Protein kinase inhibitors and uses thereof

• US 20040009996A1
• Filed: 06/14/2002
• Published: 01/15/2004
• Est. Priority Date: 06/15/2001
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Moon, Young-Choon, Ledeboer, Mark, Pierce, Albert, Green, Jeremy, Choquette, Deborah, Davies, Robert
• Granted Patent: US 6,825,190 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 25/14 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 25/28 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 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 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 9/04 : 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: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings

Abstract

Described herein are benzisoxazole compounds of formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein A-B is N—O or O—N; Ar is an optionally substituted C_5-10 aryl group; R¹ is hydrogen or an optionally substituted group selected from C_1-10 aliphatic, C_5-10 aryl, C_6-12 aralkyl, C_3-10 heterocyclyl, or C_4-12 heterocyclylalkyl; and T, n, R² and R³ are as described in the specification. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK-3 and JAK mammalian protein kinases. 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 the compound is a 2,1-benzisoxazole.

3. The compounds of claim 2 wherein each R² is independently hydrogen or a C_1-4 alkyl group and each R³ is independently selected from hydrogen, halo —

O(C_1-4 alkyl), or C_1-4 alkyl.

4. The compound of claim 3 wherein Ar is a substituted or unsubstituted five or six-membered aromatic ring having zero to two heteroatoms selected from nitrogen, sulfur, and oxygen.

5. The compound of claim 4 wherein Ar is a substituted or unsubstituted six-membered aromatic ring having zero to two ring nitrogen atoms.

6. The compound of claim 5 wherein Ar is a phenyl ring optionally substituted by one or more substituents independently selected from C_1-10 aliphatic, C_5-10 aryl, C_6-12 aralkyl, C_3-10 heterocyclyl, C_4-12 heterocyclylalkyl, halo, CN, OR, N(R)₂, SR, C(═

O)R, CO₂R, CONR₂, NRC(═

O)R, NRCO₂(C_1-6 aliphatic), OC(═

O)R, SO₂R, S(═

O)R, SO₂NR₂, or NRSO₂(C_1-6 aliphatic), or two substituents on adjacent positions are optionally taken together with their intervening atoms to form a fused 5-8 membered unsaturated or partially unsaturated ring having zero to two heteroatoms selected from nitrogen, oxygen or sulfur.

7. The compound of claim 6 wherein R¹ is a phenyl or pyridyl ring optionally substituted with halogen, —

R, —

OR, —

OH, —

SH, —

SR, protected OH, —

NO₂, —

CN, —

NH₂, —

NHR, —

N(R)₂, —

NHCOR, —

NHCONHR, —

NHCON(R)₂, —

NRCOR, —

NHCO₂R, —

CO₂R, —

CO₂H, —

COR, —

CONHR, —

CON(R)₂, —

S(O)₂R, —

SO₂NH₂, —

S(O)R, —

SO₂NHR, or —

NHS(O)₂R, wherein R is an aliphatic group or a substituted aliphatic group having one to three carbons.

8. The compound of claim 7 wherein R¹ is substituted by —

SO₂NH₂ or —

SO₂NHR.

9. The compound of claim 1 wherein the compound is selected from any one of the following:

10. A composition comprising a compound according to claim 1 in an amount to detectably inhibit GSK-3 or JAK protein kinase activity, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

11. The composition according to claim 10, additionally comprising an additional therapeutic agent selected from an a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer'"'"'s Disease, 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 cardiovascular disease, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.

12. A method of inhibiting GSK-3 or JAK kinase activity in a biological sample, comprising the step of contacting said biological sample with:

a) a composition according to claim 10;

or

b) a compound according to claim 1.

13. A method of treating or lessening the severity of a GSK-3- or JAK-mediated disease or condition in a patient, comprising the step of administering to said patient:

a) a composition according to claim 10;

or

b) a compound according to claim 1.

14. The method according to claim 13, wherein said GSK-3-mediated disease is selected from diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, ischemia/reperfusion and baldness.

15. The method according to claim 13, wherein said JAK-mediated disease is selected from an immune response, an autoimmune disease, a neurodegenerative disease, or a solid or hematologic malignancy.

16. The method according to claim 15, wherein said JAK-mediated disease is selected from an allergic or type I hypersensitivity reaction, asthma, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, Familial amyotrophic lateral sclerosis (FALS), leukemia, or lymphoma.

17. The method according to claim 13, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferatic agent, a treatment for Alzheimer'"'"'s Disease, a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder, 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.

18. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound according to claim 1.

19. A method of inhibiting the phosphorylation of β

-catenin in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound according to claim 1.

20. A composition for coating an implantable device comprising a compound according to claim 1 and a carrier suitable for coating said implantable device.

21. An implantable device coated with a composition according to claim 20.