Piperidine derivatives
View Patent ↗Compounds, compositions and methods are provided that are useful in the treatment or prevention of conditions or disorders associated with a neuropeptide receptor. The subject methods are particularly useful in the treatment and/or prevention of endocrine, metabolic, cardiovascular, neurologic, psychiatric, gastrointestinal, genitourinary and other disorders.
1. A compound of formula:
or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
A represents a substituted or unsubstituted benzene ring ring;
B is substituted or unsubstituted carbazolyl;
L is (C 1 –C 4 )alkylene;
X and Y are each independently CH or CH2 wherein the C is optionally substituted with —OR 3 , —N(R 3 )COR 4 , —C(O)NR 3 R 4 , —N(R 3 )CO 2 R 4 , —N(R 3 )C(O)N(R 4 )R 5 , or —(O);
R 1 and R 2 are independently selected from the group consisting of H, (C 1 –C 4 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 8 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, —NR 6 C(O)R 5 , —C(O)R 5 and —NR 5 C(O)NHR 6 ;
each R b is selected from the group consisting of (C 1 –C 4 )alkyl, aryl, OR 7 , C(O)R 7 and C(O)NR 7 R 8 ;
R 3 and R 4 are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, hetero(C 1 –C 8 )alkyl, aryl, aryl(C 1 –C 4 )alkyl, C(O)R′, CO 2 R′ and C(O)NR′R″;
R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, C(O)R′″, CO 2 R′″, aryl and aryl(C 1 –C 4 )alkyl;
optionally, R 7 and R 8 may be combined with the nitrogen to which each is attached to form a 5-, 6- or 7-membered ring;
R′, R″ and R′″ are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, aryl and aryl(C 1 –C 4 )alkyl; and
the subscript p is an integer of from 0 to 4.
2. The compound of claim 1 , wherein the subscript p is 0.
3. The compound of claim 1 , wherein B is substituted or unsubstituted 3-carbazolyl.
4. The compound of claim 1 , having the formula (IV):
wherein:
each R a is independently selected from the group consisting of halogen, halo(C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, aryl(C 1 –C 4 )alkyl, OC(O)R 17 , NR 17 R 18 , SR 17 , cyano, nitro, CO 2 R 17 , CONR 17 R 18 , C(O)R 17 , OC(O)NR 17 R 18 , NR 18 C(O)R 17 , NR 18 CO 2 R 17 , NR 19 C(O)NR 17 R 18 , S(O) k R 17 , S(O) k NR 17 R 18 , N 3 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, aryl and heteroaryl, and the subscript k is an integer of from 1 to 2;
R 17 , R 18 and R 19 are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl(C 1 –C 4 )alkyl and aryl; and
the subscript m is an integer of from 0 to 4.
5. The compound of claim 4 , wherein X or Y is CH, wherein the C is substituted with —OH.
6. The compound of claim 4 , wherein Y is CH, wherein the C substituted with —OH.
7. The compound of claim 4 , wherein X is CH, wherein the C is substituted with —N(R 3 )COR 4 .
8. The compound of claim 4 , wherein X is CH, wherein the C is substituted with —N(R 3 )COR 4 and Y is —C 1 alkylene-substituted with —OH.
9. The compound of claim 1 having the formula (V):
wherein:
each R a is independently halogen, halo(C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, aryl(C 1 –C 4 )alkyl, OC(O)R 17 , NR 17 R 18 , SR 17 , cyano, nitro, CO 2 R 17 , CONR 17 R 18 , C(O)R 17 , OC(O)NR 17 R 18 , NR 18 C(O)R 17 , NR 18 CO 2 R 17 , NR 19 C(O)NR 17 R 18 , S(O) k R 17 , S(O) k NR 17 R 18 , N 3 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, aryl or heteroaryl, wherein R 17 , R 18 and R 19 are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl(C 1 –C 4 )alkyl and aryl, and the subscript k is an integer of from 1 to 2; and
the subscript m is an integer of from 0 to 4.
10. The compound of claim 9 , wherein R 1 and R 2 are H.
11. The compound of claim 1 , having the formula:
wherein
R 11 is selected from the group consisting of H, (C 1 –C 4 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 8 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, heteroaryl(C 1 –C 4 )alkyl, (C 3 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, (C 3 –C 8 )cycloalkyl-alkyl, (C 3 –C 8 )cycloheteroalkyl, (C 3 –C 8 )cycloheteroalkyl-alkyl, C(O)R 12 , CO 2 R 12 , C(O)NR 12 R 13 , S(O) k R 12 and S(O) k NR 12 R 13 ;
each R c is independently selected from the group consisting of (C 1 –C 8 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 8 )heteroalkyl, halo(C 1 –C 8 )alkyl, halogen, CN, NO 2 , OR 14 , SR 14 , NR 14 R 15 , (C 3 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, (C 3 –C 8 )cycloalkyl-alkyl, (C 3 –C 8 )cycloheteroalkyl, (C 3 –C 8 )cycloheteroalkyl-alkyl, C(O)R 14 , CO 2 R 14 , C(O)NR 14 R 15 , aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, heteroaryl(C 1 –C 4 )alkyl, S(O) k R 14 , S(O) k NR 14 R 15 , N(R 15 )S(O) k R 14 , OC(O)R 14 , OCO 2 R 14 , OC(O)NR 14 R 15 , N(R 16 )C(O)NR 14 R 15 , N(R 15 )C(O)R 14 and N(R 15 )CO 2 R 14 ;
R 12 , R 13 , R 14 , R 15 and R 16 are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl(C 1 –C 4 )alkyl and aryl;
the subscript q is an integer of from 0 to 7; and
the subscript k is an integer of from 1 to 2.
