Neuropeptide Y antagonists

• US 7,265,125 B2
• Filed: 04/07/2005
• Issued: 09/04/2007
• Est. Priority Date: 09/06/2000
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Pflieger, Philippe, Nettekoven, Matthias Heinrich, Breu, Volker, Guerry, Philippe, Dautzenberg, Frank
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US11/100,938
• Publication Number:
  US 20050176698A1
• Time in Patent Office: 880 Days
• Field of Search: 514/266.2, 514/266.22, 514/210.21, 514/217.06, 514/313, 540/599, 540/600, 544/284, 546/144, 546/159
• US Class Current: 514/266.2
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07D 215/42 attached in position 4
• CPC Class Codes: C07D 239/84 Nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond

Abstract

Quinoline and quinazoline derivatives can be used in the form of pharmaceutical preparations as Neuropeptide Y antagonists for the treatment or prevention of arthritis, cardiovascular diseases, diabetes, renal failure, eating disorders and obesity.

Claims

1. A compound selected from the group consisting of compounds of Formula I

2. The compound according to claim 1, wherein R² is hydrogen.

3. The compound according to claim 1, wherein R¹ is alkyl.

4. The compound according to claim 3, wherein R¹ is methyl.

5. The compound according to claim 1, wherein R³ is attached at the 7-position of the quinazoline ring.

6. The compound according to claim 1, wherein R³ is unsubstituted phenyl, thiophenyl, pyridinyl, pyrimidinyl, 1H-indolyl, benzofuryl, benzothiophenyl or naphthyl or R³ is phenyl, thiophenyl, pyridinyl, pyrimidinyl, 1H-indolyl, benzofuryl, benzothiophenyl or naphthyl, substituted with one to three substituents each independently selected from halogen, trifluoromethyl, amino, alkoxy, methylendioxy, alkylcarbonyl, cyano, alkyl, nitro, hydroxy, trifluoromethoxy, alkylsulfanyl, alkenyl, alkoxycarbonyl, aryloxy, alkoxycarbonylamino, alkylcarbonylamino and aminocarbonyl.

7. The compound according to claim 6, wherein R³ is unsubstituted thiophenyl, pyridinyl or naphthyl or R³ is phenyl or thiophenyl substituted with one or two substituents each independently selected from halogen, trifluoromethyl, alkoxy, alkylcarbonyl, cyano and hydroxy.

35. A process for the preparation of a compound according to claim 1, comprising one of the following reactions:

a) a reaction of a compound of formula

36. A compound selected from the group of compounds defined by formula X

37. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

38. A method for the treatment of arthritis, cardiovascular diseases, diabetes, renal failure and eating disorders, which method comprises administering a therapeutically effective amount of a compound according to claim 1.

39. A method of treating obesity in a human in need of such treatment, comprising administration to the human a therapeutically effective amount of a compound according to claim 1 and a therapeutically effective amount of a lipase inhibitor, wherein said lipase inhibitor is orlistat, lipstatin or a panclicin.

40. The method according to claim 39, wherein the lipase inhibitor is orlistat.

41. The method according to claim 39, wherein the compound according to claim 1 and the lipase inhibitor are administered simultaneously.

42. The method according to claim 39, wherein the compound according to claim 1 and the lipase inhibitor are administered separately.

43. The pharmaceutical composition according to claim 37, further comprising a therapeutically effective amount of a lipase inhibitor, wherein said lipase inhibitor is orlistat, lipstatin or a panclicin.

44. The pharmaceutical composition according to claim 43, wherein the lipase inhibitor is orlistat.

45. The method according to claim 38, wherein said method is for the treatment of obesity.

8. A compound selected from the group consisting of compounds of Formula Ia

9. The compound according to claim 8, wherein R³ is unsubstituted phenyl, thiophenyl, pyridinyl, pyrimidinyl, 1H-indolyl, benzofuryl, benzothiophenyl or naphthyl or R³is phenyl, thiophenyl, pyridinyl, pyrimidinyl, 1H-indolyl, benzofuryl, benzothiophenyl or naphthyl, substituted with one to three substituents each independently selected from halogen, trifluoromethyl, amino, alkoxy, methylendioxy, alkylcarbonyl, cyano, alkyl, nitro, hydroxy, trifluoromethoxy, alkylsulfanyl, alkenyl, alkoxycarbonyl, aryloxy, alkoxycarbonylamino, alkylcarbonylamino and aminocarbonyl.

10. The compound according to claim 8, wherein R⁸ is a bond.

11. The compound according to claim 10, selected from the group consisting of 2-methyl-7-pyrimidin-5-yl-4-pyrrolidin-1-yl-quinazoline, and pharmaceutically acceptable salts thereof.

12. The compound according to claim 11, which is 2-methyl-7-pyrimidin-5-yl-4-pyrrolidin-1-yl-quinazoline.

13. The compound according to claim 10, selected from the group consisting of 2-methyl-4-pyrrolidin-1-yl-7-(3-trifluoromethyl-phenyl)-quinazoline, and pharmaceutically acceptable salts thereof.

14. The compound according to claim 13, which is 2-methyl-4-pyrrolidin-1-yl-7-(3-trifluoromethyl-phenyl)-quinazoline.

15. The compound according to claim 10, selected from the group consisting of 7-(3-chloro-phenyl)-2-methyl-4-pyrrolidin-1-yl-quinazoline, and pharmaceutically acceptable salts thereof.

16. The compound according to claim 15, which is 7-(3-chloro-phenyl)-2-methyl-4-pyrrolidin-1-yl-quinazoline.

17. The compound according to claim 8, wherein R⁸ is O.

18. The compound according to claim 8, wherein R⁸ is N.

19. The compound according to claim 8, wherein R⁸ is N-alkyl.

20. The compound according to claim 8, wherein R⁸ is lower alkyl.

21. The compound according to claim 20, wherein R⁸ is a methyl group.

22. The compound according to claim 21, selected from the group consisting of 2-methyl-4-piperidin-1-yl-7-(3-trifluoromethyl-phenyl)-quinazoline, and pharmaceutically acceptable salts thereof.

23. The compound according to claim 22, which is 2-methyl-4-piperidin-1-yl-7-(3-trifluoromethyl-phenyl)-quinazoline.

24. The compound according to claim 21, selected from the group consisting of 7-(4-methoxy-phenyl)-2-methyl-4-piperidin-1-yl-quinazoline, and pharmaceutically acceptable salts thereof.

25. The compound according to claim 24, which is 7-(4-methoxy-phenyl)-2-methyl-4-piperidin-1-yl-quinazoline.

26. The compound according to claim 21, selected from the group consisting of 3-(2-methyl-4-piperidin-1-yl-quinazolin-7-yl)-phenylamine, and pharmaceutically acceptable salts thereof.

27. The compound according to claim 26, which is 3-(2-methyl-4-piperidin-1-yl-quinazolin-7-yl)-phenylamine.

28. The compound according to claim 21, selected from the group consisting of 2-methyl-4-piperidin-1-yl-7-pyridin-3-yl-quinazoline, pharmaceutically acceptable salts thereof.

29. The compound according to claim 27, which is 2-methyl-4-piperidin-1-yl-7-pyridin-3-yl-quinazoline.

30. The compound according to claim 21, selected from the group consisting of 7-(3-chloro-phenyl)-2-methyl-4-piperidin-1-yl-quinazoline, and pharmaceutically acceptable salts thereof.

31. The compound according to claim 29, which is 7-(3-chloro-phenyl)-2-methyl-4-piperidin-1-yl-quinazoline.

32. The compound according to claim 20, wherein R⁸ is an ethyl group.

33. The compound according to claim 32, selected from the group consisting of 4-azepan-1-yl-2-methyl-7-(3-trifluoromethyl-phenyl)-quinazoline, and pharmaceutically acceptable salts thereof.

34. The compound according to claim 33, which is 4-azepan-1-yl-2-methyl-7-(3-trifluoromethyl-phenyl)-quinazoline.