Substituted pyrroline kinase inhibitors

• US 20090093515A1
• Filed: 09/22/2008
• Published: 04/09/2009
• Est. Priority Date: 03/27/2003
• Status: Abandoned Application

• Current Assignee: Bruce E. Maryanoff, Han-Cheng Zhang, Hong Ye
• Original Assignee: Bruce E. Maryanoff, Han-Cheng Zhang, Hong Ye
• Inventors: Ye, Hong, Maryanoff, Bruce E., Zhang, Han-Cheng
• Application Number:
  US12/284,452
• Publication Number:
  US 20090093515A1
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

Claims

1. A pharmaceutical composition comprising a compound of Formula (I):

2. A method for preparing a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

8. The method of claim 3 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 300 mg/kg/day.

19. A method for treating or ameliorating a kinase mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 1.

20. The method of claim 19 wherein the therapeutically effective amount of a pharmaceutical composition of claim 20 is from about 0.001 mg/kg/day to about 300 mg/kg/day.

3. A method for treating or ameliorating a kinase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

4. The method of claim 3 wherein the disorder is mediated by selective inhibition of a kinase selected from the group consisting of glycogen synthase kinase-3 and protein kinase C.

5. The method of claim 4 wherein the kinase is selected from the group consisting of glycogen synthase kinase-3β

and protein kinase C α

, protein kinase C β

-II, protein kinase C γ

.

6. The method of claim 3 wherein the disorder is mediated by dual inhibition of at least two kinases selected from the group consisting of glycogen synthase kinase-3 and protein kinase C.

7. The method of claim 6 wherein at least two kinases are selected from the group consisting of glycogen synthase kinase-3β

and protein kinase C α

, protein kinase C β

-II, protein kinase C γ

.

9. The method of claim 3 wherein the kinase mediated disorder is selected from the group consisting of cardiovascular diseases, diabetes, diabetes-associated disorders, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and CNS disorders.

10. The method of claim 9 wherein cardiovascular diseases are selected from the group consisting of acute stroke, heart failure, cardiovascular ischemia, thrombosis, atherosclerosis, hypertension, restenosis, retinopathy of prematurity and age-related macular degeneration.

11. The method of claim 9 wherein diabetes is selected from the group consisting of insulin dependent diabetes and Type II non-insulin dependent diabetes mellitus.

12. The method of claim 9 wherein diabetes-associated disorders are selected from the group consisting of impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy and neuropathy.

13. The method of claim 9 wherein inflammatory diseases are selected from the group consisting of vascular permeability, inflammation, asthma, rheumatoid arthritis and osteoarthritis.

14. The method of claim 9 wherein immunological disorders are selected from the group consisting of transplant tissue rejection, HIV-1 and PKC modulated immunological disorders.

15. The method of claim 9 wherein dermatological disorders are selected from the group consisting of psoriasis, hair loss and baldness.

16. The method of claim 9 wherein oncological disorders are selected from the group consisting of cancer or tumor growth, proliferative angiopathy and angiogenesis.

17. The method of claim 9 wherein central nervous system disorders are selected from the group consisting of chronic pain, neuropathic pain, epilepsy, chronic neurodegenerative conditions, dementia, Alzheimer'"'"'s disease, mood disorders, schizophrenia, manic depression and neurotraumatic, cognitive decline and ischemia-related diseases (as a result of head trauma or transient ischemic stroke).

18. The method of claim 3 further comprising a method for use for said compound as an adjunct to chemotherapy and radiation therapy.