IP Library › Granted Patent US 7,579,335

Granted Patent B2

US 7,579,335 · App. 11/813,227 · Granted Aug 25, 2009

Androstane 17α-carbonate derivatives for use in the treatment of allergic and inflammatory conditions

Assignee: Glaxo Group Limited

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Quick Facts

Patent No.: US 7,579,335
App. No.: 11/813,227
Granted: Aug 25, 2009
Kind: B2

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Abstract

The present invention is directed to compounds of formula (I): wherein R 1 represents C 4 -C 7 branched alkyl group, a bicycloalkyl group, or a C 5 -C 6 cycloalkyl which optionally may be substituted with a C 1 -C 4 alkyl group; R 2 represents hydrogen, a methyl group, which may be in either the α or β configuration, or a methylene group; R 3 and R 4 are the same or a different group and each independently represents hydrogen, halogen or a methyl group; represents a single or a double bond; and physiologically acceptable solvates thereof, physiologically functional derivatives thereof, pharmaceutical compositions comprising the compounds, the use of the compounds for the manufacture of medicaments particularly for the treatment of inflammatory and/or allergic conditions, processes for the preparation of the compounds, and chemical intermediates in the processes for the manufacture of the compounds.

Claims (84)

1. A compound of formula (I):

wherein

R 1 represents C 4 -C 7 branched alkyl group, a bicycloalkyl group, or a C 5 -C 6 cycloalkyl which optionally may be substituted with a C 1 -C 4 alkyl group;

R 2 represents hydrogen, a methyl group, which may be in either the α or β configuration, or a methylene group;

R 3 and R 4 are the same or a different group and each independently represents hydrogen, halogen or a methyl group;

and represents a single or a double bond.

2. A compound as claimed in claim 1 wherein R 1 represents C 4 -C 7 branched alkyl group which is a 1,1-dimethylethyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethyl-2-methylpropyl, 2-methyl-1-(1-methylethyl)propyl, 2-ethylbutyl, 1-propylbutyl or a 1-(1-methylethyl)butyl group.

3. A compound as claimed in claim 1 wherein R 1 represents a C 5 -C 6 cycloalkyl group optionally substituted with a C 1 -C 3 alkyl group.

4. A compound as claimed in claim 3 wherein R 1 represents an optionally substituted C 5 -C 6 cycloalkyl group which is a cyclopentyl, (1SR,2RS)-2-methylcyclohexyl, 4-(1-methylethyl)cyclohexyl, trans-4-ethylcyclohexyl or a cis-4-ethylcyclohexyl group.

5. A compound as claimed in claim 1 wherein R 1 represents a bicycloalkyl group which is a (1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yl, (1RS,2SR,4SR) -bicyclo[2.2.1]hept-2-yl, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl or a (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl group.

6. A compound as claimed in claim 1 wherein R 1 represents a 1,1-dimethylethyl, 1,1-dimethylpropyl, 1-ethylpropyl, 2-methyl-1-(1-methylethyl)propyl, 2,2-dimethylpropyl, (1SR,2RS)-2-methylcyclohexyl, 4-(1-methylethyl)cyclohexyl Isomer B or a (1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yl or a (1RS,2SR,4SR)-bicyclo[2.2.1]hept-2-yl group.

7. A compound as claimed in claim 1 wherein R 1 represents a 1,1-dimethylpropyl group.

8. A compound as claimed in claim 1 wherein R 1 represents a 1,1-dimethylethyl group.

9. A compound as claimed in claim 1 wherein R 2 represents a methyl group in the α-configuration.

10. A compound as claimed in claim 1 wherein R 3 and R 4 are both fluorine.

11. A compound as claimed in claim 1 wherein represents a double bond.

12. A compound which is:

Cyanomethyl (6α,11β,16α,17α)-17-({[(1,1-dimethylethyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(1,1-dimethylpropyl)oxy]carbonyl}oxy)-6,9-difluoro -11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(1-ethylpropyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1-(1-methylethyl)propyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(2-ethylbutyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(2,2-dimethylpropyl)oxy]carbonyl}oxy)-6,9-difluoro -11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(1-ethyl-2-methylpropyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(1,2-dimethylpropyl)oxy]carbonyl}oxy)-6,9-difluoro -11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-{[(cyclopentyloxy)carbonyl]oxy}-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[(1SR,2RS)-2-methylcyclohexyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[4-(1-methylethyl)cyclohexyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yloxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(1RS,2SR,4SR)-bicyclo[2.2.1]hept-2-yloxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(trans-4-ethylcyclohexyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(cis-4-ethylcyclohexyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1-propylbutyl)oxy]carbonyl}oxy)androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-[({[(1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]oxy}carbonyl)oxy]androsta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(1,2,2-trimethylpropyl)oxy]carbonyl}oxy)androsta-1,4-diene-17-carboxylate; or

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[1-(1-methylethyl)butyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate.

13. A compound as claimed in claim 12 which is:

Cyanomethyl (6α,11β,16α,17α)-17-({[(1-ethylpropyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[2-methyl-1-(1-methylethyl)propyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[4-(1-methylethyl)cyclohexyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-17-({[(2-ethylbutyl)oxy]carbonyl}oxy)-6,9-difluoro-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carboxylate;

Cyanomethyl (6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-17-[({[(1SR,2RS)-2-methylethylcyclohexyl]oxy}carbonyl)oxy]-3-oxoandrosta-1,4-diene-17-carboxylate;