Dipeptide inhibitors of beta-secretase

• US 20050182138A1
• Filed: 03/08/2005
• Published: 08/18/2005
• Est. Priority Date: 06/15/1999
• Status: Active Grant

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Tung, Jay, John, Varghese, Gailunas, Andrea, Guinn, Ashley, Fang, Lawrence, Hom, Roy, Mamo, Shumeye S.
• Granted Patent: US 7,276,484 B2
• Time in Patent Office: Days
• US Class Current: 514/616
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu

Abstract

Dipeptide derived inhibitors of the β-secretase enzyme are provided which are useful in the treatment of Alzheimer'"'"'s disease and other diseases characterized by deposition of Aβ peptide in a mammal. The compounds of the invention provide useful methods of treatment by administration of these inhibitors to reduce Aβ peptide formation and in pharmaceutical compositions.

Claims

1. ) A compound of formula 1

2. ) The compound claim 1 wherein A is:

3. ) The compound of claim 2 wherein the A is selected from 2-hydroxy-(2-phenyl)ethanoyl, 2-hydroxy-(2-naphth-1-yl)ethanoyl, and 2-hydroxy-(2-naphth-12-yl)ethanoyl.

4. ) The compound of claim 1 wherein A is selected from biphenyl, 2-phenyl-α

-hydroxytolyl, diphenyl ether and diphenyl ketone.

5. ) The compound of claim 1 wherein A is

6. ) The compound of claim 5 wherein the ring D′

is chosen from the group consisting of benzene, pyridine, furan, thiophene, thiazole, thiadiazole, oxazole, oxadiazole and 1,2,4-triazole and Rb is di(C₂-C₄)alkylamine.

7. ) The compound of claim 1 wherein A is

8. ) The compound of claim 1 wherein R1 is selected from ethyl and 2-propyl.

9. ) The compound of claim 1 wherein R2 is selected from 2-thienylmethyl, 3-trifluoromethylphenylmethyl, 4-thiazolylmethyl, 3-chlorophenylmethyl, 3,5-difluorophenylmethyl, 4-methylphenylmethyl and 2-methylprop-1-yl.

10. ) The compound of claim 1 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

11. ) The compound of claim 3 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

12. ) The compound of claim 5 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

13. ) The compound of claim 7 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

14. ) The compound of claim 1 wherein B is OH, C₁-C₆ alkoxy, mono and di(C₁-C₆) alkylamino, aminoC₁-C₄ alkyl-p-benzoic acid and C₁-C₆ alkyl and phenyl esters thereof and N-heterocyclic.

15. ) The compound of claim 1 wherein B is

16. ) The compound of claim 15 wherein B is selected from 3,5-dicarboxycyclo-hexylamine, 3,4-dicarboxycyclohexylamine, 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

17. ) The compound of claim 1 wherein A is selected according to claim 2 and B is selected according to claim 14.

18. ) The compound of claim 1 wherein A is selected according to claim 2 and B is selected according to claim 15.

19. ) The compound of claim 1 wherein A is selected according to claim 5 and B is selected according to claim 14.

20. ) The compound of claim 1 wherein A is selected according to claim 15 and B is selected according to claim 15.

21. ) The compound of claim 1 wherein A is selected according to claim 7 and B is selected according to claim 14.

22. ) The compound of claim 1 wherein A is selected according to claim 7 and B is selected according to claim 15.

31. ) The method of claim 1 wherein R1 is selected from ethyl and 2-propyl.

38. ) The method of claim 1 wherein Bis

39. ) The method of claim 38 wherein B is selected from 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine, 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

61. ) The composition of claim 47 wherein B is

62. ) The composition of claim 61 wherein B is selected from 3,5-dicarboxycyclo-hexylamine, 3,4-dicarboxycyclohexylamine, 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

23. ) A compound selected from the group consisting of:

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 2-[(4-carboxy)phenyl]ethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 3-carboxypropylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 4-carboxynaphth-1-ylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 4-carboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine

N-{N′

-[2-benzyloxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(3-hydroxy-2-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(2-bromophenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[(S)-2-hydroxy-3-phenylpropanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(3-phenoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[(R)-2-hydroxy-3-phenylpropanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(3-hydroxy-3-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-[N′

-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[(R)-2-hydroxy-4-thiomethylbutanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(2-hydroxy-2-phenylethanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-[N′

-(2-hydroxy-2-phenylethanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[(2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(4-methylphenyl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(thien-2-yl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(thiazol-4-yl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[3-(N″

,N″

-diethylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine ethylamide

N-{N′

-[3-(N″

,N″

-diethylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(2-phenylphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine ethylamide

N-[N′

-(4-N″

,N″

-dimethylamino-5-oxopentanoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dimethoxycyclohexylamide

N-[N′

-(benzo-1,4-dioxan-6-oyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-amidobenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-acetylamino)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-carbomethoxybenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(2-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(4-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-benzoyl-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-(naphth-2-oyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-methylpiperazido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(4-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3-trifluoromethylphenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)phenylmethyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis,cis-3,4,5-trimethoxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)2,6-dimethylpyrid-3-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)-2-methyoxybenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)-5-methyoxybenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(2-methylpropionyl)-benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-furan-2-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-thiophen-2-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-5-methylbenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis, cis-3,4,5-trimethoxycyclohexylamide

N-{N′

-[3-(N″

,N″

-diethylamido)phenylmethyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-phenylbenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide, and

N-[N′

-2-pyrimidyl-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide.

