Methods of using substituted isoxazolo pyridinones as dissociated glucocorticoids
A method for treating a subject having an inflammatory or auto-immune disease with a substituted isoxazolo pyridinone. Also, a method for administering a substituted isoxazolo pyridinone to a cell to retain or increase glucocorticoid receptor transrepression activity with only minimal glucocorticoid receptor transactivation activity.
1. A method of treating a disease selected from the group consisting of arthritis and asthma in warm blooded mammals which comprises administering a therapeutically effective amount of an isoxazolo[4,5-c]pyridine of formula (I)
where:
X 1 is —N═ or —CR 1 ═, wherein
R 1 is
R 2 is methyl;
R 3 is —H or F;
R 4 is —H; or R 1 and R 4 together with the carbon atoms to which they are attached form the moiety
R 5 is —H or methoxy; enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof.
2. The method according to claim 1 where the warm blooded mammal is a human.
3. The method according to claim 1 where the effective amount is from about 1 to about 100 mg/kg/day.
4. The method according to claim 3 where the effective amount is from about 5 to about 50 mg/kg/day.
5. The method according to claim 1 where the isoxazolo[4,5-c]pyridine (I) is selected from the group consisting of
6-(4-((dimethylamino)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-((dimethylamino)methyl)phenyl)-3-(4-fluorophenyl)-5methylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-diethylamino-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5c]pyridin-4-one,
6-(4-methoxyphenyl)-5-methyl-3-phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(2,4-dimethoxyphenyl)-5-methyl-3-phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(benzo[d][1,3]dioxol-5-yl)-5-methyl-3-phenylisoxazolo[4,5c]pyridin-4(5H)-one,
6-(4-((2-hydroxyethoxy)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-((2-methoxyethoxy)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-((2-isopropoxyethoxy)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
5-methyl-6-(4-phenoxyphenyl)-3-phenyl-isoxazolo[4,5-c]pyridin-4(5H)-one,
5-methyl-6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
5-methyl-3-phenyl-6-(pyridin-4-yl)isoxazolo[4,5-c]pyridin-4(5H)-one, and
5-methyl-3-phenyl-6-p-tolylisoxazolo[4,5-c]pyridin-4(5H)-one.
6. The method according to claim 5 where the isoxazolo[4,5-c]pyridine (I) is 6-(4-((dimethylamino)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one.
7. A method for retaining or increasing glucocorticoid receptor transrepression activity in a cell with only minimal glucocorticoid receptor transactivation activity comprising administering to a cell which needs modification a usable amount of an isoxazolo[4,5-c]pyridine of formula (I)
where:
X 1 is —N═ or —CR 1 ═, wherein
R 1 is
R 2 is methyl;
R 3 is —H or F;
R 4 is H; or R 1 and R 4 together with the carbon atoms to which they are attached form the moiety
R 5 is —H or methoxy; enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof.
8. The method according to claim 7 where the isoxazolo[4,5-c]pyridine (I) is selected from the group consisting of
6-(4-((dimethylamino)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-((dimethylamino)methyl)phenyl)-3-(4-fluorophenyl)-5methylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-diethylamino-phenyl)-5-methyl-3-phenyl-5H-isoxazolo[4,5c]pyridin-4-one,
6-(4-methoxyphenyl)-5-methyl-3-phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(2,4-dimethoxyphenyl)-5-methyl-3-phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(benzo[d][1,3]dioxol-5-yl)-5-methyl-3-phenylisoxazolo[4,5c]pyridin-4(5H)-one,
6-(4-((2-hydroxyethoxy)methyl)phenyl)-5-methyl-3-phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-((2-methoxyethoxy)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
6-(4-((2-isopropoxyethoxy)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
5-methyl-6-(4-phenoxyphenyl)-3-phenyl-isoxazolo[4,5-c]pyridin-4(5H)-one,
5-methyl-6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one,
5-methyl-3-phenyl-6-(pyridin-4-yl)isoxazolo[4,5-c]pyridin-4(5H)one and
5-methyl-3-phenyl-6-p-tolylisoxazolo[4,5-c]pyridin-4(5H)-one.
9. The method according to claim 8 where the isoxazolo[4,5-c]pyridine (I) is 6-(4-((dimethylamino)methyl)phenyl)-5-methyl-3phenylisoxazolo[4,5-c]pyridin-4(5H)-one.