COMPOSITIONS USEFUL AS INHIBITORS OF GSK-3

• US 20090118278A1
• Filed: 12/18/2008
• Published: 05/07/2009
• Est. Priority Date: 08/02/2002
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Park, Larry C., Wannamaker, Marion W., Forster, Cornelia J., Yao, Yung-Mae M.
• Granted Patent: US 7,872,129 B2
• Time in Patent Office: Days
• US Class Current: 514/234.200
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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 27/06 Antiglaucoma agents or miotics
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• 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 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention provides a compound of formula I:

or a pharmaceutically acceptable derivative thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK3 mammalian protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R^y is a C_1-4 aliphatic group.

3. The compound of claim 2, wherein R^y is selected from methyl, ethyl, cyclopropyl, tert-butyl, or isopropyl.

4. The compound according to claim 3, wherein R^y is selected from methyl, cyclopropyl, or tert-butyl.

5. The compound according to claim 1, wherein W is nitrogen.

6. The compound according to claim 1, wherein W is CH.

7. The compound according to claim 1, wherein R¹ is hydrogen.

8. The compound according to claim 1, wherein R¹ is fluorine.

9. The compound according to claim 1, wherein R^y is a C_1-4 aliphatic group substituted with a 6-membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

10. The compound according to claim 9, wherein R^y is a C_1-4 aliphatic group substituted with a morpholinyl, piperidinyl, or piperazinyl ring

11. The compound according to claim 1, wherein R^y is a C_1-4 aliphatic group substituted with N(R²)₂.

13. A pharmaceutically acceptable composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvent, or vehicle.

14. The composition according to claim 13, additionally comprising an additional therapeutic agent selected from a treatment for Alzheimer'"'"'s Disease (AD), a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating stroke, an agent for treating cardiovascular disease, an antidepressant, an anti-psychotic agent, or an agent for treating diabetes.

15. A method of inhibiting GSK3 kinase activity in a biological sample, comprising the step of contacting said biological sample with:

a) a composition according to claim 13;

or

b) a compound according to claim 1.

16. A method of GSK3 kinase activity in a patient, comprising the step of administering to said patient:

a) a composition according to claim 13;

or

b) a compound according to claim 1.

17. A method of treating an autoimmune disease, an inflammatory disease, a metabolic disorder, a psychiatric disorder, diabetes, an angiogenic disorder, tauopothy, a neurological or neurodegenerative disorder, a spinal cord injury, glaucoma, baldness, or a cardiovascular disease, in a patient in need thereof, comprising administering to said patient a composition according to claim 13.

18. The method according to claim 17, wherein said disease, disorder, or condition is selected from allergy, asthma, diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig'"'"'s disease), multiple sclerosis (MS), an injury due to head trauma, schizophrenia, anxiety, bipolar disorder, tauopothy, a spinal cord or peripheral nerve injury, myocardial infarction, cardiomyocyte hypertrophy, glaucoma, attention deficit disorder (ADD), depression, a sleep disorder, reperfusion/ischemia, stroke, an angiogenic disorder, or baldness,

19. The method according to claim 18, wherein said disease, disorder, or condition is stroke.

20. The method according to claim 18, wherein said disease, disorder, or condition is Alzheimer'"'"'s disease.

21. The method according to claim 17, wherein said disorder is a neurological or neurodegenerative disorder.

22. A method of decreasing sperm motility in a male patient comprising administering to said patient a composition according to claim 13.

23. The method according to claim 17, comprising the additional step of administering to said patient an additional therapeutic agent selected from a treatment for Alzheimer'"'"'s Disease (AD), a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating stroke, an agent for treating cardiovascular disease, an antidepressant, an anti-psychotic agent, or an agent for treating diabetes, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

12. A compound selected from the group consisting of: