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Details for Patent: 8,110,594

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Details for Patent: 8,110,594

Title:Diarylthiohydantoin compounds
Abstract: The present invention relates to diarylthiohydantoin compounds and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.
Inventor(s): Jung; Michael E. (Los Angeles, CA), Yoo; Dongwon (Los Angeles, CA), Sawyers; Charles L. (New York, NY), Tran; Chris (New York, NY), Wongvipat; John (New York, NY)
Assignee: The Regents of the University of California (Oakland, CA)
Filing Date:Mar 29, 2007
Application Number:11/730,168
Claims:1. A compound having the formula ##STR00148## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.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. A method for treating a prostate cancer comprising administering a pharmaceutical composition of claim 2 to a subject in need of such treatment, thereby treating the prostate cancer.

4. The method of claim 3, wherein the composition has 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.

5. The method of claim 3, wherein the composition is administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally.

6. The method of claim 3, 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.

7. The method of claim 3, 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.

8. The method of claim 3, 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.

9. The method of claim 3, wherein the composition is administered at a dosage of the compound of about 1 mg per kg body weight per day.

10. The method of claim 3, wherein the pharmaceutical composition interferes with the transcription of prostate specific antigen mRNA.

11. The method of claim 3, wherein the pharmaceutical composition prevents nuclear translocation of an androgen receptor protein.

12. The method of claim 3, wherein the pharmaceutical composition destabilizes an androgen receptor protein.

13. The method of claim 3, wherein the composition is administered orally.

14. The method of claim 3, wherein the composition has a form selected from the group consisting of a capsule, tablet, and pill.

15. A method of synthesizing a diaryl compound of formula: ##STR00149## comprising mixing Compound I ##STR00150## with Compound II ##STR00151## in a first polar solvent to form a mixture, heating the mixture, adding a second polar solvent, the same as or different from the first polar solvent, and an aqueous acid to the mixture, refluxing the mixture, cooling the mixture and combining with water, and separating the diaryl compound from the mixture, wherein R51 comprises an alkyl chain of from 1 to 2 carbon atoms, R52 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and R53 is selected from the group consisting of F and H.

16. The method of claim 15, wherein R51 comprises an alkyl chain of from 1 to 2 carbon atoms, R52 is selected from the group consisting of dimethylbutanamide and cyanopropyl, and R53 is F.

17. A method of synthesizing a compound of formula ##STR00152## comprising mixing N,N-dimethyl 4-[4-(1-cyanocyclobutylamino)phenyl]butanamide, 4-isothiocyanato-2-trifluoromethyl benzonitrile, and DMF and heating under reflux to form a first mixture; adding an alcohol and an acid to the first mixture to form a second mixture; refluxing the second mixture; cooling the second mixture; combining the second mixture with water and extracting an organic layer; and isolating the compound from the organic layer.

18. A method of synthesizing a compound of formula ##STR00153## comprising mixing DMSO, dichloromethane, and oxalyl chloride to form a first mixture, adding 4-(4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro- [3.4]octan-5-yl)phenyl)butanamide to the first mixture to form a second mixture; adding triethylamine to the second mixture to form a third mixture; warming the third mixture and quenching with aqueous NH.sub.4Cl to form a fourth mixture; extracting an organic layer from the fourth mixture; and isolating the compound from the organic layer.

19. A method comprising: providing a compound having the formula ##STR00154## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine; measuring inhibition of androgen receptor activity for the compound and determining if the inhibition is above a first predetermined level, measuring stimulation of androgen receptor activity in hormone refractory cancer cells for the compound and determining if the stimulation is below a second predetermined level, selecting the compound if the inhibition is above the first predetermined level and the stimulation is below the second predetermined level.

20. The method of claim 19, wherein the predetermined levels are those of bicalutamide.

21. The method of claim 19, wherein the step of measuring inhibition comprises measuring inhibitory concentration (IC50) in an AR response reporter system or a prostate specific antigen secreting system.

22. The method of claim 19, wherein the step of measuring stimulation comprises measuring fold induction by increasing concentrations in an AR response reporter system or a prostate specific antigen secreting system.

23. The method of claim 19, wherein the steps of measuring inhibition and/or stimulation comprise measuring an effect of the compound on tumor growth in an animal.

24. The method of claim 19, wherein the step of measuring inhibition and/or stimulation of androgen receptor activity comprises measuring the binding affinity of an androgen receptor to the compound.

25. The method of claim 19, wherein the step of measuring inhibition and/or stimulation of androgen receptor activity comprises measuring prevention of androgen receptor recruitment to at least one of prostate specific antigen enhancer and prostate specific antigen promoter.

26. The method of claim 19, wherein the step of measuring inhibition and/or stimulation of androgen receptor activity comprises measuring prevention of androgen receptor nuclear translocation.

27. The method of claim 19, wherein the step of measuring inhibition and/or stimulation of androgen receptor activity comprises measuring destabilization of an androgen receptor protein.

28. A method comprising contacting a mammalian cell capable of expressing prostate specific antigen with a sufficient amount of a compound having the formula ##STR00155## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine, to interfere with the transcription of prostate specific antigen mRNA.

29. The method of claim 28, wherein the diarylthiohydantoin compound is selected from the group consisting of ##STR00156##

30. The method of claim 28, wherein the compound prevents formation of a transcription complex on a prostate specific antigen gene.

31. The method of claim 28, wherein the compound prevents an androgen receptor protein from complexing with a prostate specific antigen gene.

32. The method of claim 28, wherein the compound prevents an RNA polymerase II from complexing with a prostate specific antigen gene.

33. A method, comprising contacting a mammalian cell with a sufficient amount of a compound having the formula ##STR00157## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine, to prevent nuclear translocation of an androgen receptor protein and/or to destabilize an androgen receptor protein.

34. The compound of claim 1, having the formula ##STR00158## wherein R.sub.1 and R.sub.2 are, together with the carbon to which they are linked, cycloalkyl of 4 to 5 carbon atoms, wherein R.sub.3 is selected from the group consisting of dimethylbutanamide and cyanopropyl, and wherein R.sub.4 is hydrogen or fluorine.

35. The compound of claim 1, having the formula ##STR00159## wherein R.sub.1 and R.sub.2 are, together with the carbon to which they are linked, cycloalkyl of 4 carbon atoms, wherein R.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen.

36. The compound of claim 1, having the formula ##STR00160## wherein R.sub.1 and R.sub.2 are, together with the carbon to which they are linked, cycloalkyl of 4 carbon atoms, wherein R.sub.3 is selected from the group consisting of dimethylbutanamide and cyanopropyl, and wherein R.sub.4 is hydrogen.

37. The compound of claim 1, having the formula ##STR00161##

38. The compound of claim 1, having the formula ##STR00162##

39. The pharmaceutical composition of claim 2, wherein the compound is selected from the group consisting of ##STR00163## pharmaceutically acceptable salts of these, and combinations.

40. A pharmaceutically acceptable salt of a compound according to claim 1.

41. A method for treating prostate cancer, comprising administering a therapeutically effective amount of a compound having the formula ##STR00164## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the prostate cancer.

42. The method of claim 41, wherein the prostate cancer is hormone sensitive prostate cancer.

43. The method of claim 41, wherein the prostate cancer is hormone refractory prostate cancer.

44. The method of claim 43, wherein the compound is ##STR00165##

45. The method of claim 43, wherein the compound is ##STR00166##

46. A method for treating benign prostate hyperplasia, comprising administering a therapeutically effective amount of a compound having the formula ##STR00167## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the benign prostate hyperplasia.

47. The method of claim 46, wherein the compound is selected from the group consisting of ##STR00168##

48. A method for treating breast cancer, comprising administering a therapeutically effective amount of a compound having the formula ##STR00169## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the breast cancer.

49. The method of claim 48, wherein the compound is selected from the group consisting of ##STR00170##

50. A method for treating ovarian cancer, comprising administering a therapeutically effective amount of a compound having the formula ##STR00171## wherein R.sub.1 and R.sub.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.sub.3 is selected from the group consisting of dimethylcarbamoylalkyl and cyanoalkyl, and wherein R.sub.4 is hydrogen or fluorine, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, thereby treating the ovarian cancer.

51. The method of claim 50, wherein the compound is selected from the group consisting of ##STR00172##
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