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 analogs 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 CH 3 or CD 3 ;
R 3 is selected from CH 3 , CH 2 D, CHD 2 , CD 3 , CF 3 , CHF 2 , CH 2 F, CDF 2 , and CD 2 F;
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 H; and
Y 6 is selected from Cl, H, and D;
provided that if R 1 is CH 3 ; R 2 is not substituted with deuterium; R 3 is CH 3 , CF 3 , CHF 2 , or CH 2 F; and Y 6 is Cl or H; then R 4 is an ethyl group substituted with one to five deuterium or a cyclopentyl group substituted with one to nine deuterium.
2. The compound of claim 1 , wherein R 3 is CH 3 or CD 3 ; and Y 6 is H.
3. A compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CH 3 and CD 3 ;
R 2 is selected from CH 3 and CD 3 ;
R 3 is selected from CH 3 , CD 3 , CF 3 , CHF 2 , CH 2 F, CDF 2 , and CD 2 F;
R 4 is selected from CH 2 CH 3 , CD 2 CD 3 , CD 2 CH 3 , and CH 2 CD 3 ;
provided that if R 1 is CH 3 ; R 2 is not substituted with deuterium; R 3 is CH 3 , CF 3 , CHF 2 , or CH 2 F; then R 4 is an ethyl group substituted with one to five deuterium.
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 Ib, 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 R 4 is CD 2 CD 3 .
7. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
8. A compound of claim 7 , having predominantly the (S) configuration.
9. A compound of claim 7 , having predominantly the (R) configuration.
10. A compound selected from the group consisting of
or a pharmaceutically acceptable salt of any of the foregoing.
11. A compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
12. A composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt of said compound; and an acceptable carrier.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt of said compound; and an acceptable carrier, wherein the composition is suitable for the treatment of a disease selected from the group consisting of psoriasis, sarcoidosis, psoriatic arthritis, Behçet's Disease, prurigo nodularis, lupus, rheumatoid arthritis, and rheumatoid spondylitis.
14. A method of inhibiting PDE4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
15. A method of reducing TNF-α, levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
16. A method of treating a disease selected from the group consisting of psoriasis, sarcoidosis, psoriatic arthritis, Behçet's Disease, prurigo nodularis, lupus, rheumatoid arthritis, and rheumatoid spondylitis, 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.
17. The method of claim 16 , wherein the condition is psoriasis or sarcoidosis.
18. The method of claim 17 , wherein psoriasis is plaque-type psoriasis or refractory psoriasis.
19. The method of claim 17 , wherein sarcoidosis is cutaneous sarcoidosis.
20. The method of claim 16 , wherein lupus is cutaneous lupus.
21. A compound of claim 1 , wherein the isotopic enrichment factor for each designated deuterium atom is at least 6000 (90%).
22. The compound of claim 21 wherein the isotopic enrichment factor for each designated deuterium atom is at least 6333.3 (95%).
23. A compound of claim 21 , having predominantly the (S) configuration.
24. A compound of claim 21 , having predominantly the (R) configuration.