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 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 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.
2. The compound 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 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.
3. The compound 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 compound 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 compound of claim 4 , wherein B has the structure:
wherein
n is an integer from 0-2;
α, ρ, 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 5 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).
6. The compound of claim 5 , wherein B has the structure:
wherein
n is 0;
R 7 is H, C 1 -C 4 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 -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 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 9 , (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 5 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 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 compound of claim 6 , wherein B has the structure:
8. The compound 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 compound of claim 6 ,
wherein
R 7 is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , or
10. The compound 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 .
11. The compound of claim 10 , wherein B has the structure:
wherein each R 8 is CN or OCH 3 .
12. The compound of claim 8 having the structure:
or a pharmaceutically acceptable salt of the compound.
13. The compound of claim 11 having the structure:
or a pharmaceutically acceptable salt of the compound.
14. The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt of the compound.
15. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.