7-Substituted Purine Derivatives for Immunosuppression

• US 20080119496A1
• Filed: 11/16/2006
• Published: 05/22/2008
• Est. Priority Date: 11/16/2006
• Status: Abandoned Application

• Current Assignee: Wyeth LLC (Pfizer Inc.)
• Original Assignee: Pharmacopeia LLC (Ligand Pharmaceuticals, Inc.)
• Inventors: Quintero, Jorge, Ho, Koc-Kan, Ohlmeyer, Michael J., Bohnstedt, Adolph, Kingsbury, Celia
• Application Number:
  US11/560,731
• Publication Number:
  US 20080119496A1
• Time in Patent Office: Days
• US Class Current: 514/263.21
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention provides novel purinone and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula III:

Claims

1. A compound of formula III

2. A compound according to claim 1 of formula:

3. A compound according to claim 2 of formula:

4. A compound according to claim 2 of formula:

5. A compound according to claim 1 of formula:

6. A compound according to claim 5 of formula:

7. A compound according to claim 5 of formula:

8. A compound according to claim 1 of formula:

9. A compound according to claim 8 of formula:

10. A compound according to claim 8 of formula:

11. A compound according to claim 1 wherein X₁ and X₂ are independently selected from hydrogen, cyano, chloro, fluoro, methyl, trifluoromethyl and trifluoromethoxy.

12. A compound according to claim 1 wherein R₁ is H.

13. A compound according to claim 1 wherein, y is 1 or 2 and R₂ and R₃ are hydrogen or methyl.

14. A compound according to claim 13 wherein R₄ is selected from phenyl, quinoline, pyridine, pyrazine and their substituted counterparts.

15. A compound according to claim 1 wherein y is zero.

16. A compound according to claim 15 wherein R₄ is selected from cyclopentyl, cyclohexyl, phenyl, indane, tetralin, piperidine, oxepane, benzoxepane dihydrocyclopentapyridine, tetrahydropyran, tetrahydrofuran, tetrahydroindole, isoquinoline, tetrahydroisoquinoline, quinoline, tetrahydroquinoline, chroman, pyridine, pyrimidine, dihydropyran, dihydrobenzofuran, tetrahydrobenzofuran, tetrahydrobenzothiophene, furan, dihydropyrano[2,3-b]pyridine, tetrahydroquinoxaline, tetrahydrothiopyran (thiane), thiochroman (dihydrobenzothiin) and their substituted counterparts.

17. A compound according to claim 1 wherein,

(a) y is zero and R₄ is selected from cyclohexyl, tetralin, indane, oxepane, benzoxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano[2,3-b]pyridine and tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo, or halogen;

or

(b) y is 1 or 2, R₂ and R₃ are hydrogen or methyl and R₄ is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen.

18. A compound according to claim 17 wherein y is 0 and R₄ is chosen from chroman-4-yl;

3,4-dihydronaphthalen-1(2H)-on-4-yl;

2,3-dihydroinden-1-on-4-yl and their fluoro substituted counterparts.

19. A compound according to claim 18 wherein R₄ is chroman-4-yl and the carbon at 4 of the chroman is of the (R) configuration.

20. A compound according to claim 17 wherein y is 0 and R₄ is

21. A compound according to claim 20 wherein the carbon marked with an asterisk

22. A compound according to claim 17 wherein y is 1 and R₄ is selected from difluorophenyl, fluorophenyl, chlorophenyl, chlorofluorophenyl, pyridin-3-yl and pyrazin-3-yl.

23. A compound according to claim 17 wherein y is zero and R₄ is selected from tetrahydropyran-4-yl, 4-hydroxycyclohexyl, 4-oxocyclohexyl and oxepan-4-yl.

24. A compound according to claim 10 wherein X₁ and X₂ are independently selected from hydrogen, cyano, chloro and fluoro and R₁ is H.

