Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs
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.