Compounds for the modulation of PPARγ activity
View Patent ↗Modulators of PPARγ activity are provided which are useful in pharmaceutical compositions and methods for the treatment of conditions such as type II diabetes and obesity.
1. A compound having the formula:
wherein
Ar 1 is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl;
X is a divalent linkage selected from the group consisting of —O—, —C(O)—, —S(O) k — and —CH 2 —,
wherein
the subscript k is an integer of from 0 to 2;
Y is N(R 12 )—S(O) m —,
wherein
R 12 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and aryl(C 1 -C 4 )alkyl; and the subscripts m and n are independently integers of from 0 to 2;
R 1 is a member selected from the group consisting of (C 2 -C 8 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, halogen, cyano, nitro, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 , —S(O) q —NR 15 R 16 , —O—C(O)—OR 17 , —O—C(O)—R 17 , —O—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—R 17 and —N(R 14 )—C(O)—OR 17 ;
wherein
R 14 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl, and aryl(C 1 -C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 17 is a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;
the subscript p is an integer of from 0 to 3; and
the subscript q is an integer of from 1 to 2; and
R 2 is a substituted or unsubstituted aryl; and
R 3 is a member selected from the group consisting of halogen, cyano, nitro and (C 1 -C 8 )alkoxy;
or a pharmaceutically acceptable salt of the compound.
2. A compound of claim 1 , wherein R 2 is a substituted or unsubstituted aryl selected from the group consisting of phenyl, pyridyl, naphthyl and pyridazinyl.
3. A compound of claim 2 , wherein Ar 1 is a substituted or unsubstituted phenyl group.
4. A compound of claim 3 , represented by a formula selected from the group consisting of
5. A compound of claim 3 , represented by a formula selected from the group consisting of
6. A compound of claim 5 , wherein
X is a divalent linkage selected from the group consisting of —CH 2 —, —O—, —C(O)—, and —S—;
Y is —N(R 12 )—S(O) 2 —,
wherein
R 12 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl;
R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 , —S(O) q —NR 15 R 16 , —O—C(O)—R 17 , and —N(R 14 )—C(O)—R 17 ;
wherein
R 14 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 17 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl;
the subscript p is an integer of from 0 to 2; and
the subscript q is 2; and
R 2 is a substituted or unsubstituted phenyl; and
R 3 is a member selected from the group consisting of halogen and (C 1 -C 8 )alkoxy.
7. A compound of claim 6 , wherein X is —O—, or —S—; Y is —NH—SO 2 —; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 and —S(O) q —NR 15 R 16 ; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
8. A compound of claim 7 , wherein Ar 1 is a phenyl group having from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 ; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and (C 1 -C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
9. A compound of claim 2 , wherein Ar 1 is a substituted or unsubstituted naphthyl group.
10. A compound of claim 9 , represented by a formula selected from the group consisting of
11. A compound of claim 10 , represented by a formula selected from the group consisting of
12. A compound of claim 11 , wherein
X is a divalent linkage selected from the group consisting of —CH 2 —, —O—, —C(O)—, and —S—;
wherein
R 11 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl;
Y is —N(R 12 )—S(O) 2 —,
wherein
R 12 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl;
R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 , —S(O) q —NR 15 R 16 , —O—C(O)—R 17 , and —N(R 14 )—C(O)—R 17 ;
wherein
R 14 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 17 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 2 -C 8 )heteroalkyl;
the subscript p is an integer of from 0 to 2; and
the subscript q is 2; and
R 2 is a substituted or unsubstituted phenyl; and
R 3 is a member selected from the group consisting of halogen and (C 1 -C 8 )alkoxy.
13. A compound of claim 12 , wherein X is —O— or —S—; Y is —NH—SO 2 —; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 and —S(O) q —NR 15 R 16 ; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
14. A compound of claim 13 , wherein Ar 1 is a naphthyl group having from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 ; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and (C 1 -C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
15. A compound of claim 2 , wherein R 2 is substituted phenyl.
16. A compound of claim 7 , wherein X is —O—.
17. A compound of claim 7 , wherein X is —S—.
18. A compound of claim 7 , wherein the compound is of formula Ii.
19. A compound of claim 9 , wherein Ar 1 is unsubstituted naphthyl.
20. A compound of claim 13 , wherein X is —S—.
21. A compound of claim 13 , wherein X is —O—.
22. A compound of claim 13 , wherein the compound is of formula Ii.
23. A composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the formula:
wherein
Ar 1 is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
X is a divalent linkage selected from the group consisting of —O—, —C(O)—, —S(O) k — and —CH 2 —,
wherein
the subscript k is an integer of from 0 to 2;
Y is N(R 12 )—S(O) m —,
wherein
R 12 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and aryl(C 1 -C 4 )alkyl; and the subscripts m and n are independently integers of from 0 to 2;
R 1 is a member selected from the group consisting of (C 2 -C 8 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, halogen, cyano, nitro, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 , —S(O) q —NR 15 R 16 , —O—C(O)—OR 17 , —O—C(O)—R 17 , —O—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—R 17 and —N(R 14 )—C(O)—OR 17 ;
wherein
R 14 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl, and aryl(C 1 -C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 17 is a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;
the subscript p is an integer of from 0 to 3; and
the subscript q is an integer of from 1 to 2; and
R 2 is a substituted or unsubstituted aryl; and
R 3 is a member selected from the group consisting of halogen, cyano, nitro and (C 1 -C 8 )alkoxy;
or a pharmaceutically acceptable salt of the compound.
