Octahydrocyclopentapyrroles, their preparation and use

1. A compound having the structure:

wherein

ψ is absent or present, and when present is a bond;

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl;

R 6 is absent or present, and when present is H, OH, or halogen;

A is absent or present, and when present is

B is substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, benzyl, CO 2 H or (C 1 -C 4 alkyl)-CO 2 H,

wherein when B is CO 2 H, then A is present and is

and

 wherein when ψ is present, then R 6 is absent and when ψ is absent, then R 6 is present,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having the structure:

3. The compound of claim 2 , wherein B is a substituted or unsubstituted heterobicycle.

4. The compound of claim 3 , wherein B has the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and φ are each independently absent or present, and when present each is a bond;

Z 1 is S, O or N;

Z 2 is S, O, N or N—R 7 ,

wherein R 7 is H, C 1 -C 10 alkyl, or oxetane;

X is C or N;

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently CR 8 , C(R 9 ) 2 , N—R 10 , O, N, SO 2 , or C═O,

wherein

R 8 is H, halogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 10 alkyl), C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)—NH 2 , C(O)—NH(C 1 -C 4 alkyl), C(O)—NH(C 1 -C 4 alkyl) 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , SO 2 —NH(C 1 -C 10 alkyl), SO 2 —N(C 1 -C 10 alkyl) 2 , CN, or CF 3 ;

R 9 is H or C 1 -C 10 alkyl;

R 10 is H, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 10 alkyl)-CF 3 , (C 1 -C 10 alkyl)-OCH 3 , (C 1 -C 10 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 10 alkyl)-CF 3 , SO 2 —(C 1 -C 10 alkyl)-OCH 3 , SO 2 —(C 1 -C 10 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 10 alkyl)-CF 3 , C(O)—(C 1 -C 10 alkyl)-OCH 3 , C(O)—(C 1 -C 10 alkyl)-halogen, C(O)—NH—(C 1 -C 10 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 10 alkyl)-C(O)OH, C(O)—NH 2 or oxetane,

wherein

when α is present, then Z 1 and Z 2 are N, X is N, β is present, and χ and δ are absent, or when α is present, then Z 1 is O or S, Z 2 is N, X is C, χ is present, and β and δ are absent;

when α is absent, then Z 1 is N, Z 2 is N—R 7 , X is C, β and δ are present, and χ is absent, or when α is absent, then Z 1 is N, Z 2 is O or S, X is C, β and δ are present, and χ is absent;

when ε and φ are each present, then n=1, and each of Y 1 , Y 2 , Y 3 , and Y 4 are independently C—R 8 or N; and

when ε and φ are each absent, then n=0, 1 or 2, each of Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are independently C(R 9 ) 2 , N—R 10 , O, or SO 2 .

5. The compound of claim 4 , wherein B has the structure:

6. The compound of claim 4 , wherein B has the structure:

7. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl)-C(O)OH or oxetane, or

B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl)-C(O)OH or oxetane.

8. The compound of claim 4 , wherein B has the structure:

wherein

R 7 is H, C 1 -C 4 alkyl, or oxetane; and

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN or CF 3 , or

B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein R 8 is H, halogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN or CF 3 .

9. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O)OH or oxetane, or

B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, O(C 1 -C 4 alkyl), CN, CF 3 , C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , or NHC(O)—N(CH 3 ) 2 , or

B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, O—(C 1 -C 4 alkyl), CN, or CF 3 .

10. The compound of claim 4 , wherein B has the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and φ are each independently absent or present, and when present each is a bond;

X is C or N;

Z 3 is CH, S, O, N or NR 11 ,

wherein R 11 is H or C 1 -C 10 alkyl;

Z 4 is CH, S, O, N or NR 12 ,

wherein R 12 is H or C 1 -C 10 alkyl;

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently CR 13 , C(R 14 ) 2 , N—R 15 , O, N, SO 2 , or C═O,

wherein

R 13 is H, halogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 10 alkyl), C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)—NH 2 , C(O)—NH(C 1 -C 4 alkyl), C(O)—NH(C 1 -C 4 alkyl) 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , SO 2 —NH(C 1 -C 10 alkyl), SO 2 —N(C 1 -C 10 alkyl) 2 , CN, CF 3 , imidazole, morpholino, or pyrrolidine

R 14 is H or C 1 -C 10 alkyl;

R 15 is H, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 10 alkyl)-CF 3 , (C 1 -C 10 alkyl)-OCH 3 , (C 1 -C 10 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 10 alkyl)-CF 3 , SO 2 —(C 1 -C 10 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 4 alkyl), C(O)—(C 1 -C 10 alkyl)-CF 3 , C(O)—(C 1 -C 10 alkyl)-OCH 3 , C(O)—(C 1 -C 10 alkyl)-halogen, C(O)—NH—(C 1 -C 10 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 10 alkyl)-C(O)OH, C(O)—NH 2 or oxetane, wherein

when α is present, then Z 3 are N, Z 4 is CH, X is N, β and δ are absent, and χ is present;

when α is absent, then Z 3 is CH or N, Z 4 is NR 12 , S, or O, X is C, β and δ are present, and χ is absent;

when ε and φ are each present, then n=1, and each of Y 1 , Y 2 , Y 3 , and Y 4 are independently C—R 13 or N;

when ε and φ are each absent, then n=0, 1 or 2, each of Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are independently C(R 14 ) 2 , N—R 15 , O or SO 2 .

11. The compound of claim 10 , wherein B has the structure:

wherein

n is 1; and

Y 1 , Y 2 , Y 3 , and Y 4 are each C—R 13 or N,

wherein R 13 is H, halogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN, CF 3 , imidazole, morpholino or pyrrolidine, or

B has the structure:

wherein

n is 1;

R 12 is H or C 1 -C 4 alkyl;

Y 1 , Y 2 , Y 3 , and Y 4 are each C—R 13 or N,

wherein R 13 is H, halogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN, CF 3 , imidazole, morpholino or pyrrolidine, or

B has the structure:

wherein

n is 1; and

Y 1 , Y 2 , Y 3 , and Y 4 are each C—R 13 or N,

wherein R 13 is H, halogen, C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN, CF 3 , imidazole, morpholino or pyrrolidine, or

B has the structure:

wherein R 16 , R 17 , and R 18 are each H, halogen, C 1 -C 4 alkyl or C 1 -C 4 cycloalkyl.

12. The compound of claim 2 , wherein B is a substituted or unsubstituted monocycle or heteromonocycle.

13. The compound of any one of claim 2 , wherein B has the structure:

wherein R 19 is H, halogen CN, CF 3 , OH, NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl), C(O)NH 2 , C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)OH, C(O)O(C 1 -C 4 alkyl), C(O) (C 1 -C 4 alkyl), C(O)NH(SO 2 )—(C 1 -C 4 alkyl), C(O)NH(SO 2 )—(C 3 -C 6 cycloalkyl), C(O)NH(SO 2 )-(aryl), O(SO 2 )—NH 2 , NHC(O)—NH(C 1 -C 4 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , SO 2 —(C 1 -C 4 alkyl) or tetrazole,

or

B has the structure:

wherein

R 20 is H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 CN or CF 3 .

