PIPERIDINE INHIBITORS OF JANUS KINASE 3

• US 20100291026A1
• Filed: 04/20/2010
• Published: 11/18/2010
• Est. Priority Date: 04/20/2009
• Status: Active Grant

• Current Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Zhang, Chengzhi, Rao, Tadimeti
• Granted Patent: US 8,299,084 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 27/04 Artificial tears; Irrigation solutions
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to new piperidine inhibitors of Janus kinase 3 activity, pharmaceutical compositions thereof, and methods of use thereof.

Claims

1. A compound of structural Formula I

2. The compound as recited in claim 1 wherein at least one of R₁-R₂₀ independently has deuterium enrichment of no less than about 10%.

3. The compound as recited in claim 1 wherein at least one of R₁-R₂₀ independently has deuterium enrichment of no less than about 50%.

4. The compound as recited in claim 1 wherein at least one of R₁-R₂₀ independently has deuterium enrichment of no less than about 90%.

5. The compound as recited in claim 1 wherein at least one of R₁-R₂₀ independently has deuterium enrichment of no less than about 98%.

6. The compound as recited in claim 1 wherein said compound has a structural formula selected from the group consisting of

7. The compound as recited in claim 6 wherein each position represented as D has deuterium enrichment of no less than about 10%.

8. The compound as recited in claim 6 wherein each position represented as D has deuterium enrichment of no less than about 50%.

9. The compound as recited in claim 6 wherein each position represented as D has deuterium enrichment of no less than about 90%.

10. The compound as recited in claim 6 wherein each position represented as D has deuterium enrichment of no less than about 98%.

11. The compound as recited in claim 6 wherein said compound has a structural formula selected from the group consisting of

12. The compound as recited in claim 11 wherein said compound has the structural formula:

13. The compound as recited in claim 11 wherein said compound has the structural formula:

14. The compound as recited in claim 11 wherein said compound has the structural formula:

15. The compound as recited in claim 11 wherein said compound has the structural formula:

16. The compound as recited in claim 11 wherein said compound has the structural formula:

17. The compound as recited in claim 11 wherein said compound has the structural formula:

18. The compound as recited in claim 11 wherein said compound has the structural formula:

19. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.

20. A method of treatment of a Janus kinase 3-mediated disorder comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient in need thereof.

21. The method as recited in claim 20 wherein said disorder is selected from the group consisting of renal transplant rejection, rheumatoid arthritis, psoriasis, inflammatory bowel disease, dry eye syndrome, asthma, and transplant rejection.

22. The method as recited in claim 20 further comprising the administration of an additional therapeutic agent.

23. The method as recited in claim 22 wherein said additional therapeutic agent is selected from the group consisting of H+, K+ ATPase inhibitors, alimentary motility modulator, non-steroidal anti-inflammatory agents, anilide analgesics, anti-rheumatic agents, glucocorticoids, and immunosuppressants.

24. The method as recited in claim 23 wherein said H+, K+ ATPase inhibitor is selected from the group consisting of esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, and tenatoprazole.

25. The method as recited in claim 23 wherein said alimentary motility modulator is selected from the group consisting of solabegron, tegaserod, alosetron, cilansetron, domperidone, metoclopramide, itopride, cisapride, renzapride, zacopride, octreotide, naloxone, erythromycin, and bethanechol.

26. The method as recited in claim 23 wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoracoxib, faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meloxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin.

27. The method as recited in claim 23 wherein said anilide analgesic is selected from the group consisting of acetaminophen and phenacetin.

28. The method as recited in claim 23 wherein said disease-modifying anti-rheumatic agent is selected from the group consisting of azathioprine, cyclosporine A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, minocycline, sulfasalazine, cyclophosphamide, etanercept, infliximab, adalimumab, anakinra, rituximab, and abatacept.

29. The method as recited in claim 23 wherein said glucocorticoid is selected from the group consisting of beclometasone, budesonide, flunisolide, betamethasone, fluticasone, triamcinolone, mometasone, ciclesonide, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, and dexamethasone.

30. The method as recited in claim 23 wherein said immunosuppressant is selected from the group consisting of fingolimod, cyclosporine A, Azathioprine, dexamethasone, tacrolimus, sirolimus, pimecrolimus, mycophenolate salts, everolimus, basiliximab, daclizumab, anti-thymocyte globulin, anti-lymphocyte globulin, and CTLA4IgG.

31. The method as recited in claim 20, further resulting in at least one effect selected from the group consisting of:

a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

32. The method as recited in claim 20, further resulting in at least two effects selected from the group consisting of:

a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

33. The method as recited in claim 20, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P₄₅₀ isoform in the subject, as compared to the corresponding non-isotopically enriched compound.

34. The method as recited in claim 33, wherein the cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

35. The method as recited claim 20, wherein said compound is characterized by decreased inhibition of at least one cytochrome P₄₅₀ or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

36. The method as recited in claim 35, wherein said cytochrome P₄₅₀ or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO_A, and MAO_B.

37. The method as recited in claim 20, wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

38. The method as recited in claim 37, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase (“

ALT”

), serum glutamic-pyruvic transaminase (“

SGPT”

), aspartate aminotransferase (“

AST,”

“

SGOT”

), ALT/AST ratios, serum aldolase, alkaline phosphatase (“

ALP”

), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“

GGTP,”

“

γ

-GTP,”

“

GGT”

), leucine aminopeptidase (“

LAP”

), liver biopsy, liver ultrasonography, liver nuclear scan, 5′

-nucleotidase, and blood protein.

39. A compound as recited in claim 1 for use as a medicament.

40. A compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by inhibiting Janus kinase 3 activity.

41. A compound having structural Formula II:

42. A compound as recited in claim 41, wherein Z₁ is benzyl.

43. A compound as recited in claim 42 wherein said compound has a structural formula selected from the group consisting of

44. A method of preparing a compound of structural Formula II:

45. A method of preparing a compound of structural Formula II:

46. A method of preparing a compound of structural Formula XIII: