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 benzothiazolyl;
X is a divalent linkage selected from the group consisting of (C 1 -C 6 )alkylene, (C 1 -C 6 )alkylenoxy, (C 1 -C 6 )alkylenamino, (C 1 -C 6 )alkylene-S(O) k —, —O—, —C(O)—, —N(R 11 )—, —N(R 11 )C(O)—, —S(O) k — and a single bond,
wherein
R 11 is a member 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 subscript k is an integer of from 0 to 2;
Y is a divalent linkage selected from the group consisting of alkylene, —O—, —C(O)—, —N(R 12 )—S(O) m —,—N(R 12 )—S(O) m —N(R 13 )—, —N(R 12 )C(O)—, and —S(O) n —,
wherein
R 12 and R 13 are members independently 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 hydrogen, (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,
with the proviso that when Ar 1 is-2-benzothiazolyl, X is S(O) k .
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 1 , represented by a formula selected from the group consisting of
4. A compound of claim 1 , represented by a formula selected from the group consisting of
and
5. A compound of claim 4 , wherein
X is a divalent linkage selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —O—, —C(O)—, —N(R 11 )— and —S—;
wherein
R 11 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl;
Y is a divalent linkage selected from the group consisting of —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 hydrogen, 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.
6. A compound of claim 5 , wherein X is —O—, —NH— 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.
7. A compound of claim 6 , wherein Ar 1 is a benzothiazolyl 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 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.
8. A compound of claim 1 , having the formula:
and
9. A composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1 , 2 , 3 - 7 , and 8 .
10. A method for treating a condition mediated by PPARγ in a host, said method comprising administering to said host an efficacious amount of a compound of any one of claims 1 , 2 , 3 – 7 , and 8 .
11. A method in accordance with claim 10 , wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
12. A method in accordance with claim 10 , wherein said administering is oral.
13. A method in accordance with claim 10 , wherein said administering is topical.
14. A method in accordance with claim 10 , wherein said administering is prophylactic to prevent the onset of a PPARγ-mediated condition.
15. A method in accordance with claim 10 , wherein said condition is a metabolic disorder or an inflammatory condition.
16. A method in accordance with claim 10 , wherein said administering is parenteral.
17. A method in accordance with claim 15 , wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions.
18. A method of treating a condition selected from the group consisting of NIDDM, obesity, hypertension, hyperlipidemia, hypercholesterolemia, and hyperlipoproteinemia in a host, said method comprising administering to said host an efficacious amount of a compound of formula:
wherein
Ar 1 is a substituted or unsubstituted benzothiazolyl;
X is a divalent linkage selected from the group consisting of (C 1 -C 6 )alkylene, (C 1 -C 6 )alkylenoxy, (C 1 -C 6 )alkylenamino, (C 1 -C 6 )alkylene-S(O) k —, —O—, —C(O)—, —N(R 11 )—, —N(R 11 )C(O)—, —S(O) k — and a single bond,
wherein
R 11 is a member 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 subscript k is an integer of from 0 to 2;
Y is a divalent linkage selected from the group consisting of alkylene, —O—, —C(O)—, —N(R 12 )—S(O) m —, —N(R 12 )—S(O) m —N(R 13 )—, —N(R 12 )C(O)—, and —S(O) n —,
wherein
R 12 and R 13 are members independently 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 hydrogen, (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, with the proviso that when Ar 1 is-2-benzothiazolyl, X is S(O) k .
19. A method in accordance with claim 18 , wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
20. A method in accordance with claim 18 , wherein said administering is oral.
21. A method in accordance with claim 18 , wherein said administering is topical.
22. A method in accordance with claim 18 , wherein said administering is parenteral.
23. A method of treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host, said method comprising administering to said host, an efficacious amount of a compound of formula:
wherein
Ar 1 is a substituted or unsubstituted benzothiazolyl;
X is a divalent linkage selected from the group consisting of (C 1 -C 6 )alkylene, (C 1 -C 6 )alkylenoxy, (C 1 -C 6 )alkylenamino, (C 1 -C 6 )alkylene-S(O) k —, —O—, —C(O)—, —N(R 11 )—, —N(R 11 )C(O)—, —S(O) k — and a single bond,
wherein
R 11 is a member 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 subscript k is an integer of from 0 to 2;
Y is a divalent linkage selected from the group consisting of alkylene, —O—, —C(O)—, —N(R 12 )—S(O) m —, —N(R 12 )—S(O) m —N(R 13 )—, —N(R 12 )C(O)—, and —S(O) n —,
wherein
R 12 and R 13 are members independently 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 hydrogen, (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 - 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,
with the proviso that when Ar 1 is-2-benzothiazolyl, X is S(O) k .
24. A method in accordance with claim 23 , wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
25. A method in accordance with claim 23 , wherein said administering is oral.
26. A method in accordance with claim 23 , wherein said administering is topical.
27. A method in accordance with claim 23 , wherein said administering is parenteral.
28. A compound of any of claims 1 , 2 , 3 – 7 , and 8 , wherein said compound is a modulator of PPARγ.
29. A compound of claim 28 , wherein said modulator has an IC 50 less than 1 μM.