Compositions useful as inhibitors of GSK-3

• US 7,872,129 B2
• Filed: 12/18/2008
• Issued: 01/18/2011
• Est. Priority Date: 08/02/2002
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Park, Larry C., Wannamaker, Marion W., Yao, Yung-Mae M., Forster, Cornelia J.
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US12/338,129
• Publication Number:
  US 20090118278A1
• Time in Patent Office: 761 Days
• Field of Search: 544/328, 544/122, 514/256, 514/275, 514/234.5, 514/252.18
• US Class Current: 544/328
• 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 R¹ is hydrogen.

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

7. 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.

8. The compound according to claim 7, wherein R^y is a C_1-4 aliphatic group substituted with a morpholinyl, piperidinyl, or piperazinyl ring.

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

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

12. The composition according to claim 11, additionally comprising an additional therapeutic agent selected from a neurotrophic factor, an agent for treating stroke, an antidepressant, an anti-psychotic agent, or an agent for treating diabetes.

13. A method of treating a disease, disorder, or condition selected from diabetes, schizophrenia, anxiety, bipolar disorder, a spinal cord or peripheral nerve injury, depression, or stroke, in a patient in need thereof, comprising administering to said patient a compound according to claim 1 or a composition according to claim 11.

14. The method according to claim 13, comprising the additional step of administering to said patient an additional therapeutic agent selected from a neurotrophic factor, an agent for treating stroke, 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.

10. A compound selected from the group consisting of: