Methods of using cyclic amides

Abstract

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

1 - 13 . (canceled)  
     
     
         14 . A method of treating in a mammal a disease selected from the group consisting of silicosis, fibrosis, HIV infection, ENL in leprosy, cytomegalia virus, influenza virus, adenovirus, herpes, rheumatoid spondylitis, septic shock, septis, wasting, multiple sclerosis, opportunistic infections in AIDS, hemodynamic shock and sepsis syndrome, mycobacterial infection, meningitis, systemic lupus erythrematosis, congestive heart failure, cancer, autoimmune disease, radiation damage, hyperoxic alveolar injury, viral conjunctivitis, feline immunodeficiency virus, equine infectious anaemia virus, caprine arthritis virus, visna virus, and maedi virus, comprising administering thereto an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a substantially chirally pure isomer thereof, wherein: 
 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 a divalent pyrrolidine, imidazole, or thiophene ring in which the divalent bonds are on vicinal ring carbon atoms;  
 R 6  is —CO—, —CH 2 —, —CH 2 CO—, or —SO 2 —;  
 Y is —CO[X]Z, —C≡N, —OR 8 , alkyl of 1 to 5 carbon atoms, or aryl;  
 [X]Z 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.  
 
     
     
         15 . A method of treating in a mammal an inflammatory disease comprising administering thereto an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a substantially chirally pure isomer thereof, wherein: 
 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 a divalent pyrrolidine, imidazole, or thiophene ring in which the divalent bonds are on vicinal ring carbon atoms;  
 R 6  is —CO—, —CH 2 —, —CH 2 CO—, or —SO 2 —;  
 Y is —CO[X]Z, —C≡N, —OR 8 , alkyl of 1 to 5 carbon atoms, or aryl;  
 [X]Z 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.