Substituted 4-phenylpiperidines, their preparation and use
The present invention provides a compound having the structure: 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, wherein two or more of R 1 , R 2 , R 3 , R 4 , or R 5 are other than H; R 6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is H, R 2 is CF 3 , R 3 is H, R 4 is CF 3 , and R 5 is H, or R 1 is Cl, R 2 is H, R 3 is H, R 4 is F, and R 5 is H, or R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H, then B is other than or a pharmaceutically acceptable salt thereof.
1. A method for treating age-related macular degeneration (AMD), dry form of age-related macular degeneration, geographic atrophy, juvenile macular degeneration (Stargardt disease), cone rod dystrophy, and retinitis pigmentosa comprising administering to a subject in need thereof a compound having the structure:
wherein
R 1 is CF 3 , R 2 is F, R 3 is F, R 4 is H, and R 5 is H;
R 6 is H, OH, or halogen; and
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 ; and
Y 3 is N—R 9 ,
wherein
R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl) (C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl);
or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
2. The method of claim 1 , wherein R 6 is H or F.
3. The method of claim 1 , wherein R 7 is H.
4. The method of claim 1 ,
wherein R 9 is H, CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , t-Bu, CH 2 CH(CH) 2 , CH 2 C(CH 3 ) 3 , CH 2 CF 2 , CH 2 CH 2 CF 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 ,
SO 2 —CH 3 , 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)—OCH 3 , C(O)—NHCH 3 ,
5. The method of claim 4 , wherein R 9 is C(O)—CH 3 , C(O)—CH 2 CH 3 , or C(O)—CH 2 CH 2 CH 3 .
6. The method of claim 1 , wherein R 9 is C(O)—CH 3 .
7. The method of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt of the compound.
8. The method of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt of the compound.
9. A method for treating age-related macular degeneration (AMD), dry form of age-related macular degeneration, geographic atrophy, juvenile macular degeneration (Stargardt disease), cone rod dystrophy, and retinitis pigmentosa comprising administering to a subject in need thereof a compound having the structure:
wherein
R 1 , is CF 3 ; 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; and
B has the structure:
wherein
Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 6 or N,
wherein each R 6 is independently H, halogen, OCH 3 , CN, or CF 3 ;
or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
10. The method of claim 9 , wherein R 6 is H or F.
11. The method of claim 9 , wherein R 2 is halogen.
12. The method of claim 9 , wherein Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 ,
wherein each R 8 is independently H, halogen, OCH 3 , CN, or CF 3 .
13. The method of claim 1 , wherein R 6 is H.
14. The method of claim 12 , wherein B has the structure:
wherein each Re is H, halogen, CF 3 , CN, or OCH 3 .
15. The method of claim 14 , wherein B has the structure:
wherein each R 8 is H, halogen, CF 3 , CN, or OCH 3 .
16. The method of claim 15 , wherein R 8 is CN, or OCH 3 .
17. The method of claim 9 , wherein the compound has the structure:
pharmaceutically acceptable salt of the compound.
18. The method of claim 9 , wherein the compound has the structure:
or a pharmaceutically acceptable salt of the compound.
19. A method for treating age-related macular degeneration (AMD), dry form of age-related macular degeneration, geographic atrophy, and juvenile macular degeneration (Stargardt disease) comprising administering to a mammal in need thereof a composition comprising a compound having the structure:
wherein
R 1 is CF 3 , R 2 is F, R 3 is F, R 4 is H, and R 5 is H;
R 6 is H, OH, or halogen; and
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 ; and
Y 3 is N—R 9 ,
wherein
R 9 is H, CN, oxetane, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl) (C 3 -C 6 cycloalkyl), (C 1 -C 6 alkyl)-OCH 3 , (C 1 -C 6 alkyl)-CF 3 , C(O)—(C 1 -C 6 alkyl), C(O) 2 —(C 1 -C 6 alkyl), C(O)—NH 2 C(O)NH—(C 1 -C 6 alkyl), C(O)—(C 6 aryl), C(O)—(C 6 heteroaryl), C(O)-pyrrolidine, C(O)-piperidine, C(O)-piperazine, (C 1 -C 6 alkyl)-CO 2 H, (C 1 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl);
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, OCH 3 , CN, or CF 3 ;
or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
20. The method of claim 19 , wherein the compound has the structure:
or a pharmaceutically acceptable salt of the compound, wherein the composition is administered as an oral dosage in the form of a capsule or tablet.