8-SUBSTITUTED 2-(BENZIMIDAZOLYL)PURINE DERIVATIVES FOR IMMUNOSUPPRESSION

• US 20080085898A1
• Filed: 10/04/2007
• Published: 04/10/2008
• Est. Priority Date: 10/04/2006
• Status: Active Grant

• Current Assignee: Wyeth LLC (Pfizer Inc.)
• Original Assignee: Pharmacopeia, Inc.
• Inventors: Lu, Yingchun, Paradkar, Vidyadhar, Bohnstedt, Adolph, Ohlmeyer, Michael, Kingsbury, Celia
• Granted Patent: US 7,915,268 B2
• Time in Patent Office: Days
• US Class Current: 514/234.2
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 473/32 Nitrogen atom

Abstract

The present invention provides novel purines 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 I:

Claims

1. A compound of formula I

2. A compound according to claim 1 wherein p is equal to one.

3. A compound according to claim 1 where in p is equal to zero, q is equal to zero, and A is cyano, CF₃ or a halogen.

4. A compound in which p is zero and q is zero of formula II according to claim 1

5. A compound according to claim 1 wherein Q is nitrogen of formula:

6. A compound according to claim 1 wherein Q is CX of formula:

7. A compound according to claim 6 wherein X is chosen from H, F, Cl, CN, CF₃ and OCF₃.

8. A compound according to claim 1 wherein y is 1 or 2 and R² and R³ are independently selected from hydrogen and methyl.

9. A compound according to claim 1 wherein y is zero and R⁴ is a residue selected from a monocycle, a bicycle, a substituted monocycle and a substituted bicycle said residue containing at least one oxygen atom.

10. A compound according to claim 9 wherein R⁴ is chosen from an oxygen heterocycle optionally substituted with halogen, and a hydroxyl- or alkoxy-substituted carbocycle optionally substituted with halogen.

11. A compound according to claim 10 wherein R⁴ is chosen from

12. A compound according to claim 11 wherein R⁴ is chosen from

13. A compound according to claim 11 wherein the carbon marked with an “

a”

is of the (R)—

absolute configuration.

14. A compound according to claim 13 wherein R⁴ is

15. A compound according to claim 13 wherein R⁴ is

16. A compound according to claim 1 wherein R⁴ is C(O)NHR⁷.

17. A compound according to claim 1 wherein p and q are both zero and A is chosen from heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, (C₁-C₆)alkyl and substituted (C₁-C₆)alkyl.

18. A compound according to claim 17 wherein A is chosen from piperidinyl, morpholinyl, pyrimidinyl, methyl, pyridinyl, 2-aminopyrimidinyl, acetamidophenyl, propyl, hydroxyphenyl, carboxyphenyl, methanesulfonamidophenyl, halopyridinyl, methoxypyridinyl, methylpyridinyl, chloromethyl, furanyl, pyrrolyl, ethyl, butyl, imidazolyl, N-methylimidazolyl, phenyl, (aminosulfonyl)phenyl, (dialkylamino)pyrimidinyl, mono- and di-hydroxypyrimidinyl, (trifluoromethyl)pyridinyl, oxopyridinyl, (alkylthio)pyrimidinyl, (trifluoromethyl)phenyl, cyanophenyl, pyridine-N-oxide, methoxyphenyl, methylpyrrolyl, methylfuranyl, tetrahydrofuranyl, methylphenyl, cyclopentyl, thiazolyl, halophenyl, benzyl, (methoxycarbonyl)phenyl, indolyl, quinolinyl, and (trifluoromethoxy)phenyl.

19. A compound according to claim 1 wherein Z is sulfur, p is one, q is zero and A is an optionally substituted alkyl.

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

21. A method of treating a disorder responsive to inhibition of Janus kinase 3, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.

22. A method according to claim 21 wherein said disorder is selected from an autoimmune disease, an inflammatory disease, a mast cell mediated disease, cancer, hematological malignancy, organ transplant rejection, and cardiovascular disease.

23. The method according to claim 22 wherein said disorder is organ transplant rejection, psoriasis, rheumatoid arthritis, asthma, or keratoconjuctivitis sicca.

24. The method according to 22 wherein said disorder is a malignancy selected from pancreatic cancer, lymphoma, chronic myelogenous leukemia, and anaplastic large cell lymphoma.