Diarylhydantoin compounds

• US 20070004753A1
• Filed: 05/15/2006
• Published: 01/04/2007
• Est. Priority Date: 05/13/2005
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Yoo, Dongwon, Wongvipat, John, Ouk, Samedy, Tran, Chris, Jung, Michael, Chen, Charlie, Welsbie, Derek, Sawyers, Charles
• Granted Patent: US 7,709,517 B2
• Time in Patent Office: Days
• US Class Current: 514/254.50
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 233/70 One oxygen atom
• CPC Class Codes: C07D 233/74 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
• CPC Class Codes: C07D 233/86 Oxygen and sulfur atoms, e.g. thiohydantoin
• CPC Class Codes: C07D 235/02 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present invention relates to diarylhydantoin compounds, including diarylthiohydantoins, and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.

Claims

1. A compound having the formula

2. The compound of claim 1, wherein R5 is

3. The compound of claim 1, having the formula

4. The compound of claim 3, wherein R10 and R11 are both H.

5. The compound of claim 3, wherein R10 and R11 are, respectively, F and H.

6. The compound of claim 3, wherein R3 is methylcarbamoyl.

7. The compound of claim 3, wherein R3 is methylcarbamoyl and R10 and R11 are, respectively, F and H.

8. The compound of claim 1,

wherein R1 and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms, and

R3 is selected from the group consisting of carbamoyl, alkylcarbamoyl, carbamoylalkyl, and alkylcarbamoylalkyl, and R4 is H or F.

9. The compound of claim 8, wherein R4 is 3-fluoro.

10. The compound of claim 1,

wherein R1 and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms,

R3 is selected from the group consisting of cyano, hydroxy, methylcarbamoyl, methylcarbamoyl-substituted alkyl, methylsulfonecarbamoyl-substituted alkyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, methoxycarbonyl, acetamido, methanesulfonamido, carbamoyl-substituted alkyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoyl-substituted alkyl, carboxy-substituted alkyl, 4-(1,1-dimethylethoxy)carbonyl)-1-piperazinyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyethoxycarbonyl-substituted alkyl, and 3-cyano-4-trifluoromethylphenylcarbamoyl, and R4 is F.

11. The compound of claim 1, having the formula

12. The compound of claim 1, having the formula

13. A compound according to claim 1, wherein R1 and R2 together with the carbon to which they are linked are

15. The compound of claim 1, having the formula

16. The compound of claim 1, having the formula

17. The compound of claim 1, having the formula

18. The compound of claim 1, having the formula

19. The compound of claim 1, having the formula

21. 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.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

28. A method for treating a hyperproliferative disorder comprising administering a composition according to claim 21 to a subject in need of such treatment, thereby treating the hyperproliferative disorder.

29. The method of claim 28, 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.

30. The method of claim 28, wherein the composition is administered at a dosage of the compound of about 1 mg per kg body weight per day.

33. The method of claim 28, wherein the composition is administered orally.

35. The method of claim 28, wherein the composition has a form selected from the group consisting of a capsule, tablet, and pill.

36. The method of claim 28, wherein the compound is selected from the group consisting of RD162′

, RD162″

, RD 169, or RD170, or a pharmaceutically acceptable salt thereof.

37. The method of claim 28, wherein the compound is N-methyl-4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-2-fluorobenzamide [RD162] or a pharmaceutically acceptable salt thereof.

41. A method of synthesizing the compound of claim 16 [RD162′

], comprising

mixing N-Methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide and 4-Isothiocyanato-2-trifluoromethylbenzonitrile in DMF and heating 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;

isolating the compound from the organic layer.

42. A method of synthesizing the compound of claim 17 [RD162″

], comprising

mixing N-Methyl-2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide, 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;

isolating the compound from the organic layer.

43. A method of synthesizing the compound of claim 18 [RD169], 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;

isolating the compound from the organic layer.

44. A method of synthesizing the compound of claim 19 [RD170], 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 NH₄Cl to form a fourth mixture;

extracting an organic layer from the fourth mixture;

isolating the compound from the organic layer.

14. A compound selected from the compounds of Tier 1 and Tier 2.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

23. A method for treating a hyperproliferative disorder comprising administering a pharmaceutical composition of claim 20 to a subject in need of such treatment, thereby treating the hyperproliferative disorder.

24. The method of claim 23, 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.

25. The method of claim 23, 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.

26. The method of claim 23, 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.

27. The method of claim 23, wherein the composition is administered at a dosage of the compound of about 1 mg per kg body weight per day.

31. The method of claim 23, wherein the hyperproliferative disorder is hormone refractory prostate cancer.

32. The method of claim 23, wherein the compound is administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally.

34. The method of claim 23, 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.

38. A method of synthesizing a diaryl compound of formula:

39. The method of claim 38, wherein R51 comprises an alkyl chain of from 1 to 2 carbon atoms, R52 is selected from the group consisting of carbamoyl and methylcarbamoyl, and R53 is F.

40. A method of synthesizing a compound of formula:

45. A compound having the formula

46. The compound of claim 45, wherein the compound has substantial androgen receptor antagonist activity and no substantial agonist activity on hormone refractory prostate cancer cells.

47. A method comprising:

providing at least one compound according to claim 45;

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.

48. The method of claim 47, wherein the predetermined levels are those of bicalutamide.

49. The method of claim 47, wherein the step of measuring inhibition comprises measuring inhibitory concentration (IC50) in an AR response reporter system or a prostate specific antigen secreting system.

50. The method of claim 47, 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.

51. The method of claim 47, wherein the steps of measuring inhibition and/or stimulation comprise measuring an effect of the compound on tumor growth in an animal.