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 reduce the levels of TNFα in a mammal. A typical embodiment is 1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline.

What is claimed is:  
     
         1 . A 2,6-dioxopiperidine selected from the group consisting of (α) 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 others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R 1 , R 2 , R 3 , and R 4  is —NHR and the remaining of R 1 , R 2 , R 3 , and R 4  are hydrogen;  
 R 5  is hydrogen, alkyl of 1 to 8 carbon atoms, or CO—R 7 —CH(R 10 )NR 8 R 9 ;  
 R 6  is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;  
 R 7  is m-phenylene or p-phenylene or —(C n H 2n )— in which n has a value of 0 to 4;  
 each of R 8  and R 9  taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R 8  and R 9  taken together are tetramethylene, pentamethylene, hexamethylene, or —CH 2 CH 2 XCH 2 CH 2 — in which X is —O—, —S— or —NH—;  
 R 10  is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and  
 (b) 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; R 6  is hydrogen, methyl, ethyl, or propyl; R 7  is m-phenylene or p-phenylene; each of R 8  and R 9  taken independently of the other is hydrogen or methyl; and R 10  is hydrogen.  
     
     
         3 . 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; R 6  is hydrogen, methyl, ethyl, or propyl; R 7  is —(C n H 2n )— in which n has a value of 0 to 4; each of R 8  and R 9  taken independently of the other is hydrogen or methyl; and R 10  is hydrogen.  
     
     
         4 . 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; R 6  is hydrogen, methyl, ethyl, or propyl; R 7  is m-phenylene or p-phenylene; each of R 8  and R 9  taken independently of the other is hydrogen or methyl; and R 10  is hydrogen.  
     
     
         5 . 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; R 6  is hydrogen, methyl, ethyl, or propyl; R 7  is or —(C n H 2n )— in which n has a value of 0 to 4; each of R 8  and R 9  taken independently of the other is hydrogen or methyl; and R 10  is hydrogen.  
     
     
         6 . A 2,6-dioxopiperidine selected from the group consisting of (α) 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 others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R 1 , R 2 , R 3 , and R 4  is —NHR and the remaining of R 1 , R 2 , R 3 , and R 4  are hydrogen;  
 R 5  is hydrogen, alkyl of 1 to 8 carbon atoms, or CO—R 7 —CH(R 10 )NR 8 R 9 ;  
 R 6  is alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;  
 R 7  is m-phenylene or p-phenylene or —(C n H 2n )— in which n has a value of 0 to 4;  
 each of R 8  and R 9  taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R 8  and R 9  taken together are tetramethylene, pentamethylene, hexamethylene, or —CH 2 CH 2 XCH 2 CH 2 — in which X is —O—, —S— or —NH—;  
 R 10  is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and  
 (b) the acid addition salts of said compounds which contain a nitrogen atom capable of being protonated.  
 
     
     
         7 . A compound according to  claim 6  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.  
     
     
         8 . A compound according to  claim 6  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, or propyl.  
     
     
         9 . 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 .  
     
     
         10 . The method of reducing undesirable levels of TNFα in a mammal which comprises administering thereto an effective amount of a compound according to  claim 6 .  
     
     
         11 . 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.  
     
     
         12 . A pharmaceutical composition comprising a quantity of a compound according to  claim 6  sufficient upon administration in a single or multiple dose regimen to reduce levels of TNFα in a mammal in combination with a carrier.