Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs

A composition comprising (i) a therapeutical effective amount of a nonsteroidal antiinflammatory drug having the structure ##STR22## wherein X is (1) --Y--›C(R.sub.b)(R.sub.c)!.sub.p --G--›C(R.sub.b)(R.sub.c)!.sub.p --T--NO, wherein G is (i) a covalent bond;

• (ii) --T--C(O)--;
• (iii) --C(O)--T;
• (iv) --C(Y--C(O)--R.sub.m)-- wherein R.sub.m is heteroaryl or heterocyclic ring;
• and in which Y is oxygen, sulfur or NR.sub.i in which NR.sub.i is hydrogen or lower alkyl, R.sub.b and R.sub.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 (2) ##STR23## in which W is a heterocyclic ring or NR.sub.h R.sub.i wherein R.sub.h and R.sub.i are independently selected from lower alkyl, aryl or alkenyl;
• and R.sub.g is selected from ##STR24## and (ii) an NSAID toxicity reducing amount of a compound that donates nitric oxide, transfers nitric oxide, releases nitric oxide, or elevates endogenous synthesis levels of nitric oxide.

A composition comprising (i) a non-steroidal antiinflammatory agent ##STR25## wherein X is (1) --Y--›C(R.sub.b)(R.sub.c)!.sub.p --G--›C(R.sub.b)(R.sub.c)!.sub.p --T--NO, wherein G is (i) a covalent bond;

• (ii) --T--C(O)--;
• (iii) --C(O)--T;
• (iv) --C(Y--C(O)--R.sub.m)-- wherein R.sub.m is heteroaryl or heterocyclic ring;
• and in which Y is oxygen, sulfur or NR.sub.i in which NR.sub.i is hydrogen or lower alkyl, R.sub.b and R.sub.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 (2) ##STR26## in which W is a heterocyclic ring or NR.sub.h R.sub.i wherein R.sub.h and R.sub.i are independently selected from lower alkyl, aryl or alkenyl;
• and
• R.sub.g is selected from ##STR27## to which is directly or indirectly linked at least one NO group and (ii) a compound that donates nitric oxide, transfers nitric oxide, releases nitric oxide, or elevates endogenous synthesis levels of nitric oxide.

A method for treating intimation, pain, gastrointestinal lesions or fever in an animal in need thereof which comprises co-administering to said animal a therapeutically effective amount of a nonsteroidal antiinflammatory drug having the structure ##STR28## wherein X is (1) --Y--›C(R.sub.b)(R.sub.c)!.sub.p --G--›C(R.sub.b)(R.sub.c)!.sub.p --T--NO, wherein G is (i) a covalent bond;

• (ii) --T--C(O)--;
• (iii) --C(O)--T;
• (iv) --C(Y--C(O)--R.sub.m)-- wherein R.sub.m is heteroaryl or heterocyclic ring;
• and in which Y is oxygen, sulfur or NR.sub.i in which NR.sub.i is hydrogen or lower alkyl, R.sub.b and R.sub.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 (2) ##STR29## in which W is a heterocyclic ring or NR.sub.h R.sub.i wherein R.sub.h and R.sub.1 are independently selected from lower alkyl, aryl or alkenyl;
• and
• R.sub.g is selected from ##STR30## and a nonsteroidal antiinflammatory drug gastrointestinal toxicity reducing amount of a compound that donates nitric oxide, transfers nitric oxide, release nitric oxide, or elevates endogenous synthesis levels of nitric oxide.

A method of reducing the gastrointestinal toxicity of nonsteroidal antiinflammatory drugs administered to an animal which comprises co-administering to said animal a nonsteroidal antiinflammatory drug gastrointestinal toxicity reducing mount of a compound that donates nitric oxide, transfers nitric oxide, releases nitric oxide, or elevates endogenous synthesis levels of nitric oxide and a nonsteroidal antiinflammatory drug having the structure ##STR31## wherein X is (1) --Y--›C(R.sub.b)(R.sub.c)!.sub.p --G--›C(R.sub.b)(R.sub.c)!.sub.p --T--NO, wherein G is (i) a covalent bond;

• (ii) --T--C(O)--;
• (iii) --C(O)--T;
• (iv) --C(Y--C(O)--R.sub.m)-- wherein R.sub.m is heteroaryl or heterocyclic ring;
• and in which Y is oxygen, sulfur or NR.sub.i in which NR.sub.i is hydrogen or lower alkyl, R.sub.b and R.sub.c are independently selected from, hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino or taken together arc cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6 and T is a covalent bond, oxygen, sulfur, or nitrogen;
• or (2) ##STR32## in which W is a heterocyclic ring or NR.sub.h R.sub.i wherein R.sub.h and R.sub.i are independently selected from lower alkyl, aryl or alkenyl;
• and
• R.sub.g is selected from ##STR33##

A method of reducing the renal toxicity of nonsteroidal antiinflammatory drugs administered to an animal which comprises co-administering to said animal a nonsteroidal antiinflammatory drug renal toxicity reducing amount of a compound that donates nitric oxide, transfers nitric oxide, release nitric oxide, or elevates endogenous synthesis levels of nitric oxide and a nonsteroidal antiinflammatory drug having the structure ##STR34## wherein X is (1) --Y--›C(R.sub.b)(R.sub.c)!.sub.p --G--›C(R.sub.b)(R.sub.c)!.sub.p --T--NO, wherein G is (i) a covalent bond;

• (ii) --T--C(O)--;
• (iii) --C(O)--T;
• (iv) --C(Y--C(O)-- wherein R.sub.m is heteroaryl or heterocyclic ring;
• and in which Y is oxygen, sulfur or NR.sub.i in which NR.sub.i is hydrogen or lower alkyl, R.sub.b and R.sub.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 (2) ##STR35## in which W is a heterocyclic ring or NR.sub.h R.sub.i wherein R.sub.b and R.sub.i are independently selected from lower alkyl, aryl or alkenyl;
• and
• R.sub.g is selected from ##STR36##