Cyclooxygenase-2 selective inhibitors, compositions and methods of use

Abstract

The invention provides novel cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions and kits comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

1 . A compound of Formula (IV) or a pharmaceutically acceptable salt thereof; 
 wherein the compound of Formula (IV) is:                          wherein:    X 4  and Z 4  are each independently: 
 (a) N; or  
 (b) CR 21 ;  
   R 20  is: 
 (a) —S(O) 2 —CH 3 ;  
 (b) —S(O) 2 —NR 8 (D 1 ); or  
 (c) —S(O) 2 —N(D 1 )—C(O)—CF 3 ;  
   R 21  and R 21′  are each independently: 
 (a) hydrogen;  
 (b) lower alkyl;  
 (c) alkoxy;  
 (d) alkylthio;  
 (e) haloalkyl, preferably fluoroalkyl;  
 (f) haloalkoxy, preferably fluoroalkoxy;  
 (g) CN;  
 (h) —CO 2 D 1 ;  
 (i) —CO 2 R 14 ;  
 (j) lower alkyl-O-D 1 ;  
 (k) lower alkyl-CO 2 D 1 ;  
 (l) lower alkyl-CO 2 R 14 ;  
 (m) halo;  
 (n) —O-D 1 ;  
 (o) —N 3 ;  
 (p) —NO 2 ;  
 (q) —NR 14 D 1 ;  
 (r) —N(D 1 )C(O)R 14 ;  
 (s) —NHK;  
 (t) aryl;  
 (u) arylalkylthio;  
 (v) arylalkoxy;  
 (w) alkylamino;  
 (x) aryloxy;  
 (y) alkylarylalkylamino;  
 (z) cycloalkylalkylamino; or  
 (aa) cycloalkylalkoxy;  
   R 22  is: 
 (a) mono-, di- or tri-substituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituent are each independently: 
 (1) hydrogen;  
 (2) halo;  
 (3) alkoxy;  
 (4) alkylthio;  
 (5) CN;  
 (6) lower alkyl;  
 (7) haloalkyl, preferably fluoroalkyl;  
 (8) N 3 ;  
 (9) —CO 2 D 1 ;  
 (10) —CO 2 -lower alkyl;  
 (11) —C(R 14 )(R 15 )—OD 1 ;  
 (12) —OD 1 ;  
 (13) lower alkyl-CO 2 —R 14 ; or  
 (14) lower alkyl-CO 2 -D 1 ;  
 
 (b) -T-C(R 23 )(R 24 )—(C(R 25 )(R 26 )) o —C(R 27 )(R 28 )—U-D 1 ;  
                     
 (d) arylalkyl; or  
 (e) cycloalkylalkyl;  
 wherein:  
   R 14  and R 15  are each independently: 
 (a) hydrogen; or  
 (b) lower alkyl;  
   R 23 , R 24 , R 25 , R 26 , R 27 , R 28  are each independently: 
 (a) hydrogen; or  
 (b) lower alkyl; or  
   R 23  and R 27 , or R 27  and R 28  together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R 23  and R 25  are joined to form a covalent bond;    Y 5  is: 
 (a) CR 29 R 30 ;  
 (b) oxygen; or  
 (c) sulfur;  
   R 29  and R 30  are each independently: 
 (a) hydrogen;  
 (b) lower alkyl;  
 (c) (CH 2 ) o —OD 1 ;  
 (d) halo; or  
   R 29  and R 30  taken together are an oxo group;    s is an integer from 2 to 4;    R 1  is: 
 (a) —S(O) 2 —CH 3 ;  
 (b) —S(O) 2 —NR 8 (D 1 );  
 (c) —S(O) 2 —N(D 1 )—C(O)—CF 3 ;  
 (d) —S(O)—(NH)—NH(D 1 );  
 (e) —S(O)—(NH)—N(D 1 )-C(O)—CF 3 ;  
 (f) —P(O)(CH 3 )NH(D 1 );  
 (g) —P(O)(CH 3 ) 2 ;  
 (h) —C(S)—NH(D 1 );  
 (i) —S(O)(NH)CH 3 ;  
 (j) —P(O)(CH 3 )OD 1 ; or  
 (k) —P(O)(CH 3 )NH(D 1 );  
   R 8  is: 
 (a) hydrogen;  
 (b) K; or  
 (c) R 9 ;  
   R 9  is: 
 (a) lower alkyl;  
 (b) lower alkyl-CO 2 D 1 ;  
 (c) lower alkyl-NHD 1 ;  
 (d) phenyl or mono-, di- or tri-substituted phenyl, wherein the substituents are each independently: 
 (1) halo;  
 (2) lower alkyl;  
 (3) alkoxy;  
 (4) alkylthio;  
 (5) lower alkyl-CO 2 D 1 ;  
 (6) lower alkyl-NHD 1 ;  
 (7) CN;  
 (8) CO 2 D 1 ; or  
 (9) haloalkyl, preferably fluoroalkyl;  
 
 (e) benzyl, mono-, di- or tri-substituted benzyl, wherein the substituents are each independently: 
 (1) halo;  
 (2) lower alkyl;  
 (3) alkoxy;  
 (4) alkylthio;  
 (5) lower alkyl-CO 2 D 1 ;  
 (6) lower alkyl-NHD;  
 (7) CN;  
 (8) —CO 2 D 1 ; or  
 (9) haloalkyl, preferably CF 3 ;  
 
 (f) cycloalkyl;  
 (g) K; or  
 (h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein the substituents are each independently: 
 (1) halo;  
 (2) lower alkyl;  
 (3) alkoxy;  
 (4) alkylthio;  
 (5) lower alkyl-CO 2 D 1 ;  
 (6) lower alkyl-NHD 1 ;  
 (7) CN;  
 (8) —CO 2 D 1 ; or  
 (9) haloalkyl, preferably CF 3 ;  
 
   X 5  is: 
 (a) —(CR 31 R 32 ) a —;  
 (b) —(CR 31 R 32 ) bb -A 1 -;  
 (c) -A 1 -(CR 31 R 32 ) bb —;  
 (d) —CR 31 R 32 -A 1 -CR 31 R 32 —;  
 (e) —CR 31 ═; or  
 (f) -A 1 ;  
   A 1  is: 
 (a) oxygen;  
 (b) thio;  
 (c) sulfinyl;  
 (d) sulfonyl; or  
 (c) —N(R 33 )—;  
   R 31  and R 32  are each independently: 
 (a) hydrogen;  
 (b) lower alkyl;  
 (c) substituted lower alkyl;  
 (d) lower alkoxy;  
 (e) lower haloalkyl; or  
 (f) halo; or  
   R 31  and R 32  taken together are; 
 (a) oxo;  
 (b) thial;  
 (c) oxime; or  
 (d) hydrazone;  
   R 33  is: 
 (a) lower alkyl;  
 (b) hydrogen; or  
 (c) —C(O)H;  
   a is an integer equal to 1 or 3;    bb is an integer equal to 2 or 3;    D 1  is: 
 (a) hydrogen or  
 (b) D;  
   D is: 
 (a) V; or  
 (b) K;  
   U is: 
 (a) oxygen;  
 (b) sulfur; or  
 (c) —N(R a )(R i )—;  
   V is: 
 (a) —NO;  
 (b) —NO 2 ; or  
 (c) hydrogen  
   K is —W aa -E b -(C(R e )(R f )) p -E c -(C(R e )(R f )) x —W d —(C(R e )(R f )) y —W i -E j -W g —(C(R e )(R f )) z —U—V; wherein aa, b, c, d, g, i and j are each independently an integer from 0 to 3;    p, x, y and z are each independently an integer from 0 to 10;    W at each occurrence is independently: 
 (a) —C(O)—;  
 (b) —C(S)—;  
 (c) -T-;  
 (d) —(C(R e )(R i )) h —;  
 (e) alkyl;  
 (f) aryl;  
 (g) heterocyclic ring;  
 (h) arylheterocyclic ring, or  
 (i) —(CH 2 CH 2 O) q —;  
   E at each occurrence is independently a -T- group, an alkyl group, an aryl group, a heterocyclic ring, —(C(R e )(R f )) h —, an arylheterocyclic ring or —(CH 2 CH 2 O) q —;    h is an integer form 1 to 10;    q is an integer from 1 to 5;    R e  and R f  are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or —(C(R g )(R h )) k -T-Q′ or R e  and R f  taken together are an oxo, a thial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone or a bridged cycloalkyl group;    Q′ is —NO or —NO 2 ;    k is an integer from 1 to 3;    T is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R a )R i —,    o is an integer from 0 to 2,    R a  is a lone pair of electrons, a hydrogen or an alkyl group;    R i  is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —OR′ i , —CH 2 —C(T-Q′)(R g )(R h ), a bond to an adjacent atom creating a double bond to that atom or —(N 2 O 2 -) − .M + , wherein M +  is an organic or inorganic cation; with the proviso that when R i  is —CH 2 —C(T-Q′)(R g )(R h) or —(N   2 O 2 -).M + ; then “-T-Q′” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group;    R g  and R h  at each occurrence are independently R e;  and    R′ i  is independently selected from R i .    
     
     
         2 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         3 . A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 .  
     
     
         4 . A method for treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 .  
     
     
         5 . The method of  claim 4 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia  
     
     
         6 . A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 .  
     
     
         7 . The method of  claim 6 , wherein the wound is an ulcer.  
     
     
         8 . A method for treating or reversing renal and/or respiratory toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 .  
     
     
         9 . A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 .  
     
     
         10 . The method of  claim 9 , wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.  
     
     
         11 . The method of  claim 10 , wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.  
     
     
         12 . The method of  claim 10 , wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.  
     
     
         13 . A method for inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 2 .  
     
     
         14 . The composition of  claim 2 , further comprising at least one therapeutic agent.  
     
     
         15 . The composition of  claim 14 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B 4  receptor antagonist, a leukotriene A 4  hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H 2  antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a  Helicobacter pylori  inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof.  
     
     
         16 . The composition of  claim 15 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.  
     
     
         17 . A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 .  
     
     
         18 . A method for treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 .  
     
     
         19 . The method of  claim 18 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.  
     
     
         20 . A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 .  
     
     
         21 . The method of  claim 20 , wherein the wound is an ulcer.  
     
     
         22 . A method for treating or reversing renal and/or respiratory toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 .  
     
     
         23 . A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 .  
     
     
         24 . The method of  claim 23 , wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.  
     
     
         25 . The method of  claim 24 , wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.  
     
     
         26 . The method of  claim 24 , wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.  
     
     
         27 . A method for inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 14 .  
     
     
         28 . A composition comprising at least one compound of  claim 1  and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.  
     
     
         29 . The composition of  claim 28 , further comprising a pharmaceutically acceptable carrier.  
     
     
         30 . The composition of  claim 28 , wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.  
     
     
         31 . The composition of  claim 30 , wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.  
     
     
         32 . The composition of  claim 30 , wherein the S-nitrosothiol is: 
 (i) HS(C(R e )(R f )) m SNO;    (ii) ONS(C(R e )(R f )) m R e ; or    (iii) H 2 N—CH(CO 2 H)—(CH 2 ) m —C(O)NH—CH(CH 2 SNO)—C(O)NH—CH 2 —CO 2 H;    wherein m is an integer from 2 to 20; R e  and R f  are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or —(C(R g )(R h )) k -T-Q′ or R e  and R f  taken together are an oxo, a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone or a bridged cycloalkyl group; Q′ is —NO or —NO 2 ; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R a )R i —, wherein o is an integer from 0 to 2, R a  is a lone pair of electrons, a hydrogen or an alkyl group; R i  is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH 2 —C(T-Q′)(R g )(R h ), or —(N 2 O 2 -) − .M + , wherein M +  is an organic or inorganic cation; with the proviso that when R i  is —CH 2 —C(T-Q′)(R g )(R h ) or —(N 2 O 2 -).M + ; then “-T-Q′” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group; and R g  and R h  at each occurrence are independently R e .    
     
     
         33 . The composition of  claim 28 , wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylated L-homoarginine), citrulline, ornithine, glutamine, lysine, an arginase inhibitor or a nitric oxide mediator.  
     
     
         34 . The composition of  claim 28 , wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is: 
 (i) a compound that comprises at least one ON—O— or ON—N— group;    (ii) a compound that comprises at least one O 2 N—O—, O 2 N—N— or O 2 N—S— or group;    (iii) a N-oxo-N-nitrosoamine having the formula: R 1″ R 2″ N—N(O-M + )-NO, wherein R 1″  and R 2″  are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M +  is an organic or inorganic cation.    
     
     
         35 . The composition of  claim 34 , wherein the compound comprising at least one ON—O— or ON—N— group is an ON—O-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, an ON—N-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, an ON—O-heterocyclic compound or an ON—N-heterocyclic compound.  
     
     
         36 . The composition of  claim 34 , wherein compound comprising at least one O 2 N—O—, O 2 N—N— or O 2 N—S— group is an O 2 N—O-polypeptide, an O 2 N—N-polypeptide, an O 2 N—S-polypeptide, an O 2 N—O-amino acid, O 2 N—N-amino acid, O 2 N—S-amino acid, an O 2 N—O-sugar, an O 2 N—N-sugar, O 2 N—S-sugar, an O 2 N—O-oligonucleotide, an O 2 N—N-oligonucleotide, an O 2 N—S-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—S-hydrocarbon, an O 2 N—O-heterocyclic compound, an O 2 N—N-heterocyclic compound or an O 2 N—S-heterocyclic compound.  
     
     
         37 . The composition of  claim 28 , further comprising at least one therapeutic agent.  
     
     
         38 . The composition of  claim 37 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B 4  receptor antagonist, a leukotriene A 4  hydrolase inhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H 2  antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a  Helicobacter pylori  inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof.  
     
     
         39 . The composition of  claim 38 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.  
     
     
         40 . A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 29  or  37 .  
     
     
         41 . A method for treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 29  or  37 .  
     
     
         42 . The method of  claim 41 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.  
     
     
         43 . A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 29  or  37 .  
     
     
         44 . The method of  claim 43 , wherein the wound is an ulcer.  
     
     
         45 . A method for treating or reversing renal and/or respiratory toxicity in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 29  or  37 .  
     
     
         46 . A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 29  or  37 .  
     
     
         47 . The method of  claim 46 , wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.  
     
     
         48 . The method of  claim 47 , wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.  
     
     
         49 . The method of  claim 47 , wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.  
     
     
         50 . A method for inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 29  or  37 .  
     
     
         51 . A kit comprising at least one compound of  claim 1 .  
     
     
         52 . The kit of  claim 51 , further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent.  
     
     
         53 . The kit of  claim 52 , wherein the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; the at least one therapeutic agent; or the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent; are in the form of separate components in the kit  
     
     
         54 . A kit comprising the composition of  claim 14 ,  29  or  37 .  
     
     
         55 . A compound selected from the group consisting of: 
 3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl)phenyl ketone;    2-(3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl))-2-phenylethanenitrile;    3-fluorophenyl 2-(4-methylsulfonylphenyl)(3-pyridyl) ketone;    2-(4-(methylsulfonyl)phenyl)(3-pyridyl) 2-pyridyl ketone;    ethyl 3-((2-(4-(methylsulfonyl)phenyl)-3-pyridyl)carbonyl)benzoate; or a pharmaceutically acceptable salt thereof.    
     
     
         56 . A composition comprising at least one compound of  claim 55  and a pharmaceutically acceptable carrier.  
     
     
         57 . The composition of  claim 56 , further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent.  
     
     
         58 . A kit comprising at least one compound of  claim 55.