AMINOPYRIMIDINE INHIBITORS OF TYROSINE KINASE

• US 20110053968A1
• Filed: 06/03/2010
• Published: 03/03/2011
• Est. Priority Date: 06/09/2009
• Status: Abandoned Application

• Current Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Zhang, Chengzhi
• Application Number:
  US12/793,205
• Publication Number:
  US 20110053968A1
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The present invention relates to new aminopyrimidine inhibitors of tyrosine kinase 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 said pharmaceutically acceptable salt is a hydrochloride monohydrate.

3. The compound as recited in claim 1 wherein at least one of R₁-R₂₂ independently has deuterium enrichment of no less than about 10%.

4. The compound as recited in claim 1 wherein at least one of R₁-R₂₂ independently has deuterium enrichment of no less than about 50%.

5. The compound as recited in claim 1 wherein at least one of R₁-R₂₂ independently has deuterium enrichment of no less than about 90%.

6. The compound as recited in claim 1 wherein at least one of R₁-R₂₂ independently has deuterium enrichment of no less than about 98%.

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

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

9. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 50%.

10. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 90%.

11. The compound as recited in claim 7 wherein each position represented as D has deuterium enrichment of no less than about 98%.

12. The compound as recited in claim 7 wherein said compound has a structural formula selected from the group consisting of:

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

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

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

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

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

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

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

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

21. A pharmaceutical composition comprising a pharmaceutically acceptable together with a compound of structural Formula I:

22. A method of treatment of a tyrosine kinase-mediated disorder comprising the administration of a therapeutically effective amount of a compound of structural Formula I:

23. The method as recited in claim 22 wherein said disorder is selected from the group consisting of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia, gastrointestinal stromal cancer, and melanoma.

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

25. The method as recited in claim 24 wherein said additional therapeutic agent is selected from the group consisting of alkylating agents, anti-metabolite agents, mitotic inhibitors, tyrosine kinase inhibitors, topoisomerase inhibitors, cancer immunotherapy monoclonal antibodies, anti-tumor antibiotic agents, and anti-cancer agents.

26. The method as recited in claim 25 wherein said alkylating agent is selected from the group consisting of chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.

27. The method as recited in claim 25 wherein said anti-metabolite agent is selected from the group consisting of aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur, capecitabine and gemcitabine.

28. The method as recited in claim 25 wherein said mitotic inhibitor is selected from the group consisting of docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.

29. The method as recited in claim 25 wherein said tyrosine kinase inhibitor is selected from the group consisting of dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.

30. The method as recited in claim 25 wherein said topoisomerase inhibitor is selected from the group consisting of etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.

31. The method as recited in claim 25 wherein said cancer immunotherapy monoclonal antibody is selected from the group consisting of rituximab, alemtuzumab, bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, and trastuzumab.

32. The method as recited in claim 25 wherein said anti-tumor antibiotic agent is selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea.

33. The method as recited in claim 25 wherein said anti-cancer agent is selected from the group consisting of amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.

34. The method as recited in claim 22, 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.

35. The method as recited in claim 22, 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.

36. The method as recited in claim 22, 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.

37. The method as recited in claim 36, wherein the cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

38. The method as recited claim 22, 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.

39. The method as recited in claim 38, 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.

40. The method as recited in claim 22, wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

41. The method as recited in claim 40, 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.

42. A compound for use as a medicament, wherein said compound has structural Formula I:

43. A compound for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by inhibiting tyrosine kinase activity, wherein said compound has structural Formula I: