4-phenylpiperidines, their preparation and use
The present invention provide a compound having the structure: (structurally represented) wherein 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 H, OH, or halogen; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterocycle is other than chloro substituted indole; and the pyrazole, when substituted, is substituted with other than trifluoromethyl, or a pharmaceutically acceptable salt thereof.
1. 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 a compound having the structure:
R 1 , R 2 , R 3 , and R 4 , are each independently H, halogen, CF 3 or C 1 -C 4 alkyl, and wherein R 5 is CF 3 ;
R 6 is H, OH, or halogen;
B is a substituted or unsubstituted pyridazine, pyrimidine, pyrazine, or B has the structure:
wherein
n is 1;
R 7 is H, C 1 -C 4 alkyl, or oxetane;
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
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 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 ;
and
wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration, dry Age-Related Macular Degeneration, Geographic atrophy, Stargardt Disease, Best disease, adult vitelliform maculopathy, or Stargardt-like macular dystrophy;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Age-Related Macular Degeneration.
3. The method of claim 1 , wherein the compound has the structure:
4. A method of lowering the serum or plasma concentration of RBP4 in a mammal comprising administering to the mammal an effective amount of a compound having the structure:
R 1 , R 2 , R 3 , and R 4 , are each independently H, halogen, CF 3 or C 1 -C 6 alkyl, and wherein R 5 is CF 3 ;
R 6 is H, OH, or halogen;
B is a substituted or unsubstituted pyrimidine, pyridazine, pyrazine, or B has the structure:
wherein
n is 1;
R 7 is H, C 1 -C 4 alkyl, or oxetane;
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
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 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 a pharmaceutically acceptable salt thereof.
5. The method of claim 4 , wherein B has the structure:
wherein
n is 1;
R 7 is H, C 1 -C 4 alkyl, or oxetane;
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.
6. The method of claim 5 , wherein B has the structure:
7. The method of claim 6 , wherein B has the structure:
wherein
n is 1;
R 7 is H, C 1 -C 4 alkyl, or oxetane;
Y 1 and Y 4 are each CH 2 or C(CH 3 ) 2 ; and
one of Y 2 or Y 3 is CH 2 , and the other of Y 2 or Y 3 is N—R 10 ; and
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,
8. The method 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 .
9. The method of claim 4 , 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), 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 .
10. The method of claim 4 , wherein B is pyridazine, pyrazine, or pyrimidine.
11. The method of claim 10 , 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.
12. The method of claim 10 , 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
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), O(SO 2 )—NH 2 , NHC(O)—NH(C 1 -C 4 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , or SO 2 —(C 1 -C 4 alkyl).
13. The method of claim 12 , wherein B has the structure:
14. The method of claim 4 , wherein the compound is administered to the mammal intravenously, intravitreally, or orally.
15. The method of claim 4 , wherein the compound is administered in an oral dosage form as a tablet, capsule, or liquid suspension.
16. A method for lowering the serum or plasma concentration of RBP4 in a mammal comprising administering to the mammal an effective amount of a compound having the structure:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is dry Age-Related Macular Degeneration.
18. The method of claim 1 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Geographic atrophy.
19. The method of claim 1 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is Stargardt Disease or Best disease.
20. The method of claim 1 , wherein the disease characterized by excessive lipofuscin accumulation in the retina is adult vitelliform maculopathy or Stargardt-like macular dystrophy.