Substituted 4-phenylpiperidines, their preparation and use

1. A method for lowering the serum concentration of RBP4 in a mammal, comprising administering to the subject an effective amount of 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 has the structure:

 wherein

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

X is C or N;

Z 1 is N;

Z 2 is N or NR 7 ,

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

Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure,

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 3 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, so as to thereby treat the subject.

2. The method of claim 1 ,

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 3 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.

3. The method of claim 1 ,

wherein

R 1 is CF 3 , R 2 is F, 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 CF 3 , R 2 is F, 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 F, and R 5 is H, or

R 1 is CF 3 , R 2 is H, R 3 is H, R 4 is H, and R 5 is F, 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 H, R 3 is H, R 4 is Cl, and R 5 is H, or

R 1 is CF 3 , R 2 is Cl, R 3 is H, 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 Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H.

4. The method of claim 1 , wherein B has the structure:

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; and

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.

5. The method 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;

Z 1 is N;

Z 2 is N or N—R 7 ,

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

X is C or N; and

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently CR 8 , CH 2 , or N—R 9 ,

wherein

R 8 is H, halogen, OCH 3 , CN, or CF 3 ; and

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)-piperazin, (C 1 -C 6 alkyl) CO 2 H, (C 3 -C 6 alkyl)-CO 2 (C 1 -C 6 alkyl) or SO 2 —(C 1 -C 6 alkyl).

6. The method of claim 5 , wherein B has the structure:

wherein

n is 0;

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

Y 1 and Y 3 are each CH 2 ; and

Y 2 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 1-6 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

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

n is 1;

R 7 is H, C 1 -C 6 alkyl, or oxetane;

Y 1 , Y 3 and Y 4 are each CH 2 ; and

Y 2 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).

7. The method of claim 6 , wherein B has the structure:

8. The method of claim 7 ,

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 3 ) 2 , CH 2 C(CH 3 ) 3 , CH 2 CF 3 , 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 ,

9. The method of claim 6 ,

wherein

R 7 is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or

10. The method of claim 6 , wherein the compound has the structure:

or a pharmaceutically acceptable salt of the compound.

11. The method of claim 6 , wherein the compound has the structure:

or a pharmaceutically acceptable salt of the compound.

12. The method of claim 5 , 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, OCH 3 , CN, or CF 3 .

13. The method of claim 12 , wherein B has the structure:

wherein each R 8 is CN or OCH 3 .

14. The method of claim 12 , wherein the compound has the structure:

or a pharmaceutically acceptable salt of the compound.

15. The method of claim 1 , wherein the compound is administered to the mammal intravenously, intravitreally, or orally.

16. The method of claim 1 , wherein the compound is administered to the mammal orally.

17. The method of claim 16 , wherein the compound is administered as an oral dosage in the form of a capsule or tablet.

18. A method for treating a disease characterized by excessive lipofuscin accumulation in the retina of a mammal afflicted therewith, comprising orally administering to the subject an effective amount of 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 has the structure:

wherein

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

X is C or N;

Z 1 is N;

Z 2 is N or NR 7 ,

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

Q is a substituted or unsubstituted 5, 6, or 7 membered ring structure,

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, so as to thereby treat the mammal,

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.

19. The method of claim 18 , wherein the compound has the structure:

or a pharmaceutically acceptable salt of the compound.

20. The method of claim 18 , wherein the compound is administered as an oral dosage in the form of a capsule, or tablet.