic cancer, a hormone refractory cancer, prostate cancer, hormone refractory prostate cancer, hormone sensitive prostate cancer, breast cancer, hormone refractory breast cancer, and ovarian cancer.
18. The method of claim 6 , further comprising administering a hormone therapy to the subject before the therapeutically effective amount of the compound is administered.
19. A method for treating a cancer, comprising administering a therapeutically effective amount of a compound having the formula
or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the cancer,
wherein R 1 and R 2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms,
wherein R 3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and
wherein R 4 is hydrogen or fluorine.
20. The method of claim 19 , wherein the cancer is a metastatic cancer.
21. The method of claim 19 , wherein the cancer is a hormone refractory cancer.
22. The method of claim 19 , wherein the cancer is hormone refractory breast cancer.
23. The method of claim 22 , wherein the compound is
24. The method of claim 22 , wherein the compound is
25. The method of claim 19 , further comprising administering a hormone therapy to the subject.
26. The method of claim 25 , wherein the hormone therapy is administered prior to the therapeutically effective amount of the compound being administered.
27. The method of claim 25 ,
wherein the cancer is prostate cancer,
wherein the hormone therapy is administered prior to the therapeutically effective amount of the compound being administered, and
wherein the hormone therapy comprises the administration of bicalutamide.