Substituted isoindoline-1,3-dione derivatives

Abstract

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.

What is claimed is: 
     
         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 selected from the group consisting of methyl, isopropyl, cyclopentyl, cyclopropyl, 2-furanyl, trifluoromethyl, methoxymethyl, aminomethyl, dimethylaminomethyl, dimethylamino-1-ethyl, 1-dimethylamino-ethyl, and 2-dimethylamino-ethyl, wherein R 2  is optionally substituted with deuterium; 
 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 selected from CH 2 , CHD, CD 2 , and 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; 
 
       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; R 4  is an ethyl group not substituted with deuterium or a cyclopentyl group not substituted with deuterium; X is CH 2  or C═O; and Y 6  is Cl or H; then at least one of Y 1a , Y 1b , Y 2 , Y 3 , Y 4 , Y 5 , Y 7  and Y 8  is D. 
     
     
         2 . The compound of  claim 1 , wherein R 2  is CH 3  or CD 3 ; R 3  is CH 3  or CD 3 ; 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 2 , 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 2  is selected from the group consisting of methyl, isopropyl, cyclopentyl, cyclopropyl, 2-furanyl, trifluoromethyl, methoxymethyl, aminomethyl, dimethylaminomethyl, dimethylamino-1-ethyl, 1-dimethylamino-ethyl, and 2-dimethylamino-ethyl, wherein R 2  is optionally substituted with deuterium; 
 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 ; and 
 each Y is independently selected from 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 R 4  is CH 2 CH 3 ; then at least one Y is 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 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein R 2  is CH 3  or CD 3 . 
     
     
         7 . The compound of  claim 1 , wherein R 3  is CH 3  or CD 3 . 
     
     
         8 . The compound of  claim 1 , wherein Y 6 , Y 7  and Y 8  are the same. 
     
     
         9 . The compound of  claim 1 , wherein Y 1a  and Y 1b  are the same. 
     
     
         10 . The compound of  claim 1 , wherein Y 3 , Y 4  and Y 5  are the same. 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein R 4  is CD 2 CD 3 . 
     
     
         13 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         14 . A compound of  claim 13 , having predominantly the (S) configuration. 
     
     
         15 . (canceled) 
     
     
         16 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         17 . The compound of  claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
     
     
         18 . A composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt of said compound; and an acceptable carrier. 
     
     
         19 . (canceled) 
     
     
         20 . 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. 
     
     
         21 . 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. 
     
     
         22 . A method of treating a disease selected from the group consisting of septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, sarcoidosis, psoriatic arthritis, Behçet's Disease, prurigo nodularis, lupus, uveitis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, opportunistic infections in AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, radiation damage, hyperoxic alveolar injury, undesirable angiogenesis, inflammatory disease, arthritis, inflammatory bowel disease, aphthous ulcers, asthma, adult respiratory distress syndrome, and AIDS, 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. 
     
     
         23 . The method of  claim 22 , wherein the condition is psoriasis or sarcoidosis. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 23 , wherein sarcoidosis is cutaneous sarcoidosis. 
     
     
         26 . (canceled)