Substituted N-Arylsulfonylheterocyclic Amines As Gamma-Secretase Inhibitors

• US 20100087425A1
• Filed: 12/08/2009
• Published: 04/08/2010
• Est. Priority Date: 06/30/2004
• Status: Abandoned Application

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Clader, John W., Pissarnitaki, Dmitri A., Li, Hongmei, Zhao, Zhiqiang, Josien, Hubert B., Xu, Ruo, Bara, Thomas A.
• Application Number:
  US12/633,286
• Publication Number:
  US 20100087425A1
• Time in Patent Office: Days
• US Class Current: 514/227.800
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

This invention discloses novel gamma secretase inhibitors of the formula:

• • wherein:
  • L is —O—, —N(R⁶)—, —S—, —S(O)—, or —S(O₂)—;
  • R¹ is selected from the group consisting of aryl and heteroaryl;
  • R² is selected from the group consisting of alkyl, —C(O)—Y, —X—C(O)—Y, -alkylene-X—C(O)—Y, -alkylene-C(O)—Y, -alkylene-cycloalkylene-X—C(O)—Y, -alkylene-cycloalkylene-C(O)—Y, -cycloalkylene-alkylene-X—C(O)—Y, -cycloalkylene-alkylene-C(O)—Y, -cycloalkylene-X—C(O)—Y, -cycloalkylene-C(O)—Y, -alkylene-cycloalkylene-alkylene-X—C(O)—Y, -alkylene-cycloalkylene-alkylene-C(O)—Y, aryl, and heteroaryl;
  • R³ is selected from the group consisting of aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, and alkoxyalkyl;
  • each R⁴ and R⁵ is independently selected from the group consisting of H and alkyl; and
  • Y is selected from the group consisting of —NR⁸R⁹, —N(R⁶)—(CH₂)_b—NR⁸R⁹, aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, and aryl heterocycloalkyl; or
  • Y is selected from the group consisting of:

One or more compounds of formula I, or formulations comprising such compounds, may be useful, e.g. in treating Alzheimer'"'"'s Disease.

Claims

1. A compound of the formula I:

2. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein:

R¹ is aryl or heteroaryl substituted with one or more substituents R⁷;

R² is —

(C₀-C₆)alkylene-(C₃-C₆)cycloalkylene-(C₀-C₆)alkylene-X—

C(O)—

Y, —

(C₀-C₆)alkylene-(C₃-C₆)cycloalkylene-(C₀-C₆)alkylene-C(O)—

Y, or —

(C₃-C₆)cycloalkylene-(C₁-C₆)alkylene-C(O)—

Y substituted on the alkylene moiety with one or more hydroxy groups;

R³ is aryl, alkyl, or cycloalkyl, each of which may be unsubstituted or substituted with one or more substituents R⁷ which can be the same or different;

L is —

O—

or —

N(R⁶)—

;

X is —

O—

or —

N(R⁶)—

; and

m and n are independently 0, 1, or 2, with the proviso that m+n is 1 or 2.

3. The compound of claim 2, or a pharmaceutically acceptable salt and/or solvate thereof, wherein:

R¹ is phenyl, pyridyl, or thiophenyl substituted with one or more substituents R⁷;

R² is —

(C₁-C₆)alkylene-X—

C(O)—

Y, —

(C₃-C₆)cycloalkylene-X—

C(O)—

Y, —

(C₃-C₆)cycloalkylene-(C₁-C₆)alkylene-C(O)—

Y, or —

(C₃-C₆)cycloalkylene-(C₁-C₆)alkylene-C(O)—

Y substituted on the (C₁-C₆)alkylene moiety with one or more hydroxy groups;

R³ is phenyl, ethyl, n-propyl, iso-propyl, cyclopropyl, or —

CH₂-cyclopropyl, each of which may be unsubstituted or substituted with one or more substituents R⁷ which can be the same or different; and

m and n are each 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein L is —

O—

.

5. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein L is —

N((C₁-C₆)alkyl).

6. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein L is —

S—

.

7. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein L is —

S(O)—

.

8. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R² is selected from the group consisting of —

(C₁-C₆)alkylene-X—

C(O)—

Y, —

(C₀-C₆)alkylene-(C₃-C₆)cycloalkylene-(C₀-C₆)alkylene-X—

C(O)—

Y, and —

(C₀-C₆)alkylene-(C₃-C₆)cycloalkylene-(C₀-C₆)alkylene-C(O)—

Y.

9. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R² is —

CH₂—

X—

C(O)—

Y.

10. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R² is —

CH₂—

O—

C(O)—

Y.

11. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R² is -1,1-cyclopropylene-O—

C(O)—

Y.

12. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R² is -1,1-cyclopropylene-CH₂—

C(O)—

Y or -1,1-cyclopropylene-CH(OH)—

C(O)—

Y.

13. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R³ is selected from the group consisting of 3,5-difluorophenyl, cyclopropyl, methyl, ethyl, iso-propyl, n-propyl, —

CH₂-cyclopropyl, —

CH₂-(2,2-difluorocyclopropyl).

14. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein R¹ is 4-chlorophenyl.

15. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, wherein Y is selected from the group consisting of —

NR⁸R⁹,

16. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, selected from the group consisting of:

17. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

18. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

19. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

20. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

21. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

22. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

24. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

25. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

26. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

27. The compound of claim 1, A compound, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

29. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

30. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

31. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

32. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

34. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

35. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

36. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

37. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

38. The compound of claim 1, or a pharmaceutically acceptable salt and/or solvate thereof, having the following structure:

39. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

40. A method of inhibiting gamma-secretase in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one or more compounds of claim 1.

41. A method of treating one or more neurodegenerative diseases in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one or more compounds of claim 1.

42. A method of inhibiting the deposition of beta amyloid protein in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one more compounds of claim 1.

43. A method of treating Alzheimer'"'"'s disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of one or more compounds of claim 1.

44. The compound of claim 1 in purified form.

23. (canceled)

28. (canceled)

33. (canceled)