Guanylhydrazones and their use to treat inflammatory conditions

Abstract

This invention concerns new methods and compositions that are useful in preventing and ameliorating cachexia, the clinical syndrome of poor nutritional status and bodily wasting associated with cancer and other chronic diseases. More particularly, the invention relates to aromatic guanylhydrazone (more properly termed amidinohydrazone) compositions and their use to inhibit the uptake of arginine by macrophages and/or its conversion to urea. These compositions and methods are also useful in preventing the generation of nitric oxide (NO) by cells, and so to prevent NO-mediated inflammation and other responses in persons in need of same. In another embodiment, the compounds can be used to inhibit arginine uptake in arginine-dependent tumors and infections.

What is claimed is:  
     
         1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X 2 =GhyCH—, GhyCCH 3 — or H—;  
 X 1 , X′ 1  and X′ 2 , independently=GhyCH— or GhyCCH 3 —;  
 Z=—NH(CO)NH—, —(C 6 H 4 )—, —(C 5 NH 3 )— or —A—(CH 2 ) n —A—, n=2-10,  
 which is unsubstituted, mono- or di-C-methyl substituted, or a mono- or di- unsaturated derivative thereof; and  
 A=—NH(CO)—, —NH(CO)NH—, —NH— or —O— and salts thereof.  
 
     
     
         2 . The compound of  claim 1  wherein, when X 2  is GhyCH— or GhyCCH 3 —, X 2  is meta or para to X 1  and X′ 2  is meta or para to X′ 1 .  
     
     
         3 . The compound of  claim 2  which is N,N′-bis(3,5-diacetylphenyl)decanediamide tetrakis(amidinohydrazone) tetrahydrochloride.  
     
     
         4 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X 1 , X 2  and X 3 , independently=GhyCH— or GhyCCH 3 —;  
 X′ 1 , X′ 2  and X′ 3 , independently=H, GhyCH— or GhyCCH 3 —;  
 Z=(C 6 H 3 ), when m 1 , m 2 , m 3 =0, or Z=N, when, independently, m 1 , m 2 , m 3 =2-6; and  
 A=—NH(CO)—, —NH(CO)NH—, —NH— or —O— and salts thereof.  
 
     
     
         5 . The compound of  claim 4  wherein, when any of X′ 1 , X′ 2  and X′ 3  are other than H, then the corresponding substituent of the group consisting of X 1 , X 2  and X 3  is meta or para to X′ 1 , X′ 2  and X′ 3 , respectively.  
     
     
         6 . The compound of  claim 4  wherein, m 1 , m 2 , m 3 =0 and A=—NH(CO)—.  
     
     
         7 . The compound of  claim 4  wherein, m 1 , m 2 , m 3 =2-6 and A=—NH(CO)NH—.  
     
     
         8 . A pharmaceutical composition comprising the compound of  claim 1 ,  3  or  4  and a pharmaceutically acceptable carrier.  
     
     
         9 . A method for inhibiting synthesis of urea from plasma arginine in a subject which comprises administering an effective amount of the compound of  claim 8  to the subject in need of said inhibition.  
     
     
         10 . A method for ameliorating cachexia in a subject which comprises administering an effective amount of the compound of  claim 8  to the subject in need of said amelioration.  
     
     
         11 . A method for ameliorating the deleterious effects of nitric oxide synthesis in a subject which comprises administering an effective amount of the compound of  claim 8  to the subject in need of said amelioration.  
     
     
         12 . A method for ameliorating the deleterious effects of cytokine secretion in a subject which comprises administering an effective amount of the compound of  claim 8  to the subject in need of said amelioration.  
     
     
         13 . The method of  claim 12  wherein the subject is in need of amelioration of the deliterious effects of Tumor Necrosis Factor secretion.  
     
     
         14 . A method for treatment of endotoxic shock in a subject which comprises administering an effective amount of the compound of  claim 8  to a subject in need of said treatment.  
     
     
         15 . A method for treatment of neoplastic disease in a subject which comprises administering an effective amount of the compound of  claim 8  to a subject having a neoplasm responsive to said administration.  
     
     
         16 . A method for inhibiting synthesis of nitric oxide from plasma arginine in a subject which comprises administering an effective amount of the compound of  claim 8  to the subject in need of said inhibition.  
     
     
         17 . A method for ameliorating cachexia in a subject in need of said amelioration which comprises blocking the uptake of arginine by macrophages in the subject.  
     
     
         18 . A method for ameliorating cachexia in a subject in need of said amelioration which comprises blocking the activity of argininase in macrophages in the subject.  
     
     
         19 . A method of ameliorating cachexia in a subject which comprises administering to the subject in need of said amelioration a compound effective to inhibit synthesis of urea by macrophages.  
     
     
         20 . A method for ameliorating the deleterious effects of nitric oxide synthesis in a subject which comprises blocking the uptake of arginine by blood and blood vessel cells of the subject.