24. A composition of claim 23 , wherein R 2 is a substituted or unsubstituted aryl selected from the group consisting of phenyl, pyridyl, naphthyl and pyridazinyl.
25. A composition of claim 24 , wherein Ar 1 is a substituted or unsubstituted phenyl group.
26. A composition of claim 25 , wherein the compound is represented by a formula selected from the group consisting of
and wherein X is —O— or —S—; Y is —NH—SO 2 —; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 and —S(O) q —NR 15 R 16 ; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
27. A composition of claim 26 , wherein Ar 1 is a phenyl group having from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 ; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and (C 1 -C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
28. A composition of claim 27 , wherein the compound is of formula Ii.
29. A composition of claim 23 , wherein Ar 1 is substituted or unsubstituted naphthyl group.
30. A composition of claim 29 , wherein the compound is represented by a formula selected from the group consisting of
and wherein X is —O— or —S—; Y is —NH—SO 2 —; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 and —S(O) q —NR 15 R 16 ; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
31. A composition of claim 30 , wherein Ar 1 is a naphthyl group having from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 ; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and (C 1 -C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, − O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
32. A composition of claim 31 , wherein the compound is of formula Ii.
33. A method for treating a metabolic disorder in a host, said method comprising administering to said host an efficacious amount of a compound having the formula:
wherein
Ar 1 is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl;
X is a divalent linkage selected from the group consisting of —O—, —C(O)—, —S(O) k — and CH 2 —,
wherein
the subscript k is an integer of from 0 to 2;
Y is N(R 12 )—S(O) m —,
wherein
R 12 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and aryl(C 1 -C 4 )alkyl; and the subscripts m and n are independently integers of from 0 to 2;
R 1 is a member selected from the group consisting of (C 2 -C 8 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, halogen, cyano, nitro, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 , —S(O) q —NR 15 R 16 , —O—C(O)—OR 17 , —O—C(O)—R 17 , —O—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—R 17 and —N(R 14 )—C(O)—OR 17 ;
wherein
R 14 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl, and aryl(C 1 -C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 17 is a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;
the subscript p is an integer of from 0 to 3; and
the subscript q is an integer of from 1 to 2; and
R 2 is a substituted or unsubstituted aryl; and
R 3 is a member selected from the group consisting of halogen, cyano, nitro and (C 1 -C 8 )alkoxy;
or a pharmaceutically acceptable salt of the compound;
wherein said metabolic disorder is selected from the group consisting of non-insulin-dependent diabetus mellitus (NIDDM), obesity and hypercholesterolemia.
34. The method of claim 33 , wherein R 2 is a substituted or unsubstituted aryl selected from the group consisting of phenyl, pyridyl, naphthyl and pyridazinyl.
35. The method of claim 33 , wherein Ar 1 is a substituted or unsubstituted phenyl group.
36. The method of claim 35 , wherein the compound is represented by a formula selected from the group consisting of
and wherein X is —O— or —S—; Y is —NH—SO 2 —; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 and —S(O) q —NR 15 R 16 ; R 2 is a phenyl group having from 0 to 3 substitutents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
37. The method of claim 36 , wherein Ar 1 is a phenyl group having from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 ; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and (C 1 -C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
38. The method of claim 37 , wherein the compound is of formula Ii.
39. The method of claim 33 , wherein Ar 1 is a substituted or unsubstituted naphthyl group.
40. The method of claim 39 , wherein the compound represented by a formula selected from the group consisting of
and wherein X is —O— or —S—; Y is —NH—SO 2 —; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 —C(O)NR 15 R 16 , —S(O) p —R 14 and —S(O) q —NR 15 R 16 ; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
41. The method of claim 40 , wherein Ar 1 is a naphthyl group having from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 ; R 1 is a member selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl and (C 1 -C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkyl, —CN, —CF 3 , (C 1 -C 8 )alkyl and —NH 2 ; and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
42. The method of claim 41 , wherein the compound is of formula Ii.
43. The method of claim 33 , wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
44. The method of claim 33 , wherein said administering is oral.
45. The method of claim 33 , wherein said metabolic disorder is NIDDM.
46. The method of claim 33 , wherein said metabolic disorders are mediated by PPARγ.