NITROSATED AND NITROSYLATED CYCLOOXYGENASE-2 INHIBITORS, COMPOSITIONS AND METHODS OF USE

1 . A compound of Formula (V) or a pharmaceutically acceptable salt thereof: wherein the compound of formula (V) is:

wherein:

X 5 is:

(a) oxygen; or

(b) sulfur;

R 31 is:

(a) alkoxy;

(b) haloalkoxy preferably —OCH 2 F, —OCHF 2 , or —OCHF 2 ;

(c) alkylthio;

(d) haloalkyl, preferably CF 3 ;

(e) halo; or

(f) lower alkyl;

R 32 , R 33 , R 34 , R 35 , R 36 and R 37 are each independently:

(a) hydrogen;

(b) halo, preferably F or Cl;

(c) lower alkyl;

(d) cycloalkyl;

(e) haloalkyl, preferably CF 3 , CF 2 H or CFH 2 ;

(f) —OD 1 ;

(g) —OR 43 ;

(h) —SD 1 ;

(i) —SR 43 ;

(j) —S(O)R 43 ;

(k) —S(O) 2 R 43 ;

(l) unsubstituted, mono- or di-substituted benzyl, wherein the substituents are each independently:

(1) haloalkyl, preferably CF 3 ;

(2) CN;

(3) halo;

(4) lower alkyl;

(5) —OR 43 ;

(6) —SR 43 ;

(7) —S(O)R 43 ; or

(8) —S(O) 2 R 41 ;

(m) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently:

(1) haloalkyl, preferably CF 3 ;

(2) CN;

(3) halo;

(4) lower alkyl;

(5) —OR 43 ;

(6) —SR 43 ;

(7) —S(O)R 43 ; or

(8) —S(O) 2 R 41 ; or

R 32 together with R 33 form an oxo group; or

R 34 together with R 35 form an oxo group; or

R 36 together with R 37 form an oxo group; or

R 32 and R 33 are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and, optionally, contain one heteroatom which is preferably oxygen; or

R 33 and R 34 are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or

R 33 and R 36 are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or

R 34 and R 35 are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and optionally, contain one heteroatom which is preferably oxygen; or

R 34 and R 36 are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or

R 36 and R 37 are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and, optionally, contain one heteroatom which is preferably oxygen;

R 38 and R 39 are hydrogen or R 38 and R 39 when taken together are oxo;

R 40 , R 41 and R 42 are each independently:

(c) hydrogen;

(d) halo;

(c) lower alkyl;

(d) alkoxy;

(e) alkylthio;

(f) —S(O)-lower alkyl;

(g) haloalkyl, preferably CF 3 ;

(h) CN;

(i) —N 3 ;

(j) —NO 2 ;

(k) —SCF 3 ; or

(l) —OCF 3 ;

R 43 is:

(a) lower alkyl; or

(b) benzyl, optionally mono- or di-substituted, wherein the substituents are each independently:

(1) haloalkyl, preferably CF 3 ;

(2) CN;

(3) halo; or

(4) lower alkyl;

alternatively, X 5 and U taken together with the carbon atom to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring;

n at each occurrence is an integer from 0 to 1;

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 f )) 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-;

(b) alkyl;

(c) aryl;

(d) —(C(R e )(R f )) h —;

(e) heterocyclic ring;

(f) arylheterocyclic ring; or

(g) -(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;

(b) alkyl;

(c) cycloalkoxy;

(d) halogen;

(e) hydroxy;

(f) hydroxyalkyl;

(g) alkoxyalkyl;

(h) arylheterocyclic ring;

(i) cycloalkylalkyl;

(j) heterocyclicalkyl;

(k) alkoxy;

(l) haloalkoxy;

(m) amino;

(n) alkylamino;

(o) dialkylamino;

(p) arylamino;

(q) diarylamino;

(r) alkylarylamino;

(s) alkoxyhaloalkyl;

(t) haloalkoxy;

(u) sulfonic acid;

(v) alkylsulfonic acid;

(w) arylsulfonic acid;

(x) arylalkoxy;

(y) alkylthio;

(z) arylthio;

(aa) cyano;

(bb) aminoalkyl;

(cc) aminoaryl;

(dd) alkoxy;

(ee) aryl;

(ff) arylalkyl;

(gg) carboxamido;

