Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs

Abstract

Nonsteroidal antiinflammatory drugs which have been substituted with a nitrogen monoxide group; compositions comprising (i) a nonsteroidal antiinflammatory drug, which can optionally be substituted with a nitrogen monoxide group and (ii) a compound that directly donates, transfers or releases a nitrogen monoxide group (preferably as a charged species, particularly nitrosonium); and methods of treatment of inflammation, pain, gastrointestinal lesions and/or fever using the compositions are disclosed. The compounds and compositions protect against the gastrointestinal, renal and other toxicities that are otherwise induced by nonsteroidal antiinflammatory drugs.

1 . A non-steroidal antiinflammatory agent to which is directly or indirectly linked at least one NO group.  
     
     
         2 . The non-steroidal antiinflammatory agent of  claim 1  which is selected from the group consisting of compounds having the structures:  
       
         
           
           
               
               
           
         
       
       wherein 
 D is selected from (i) a covalent bond; (ii) —C(R a )—O—C(O)—Y—[C(R b )(R c )] P -T- in which R a  is lower alkyl, cycloalkyl, aryl or heteroaryl, Y is oxygen, sulfur, or NR i  in which R i  is hydrogen or lower alkyl, R b  and R c  are independently selected from, hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino or taken together are cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6 and T is a covalent bond, oxygen, sulfur, or nitrogen; or (iii) —(CO)-T 1 -[C(R b )(R c )] P -T 2 - wherein T 1  and T 2  are independently selected from T, and wherein R b , R c , p and T are as defined above;  
 Z is an aryl or heteroaryl; and  
 A 1 , A 2  and A 3  comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and each is independently selected from (1) C—R 1  wherein R 1  at each occurrence is independently selected from hydrogen, lower alkyl, lower haloalkyl, alkoxyalkyl, halogen or nitro; (2) N—R d  wherein R d  at each occurrence is independently selected from a covalent bond to an adjacent ring atom in order to render the ring aromatic, hydrogen, lower alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl; (3) sulfur; (4) oxygen; and (5) B a =B b  wherein B a  and B b  are each independently selected from nitrogen or C—R 1  wherein at each occurrence R 1  is as defined above; the structures:  
                     
 wherein  
 R b , R c , D, Z, A 1 , A 2  and A 3  are as defined above;  
 the structures:  
                     
 wherein  
 R e  is hydrogen or lower alkyl;  
 R f  is selected from  
                                                                           
 in which n is 0 or 1; and  
 X is (1)-Y-[C(R b )(R c )] P -G-[C(R b )(R c ) p -T-NO, wherein G is (i) a covalent bond; (ii) -T-C(O)—; (iii) —C(O)-T; (iv) —C(Y—C(O)—R m )— wherein R m  is heteroaryl or heterocyclic ring; and in which Y, R b , R c , p and T are as defined above; or (2)  
                     
 in which W is a heterocyclic ring or NR h R i  wherein R h  and R i  are independently selected from lower alkyl, aryl or alkenyl; and the structures:  
                     
 wherein  
 R g  is selected from  
                                       
 and X is defined as above.