Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases

• US 20110189167A1
• Filed: 08/04/2010
• Published: 08/04/2011
• Est. Priority Date: 04/20/2007
• Status: Abandoned Application

• Current Assignee: Deciphera Pharmaceuticals, LLC (ONO Pharmaceutical Company Limited)
• Original Assignee: Deciphera Pharmaceuticals, LLC (ONO Pharmaceutical Company Limited)
• Inventors: KAUFMAN, Michael D., FLYNN, Daniel L., PETILLO, Peter A.
• Application Number:
  US12/850,256
• Publication Number:
  US 20110189167A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Methods 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, are provided which employ compounds of the formula Ia:

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, 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 formula Ia.

3. A 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 T315I 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. 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, rheumatoid arthritis, respiratory diseases, stroke, systemic shock, immunological diseases, automimmune 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 formula Ia.

10. The method of claim 7 or 8, wherein the pharmaceutical composition further comprises at least one other therapeutic agent.

11. The method of claim 10, wherein the at least one other therapeutic agent is useful for treating cancer.

12. The method of claim 11, wherein the other therapeutic agent is selected from the group consisting of imatinib, nilotinib, dasatinib, and bosutinib.

13. The method of claim 12, wherein the other therapeutic agent is imatinib.

14. The method of claim 10, wherein the at least one other therapeutic agent is useful for treating autoimmune diseases or inflammatory diseases.

15. The method of claim 14, wherein the other therapeutic agent is selected from the group consisting of methotrexate or other anti-folate agent.

16. The method of claim 14, wherein the other therapeutic agent is an anti-TNF agent.

17. The method of claim 16, wherein the other therapeutic agent is selected from the group consisting Humira®

, Enbrel®

, and Remicade®

.

8. 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 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 pulmonary disease, bone resorptive diseases, bone cancer, graft-versus-host reaction, Chron'"'"'s disease, ulcerative colitis, inflammatory bowel disease, pyresis, gastrointestinal stromal tumors, mastocytosis, mast cell leukemia, and combinations thereof, comprising the step of administering to such individual a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula Ia.

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