JNK inhibitors

• US 7,432,375 B2
• Filed: 03/05/2004
• Issued: 10/07/2008
• Est. Priority Date: 03/06/2003
• Status: Expired due to Fees

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Inventors: Khan, Afzal, Bhatia, Gurpreet, Graczyk, Piotr, Iimura, Yoichi
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US10/548,163
• Publication Number:
  US 20060270646A1
• Time in Patent Office: 1,677 Days
• Field of Search: 546/113
• US Class Current: 546/113
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
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• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
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• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
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• 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 25/28 : 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 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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• 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 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• 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 9/10 : 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 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 of formula (I) as claimed in claim 1, wherein R¹ is an optionally substituted five or six membered carbocyclyl group wherein the carbocyclyl group is optionally fused to one or more unsaturated rings.

3. A compound as claimed in claim 1 wherein R¹ is selected from optionally substituted phenyl, cyclohexyl furan, and naphthaline.

4. A compound as claimed in claim 1 wherein R¹ is substituted with one or more of OR¹², halogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, haloalkyl, C_1-6 alkylaryl, C_1-6 alkylheterocyclyl, (CH₂)_nOR¹², (CH₂)_nNR¹²₂, SR¹², NO₂, CN, NR¹²₂, NHC(O)R¹², NHS(O)₂R¹², CO₂R¹², COR¹², CONR¹²₂, S(O)₂R¹², S(O)R¹² or SO₂NR¹²₂;

wherein R¹² is hydrogen, C_1-4 alkyl or aryl, or heterocyclyl, and n is 1, 2, 3, 4, 5 or 6.

5. A compound of formula (I) as claimed in claim 1 wherein R² is selected from optionally substituted imidazole, isoxazole, isothiazole, oxazole, oxadiazole, oxathiazole, pyrazole, pyrrole, tetrazole, thiadiazole, thiatriazole, thiazole or triazole.

6. A compound as claimed in claim 1 wherein R² is a group

7. A compound of formula (I) as claimed in claim 6 wherein R²², R²³, R²⁴ or R²⁵ are independently selected from a lone electron pair, hydrogen, halogen, C_1-6 alkyl, haloalkyl, OR³⁰, SR³⁰, CN, NR³⁰₂, NR³⁰COR³⁰, CO₂R³⁰, COR³⁰, CONR³⁰₂, S(O)₂R³⁰, or S(O)R³⁰;

wherein R³⁰ is hydrogen, C_1-4 alkyl, or carbocyclyl.

9. A process for the manufacture of a compound of formula (I) as claimed in claim 1 comprising removal of group R⁴⁰ from an intermediate (III)

10. A process as claimed in claim 9 wherein R⁴⁰ is R³¹SO₂, R³¹C(O), R³¹₃Si, R³¹OCH₂, (R³¹)₂NSO₂, (R³¹)₂NC(O), R³¹OC(O), R³¹(R³¹O)CH, R³¹CH₂CH₂, R³¹CH₂, PhC(O)CH₂, CH₂═

CH, ClCH₂CH₂, Ph₃C, Ph₂(4-pyridyl)C, Me₂N, HO—

CH₂, R³¹OCH₂, (R³¹)₃SiOCH₂, (R³¹O)₂CH, t-BuOC(O)CH₂, Me₂NCH₂, or tetrahydropyranylamine,

wherein R³¹ is C_1-6 alkyl or C_6-12 aryl.

11. A compound of formula (III)

12. A process for the manufacture of a compound of formula (III) comprising a) reaction of a compound of formula (II) with stannane R¹—

Sn(R³²)₃ in the presence of a palladium catalyst or b) reaction of a compound of formula (II) with boronic acid or ester R¹—

B(OR³³)₂ in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (II) with silane R¹—

Si(R³⁴)₃ in the presence of a palladium catalyst;

13. A process as claimed in claim 12 wherein the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, Pd(dba)₂ (dba=dibenzylidenacetone), or Pd/P(t-Bu)₃.