24. ) A method of slowing or ameliorating the progression of a disease state characterized by deposition of AD peptide in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula 1

25. ) The method claim 24 wherein A is:

26. ) The method of claim 25 wherein the A is selected from 2-hydroxy-(2-phenyl)ethanoyl, 2-hydroxy-(2-naphth-1-yl)ethanoyl, and 2-hydroxy-(2-naphth-12-yl)ethanoyl.

27. ) The method of claim 24 wherein A is selected from biphenyl, 2-phenyl-α

-hydroxytolyl, diphenyl ether and diphenyl ketone.

28. ) The method of claim 24 wherein A is

29. ) The method of claim 28 wherein the ring D′

is chosen from the group consisting of benzene, pyridine, furan, thiophene, thiazole, thiadiazole, oxazole, oxadiazole and 1,2,4-triazole and Rb is di(C₂-C₄)alkylamine.

30. ) The method of claim 24 wherein A is

32. ) The method of claim 24 wherein R2 is selected from 2-thienylmethyl, 3-trifluoromethylphenylmethyl, 4-thiazolylmethyl, 3-chlorophenylmethyl, 3,5-difluorophenylmethyl, 4-methylphenylmethyl and 2-methylprop-1-yl.

33. ) The method of claim 24 wherein R1 is 2-propyl and R2 is 3,5-difluorophenylmethyl.

34. ) The method of claim 26 wherein R1 is 2-propyl and R2 is 3,5-difluorophenylmethyl.

35. ) The method of claim 28 wherein R1 is 2-propyl and R2 is 3,5-difluorophenylmethyl.

36. ) The method of claim 30 wherein R1 is 2-propyl and R2 is 3,5-difluorophenylmethyl.

37. ) The method of claim 24 wherein B is —

OH, C₁-C₆ alkoxy, mono and di(C₁-C₆) alkylamino, aminoC₁-C₄ alkyl-p-benzoic acid and C₁-C₆ alkyl and phenyl esters thereof and N-heterocyclic.

40. ) The method of claim 24 wherein A is selected according to claim 25 and B is selected according to claim 37.

41. ) The method of claim 24 wherein A is selected according to claim 25 and B is selected according to claim 38.

42. ) The method of claim 24 wherein A is selected according to claim 28 and B is selected according to claim 37.

43. ) The method of claim 24 wherein A is selected according to claim 28 and B is selected according to claim 38.

44. ) The method of claim 24 wherein A is selected according to claim 30 and B is selected according to claim 37.

45. ) The method of claim 24 wherein A is selected according to claim 30 and B is selected according to claim 38.

46. ) A method of slowing or ameliorating the progression of a disease state characterized by deposition of Aβ

peptide in a mammal comprising administering to a mammal in need thereof an effective amount of a compound selected from the group consisting of;

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 2-[(4-carboxy)phenyl]ethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 3-carboxypropylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 4-carboxynaphth-1-ylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 4-carboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine

N-{NA-[2-benzyloxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N-(3-hydroxy-2-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(2-bromophenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[(S)-2-hydroxy-3-phenylpropanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(3-phenoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[(R)-2-hydroxy-3-phenylpropanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[A7-(3-hydroxy-3-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-[A7-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[(R)-2-hydroxy-4-thiomethylbutanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(2-hydroxy-2-phenylethanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-[N′

-(2-hydroxy-2-phenylethanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[(2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(4-methylphenyl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(thien-2-yl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(thiazol-4-yl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[3-(N″

,N″

-diethylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine ethylamide

N-{N′

-[3-(N″

, N″

-diethylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(2-phenylphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine ethylamide

N-[N′

-(4-N″

, N″

-dimethylamino-5-oxopentanoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dimethoxycyclohexylamide

N-[N′

-(benzo-1,4-dioxan-6-oyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-amidobenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-acetylamino)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-carbomethoxybenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(2-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl)}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(4-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-benzoyl-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-[N′

-(naphth-2-oyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-methylpiperazido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(4-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3-trifluoromethylphenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)phenylmethyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis,cis-3,4,5-trimethoxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)2,6-dimethylpyrid-3-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)-2-methyoxybenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)-5-methyoxybenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(2-methylpropionyl)-benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-furan-2-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-thiophen-2-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-5-methylbenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis,cis-3,4,5-trimethoxycyclohexylamide

N-{N′

-[3-(N″

,N″

-diethylamido)phenylmethyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-phenylbenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide, and

N-[N′

-2-pyrimidyl-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide.

