US2003171399A1PendingUtilityA1
Quinolinyl and benzothiazolyl modulators
Est. expiryJun 28, 2020(expired)· nominal 20-yr term from priority
Inventors:Lawrence R. McgeeJonathan HouzeSteven RubensteinAtsushi HagiwaraNoboru FurukawaHisashi Shinkai
C07D 417/12C07D 215/20C07D 417/14C07D 277/82C07D 417/04C07D 277/64C07D 277/68C07D 215/36C07D 215/48A61P 29/00C07D 215/12
50
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Claims
Abstract
Compounds, compositions and methods are provided that are useful in the treatment or prevention of a condition or disorder mediated by PPARγ. In particular, the compounds of the invention modulate the function of PPARγ. The subject methods are particularly useful in the treatment and/or prevention of diabetes, obesity, hypercholesterolemia, rheumatoid arthritis and atherosclerosis.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the formula (I):
wherein
Ar 1 is a member selected from the group consisting of substituted or unsubstituted 2-benzothiazolyl and substituted or unsubstituted quinolinyl;
X is selected from the group consisting of —O—, —C(O)—, —CH(R 10 )—, —N(R 11 )—, and —S(O) k —,
wherein
R 10 is a member selected from the group consisting of hydrogen, cyano and (C 1 -C 4 )alkyl;
R 11 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, and the subscript k is an integer of from 0 to 2; with the proviso that when Ar 1 is a substituted or unsubstituted 2-benzothiazolyl, then X is other than —S(O) k —;
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 hydrogen, (C 2 -C 8 )heteroalkyl, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 4 , —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 4 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;
R 2 is substituted or unsubstituted aryl; and
R 3 is a member selected from the group consisting of halogen and (C 1 -C 8 )alkoxy.
2 . A compound of claim 1 , wherein
Ar 1 is a substituted or unsubstituted 2-benzothiazolyl; X is selected from the group consisting of —O— and —N(R 11 )—; Y is —NH—S(O) 2 —; R 1 is a member selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —CO 2 R 14 and —C(O)NR 15 R 16 ; 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 2 is substituted or unsubstituted phenyl; and R 3 is a member selected from the group consisting of halogen and (C 1 -C 4 )alkoxy.
3 . A compound of claim 2 , wherein R 1 is selected from the group consisting of halogen, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —CO 2 R 14 and —C(O)NR 15 R 16 wherein R 14 is (C 1 -C 8 )alkyl; R 15 and R 16 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring.
4 . A compound of claim 2 , wherein R 1 is selected from the group consisting of halogen, cyano, (C 1 -C 8 )alkoxy and (C 1 -C 8 )alkyl.
5 . A compound of claim 2 , wherein X is selected from the group consisting of-O— and —NH—.
6 . A compound of claim 2 , wherein R 2 is substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl.
7 . A compound of claim 2 , wherein
X is selected from the group consisting of —O— and —NH—; R 1 is a member selected from the group consisting of hydrogen, halogen, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —CO 2 R 14 and —C(O)NR 15 R 16 ; wherein
R 14 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 2 is substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl; and R 3 is a member selected from the group consisting of halogen and (C 1 -C 4 )alkoxy.
8 . A compound of claim 2 , represented by a formula selected from the group consisting of
9 . A compound of claim 2 , selected from the group consisting of
10 . A compound of claim 1 , wherein
Ar 1 is a substituted or unsubstituted quinolinyl group; X is selected from the group consisting of —O—, —S— and —N(R 11 )—;
wherein R 12 is 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, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —CO 2 R 14 and —C(O)NR 15 R 16 ; wherein
R 14 is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -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 2 is substituted or unsubstituted phenyl; and R 3 is a member selected from the group consisting of halogen and (C 1 -C 8 )alkoxy.
11 . A compound of claim 10 , wherein R 1 is selected from the group consisting of halogen, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —CO 2 R 14 and —C(O)NR 15 R 16 wherein R 14 is (C 1 -C 8 )alkyl; R 15 and R 16 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring.
12 . A compound of claim 10 , wherein R 1 is selected from the group consisting of halogen, cyano, (C 1 -C 8 )alkoxy and (C 1 -C 8 )alkyl.
13 . A compound of claim 10 , wherein X is selected from the group consisting of —O—, —S— and —NH—.
14 . A compound of claim 10 , wherein R 2 is substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl.
15 . A compound of claim 10 , wherein
X is selected from the group consisting of —O—, —S— and —NH—; R 1 is a member selected from the group consisting of hydrogen, halogen, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —CO 2 R 14 and —C(O)NR 15 R 16 ; wherein
R 14 is a member selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl;
R 15 and R 16 are members independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R 2 is substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl; and R 3 is a member selected from the group consisting of halogen and (C 1 -C 4 )alkoxy.
16 . A compound of claim 10 , represented by a formula selected from the group consisting of
17 . A compound of claim 10 , selected from the group consisting of
18 . A compound of claim 1 , wherein said compound is represented by a formula selected from the group consisting of
19 . A composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claims 1 - 18 .
20 . A method for treating or preventing a metabolic disorder or an inflammatory condition, comprising
administering to a subject in need thereof a therapeutically effective amount of a compound of claims 1 - 18 .
21 . A method in accordance with claim 20 , wherein said subject is a human.
22 . A method in accordance with claim 20 , wherein said administering is oral.
23 . A method in accordance with claim 20 , wherein said administering is parenteral.
24 . A method in accordance with claim 20 , wherein said administering is topical.
25 A method in accordance with claim 20 , wherein said metabolic disorder is selected from the group consisting of diabetes, obesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, hypertriglylceridemia, hyperglycemia, insulin resistance and hyperinsulinemia.
26 . A method in accordance with claim 20 , wherein said inflammatory condition is selected from the group consisting of rheumatoid arthritis and atherosclerosis.
27 . A method in accordance with claim 20 , wherein said metabolic disorder or inflammatory condition is mediated by PPARγ.
28 . A method for treating or preventing a condition or disorder mediated by PPARγ, comprising
administering to a subject in need thereof a therapeutically effective amount of a compound of claims 1 - 18 .
29 . A method in accordance with claim 28 , wherein said subject is a human.
30 . A method in accordance with claim 28 , wherein said administering is oral.
31 . A method in accordance with claim 28 , wherein said administering is parenteral.
32 . A method in accordance with claim 28 , wherein said administering is topical.
33 . A method in accordance with claim 28 , wherein said condition or disorder is a metabolic disorder or an inflammatory condition.
34 . A method in accordance with claim 33 , wherein said metabolic disorder is selected from the group consisting of diabetes, obesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, hypertriglylceridemia, hyperglycemia, insulin resistance and hyperinsulinemia.
35 . A method in accordance with claim 33 , wherein said inflammatory condition is selected from the group consisting of rheumatoid arthritis and atherosclerosis.
36 . A method for modulating PPARγ, comprising
contacting a cell with a compound of claims 1 - 18 .
37 . The method of claim 36 , wherein said compound is a PPARγ antagonist.
38 . The method of claim 36 , wherein said compound is a PPARγ agonist.Join the waitlist — get patent alerts
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