Novel immunotherapeutic agents

Abstract

Novel amides and imides are inhibitors of tumor necrosis factorα and phosphodiesterase and can be used to combat cachexia, endotoxic shock, retrovirus replication, asthma, and inflammatory conditions.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 5  is the divalent residue of pyrrolidine, wherein the two bonds of the divalent residue are on vicinal ring carbon atoms;  
 R 6  is —CO—, —CH 2 —, or —CH 2 CO—;  
 R 7  is 
 (i) cyclic or bicyclic alkyl of 4 to 12 carbon atoms;  
 (ii) pyridyl;  
 (iii) phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight or branched alkyl of 1 to 10 carbon atoms, straight or branched alkoxy of 1 to 10 carbon atoms, or halo;  
 (iv) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo;  
 (v) naphthyl; or  
 (vi) benzyloxy;  
 
 Y is —COX, —C≡N, —OR 8 , alkyl of 1 to 5 carbon atoms, or aryl;  
 X is —NH 2 ,—OH, —NHR, —R 9 , —OR 9 , or alkyl of 1 to 5 carbon atoms;  
 R 8  is hydrogen or lower alkyl;  
 R 9  is alkyl or benzyl; and,  
 n has a value of 0, 1, 2, or 3.  
 
     
     
         2 . A compound according to  claim 1  wherein Y is —C≡N or —CO(CH 2 ) m CH 3  in which m has a value of 0, 1, 2, or 3; and  
     
     
         3 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       in which: 
 one of R 1  and R 2  is R 3 —X— and the other is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R 3 —X—;  
 R 3  is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms;  
 X is —CH 2 — or —O—;  
 R 5  is the vicinally divalent residue of pyrrolidine, wherein the two bonds of the divalent residue are on vicinal ring carbon atoms;  
 R 6  is —CO—, —CH 2 —, or —CH 2 CO—;  
 Y is —COX, —C≡—N, —OR 8 , alkyl of 1 to 5 carbon atoms, or aryl;  
 X is —NH 2 ,—OH, —NHR, —R 9 , —OR 9 , or alkyl of 1 to 5 carbon atoms;  
 R 8  is hydrogen or lower alkyl;  
 R 9  is alkyl or benzyl; and,  
 n has a value of 0, 1, 2, or3.  
 
     
     
         4 . A compound according to  claim 3  wherein one of R 1  and R 2  is R 3 —O— and the other is lower alkyl, lower alkoxy, or R 3 —O—; 
 R 3  is cyclic or bicyclic alkyl of up to 10 carbon atoms;  
 R 5  is the vicinally divalent residue of pyrrolidine, wherein the two bonds of the divalent residue are on vicinal ring carbon atom;  
 R 6  is —CO— or —CH 2 —;  
 Y is —COX;  
 X is —NH 2 ,—OH, —NHR, —R 9 , or —OR 9 ;  
 R 9  is alkyl or benzyl; and  
 n has a value of 1 or 2.  
 
     
     
         5 . A compound according to  claim 4  wherein one of R 1  and R 2  is R 3 —O— and the other is methoxy or ethoxy; 
 R 3  is cyclopentyl or cyclohexyl;  
 R 5  is —CO— or —CH 2 —;  
 Y is —COX;  
 X is —NH 2 ,—OH, or —OR 9 ;  
 R 9  is methyl or ethyl; and  
 n has a value of 1.  
 
     
     
         6 . A compound according to  claim 3  wherein one of R 1  and R 2  is R 3 —O— and the other is lower alkyl, lower alkoxy, or R 3 —O—; 
 R 3  is cyclic or bicyclic alkyl of up to 10 carbon atoms;  
 R 5  is the vicinally divalent residue of pyrrolidine;  
 R 6  is —CO— or —CH 2 —;  
 Y is —COX;  
 X is —NH 2 ,—OH, —NHR, —R 9 , or —OR 9 ;  
 R 9  is alkyl or benzyl; and  
 n has a value of 1 or 2.  
 
     
     
         7 . A compound according to  claim 4  wherein one of R 1  and R 2  is R 3 —O— and the other is methoxy or ethoxy; 
 R 3  is cyclopentyl or cyclohexyl;  
 R 6  is —CO— or —CH 2 —;  
 Y is —COX;  
 X is —NH 2 ,—OH, or —OR 9 ;  
 R 9  is methyl or ethyl; and  
 n has a value of 1.  
 
     
     
         8 . The method of inhibiting phosphodiesterase in a mammal which comprises administering thereto an effective amount of a compound of  claim 3 .  
     
     
         9 . The method of inhibiting TNFα in a mammal which comprises administering thereto an effective amount of a compound of  claim 3 .  
     
     
         10 . A pharmaceutical composition comprising an amount of a compound according to  claim 3  effective upon single or multiple dosage sufficient to inhibit phosphodiesterase or TNFα.  
     
     
         11 . The method of inhibiting phosphodiesterase in a mammal which comprises administering thereto an effective amount of a compound of  claim 1 .  
     
     
         12 . The method of inhibiting TNFα in a mammal which comprises administering thereto an effective amount of a compound of  claim 1 .  
     
     
         13 . A pharmaceutical composition comprising an amount of a compound according to  claim 1  effective upon single or multiple dosage sufficient to inhibit phosphodiesterase or TNFα.