Octahydrocyclopentapyrroles, their preparation and use
The present invention provides Octahydrocyclopentapyrrole compounds having the structure: (structurally represented) wherein psi is absent or present, and when present is a bond; R1, R2, R3, R4, and R5 are each independently H, halogen, CF, or C1-C4 alkyl; R6 is absent or present, and when present is H, OH, or halogen; A is absent or present, and when present is C(O) or C(O)NH; B is substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, benzyl, CO2H or (C1-C4 alkyl)-CO2H, wherein when B is CO2H, then A is present and is C(O); and when psi is present, then R6 is absent and when psi is absent, then R6 is present, or a pharmaceutically acceptable salt thereof, for treatment of diseases characterized by excessive lipofuscin accumulation in the retina.
1. A compound having the structure:
wherein
ψ is absent;
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 heteromonocycle or heterobicycle; 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 1 having the structure:
4. The compound of claim 1 , wherein B has the structure:
wherein
n is 1;
R 7 is H, C 1 -C 4 alkyl, or oxetane;
Y 1 , Y 2 and Y 4 are each CH 2 or C(CH 3 ) 2 ; and
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, C(O)—NH 2 or oxetane.
5. The compound of claim 4 , wherein B has the structure:
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, C(O)—NH 2 or oxetane.
6. The compound of claim 5 ,
wherein R 10 is C(O)—CH 3 , C(O)—CH 2 CH 3 , C(O)—CH 2 CH 2 CH 3 , C(O)—CH(CH 3 ) 2 , C(O)—CH 2 CH(CH 3 ) 2 , C(O)-t-Bu, C(O)—CH 2 OCH 3 , C(O)—CH 2 CF 3 , C(O)—CH 2 Cl, C(O)—CH 2 F, C(O)—CH 2 CH 2 OCH 3 , C(O)—CH 2 CH 2 CF 3 , C(O)—CH 2 CH 2 Cl, C(O)—CH 2 CH 2 F,
7. The compound of claim 1 , wherein 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 .
8. The compound of claim 7 , wherein B has the structure:
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 .
9. The compound of claim 8 , wherein B has the structure:
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 .
10. The compound of claim 8 ,
wherein each R 8 is independently H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 3 CH 3 , C(O) OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , SO 2 —NHCH 3 or SO 2 —N(CH 3 ) 2 .
11. The compound of claim 9 ,
wherein R 8 is H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 3 CH 3 , C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , SO 2 —NHCH 3 or SO 2 —N(CH 3 ) 2 .
12. The compound of claim 1 , 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 , SO 2 —(C 1 -C 10 alkyl).
13. The compound of claim 12 , wherein 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 , SO 2 —(C 1 -C 4 alkyl).
14. The compound of claim 12 , wherein B has the structure:
wherein R 22 and R 24 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 , SO 2 —(C 1 -C 4 alkyl).
15. The compound of claim 13 , wherein R 21 , R 22 , R 24 and R 25 are each independently H, F, Cl, CF 3 , CH 3 , OCH 3 , OH, SO 2 —CH 3 , C(O)NH 2 , C(O)OH, C(O)OCH 3 ,
16. The compound of claim 14 , wherein R 22 and R 24 are each independently H, F, Cl, CF 3 , CH 3 , OCH 3 , OH, SO 2 —CH 3 , C(O)NH 2 , C(O)OH, C(O)OCH 3 ,
17. The compound of claim 12 , wherein B has the structure
18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
19. 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 .
20. The method of claim 19 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Stargardt Disease, Best disease, adult vitelliform maculopathy or Stargardt-like macular dystrophy.
21. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising the compound of claim 21 and a pharmaceutically acceptable carrier.
23. 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 21 .
24. The method of claim 23 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Stargardt Disease, Best disease, adult vitelliform maculopathy or Stargardt-like macular dystrophy.
25. The method of claim 23 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration or dry (atrophic) Age-Related Macular Degeneration.
26. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
27. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
28. A compound having the structure:
or a pharmaceutically acceptable salt thereof.