14. The compound of claim 2 , wherein B is a substituted or unsubstituted phenyl, pyridine, pyrimidine, benzyl, pyrrolidine, sulfolane, oxetane, CO 2 H or (C 1 -C 4 alkyl)-CO 2 H; or

B is

15. The compound of claim 14 , wherein B has the structure:

wherein R 21 , R 22 , R 23 , R 24 and R 25 are each independently H, halogen CN, CF 3 , OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl), C(O)NH 2 , C(O)NH(C 1 -C 10 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)(C 1 -C 10 alkyl), C(O)NH(SO 2 )—(C 1 -C 4 alkyl), C(O)NH(SO 2 )—(C 3 -C 6 cycloalkyl), C(O)NH(SO 2 )-(aryl), O(SO 2 )—NH 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , SO 2 —(C 1 -C 10 alkyl) or tetrazole, or

B has the structure:

wherein R 22 , R 23 , R 24 and R 25 are each independently H, halogen, OH, CF 3 , NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl), C(O)NH 2 , C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)OH, C(O)O(C 1 -C 4 alkyl), C(O)(C 1 -C 4 alkyl), C(O)NH(SO 2 )—C 1 -C 4 alkyl), C(O)NH(SO 2 )—(C 3 -C 6 cycloalkyl), C(O)NH(SO 2 )-(aryl), O(SO 2 )—NH 2 , or SO 2 —(C 1 -C 4 alkyl), or

B has the structure:

wherein R 21 , R 22 , R 23 , R 24 and R 25 are each independently H, halogen CN, CF 3 , OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 10 alkyl), C(O)NH 2 , C(O)NH(C 1 -C 10 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)(C 1 -C 10 alkyl), C(O)NH(SO 2 )—(C 1 -C 10 alkyl), C(O)NH(SO 2 )—(C 3 -C 6 cycloalkyl), C(O)NH(SO 2 )-(aryl), O(SO 2 )—NH 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 or SO 2 —(C 1 -C 10 alkyl).

16. The compound of claim 14 , wherein B has the structure:

wherein R 21 , R 22 , R 23 , R 24 , and R 25 are each independently H, halogen CN, CF 3 , OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 10 alkyl), C(O)NH 2 , C(O)NH(C 1 -C 10 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)(C 1 -C 10 alkyl), C(O)NH(SO 2 )—C 1 -C 10 alkyl), C(O)NH(SO 2 )—(C 3 -C 6 cycloalkyl), C(O)NH(SO 2 )-(aryl), O(SO 2 )—NH 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 or SO 2 —(C 1 -C 10 alkyl), or

B has the structure:

wherein R 21 , R 22 , R 24 and R 25 are each independently H, halogen, OH, NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl), C(O)NH 2 , C(O)NH(C 1 -C 4 alkyl), C(O)N(C 1 -C 4 alkyl) 2 , C(O)OH, C(O)O(C 1 -C 4 alkyl), C(O)(C 1 -C 4 alkyl), C(O)NH(SO 2 )—(C 1 -C 4 alkyl), C(O)NH(SO 2 )—(C 3 -C 6 cycloalkyl), C(O)NH(SO 2 )-(aryl) or O(SO 2 )—NH 2 or SO 2 —(C 1 -C 4 alkyl).

17. The compound of claim 16 , wherein B has the structure

18. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

20. A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith comprising administering to the mammal an effective amount of the compound of claim 1 .

21. The method of claim 20 , wherein the disease is further characterized by bisretinoid-mediated macular degeneration.

22. The method of claim 21 , wherein the bisretinoid is A2E, isoA2E, A2-DHP-PE or atRAL di-PE.

23. The method of claim 20 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration or dry (atrophic) Age-Related Macular Degeneration.

24. The method of claim 20 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease, Best disease, adult vitelliform maculopathy, Stargardt-like macular dystrophy.

25. A pharmaceutical composition comprising the compound of claim 18 and a pharmaceutically acceptable carrier.

26. A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in a mammal afflicted therewith comprising administering to the mammal an effective amount of the compound of claim 18 .

27. The method of claim 26 , wherein the disease is further characterized by bisretinoid-mediated macular degeneration.

28. The method of claim 27 , wherein the bisretinoid is A2E, isoA2E, A2-DHP-PE or atRAL di-PE.

29. The method of claim 26 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration or dry (atrophic) Age-Related Macular Degeneration.

30. The method of claim 26 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease, Best disease, adult vitelliform maculopathy, Stargardt-like macular dystrophy.