14. A process for the manufacture of a compound of formula (I) as claimed in claim 1 comprising a) reaction of a compound of formula (IV) with stannane R¹—

Sn(R³²)₃ in the presence of a palladium catalyst or b) reaction of a compound of formula (IV) with boronic acid or ester R¹—

B(OR³³)₂ in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (IV) with silane R¹—

Si(R³⁴)₃ in the presence of a palladium catalyst;

15. A process as claimed in claim 14 wherein the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, Pd(dba)₂ (dba=dibenzylidenacetone), or Pd/P(t-Bu)₃.

16. A process for the production of a compound of formula (III) comprising reaction of a) boronic acid or ester (X) or b) stannane (XI) or c) silane (XII) with R¹-Hal in the presence of a suitable palladium catalyst,

17. A process as claimed in claim 16 wherein the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, and/or Pd(dba)₂ (dba=dibenzylidenacetone), or Pd/P(t-Bu)₃.

18. A process for the production of a compound of formula (I) comprising reaction of a) boronic acid or ester (L) or b) stannane (LI) or c) silane (LII) with R¹-Hal in the presence of a suitable palladium catalyst,

19. A process as claimed in claim 18 wherein the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, Pd(dba)₂ (dba=dibenzylidenacetone), and/or Pd/P(t-Bu)₃.

20. A process for the manufacture of an intermediate of formula (III) comprising a) reaction of a compound of formula (XIII) with stannane R²—

Sn(R³²)₃ in the presence of a palladium catalyst or b) reaction of a compound of formula (XIII) with boronic acid or ester R²—

B(OR³³)₂ in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (XIII) with silane R²—

Si(R³⁴)₃ in the presence of a palladium catalyst;

21. A process as claimed in claim 20 wherein the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, Pd(dba)₂ (dba=dibenzylidenacetone), and/or Pd/P(t-Bu)₃.

22. A process for the production of a compound of formula (III) comprising reaction of a) boronic acid or ester (XIV) or b) stannane (XV) or c) silane (XVI) with R²-Hal in the presence of a suitable palladium catalyst,

23. A process as claimed in claim 22 where the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, Pd(dba)₂ (dba=dibenzylidenacetone), and/or Pd/P(t-Bu)₃.

24. A process for the production of a compound of formula (I) comprising reaction of a) boronic acid or ester (LIV) or b) stannane (LV) or c) silane (LVI) with R²-Hal in the presence of a suitable palladium catalyst,

25. A process as claimed in claim 24 wherein the catalyst is (PPh₃)₂PdCl₂, (PPh₃)₄Pd, Pd(OAc)₂, [PdCl(η

³-C₃H₅]₂, Pd₂(dba)₃, Pd(dba)₂ (dba=dibenzylidenacetone), and/or Pd/P(t-Bu)₃.

27. The compound of as claimed in claim 1, wherein each n is 1, 2 or 3.

28. The compound of as claimed in claim 1, wherein each substitutable carbon or hetero-atom in R² is optionally and independently substituted by one or more of C_1-6 alkyl, OR¹⁰, SR¹⁰, NO₂, CN, NR¹⁰₂, NR¹⁰COR¹⁰, NR¹⁰CONR¹⁰₂, NR¹⁰COR¹⁰, NHCO₂R¹⁰, CO₂R¹⁰, COR¹⁰, CONR¹⁰₂, S(O)₂R¹⁰, SONR¹⁰₂, S(O)R¹⁰, SO₂NR¹⁰₂, or NR¹⁰S(O)₂R¹⁰.

29. The compound of as claimed in claim 4, wherein R¹² is phenyl or pyridine.

30. The compound of as claimed in claim 6, wherein each n is 1, 2 or 3.

31. The compound of as claimed in claim 6, wherein R² is imidazole, isoxazole, isothiazole, oxazole, oxadiazole, oxatriazole, pyrazole, pyrrole, tetrazole, thiadiazole, thiatriazole, thiazole or triazole.

32. The compound of as claimed in claim 7, wherein R³⁰ is methyl, ethyl or phenyl.

33. The compound of as claimed in claim 12, wherein X is I or Br.

34. The compound of as claimed in claim 14, wherein R³³ is hydrogen or both R³³ groups form the group —

C(CH₃)₂—

C(CH₃)₂.

8. A compound of formula (I) selected from the group consisting of:

26. A compound selected from the group consisting of: