Cyclooxygenase-2 selective inhibitors, compositions and methods of use

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.