D-homoandrosta-17-yl carbamate derivatives as selective glucocorticoid receptor ligands
View Patent ↗The present invention is directed to D-homoandrosta-17-yl-carbamate derivatives as selective glucocorticoid receptor ligands useful for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are independently selected from the group consisting of: R a , —C(O)—R a , and —C(O)—N(R a )R a ;
R 3 and R 4 are independently selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, aryl, heteroaryl, heterocyclyl, and C 1-10 fluoroalkyl; and
each Ra is independently selected from the group consisting of: hydrogen, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, and C 1-10 fluoroalkyl.
2. The compound according to claim 1 wherein R 2 is selected from hydrogen and CH 3 —C(O)—.
3. The compound according to claim 1 wherein R 1 is selected from hydrogen and CF 3 —(CO)—.
4. The compound according to claim 1 wherein R 3 is hydrogen.
5. The compound according to claim 4 wherein R 4 is selected from C 1-10 alkyl and C 3-10 cycloalkyl.
6. The compound according to claim 1 wherein:
R 1 is selected from hydrogen or CF 3 —(CO)—;
R 2 is selected from hydrogen and CH 3 —C(O)—;
R 3 is hydrogen; and
R 4 is selected from C 1-10 alkyl and C 3-10 cycloalkyl.
7. The compound according to claim 6 wherein R 4 is C 1-6 alkyl.
8. The compound according to claim 6 wherein R 4 is selected from: cyclopentyl, cyclohexyl and adamantanyl.
9. The compound according to claim 6 wherein R 1 and R 2 are hydrogen.
10. The compound according to claim 1 selected from the following group:
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(1-adamantyl)carbamate,
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(2-pentyl)carbamate,
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(2-methyl-pentyl)carbamate,
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(3-methyl-2-propyl)carbamate,
(11β,16β,17α)-9-fluoro-11-trifluoroacetoxy-16-methyl-3,17a-dioxo-17-[(acetyloxy)methyl]-D-homoandrosta-1,4-dien-17-yl-(1-adamantyl)carbamate,
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-[(acetyloxy)methyl]-D-homoandrosta-1,4-dien-17-yl-(1-adamantyl)carbamate,
(11β,16β,17α)-9-fluoro-11-trifluoroacetoxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(1-adamantyl)carbamate,
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(cyclopentyl)carbamate,
(11β,16β,17α)-9-fluoro-11-hydroxy-16-methyl-3,17a-dioxo-17-(hydroxymethyl)-D-homoandrosta-1,4-dien-17-yl-(cyclohexyl)carbamate
or a pharmaceutically acceptable salt of any of the above.
11. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.