25. A compound according to claim 24 wherein,

(a) y is zero and R₄ is selected from cyclohexyl, tetralin, indane, oxepane, benzoxepane, dihydrocyclopentapyridine, tetrahydropyran, tetrahydroquinoline, chroman, dihydrobenzofuran, tetrahydrobenzofuran, dihydropyrano[2,3-b]pyridine and tetrahydroquinoxaline, each optionally substituted with hydroxy, oxo, or halogen;

or

(b) y is 1 or 2, R₂ and R₃ are hydrogen or methyl and R₄ is selected from phenyl, pyridine and pyrazine, each optionally substituted with halogen.

26. A compound according to claim 25 wherein R₅ is C₁-C₆ alkyl wherein

(a) one or two CH₂ is replaced by a group chosen from NH and N(alkyl);

(b) one or two CH₂ is replaced by O;

(c) one or two CH₂ is replaced by (C═

O);

(d) two CH₂ are replaced by CH═

CH or C≡

C;

or

(e) any chemically stable combination of (a), (b) (c) and (d);

and wherein from zero to three hydrogens is replaced by a substituent chosen from;

(a) halogen, hydroxy, cyano, loweralkylsulfonyl, loweralkylsulfonyloxy, amino, loweralkylamino, diloweralkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino, loweralkoxy;

(b) heterocyclyl and heterocyclyl substituted with from one to three substituents chosen from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl;

(c) phenyl and phenyl substituted with from one to three substituents chosen from halogen, hydroxy, alkoxy, alkyl, acylamino, cyano, carboxy, alkoxycarbonyl, haloalkyl and heterocyclyl; and

(d) heteroaryl and heteroaryl substituted with from one to three substituents chosen from halogen, hydroxy, alkoxy, alkyl and alkoxycarbonyl.

27. A compound according to claim 26 wherein y is 0 and R₄ is

28. A compound according to claim 27 wherein X₁ is hydrogen, X₂ is a substituent at the 6 position of the benzimidazole, and X₂ is chosen from hydrogen, fluoro and cyano.

29. A compound according to claim 1 wherein R₅ is C₁-C₆ alkyl or C₁-C₆ fluoroalkyl.

30. A compound according to claim 29 wherein y is 0 and R₄ is

31. A compound according to claim 1 wherein R₅ is C₁-C₆ alkyl and wherein from zero to three hydrogens is replaced by a substituent chosen from:

hydroxy, carboxy, cyano, loweralkylsulfonyl, loweralkylsulfonyloxy, amino, loweralkylamino, diloweralkylamino, alkoxyamino, sulfonylamino, acylamino, arylamino and loweralkoxy.

32. A compound according to claim 31 wherein y is 0 and R₄ is

33. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 1.

34. A method of treating a disorder which is dependent upon inhibition of Janus kinase 3, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to a compound of formula III

36. The method according to claim 34 wherein said disorder is selected from an autoimmune disease, an inflammatory disease, a mast cell mediated disease, hematological malignancy and organ transplant rejection.

37. The method according to claim 36 wherein said disorder is bone marrow transplant rejection.

38. The method according to claim 36 wherein said hematological malignancy is selected from leukemia and lymphoma.

39. The method according to claim 36 wherein said disorder is asthma.

40. The method according to claim 36 wherein said autoimmune disease is selected from an organ specific and a non-organ specific autoimmune disease.

41. The method according to claim 36 wherein said disorder is keratoconjuctivitis sicca.

42. The method according to claim 36 wherein said hematological malignancy is chronic myelogenous leukemia.

43. The method according to claim 34 wherein said disorder is selected from a leukemic form of cutaneous T-cell form lymphoma and acute lymphoblastic leukemia.

35. A method of treating a disorder which is dependent upon inhibition of Janus kinase 3, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound formula III

44. A method for treating a disorder selected from an autoimmune disease, an inflammatory disease, a mast cell mediated disease, hematological malignancy and organ transplant rejection, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to a compound of formula III