ENANTIOMERICALLY ENRICHED IMIDAZOAZEPINONE COMPOUNDS
The present invention provides an enantiomerically pure compound of Formula I: along with pharmaceutical formulations containing the same and methods of use thereof.
1 . An enantiomerically pure compound of Formula Ia:
wherein:
R 1 is C 1-3 alkyl;
X is methylene, ethylene, propylene, ethenylene,_propenylene, or butenylene;
R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from C 1-4 alkyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benzyloxy, acetyl, (cyanyl)C 1-3 alkyl, (phenyl)C 2-3 alkenyl; and halo;
R 8 is H, methyl, ethyl, propyl, (C 1-3 alkoxy)C 1-3 alkyl, (C 1-3 alkylthio)C 1-3 alkyl, C 1-3 hydroxyalkyl, phenyl, benzyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isooxazolyl, pyridyl, and thienyl;
wherein R 8 is substituted with between 0 and 3 substituents independently selected from methyl, ethyl, halo, hydroxyl, C 1-3 alkoxy, C 1-3 alkylthio, (C 1-3 alkoxy)C 1-3 alkyl, (C 1-3 alkylthio)C 1-3 alkyl, C 1-3 hydroxyalkyl, (C 1-3 mercaptoalkyl)phenyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isooxazolyl, pyridyl, and thienyl; and
each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, chloro, amino, methylamino, dimethylamino, and phenoxy;
or one pair selected from R a and R b , and R b and R c , taken together, is —O—(CH 2 )—O— or —O—CH 2 —CH 2 —O—;
or a pharmaceutically acceptable salt, a C 1-6 alkyl ester or amide, or a C 2-6 alkenyl ester or amide thereof.
2 . A compound of claim 1 , wherein:
R 1 is C 1-2 alkyl;
R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from C 1-4 alkyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benzyloxy, acetyl, (cyanyl)C 1-3 alkyl, (phenyl)C 2-3 alkenyl; and halo;
R 8 is, methyl, ethyl, or propyl, wherein R 8 is substituted with from 0 and 3 hydroxyl substituents;
X is methylene or ethylene;
R a R b and R c are each independently selected from the group consisting of H and methoxy;
or a pharmaceutically acceptable salt thereof.
3 . A compound of claim 1 , wherein:
R 1 is methyl;
R 5 is phenyl, pyrrolyl or pyrazolyl, each of which is substituted 0, 1 or 2 times with methyl;
R 8 is ethyl;
X is methylene;
R a and R c are each methoxy;
R b is H;
or a pharmaceutically acceptable salt thereof.
4 . A compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
5 . A compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
6 . A compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
7 . A compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
8 . A composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
9 . A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to said subject a compound of claim 1 in a treatment effective amount.
10 . The method of claim 9 , wherein:
R 1 is C 1-2 alkyl;
R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from C 1-4 alkyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benzyloxy, acetyl, (cyanyl)C 1-3 alkyl, (phenyl)C 2-3 alkenyl; and halo;
R 8 is, methyl, ethyl, or propyl, wherein R 8 is substituted with from 0 and 3 hydroxyl substituents;
X is methylene or ethylene;
R a R b and R c are each independently selected from the group consisting of H and methoxy;
or a pharmaceutically acceptable salt thereof.
11 . the method of claim 9 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
12 . The method of claim 9 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
13 . The method of claim 9 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
14 . The method of claim 9 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
15 . A method of treating multiple sclerosis in a subject in need thereof, comprising administering to said subject a compound of claim 1 in a treatment effective amount.
16 . The method of claim 15 , wherein:
R 1 is C 1-2 alkyl;
R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from C 1-4 alkyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benzyloxy, acetyl, (cyanyl)C 1-3 alkyl, (phenyl)C 2-3 alkenyl; and halo;
R 8 is, methyl, ethyl, or propyl, wherein R 8 is substituted with from 0 and 3 hydroxyl substituents;
X is methylene or ethylene;
R a R b and R c are each independently selected from the group consisting of H and methoxy;
or a pharmaceutically acceptable salt thereof.
17 . the method of claim 15 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
18 . The method of claim 15 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
20 . The method of claim 15 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
21 . The method of claim 15 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
22 . A method of treating an autoimmune disease in a subject in need thereof, comprising administering to said subject a compound of claim 1 in a treatment effective amount;
wherein said autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type 1 diabetes mellitus, psoriasis, and atherosclerosis.
23 . The method of claim 22 , wherein:
R 1 is C 1-2 alkyl;
R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from C 1-4 alkyl, C 1-3 alkoxy, hydroxyl, C 1-3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benzyloxy, acetyl, (cyanyl)C 1-3 alkyl, (phenyl)C 2-3 alkenyl; and halo;
R 8 is, methyl, ethyl, or propyl, wherein R 8 is substituted with from 0 and 3 hydroxyl substituents;
X is methylene or ethylene;
R a R b and R c are each independently selected from the group consisting of H and methoxy;
or a pharmaceutically acceptable salt thereof.
24 . the method of claim 22 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
25 . The method of claim 22 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
26 . The method of claim 22 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
27 . The method of claim 22 , said compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.