Inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders relating to apoptosis and/or inflammation

• US 20070072896A1
• Filed: 08/04/2006
• Published: 03/29/2007
• Est. Priority Date: 08/05/2005
• Status: Active Grant

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Inventors: Khan, Afzal, Bhatia, Gurpreet, Medland, Darren
• Granted Patent: US 7,645,769 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• 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: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides novel compounds of formula I and their use in the inhibition of c-Jun N-terminal kinases. The present invention further provides the use of these compounds in medicine, in particular in the prevention and/or treatment of neurodegenerative disorders related to apoptosis and/or inflammation.

Claims

1. A compound of formula (I):

2. A compound as claimed in claim 1 wherein R¹ is an unbranched alkyl group having 2, 3, 4, 5 or 6 carbon atoms.

3. A compound as claimed in claim 1 wherein R¹ is an unbranched alkenyl or alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

4. A compound as claimed in claim 1 wherein R¹ is a C₅ or C₆ cycloalkyl or aryl group optionally substituted with one or more of C_1-4 alkyl or a halogen.

5. A compound as claimed in claim 4 wherein the aryl group is substituted at the ortho or para position.

6. A compound as claimed in claim 4 wherein R¹ is phenyl.

7. A compound as claimed in claim 1 wherein R² is a 5-membered heterocycle comprising one or more heteroatoms selected from O, S or N,

8. A compound as claimed in claim 1 wherein R² is a 5-membered heterocycle comprising two or more heteroatoms selected from O, S or N.

9. A compound as claimed in claim 7 wherein one or more of the heteroatoms of R² is substituted with C_1-6 alkyl.

10. A compound as claimed in claim 1 wherein R² is a 5-membered heterocycle selected from, furan, imidazole, imidazoline, imidazolidine, isoxazole, isothiazole, oxazole, oxadiazole, oxathiazole, oxathiazolidine, pyrazole, pyrazoline, pyrazolidine, pyrrole, tetrahydrofuran, tetrazole, thiophene, thiadiazole, thiazole or triazole;

wherein said heterocycle is optionally substituted with an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

11. A compound as claimed in claim 10 wherein said optional substitution occurs at one or more of O, S or N in the heterocycle.

12. A compound as claimed in claim 10 wherein R² is substituted with a group

15. A compound as claimed in claim 1 selected from

16. A prodrug of a compound as defined in claim 1.

17. A composition comprising a compound as defined in claim 15 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

18. A composition as claimed in claim 17 further comprising one or more other active agent.

19. A composition as claimed in claim 18 wherein said other active agent is an anti-inflammatory agent.

20. A method of preventing or treating a JNK-mediated disorder in an individual, which method comprises administering to said individual a composition of claim 17.

21. The method as claimed in claim 20 wherein the JNK-mediated disorder, wherein the disorder is a neurodegenerative disorder, inflammatory disease, an apoptosis disorder, particularly neuronal apoptosis, autoimmune disease, destructive bone disorder, proliferative disorder, cancer, infectious disease, allergy, ischemia reperfusion injury, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin induced platelet aggregation and/or a prostaglandin endoperoxidase synthase-2 condition.

22. The method as claimed in claim 20, wherein the neurodegenerative disorder is an apoptosis neurodegenerative disorder and/or an inflammation neurodegenerative disorder.

23. The method as claimed in claim 22, wherein the neurodegenerative disorder is:

dementia;

Alzheimer'"'"'s disease;

Parkinson'"'"'s disease;

Amyotrophic Lateral Sclerosis;

Huntington'"'"'s disease;

senile chorea;

Sydenham'"'"'s chorea;

hypoglycemia;

head and spinal cord trauma;

traumatic head injury;

acute and chronic pain;

epilepsy and seizures;

olivopontocerebellar dementia;

neuronal cell death;

hypoxia-related neurodegeneration;

acute hypoxia;

glutamate toxicity;

glutamate neurotoxicity;

cerebral ischemia;

dementia in a meningitis patient and/or dementia in a neurosis patient;

cerebrovascular dementia;

or dementia in an HIV-infected patient or wherein the neurodegenerative disorder is a peripheral neuropathy, including mononeuropathy, multiple mononeuropathy or polyneuropathy, such as may be found in diabetes mellitus, Lyme disease or uremia;

peripheral neuropathy;

demyelinating disease, leukodystrophies or Guillain-Barré

syndrome;

multiple mononeuropathy secondary to a collagen vascular disorder, multiple mononeuropathy secondary to sarcoidosis;

multiple mononeuropathy secondary to a metabolic disease;

or multiple mononeuropathy secondary to an infectious disease.

24. The method as claimed in claim 21, wherein the disorder is inflammatory bowel disorder;

bronchitis;

asthma;

acute pancreatitis;

chronic pancreatitis;

allergies of various types;

Alzheimer'"'"'s disease;

autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, glumerulonephritis, scleroderma, chronic thyroiditis, Graves'"'"'s disease, autoimmune gastritis, diabetes, autoimmune haemolytis anaemia, autoimmune neutropaenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, ulcerative colitis, Crohn'"'"'s disease, psoriasis or graft vs host disease.

13. A compound of formula II

14. A compound as claimed in claim 13 wherein R¹ is a branched alkyl having 3, 4, 5 or 6 carbon atoms.

25. An assay for determining the JNK inhibiting activity of a compound comprising a Scintillation Proximity Assay (SPA) using radiolabelled ATP, or an ELISA.

26. An assay as claimed in claim 25, wherein the assay is for the JNK3-specific inhibiting assay of the compound.