US2011218225A1PendingUtilityA1
Non-steroidal ligands for the glucocorticoid receptor, compositions and uses thereof
Est. expiryJan 22, 2022(expired)· nominal 20-yr term from priority
A61P 43/00A61P 5/46A61P 3/10A61P 5/44C07D 487/04A61P 29/00A61P 3/04C07D 409/06C07D 403/06A61P 25/22A61P 25/24A61P 25/00A61P 25/28
55
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Claims
Abstract
The invention provides non-steroidal ligands for the glucocorticoid receptor, methods for making non-steroidal ligands of the glucocorticoid receptor, compositions of non-steroidal ligands of the glucocorticoid receptor and methods of using non-steroidal ligands and compositions of non-steroidal ligands of the glucocorticoid receptor for treating or preventing diseases (e.g., obesity, diabetes, depression, neurodegeneration or an inflammatory disease) associated with glucocorticoid binding to the glucocorticoid receptor.
Claims
exact text as granted — not AI-modified1 . A compound according to the structural formula:
or a pharmaceutically available salt, solvate, or hydrate thereof wherein:
A, B and C are independently carbon, nitrogen, oxygen or sulfur provided that at least one of A, B and C is nitrogen, oxygen or sulfur and that no more than one of A, B and C are oxygen or sulfur;
W is carbon, oxygen, nitrogen, or sulfur and, when W is other than carbon and nitrogen, one or more of R 8 , R 9 and R 10 is absent so that a normal valence on W is maintained;
R 1 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl or substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl;
R 2 , R 3 , R 5 , R 6 , R 6 ′ and R 7 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy;
R 2 ′, R 3 ′, R 5 ′, R 7 ′ and R 8 are absent or are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy;
R 4 is absent or is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl;
R 9 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, carboxy, cyano, halo, oxo, thio, hydroxy or is absent; and
R 10 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or is absent;
R 10 and R 2 may bond directly to one another to form a ring, and an additional ring, which may itself be substituted with an alkyl, alkoxy, halo, alkyl, substituted alkyl, acyl, substituted acyl, cycloalkyl, or substituted cycloalkyl, may fuse to the bond between R 10 and R 2 ;
R 11 and R 12 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkoxy, substituted alkoxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, oxo, thio, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy; and
one of the bonds in formula (I) that are shown with single and dashed lines is a double bond provided that normal valences of the atoms in the rings are satisfied.
2 . The compound of claim 1 , wherein A, B and C are carbon or nitrogen.
3 . The compound of claim 2 , wherein A is carbon and B and C are nitrogen.
4 . The compound of claim 1 , wherein A, B and C are carbon, nitrogen or sulfur.
5 . The compound of claim 4 , wherein A is sulfur, B is carbon and C is nitrogen.
6 . The compound of claim 1 , wherein A, B and C are carbon, nitrogen or oxygen.
7 . The compound of claim 6 , wherein A is carbon, B is oxygen and C is nitrogen.
8 . The compound of claim 6 , wherein A is carbon, B is nitrogen and C is oxygen.
9 . The compound of claim 1 , wherein R 1 and R 4 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, carboxy, cyano, carbamoyl, substituted carbamoyl, heteroalkyl and substituted heteroarylalkyl.
10 . The compound of claim 1 , wherein R 1 and R 4 are independently hydrogen, alkanyl or substituted alkanyl.
11 . The compound of claim 1 , wherein R 1 and R 4 are independently hydrogen or methyl.
12 . The compound of claim 1 , wherein R 2 , R 3 , R 5 , R 6 , R 6 ′, and R 7 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxy, substituted alkoxy, amino, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, or hydroxy.
13 . The compound of claim 1 , wherein R 2 , R 2 ′, R 3 , R 5 , R 6 , R 6 ′, R 7 and R 8 are independently hydrogen, alkanyl or substituted alkanyl.
14 . The compound of claim 1 , wherein R 2 , R 2 ′, R 3 , R 5 , R 6 , R 6 ′, R 7 and R 8 are hydrogen or methyl.
15 . The compound of claim 1 , wherein R 4 and R 5 ′ are absent.
16 . The compound of claim 1 , wherein R 4 and R 7 ′ are absent.
17 . The compound of claim 1 , wherein R 3 ′ and R 7 ′ are absent.
18 . The compound of claim 1 , wherein R 3 ′, R 5 ′ and R 7 ′ are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxy, substituted alkoxy, amino, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, cyano, halo, heteroalkyl, substituted heteroalkyl, or hydroxy.
19 . The compound of claim 1 , wherein R 3 ′, R 5 ′ and R 7 ′ are independently hydrogen, alkanyl or substituted alkanyl.
20 . The compound of claim 1 , wherein R 3 ′, R 5 ′ and R 7 ′ are hydrogen or methyl.
21 . The compound of claim 1 , wherein R 9 is hydrogen, alkoxy, substituted alkoxy, halo, oxo, thio, hydroxy or is absent.
22 . The compound of claim 1 , wherein R 9 is alkoxy, oxo or hydroxy.
23 . The compound of claim 1 , wherein R 10 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or is absent.
24 . The compound of claim 1 , wherein R 10 is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
25 . The compound of claim 1 , wherein R 11 and R 12 are independently hydrogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, carboxy, cyano, halo, oxo, thio, heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy.
26 . The compound of claim 1 , wherein R 11 and R 12 are independently hydrogen, aryl, substituted aryl, arylalkyl, substituted arylalkyl, oxo, heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or hydroxy.
27 . The compound of claim 1 , wherein R 11 and R 12 are independently hydrogen, aryl or substituted aryl.
28 . The compound of claim 1 , wherein R 1 , R 2 , R 2 ′, R 3 , R 3 ′, R 5 , R 6 , R 6 ′, R 7 , R 7 ′ and R 8 are hydrogen, alkyl or arylalkyl and R 4 and R 5 ′ are absent.
29 . The compound of claim 1 , wherein R 1 is methyl, R 2 , R 2 ′, R 3 , R 3 ′, R 5 , R 6 , R 6 ′, R 7 , R 7 ′ and R 8 are hydrogen and R 4 and R 5 ′ are absent.
30 . The compound of claim 28 or 29 , wherein R 9 is alkoxy, oxo or hydroxy.
31 . The compound of claim 28 or 29 , wherein R 10 is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
32 . The compound of claim 28 or 29 , wherein A is carbon, B and C are nitrogen, R 11 is hydrogen and R 12 is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
33 . The compound of claim 28 or 29 , wherein A is sulfur, B is carbon and C is nitrogen.
34 . The compound of claim 28 or 29 wherein A is carbon, B is oxygen and C is nitrogen.
35 . The compound of claim 28 or 29 , wherein A is carbon, B is nitrogen and C is oxygen.
36 . The compound of claim 1 , wherein R 1 is methyl, R 2 , R 2 ′, R 3 , R 3 ′, R 5 , R 6 , R 6 ′, R 7 , R 7 ′ and R 8 are hydrogen, R 4 and R 5 ′ are absent, R 9 is alkoxy, oxo or hydroxy, R 10 is aryl, substituted aryl, heteroaryl or substituted heteroaryl, A is carbon, B and C are nitrogen, R 11 is hydrogen and R 12 is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
37 . The compound of claim 36 wherein R 9 is hydroxy and R 10 is
38 . The compound of claim 1 , wherein W is oxygen, and R 8 , R 9 and R 10 are all absent.
39 . The compound of claim 1 , wherein R 10 and R 2 bond directly to one another to form a 5-membered ring, W is nitrogen, R 9 is hydrogen, R 6 and R 2 ′ are both absent, and a benzene ring is fused to the bond between R 10 and R 2 .
40 . A method for treating or preventing obesity, diabetes, anxiety, depression, neurodegeneration or an inflammatory disease in a patient comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound according to claim 1 .
41 . A pharmaceutical composition comprising the compound of claim 1 .
42 . A method for treating or preventing obesity, diabetes, anxiety, depression, neurodegeneration or an inflammatory disease in a patient, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to claim 41 .
43 . A method for selectively modulating the activation, repression, agonism, or antagonism effects of the glucocorticoid receptor in a patient, comprising administering to said patient a therapeutically effective amount of a composition according to claim 41 .
44 . A method for selectively modulating the activation, repression, agonism, or antagonism effects of the glucocorticoid receptor in a patient, comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .
45 . A pharmaceutical composition comprising the compound of claim 1 for treating or preventing obesity, diabetes, anxiety, depression, neurodegeneration or an inflammatory disease in a patient in need of such treatment.
46 . A compound according to claim 1 , wherein the compound is an antagonist of the glucocorticoid receptor.
47 . A compound according to claim 1 , wherein the compound is an agonist of the glucocorticoid receptor.
48 . A method of synthesizing a compound according to claim 1 , the method comprising:
derivatizing a Wieland-Miescher ketone.
49 . A method of synthesizing a compound according to claim 1 , the method comprising:
preparing an intermediate of formula
and
derivatizing the intermediate to produced the compound.Join the waitlist — get patent alerts
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