12. The compound of claim 11 , having the formula:
wherein
each R a is independently selected from the group consisting of halogen, halo(C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, aryl(C 1 –C 4 )alkyl, OC(O)R 17 , NR 17 R 18 , SR 17 , cyano, nitro, CO 2 R 17 , CONR 17 R 18 , C(O)R 17 , OC(O)NR 17 R 18 , NR 18 C(O)R 17 , NR 18 CO 2 R 17 , NR 19 C(O)NR 17 R 18 , S(O) k R 17 , S(O) k NR 17 R 18 , N 3 , (C 4 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, aryl and heteroaryl;
R 17 , R 18 and R 19 are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl(C 1 –C 4 )alkyl and aryl;
the subscript m is an integer of from 0 to 4; and
each subscript k is an integer of from 1 to 2.
13. The compound of any one of claims 1 , 9 and 12 , wherein L is methylene.
14. The compound of claim 12 , having the formula (Xa):
wherein
L is methylene; and
X and Y are independently selected from —(C 1 –C 2 )alkylene-, wherein C 1 or C 2 is optionally subtituted with —OR 3 , —N(R 3 )COR 4 , —C(O)NR 3 R 4 or —N(R 3 )C(O)N(R 4 )R 5 .
15. The compound of claim 14 , having a formula selected from the group consisting of:
16. A compound of formula:
or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
R 20 and R 23 independently represent H or OR 3 ;
R 21 and R 22 independently represent H, OR 3 , N(R 3 )COR 4 , C(O)NR 3 R 4 , N(R 3 )CO 2 R 4 , N(R 3 )C(O)N(R 4 )R 5 , N(R 3 )R 4 , C(O)N(R 3 )R 4 , N(R 3 )C(O)R 4 , (CH 2 )C(O)N(R 3 )(R 4 ), (CH 2 )CO 2 R 3 , or (C 1 –C 4 )alkyl;
R 11 represents H, (C 1 –C 4 )alkyl, (C 2 –C 8 )alkenyl, (C 2 –C 8 )alkynyl, (C 1 –C 8 )heteroalkyl, aryl, aryl(C 1 –C 4 )alkyl, heteroaryl, heteroaryl(C 1 –C 4 )alkyl, (C 3 –C 8 )cycloalkyl, (C 5 –C 8 )cycloalkenyl, (C 3 –C 8 )cycloalkyl-alkyl, (C 3 –C 8 )cycloheteroalkyl, (C 3 –C 8 )cycloheteroalkyl-alkyl, C(O)R 12 , CO 2 R 12 , C(O)NR 12 R 13 , S(O) k R 12 or S(O) k NR 12 R 13 , and the subscript k is an integer of from 1 to 2;
R 12 and R 13 independently represent H, (C 1 –C 8 )alkyl, (C 1 –C 8 )heteroalkyl, aryl(C 1 –C 4 )alkyl or aryl;
R 3 and R 4 independently represent H, (C 1 –C 8 )alkyl, hetero(C 1 –C 8 )alkyl, aryl, aryl(C 1 –C 4 )alkyl, C(O)R′, CO 2 R′ or C(O)NR′R″; and
R′, R″ and R′″ are independently selected from the group consisting of H, (C 1 –C 8 )alkyl, aryl and aryl(C 1 –C 4 )alkyl.
17. The compound of claim 16 , wherein R 20 and R 23 each represent H, R 22 represents OH, and R 21 represents N(R 3 )C(O)R 4 .
18. The compound of claim 16 , wherein R 20 represents OH, and R 22 and R 23 each represent H, and R 21 represents C 2 alkyl.
19. The compound of claim 16 , wherein R 20 , R 22 , and R 23 each represent H and R 21 represents N(R 3 )C(O)R 4 .
20. The compound of claim 16 , wherein R 20 , R 22 , and R 23 each represent H and R 21 represents (CH 2 )CO 2 R 3 .
21. The compound of claim 16 , wherein R 20 , R 22 , and R 23 each represent H and R 21 represents (CH 2 )C(O)N(R 3 )(R 4 ).
22. The compound of claim 16 , having a formula that is selected from the group consisting of:
23. The compound of claims 14 , wherein L is methylene.
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 .
25. A method of treating a condition or disorder selected from the group consisting of obesity, type II diabetes, hypertension, hyperuricemia, stroke, dyslipidemia, coronary artery disease, hypercholesterolemia and atherosclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .