METHODS AND COMPOSITIONS FOR THE TREATMENT OF MYELOPROLIFERATIVE DISEASES AND OTHER PROLIFERATIVE DISEASES

• US 20120225057A1
• Filed: 09/08/2011
• Published: 09/06/2012
• Est. Priority Date: 10/11/2006
• Status: Abandoned Application

• Current Assignee: Deciphera Pharmaceuticals, LLC (ONO Pharmaceutical Company Limited)
• Original Assignee: Deciphera Pharmaceuticals, LLC (ONO Pharmaceutical Company Limited)
• Inventors: Flynn, Daniel L., Kaufman, Michael D.
• Application Number:
  US13/228,288
• Publication Number:
  US 20120225057A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• 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 11/00 Drugs for disorders of the respiratory system
• 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 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Compounds of the present invention, alone and in combination with other active agents, find utility in the treatment of hyperproliferative diseases, mammalian cancers and especially human cancers including but not limited to for example malignant melanomas, myeloproliferative diseases, chronic myelogenous leukemia, acute lymphocytic leukemia, a disease caused by c-ABL kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

Claims

1. A method of modulating a kinase activity of a wild-type kinase species, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of formula Ia′

;

2. A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by the kinase activity of c-ABL kinase, BCR-ABL kinase, FLT-3 kinase, TIE-2 kinase, TRK-A kinase, TRK-B kinase, TRK-C kinase, VEGFR-2 kinases, c-MET kinase, PDGFR-alpha kinase, PDGFR-beta kinase, HER-1 kinase, HER-2 kinase, HER-3 kinase, HER-4 kinase, FGFR kinases, c-KIT kinase, RET kinase, c-FMS kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1;

and

further comprising administering at least one other pharmaceutically active agent.

3. The method of claim 2 wherein said kinase is selected from the group consisting of BCR-ABL fusion protein kinases p210, BCR-ABL fusion protein kinases p190, BCR-ABL fusion protein kinases bearing the T315I gatekeeper mutant in the ABL kinase domain of p210, BCR-ABL fusion protein kinases bearing the T3151 gatekeeper mutant in the ABL kinase domain of p190, and other BCR-ABL polymorphs of any of the foregoing kinases.

4. The method of claim 3, wherein said BCR-ABL fusion protein kinases p210 have Seq. IDs 3 &

4, wherein said BCR-ABL fusion protein kinase p190 has Seq. ID 5, wherein said BCR-ABL fusion protein kinases p210 bearing the T315I mutation in the ABL kinase domain have Seq. IDs 6 &

7, and wherein said BCR-ABL fusion protein kinase p190 bearing the T315I mutation in the ABL kinase domain has Seq. ID 8.

5. The method of claim 2 wherein said kinase is selected from the group consisting of c-KIT protein kinase, PDGFR-alpha kinase, PDGFR-beta kinase, c-FMS kinase, and any fusion protein, mutation and polymorph of any of the foregoing.

6. The method of claim 2 wherein said kinase is selected from the group consisting of c-MET protein kinase, RET kinase, FGFR kinases, HER kinases, and any fusion protein, mutation and polymorph of any of the foregoing.

7. The method of claim 2 wherein said kinase is selected from the group consisting of FLT-3 kinase, TIE-2 kinase, TRK kinases, and any fusion protein, mutation and polymorph of any of the foregoing.

8. A method of treating an individual suffering from a condition selected from the group consisting of cancer, secondary cancer growth arising from metastasis, hyperproliferative diseases, diseases characterized by hyper-vascularization, inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, autoimmune diseases, bone resorptive diseases, cardiovascular disease and diseases characterized by angiogenesis, comprising the step of administering to such individual a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1;

and

further comprising administering at least one other pharmaceutically active agent.

9. A method of treating an individual suffering from a disease caused by c-ABL kinase, oncogenic forms thereof, aberrant fusion proteins thereof including BCR-ABL kinase and polymorphs thereof;

a disease caused by FLT-3 kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof;

a disease caused by TIE-2 kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof;

a disease caused by TRK kinases, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof;

a disease caused by cMET kinase, oncogenic forms thereof, aberrant fusion proteins thereof including TPR-MET;

a disease caused by KDR kinase or PDGFR kinases;

a disease caused by HER kinases, oncogenic forms thereof and polymorphs thereof;

a disease caused by RET kinase, oncogenic forms thereof, aberrant fusion proteins thereof;

a disease caused by c-FMS kinase, oncogenic forms thereof and polymorphs thereof;

a disease caused by a c-KIT kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof; and

diseases caused by any of the foregoing kinases, oncogenic forms thereof, and aberrant fusion proteins thereof, including but not limited to, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia, other myeloproliferative disorders, a disease caused by metastasis of primary solid tumors to secondary sites, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, mesothelioma, hypereosinophilic syndrome, a disease caused or maintained by pathological vascularization, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, i.e. diabetic retinopathy and age-related macular degeneration, non small cell lung cancer, breast cancers, kidney cancers, colon cancers, cervical carcinomas, papillary thyroid carcinoma, melanomas, autoimmune diseases including rheumatoid arthritis, multiple sclerosis, lupus, asthma, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonarydisease, bone resorptive diseases, bone cancer, graft-versus-host reaction, Crohn'"'"'s disease, ulcerative colitis, inflammatory bowel disease, pyresis, gastrointestinal stromal tumors, and combinations, comprising the step of administering to such individual a therapeutically effective amount of a pharmaceutical composition comprising a compound of Claim 1; and

further comprising administering at least one other pharmaceutically active agent.

10. The method of claim 8 or 9, said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.

11. The method of claim 1, 2, 8, 9, or 10 wherein the compound is 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea.

12. The method of claim 8 or 9, wherein the pharmaceutical composition further comprises at least one other pharmaceutically active agent.

13. The method of claim 12, wherein the at least one other pharmaceutically active agent is useful for treating cancer.

14. The method of claim 13, wherein the other pharmaceutically active agent is selected from the group consisting of imatinib, nilotinib, dasatinib, ponatinib, and bosutinib.

15. The method of claim 14 wherein the compound of formula Ia′

is 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea.

16. The method of claim 14, wherein the other pharmaceutically active agent is imatinib.

17. The method of claim 16 wherein the compound of formula Ia′

is 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea.

18. The method of claim 14, wherein the other therapeutic agent is dasatinib.

19. The method of claim 18 wherein the compound of formula Ia is 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea.

20. The method of claim 12, 15, 17, or 19, wherein the other pharmaceutically active agent is combined with the compound of formula Ia′

in a single dosage form.

21. The method of claim 12, 15, 17, or 19, wherein the other pharmaceutically active agent is in a separate dosage form than the compound of formula Ia′

.

22. The method of claim 21, wherein the compound of formula Ia and the other pharmaceutically active agent are dosed simultaneously or sequentially within a period of time from one hour to less than two weeks.

23. The method of claim 22, wherein the compound of formula Ia and the other pharmaceutically active agent are dosed alternately, wherein the compound of formula Ia is administered for a period of time ranging from two weeks to six months, followed by administration of the other pharmaceutically active agent for a second period of time ranging from two weeks to six months.

24. The method of claim 23, wherein the alternate dosing of the compound of formula Ia and the other pharmaceutically active agent is repeated multiple times.

25. The method of claim 24, wherein a drug holiday is implemented between the dosing of the compound of formula Ia′

and the other pharmaceutically active agent, wherein neither agent is dosed during the drug holiday.

26. The method of claim 25, wherein the drug holiday is a period of time ranging from one day to one month.

27. The method of claim 12, wherein at least one other pharmaceutically active agent is useful for treating autoimmune diseases or inflammatory diseases.

28. The method of claim 27, wherein the other pharmaceutically active agent is selected from the group consisting of methotrexate or other anti-folate agent.

29. The method of claim 27, wherein the other pharmaceutically active agent is an anti-TNF agent.

30. The method of claim 27, wherein the other pharmaceutically active agent is selected from the group consisting of Humira®

, Enbrel®

, and Remicade®

.