47. ) A pharmaceutical composition comprising a compound of formula 1

48. ) The composition claim 47 wherein A is:

49. ) The composition of claim 48 wherein the A is selected from 2-hydroxy-(2-phenyl)ethanoyl, 2-hydroxy-(2-naphth-1-yl)ethanoyl, and 2-hydroxy-(2-naphth-12-yl)ethanoyl.

50. ) The composition of claim 47 wherein A is selected from biphenyl, 2-phenyl-α

-hydroxytolyl, diphenyl ether and diphenyl ketone.

51. ) The composition of claim 47 wherein A is

52. ) The composition of claim 51 wherein the ring D′

is chosen from the group consisting of benzene, pyridine, furan, thiophene, thiazole, thiadiazole, oxazole, oxadiazole and 1,2,4-triazole and Rb is di(C₂-C₄)alkylamine.

53. ) The composition of claim 47 wherein A is

54. ) The composition of claim 47 wherein R1 is selected from ethyl and 2-propyl.

55. ) The composition of claim 47 wherein R2 is selected from 2-thienylmethyl, 3-trifluoromethylphenylmethyl, 4-thiazolylmethyl, 3-chlorophenylmethyl, 3,5-difluorophenylmethyl, 4-methylphenylmethyl and 2-methylprop-1-yl.

56. ) The composition of claim 47 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

57. ) The composition of claim 49 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

58. ) The composition of claim 51 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

59. ) The composition of claim 53 wherein R1 is 2-propyl and R2 is 3,5-difluorophenyl-methyl.

60. ) The composition of claim 47 wherein B is OH, C₁-C₆ alkoxy, mono and di(C₁-C₆) alkylamino, aminoC₁-C₄ alkyl-p-benzoic acid and C₁-C₆ alkyl and phenyl esters thereof and N-heterocyclic.

63. ) The composition of claim 47 wherein A is selected according to claim 48 and B is selected according to claim 60.

64. ) The composition of claim 47 wherein A is selected according to claim 48 and B is selected according to claim 61.

65. ) The composition of claim 47 wherein A is selected according to claim 51 and B is selected according to claim 60.

66. ) The composition of claim 47 wherein A is selected according to claim 51 and B is selected according to claim 61.

67. ) The composition of claim 47 wherein A is selected according to claim 53 and B is selected according to claim 60.

68. ) The composition of claim 47 wherein A is selected according to claim 53 and B is selected according to claim 61.

69. ) A pharmaceutical composition comprising a compound selected from the group consisting of:

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 2-[(4-carboxy)phenyl]ethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 3-carboxypropylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 4-carboxynaphth-1-ylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine 4-carboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine

N-{N′

-[2-benzyloxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(3-hydroxy-2-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(2-bromophenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[(S)-2-hydroxy-3-phenylpropanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(3-phenoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[(R)-2-hydroxy-3-phenylpropanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(3-hydroxy-3-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-[N′

-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{N′

-[(R)-2-hydroxy-4-thiomethylbutanoyl]-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl}valine (4-carboxy)phenylmethylamide

N-[N′

-(2-hydroxy-2-phenylethanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-[N′

-(2-hydroxy-2-phenylethanoyl)-(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoyl]valine (4-carboxy)phenylmethylamide

N-{NA-[(2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(4-methylphenyl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(thien-2-yl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(thiazol-4-yl)pentanoyl}valine (4-carboxy)phenylmethylamide

N-{N′

-[3-(N″

,N″

-diethylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine ethylamide

N-{N′

-[3-(N″

,N″

-diethylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine

N-{N′

-[2-hydroxy-2-(naphth-1-yl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(2-phenylphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine ethylamide

N-[N′

-(4-N″

, N″

-dimethylamino-5-oxopentanoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-ethyl-N″

-methylamido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dimethoxycyclohexylamide

N-[N′

-(benzo-1,4-dioxan-6-oyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-amidobenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-acetylamino)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-carbomethoxybenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(2-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(4-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-benzoyl-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-[N′

-(naphth-2-oyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

-methylpiperazido)benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[2-hydroxy-2-(4-methoxyphenyl)ethanoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3-trifluoromethylphenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)phenylmethyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis,cis-3,4,5-trimethoxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)2,6-dimethylpyrid-3-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

, N″

-dipropylamido)-2-methyoxybenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(N″

,N″

-dipropylamido)-5-methyoxybenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[3-(2-methylpropionyl)-benzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-furan-2-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-thiophen-2-ylcarbonyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis-3,5-dicarboxycyclohexylamide

N-{N′

-[5-(N″

,N″

-dipropylamido)-5-methylbenzoyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis, cis, cis-3,4,5-trimethoxycyclohexylamide

N-{N′

-[3-(N″

,N″

-diethylamido)phenylmethyl]-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl}valine cis,cis-3,5-dicarboxycyclohexylamide

N-[N′

-(3-phenylbenzoyl)-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide, and

N-[N′

-2-pyrimidyl-(3S, 4S)-4-amino-3-hydroxy-5-(3,5-difluorophenyl)pentanoyl]valine cis,cis-3,5-dicarboxycyclohexylamide,

and pharmaceutically acceptable salts and esters thereof, and a pharmaceutically acceptable diluent.