Substituted isoindoline-1,3-dione derivatives
This invention relates to novel substituted isoindoline-1,3-dione derivatives and pharmaceutically acceptable salts thereof. More specifically, the invention relates to novel substituted isoindoline-1,3-dione derivatives that are analogues of apremilast. This invention also provides compositions comprising a compound of this invention and a carrier and the use of disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering apremilast.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CH 3 , CH 2 D, CHD 2 , and CD 3 ;
R 2 is methyl or CD 3 ;
R 3 is CD 3 ;
R 4 is an ethyl group substituted with zero to five deuterium, or is a cyclopentyl group substituted with zero to nine deuterium;
X is C═O;
each of Y 1a , Y 1b , Y 2 , Y 3 , Y 4 , Y 5 , Y 7 and Y 8 is independently selected from H and D; and
Y 6 is selected from Cl, H, and D.
2. The compound of claim 1 , wherein Y 6 , Y 7 and Y 8 are the same; Y 1a and Y 1b are the same; and Y 3 , Y 4 and Y 5 are the same.
3. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CH 3 and CD 3 ;
R 3 is CD 3 ;
R 4 is selected from CH 2 CH 3 , CD 2 CD 3 , CD 2 CH 3 , and CH 2 CD 3 ; and
each Y is independently selected from H and D.
4. The compound of claim 2 , wherein the compound of Formula I is a compound of Formula Ia, having predominantly the (S) configuration at the carbon attached to Y 2 :
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 2 , wherein the compound of Formula I is a compound of Formula Ia, having predominantly the (R) configuration at the carbon attached to Y 2 :
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein Y 6 , Y 7 and Y 8 are the same.
7. The compound of claim 1 , wherein Y 1a and Y 1b are the same.
8. The compound of claim 1 , wherein Y 3 , Y 4 and Y 5 are the same.
9. The compound of claim 1 , wherein R 1 is CH 3 or CD 3 .
10. The compound of claim 1 , wherein R 4 is CD 2 CD 3 .
11. A compound selected from the group consisting of :
or a pharmaceutically acceptable salt of any of the foregoing.
12. A compound of claim 11 , having predominantly the (S) configuration.
13. A compound of claim 11 , having predominantly the (R) configuration.
14. A compound selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.
15. A compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
16. A composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt of said compound; and an acceptable carrier.
17. A method of treating a disease selected from the group consisting of psoriasis and psoriatic arthritis in a patient in need thereof comprising administering to the patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein psoriasis is plaque-type psoriasis or refractory psoriasis.
19. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ia, having predominantly the (S) configuration at the carbon attached to Y 2 :
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ib, having predominantly the (R) configuration at the carbon attached to Y 2 :
or a pharmaceutically acceptable salt thereof.