(hh) alkylcarboxamido;

(ii) arylcarboxamido;

(jj) amidyl;

(kk) carboxyl;

(ll) carbamoyl;

(mm) alkylcarboxylic acid;

(nn) arylcarboxylic acid;

(oo) alkylcarbonyl;

(pp) arylcarbonyl;

(qq) ester;

(rr) carboxylic ester;

(ss) alkylcarboxylic ester;

(tt) arylcarboxylic ester;

(uu) haloalkoxy;

(vv) sulfonamido;

(ww) alkylsulfonamido;

(xx) arylsulfonamido;

(yy) alkylsulfonyl,

(zz) alkylsulfonyloxy,

(aaa) arylsulfonyl,

(bbb) arylsulphonyloxy

(ccc) sulfonic ester;

(ddd) carbamoyl;

(eee) urea;

(fff) nitro; or

(ggg) —U—V; or

R e and R f taken together are:

(a) oxo;

(b) thial; or

R e and R f taken together with the carbon to which they are attached are:

(a) heterocyclic ring;

(b) cycloalkyl group; or

(c) bridged cycloalkyl group;

k is an integer from 1 to 2;

T at each occurrence is independently:

(a) a covalent bond,

(b) carbonyl,

(c) an oxygen,

(d) —S(O) o —; or

(e) —N(R a )R i —;

o is an integer from 0 to 2;

Q is:

(a) —C(O)—U-D 1 ;

(b) —CO 2 -lower alkyl;

(c) tetrazolyl-5-yl;

(d) —C(R 7 )(R 8 )(S-D 1 );

(e) —C(R 7 )(R 8 )(O-D 1 ); or

(f) —C(R 7 )(R 8 )(O-lower alkyl);

R a is:

(a) a lone pair of electron;

(b) hydrogen; or

(c) lower alkyl;

R i is:

(a) hydrogen;

(b) alkyl;

(c) aryl;

(d) alkylcarboxylic acid;

(e) arylcarboxylic acid;

(f) alkylcarboxylic ester;

(g) arylcarboxylic ester;

(h) alkylcarboxamido;

(i) arylcarboxamido;

(j) alkylsulfinyl;

(k) alkylsulfonyl;

(l) alkylsulfonyloxy,

(m) arylsulfinyl;

(n) arylsulfonyl;

(o) arylsulphonyloxy;

(p) sulfonamido;

(q) carboxamido;

(r) carboxylic ester;

(s) aminoalkyl;

(t) aminoaryl;

(u) —CH 2 —C(U—V)(R e )(R f );

(v) a bond to an adjacent atom creating a double bond to that atom; or

(w) —(N 2 O 2 —) − M + , wherein M + is an organic or inorganic cation; and

with the proviso that the compounds of Formula V must contain at least one nitrite, nitrate, thionitrite or thionitrate group.

2 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

3 . A method for (i) treating or reducing inflammation, pain or fever; (ii) treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor; (iii) facilitating wound healing; (iv) treating or reversing renal toxicity; (v) treating a disorder resulting from elevated levels of COX-2; or (vi) inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2 .

4 . The composition of claim 2 , 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.

5 . The composition of claim 4 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase 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 receptor antagonist, an antineoplastic agent, an antiplatelet agent, 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.

6 . The composition of claim 5 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen or naproxen.

7 . The composition of claim 4 , further comprising a pharmaceutically acceptable carrier.

8 . A method for (i) treating or reducing inflammation, pain or fever; (ii) treating a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor; (iii) facilitating wound healing; (iv) treating or reversing renal toxicity; (v) treating a disorder resulting from elevated levels of COX-2; or (vi) inhibiting platelet aggregation in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 7 .

9 . A kit comprising at least one compound of claim 1 .

10 . The kit of claim 9 , 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.

11 . The kit of claim 10 , 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

12 . A compound selected from the group consisting of (2-(1-((4-chlorophenyl)methyl)-5-methoxy-2-methylindol-3-yl)ethyl)nitrooxy, 2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)-N-(2-methyl-2-(nitrosothio)propyl)acetamide, or a pharmaceutically acceptable salt thereof.

13 . A composition comprising at least one compound of claim 12 and a pharmaceutically acceptable carrier.

14 . The composition of claim 13 , 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.

15 . A kit comprising at least one compound of claim 12 .