Inhibitors of prolyl endopeptidase

• US 7,592,467 B2
• Filed: 04/07/2006
• Issued: 09/22/2009
• Est. Priority Date: 04/11/2005
• Status: Expired due to Fees

• Current Assignee: Probiodrug AG
• Original Assignee: Probiodrug AG
• Inventors: Niestroj, Andre Johannes, Aust, Susanne, Demuth, Hans-Ulrich, Heiser, Ulrich
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): JACKSON, SHAWQUIA
• Application Number:
  US11/400,582
• Publication Number:
  US 20060229357A1
• Time in Patent Office: 1,264 Days
• Field of Search: 549/72
• US Class Current: 549/72
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 25/32 Alcohol-abuse
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• 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 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 307/46 : Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
• CPC Class Codes: C07D 333/22 : Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/56 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to novel inhibitors of prolyl endopeptidase of formula (1)

wherein I, A, X, Y and Z are specified in the description. The compounds are useful for the treatment of diseases such as mild cognitive impairment (MCI), Alzheimer'"'"'s disease, Down Syndrome, Parkinson disease and Chorea Huntington.

Claims

1. A compound of the general formula 1, or a pharmaceutically acceptable salt thereof, including all stereoisomers thereof:

2. A compound according to claim 1, wherein I represents 2-furyl.

3. A compound according to claim 1, wherein I represents thienyl.

4. A compound according to claim 3, wherein I represents 2-thienyl.

5. A compound according to claim 1, wherein A represents a group of formula (II).

6. A compound according to claim 5, wherein n² is 2.

7. A compound according to claim 1, wherein A represents a group of formula (III).

8. A compound according to claim 7, wherein R¹ represents Me or H.

9. A compound according to claim 8, wherein R¹ represents H.

10. A compound according to claim 7, wherein J represents CH₂.

11. A compound according to claim 7, wherein K represents CH.

12. A compound according to claim 1, wherein A represents a group of formula (IV).

13. A compound according to claim 12, wherein L-R² represents CH or CMe.

14. A compound according to claim 13, wherein L-R² represents CH.

15. A compound according to claim 12, wherein M-R³ represents CH or CMe.

16. A compound according to claim 15, wherein M-R³ represents CH.

17. A compound according to claim 12, wherein Q-R⁴ represents CH or CMe.

18. A compound according to claim 17, wherein Q-R⁴ represents CH.

19. A compound according to claim 12, wherein U—

R⁵ represents CH or CMe.

20. A compound according to claim 19, wherein U—

R⁵ represents CH.

21. A compound according to claim 12, wherein L-R³, M-R⁴, U—

R⁵ and U—

R⁵ represent CH.

22. A compound according to claim 1, wherein X is O or NH.

23. A compound according to claim 22, wherein X is O.

24. A compound according to claim 1, wherein Y is a bond or represents CH₂, (CH₂)₂ or (CH₂)₃.

25. A compound according to claim 24, wherein Y represents (CH₂)₂.

26. A compound according to claim 24, wherein Y represents (CH₂)₃.

27. A compound according to claim 1, wherein Z represents optionally substituted phenyl or thienyl.

28. A compound according to claim 27, wherein Z represents a group selected from phenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, thien-2-yl and thien-3-yl.

29. A compound according to claim 27, wherein Z is 3-fluorophenyl.

30. A compound according to claim 1 selected from the group consisting of Formula (1) through (32), or a pharmaceutical salt, or stereoisomer thereof:

31. A compound according to claim 1 selected from the group consisting of Formula (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), and (46), or a pharmaceutical salt, stereoisomer thereof:

32. A compound according to claim 1 wherein

I is furyl or thienyl;

A is phenyl;

X is O or NH;

Y is alkyl or C₃-C₅ cycloalkyl; and

Z is 9-fluorene, phenyl, 3-methylphenyl, 4-methylphenyl, 2-thienyl, 3-thienyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl or 3-hydroxyphenyl.

33. A compound according to claim 32, wherein I is 2-furyl or 2-thienyl.

34. A compound according to claim 32, wherein Y is CH₂, CH₂CH₂, CH₂CH₂CH₂ or

35. A compound according to claim 32, wherein Z is phenyl, 4-methylphenyl, 3-thienyl, 2,3-dichlorophenyl, 4-fluorophenyl or 3-hydroxyphenyl.

36. A compound according to claim 1 wherein

I is furyl or thienyl;

A is phenyl;

X is O or NH;

Y is alkyl or a bond; and

Z is 9-fluorene, 2-indanyl, phenyl, 3-methylphenyl, 4-methylphenyl, 2-thienyl, 3-thienyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-benzothienyl.

37. A compound of claim 36, wherein I is 2-furyl or 2-thienyl.

38. A compound according to claim 36, wherein Y is CH₂, CH₂CH₂, or CH₂CH₂CH₂.

39. A compound according to claim 36, wherein Z is 9-fluorene, 2-indanyl, phenyl, 3-methylphenyl, 2-thienyl, 3-thienyl, 2-chlorophenyl or 2-nitrophenyl.

40. A compound according to claim 32, wherein X is O.

41. A pharmaceutical composition comprising at least one compound according to claim 1 together with one or more therapeutically acceptable diluents or carriers.

42. A pharmaceutical composition according to claim 41 for parenteral, enteral or oral administration.

43. A pharmaceutical composition according to claim 41 which comprises additionally at least one compound selected from the group consisting of QC-inhibitors, LiCl, inhibitors of dipeptidyl aminopeptidases, preferably inhibitors of DP IV or DP IV-like enzymes, NPY-receptor ligands, NPY agonists, ACE inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, PDE-4 inhibitors, MAO inhibitors, TNFalpha inhibitors, amyloid protein or amyloid peptide deposition inhibitors, sigma-1 receptor inhibitors and histamine H3 antagonists.

44. A process for preparing a compound of claim 1 comprising reacting a compound of formula (IA), with a compound of formula (IB):