Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and -1-oxoisoindolines and method of reducing tnfalpha levels

Abstract

Substituted 2-(2,6-dioxopiperidin-3-yl)phthalimides and 1-oxo-2-(2,6-dioxopiperidin-3-yl)isoindolines are disclosed. The compounds are useful, for example, in reducing the levels of TNFα in a mammal.

1 . A 2,6-dioxopiperidine selected from the group consisting of (a) a compound of the formula: 
       
         
           
           
               
               
           
         
         in which: 
         one of X and Y is C═O and the other of X and Y is C═O or CH 2 ; 
         (i) each of R 1 , R 2 , R 3 , and R 4 , independently of the other, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (if) one of R 1 , R 2 , R 3 , and R 4  is —NHR 5  and the remaining of R 1 , R 2 , R 3 , and R 4  are hydrogen; 
         R 5  is hydrogen or alkyl of 1 to 8 carbon atoms; 
         R 6  is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, or halo; 
         provided that R 6  is other than hydrogen if X and Y are C═O and (i) each of R 1 , R 2 , R 3 , and R 4  is fluoro or (if) one of R 1 , R 2 , R 3 , or R 4  is amino; and 
         (h) the acid addition salts of said compounds which contain a nitrogen atom capable of being protonated. 
       
     
     
         2 . A compound according to  claim 1  in which each of R 1 , R 2 , R 3 , and R 4 , independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms and R 6  is methyl, ethyl, or propyl. 
     
     
         3 . A compound according to  claim 1  in which one of, R 1 , R 2 , R 3 , and R 4  is NH 2  and the remaining of R 1 , R 2 , R 3 , and R 4  are hydrogen and R 6  is methyl, ethyl, propyl, or benzyl. 
     
     
         4 . A compound according to  claim 1  which is 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3yl)-4,5,6,7-tetrachloroisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,5,6,7-tetramethylisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,5,6,7-tetramethoxyisoidoline, 3-(1-oxo-4-aminoisoindolin-1-yl)-3-methylpiperidine-2,6-dione 3-(1-oxo-4-aminoisoindolin-1-yl)-3-ethylpiperidine-2,6-dione, 3-(1-oxo-4-aminoisoindolin-1-yl)-3-propylpiperidine-2,6-dione, or 3-(3-aminophthalimido)-3-methylpiperidine-2,6-dione. 
     
     
         5 . The method of reducing undesirable levels of TNFα in a mammal which comprises administering thereto an effective amount of a compound according to  claim 1 . 
     
     
         6 . A pharmaceutical composition comprising a quantity of a compound according to  claim 1  sufficient upon administration in a single or multiple dose regimen to reduce levels of TNFα in a mammal in combination with a carrier. 
     
     
         7 . The method of reducing undesirable levels of TNFα in a mammal which comprises administering thereto an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       in which in said compound one of X and Y is C═O and the other of X and Y is C═O or CH 2 . 
     
     
         8 . The method according to  claim 7  in which said compound is 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline, 1-oxo-2(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline, 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline, or 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.