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 method of inhibiting PDE4 in a subject in need thereof, comprising administering to the subject an effective amount of 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. A method of reducing TNF-α levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound 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.
3. A method of treating a disease selected from the group consisting of in a patient in need thereof comprising administering to the patient an effective amount of 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.
4. The method of claim 3 , wherein the condition is sarcoidosis.
5. The method of claim 4 , wherein sarcoidosis is cutaneous sarcoidosis.
6. The method of claim 3 , wherein lupus is cutaneous lupus.
7. The method of claim 3 , wherein the disease is selected from Behçet's Disease and rheumatoid arthritis.
8. The method of claim 3 , wherein the compound of Formula I has predominantly the (S) configuration at the carbon attached to Y 2 and is represented by the following Formula Ia:
9. The method of claim 3 , wherein Y 6 , Y 7 and Y 8 are the same.
10. The method of claim 3 , wherein Y 1a and Y 1b are the same.
11. The method of claim 3 , wherein Y 3 , Y 4 and Y 5 are the same.
12. The method of claim 3 , wherein R 1 is CH 3 or CD 3 .
13. The method of claim 3 , wherein R 4 is CD 2 CD 3 .
14. The method of claim 8 , wherein Y 6 , Y 7 and Y 8 are the same.
15. The method of claim 8 , wherein Y 1a and Y 1b are the same.
16. The method of claim 8 , wherein Y 3 , Y 4 and Y 5 are the same.
17. The method of claim 8 , wherein R 1 is CH 3 or CD 3 .
18. The method of claim 8 , wherein R 4 is CD 2 CD 3 .
19. The method of claim 3 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.
20. The method of claim 8 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.
21. The method of claim 3 wherein any atom not designated as deuterium is present at its natural isotopic abundance.