ORGANIC NITRIC OXIDE DONOR SALTS OF NONSTEROIDAL ANTIINFLAMMATORY COMPOUNDS, COMPOSITIONS AND METHODS OF USE

1 . A compound of Formula (I) or (II):

wherein the compound of Formula (I) is:

wherein:

R m is a hydrogen or a lower alkyl group;

R n is:

s is an integer of 0 or 1;

Z is an organic base or —N(R 38 )(R 39 )(R 40 );

R 38 , R 39 and R 40 are each independently selected from K or R e , or R 38 and R 39 taken together with the nitrogen to which they are attached are a heterocyclic ring, with the proviso that when the heterocyclic ring is an aromatic ring it can be substituted at any position by L and R 39 is not present;

L is —(W 3 ) a -E b -(C(R e )(R f )) p1 -E c -(C(R e )(R f )) x —(W 3 ) d —(C(R e )(R f )) y —(W 3 ) i -E j -(W 3 ) g —(C(R e )(R f )) z —V 4 ;

K is —(W 3 ) a -E b -(C(R e )(R f )) p1 -E c -(C(R e )(R f )) x —(W 3 ) d —(C(R e )(R f )) y —(W 3 ) i -E j -(W 3 ) g —(C(R e )(R f )) z —V 4 ;

a, b, c, d, g, i and j are each independently an integer from 0 to 3;

p 1 , x, y and z are each independently an integer from 0 to 10;

V 4 is V 3 , R e , —U 3 —V 5 or V 6 ;

V 3 is:

R 24 is —C 6 H 4 R 37 , —CN, —S(O) 2 —C 6 H 4 R 37 , —C(O)—N(R a )(R i ), —NO 2 , —C(O)—OR 25 or —S(O) 2 —R 25 ;

R 25 is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;

R 26 is —C(O)— or —S(O) 2 —;

R 37 is a hydrogen, —CN, —S(O) 2 —R 25 , —C(O)—N(R a )(R i ), —NO 2 or —C(O)—OR 25 ;

T′ is oxygen, sulfur or NR 16 ;

R 16 is a hydrogen, a lower alkyl group, or an aryl group;

V 6 is:

Z 5 is —CH 2 or oxygen;

Z 6 is —CH or nitrogen;

W 3 at each occurrence is independently —C(O)—, —C(S)—, -T 3 -, —(C(R e )(R f )) h —, —N(R a )R i , an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, —(CH 2 CH 2 O) q1 — or a heterocyclic nitric oxide donor;

E at each occurrence is independently -T 3 -, an alkyl group, an aryl group, —(C(R e )(R f )) h —, a heterocyclic ring, an arylheterocyclic ring, —(CH 2 CH 2 O) q1 — or Y 4 ;

Y 4 is:

T is a —S(O) o —; a carbonyl or a covalent bond;

o is an integer from 0 to 2;

R j and R k are independently selected from an alkyl group, an aryl group, or R j and R k taken together with the nitrogen atom to which they are attached are a heterocylic ring;

T 3 at each occurrence is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R a )R i ;

h is an integer form 1 to 10;

q 1 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, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, 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, an alkylaryl, a carboxamido, an 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 sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, —U 3 —V 5 , V 6 , —(C(R o )(R p )) k1 —U 3 —V 5 , —(C(R o )(R p )) k1 —U 3 —V 3 , —(C(R o )(R p )) k1 —U 3 —V 6 , —(C(R o )(R p )) k1 —U 3 —C(O)—V 6 , or R e and R f taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone, a bridged cycloalkyl group,

R o and R p are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, 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, an alkylaryl, a carboxamido, an 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 sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, —U 3 —V 5 , V 6 , or R o and R p taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone a bridged cycloalkyl group,

U 3 is an oxygen, sulfur or —N(R a )R i ;

V 5 is —NO or —NO 2 (i.e. an oxidized nitrogen);

k 1 is an integer from 1 to 3;

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 alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH 2 —C—(U 3 —V 5 )(R e )(R f ), a bond to an adjacent atom creating a double bond to that atom or —(N 2 O 2 —).M 1 + , wherein M 1 + is an organic or inorganic cation; and

with the proviso that the compound of Formula (I) must contain at least one organic nitric oxide enhancing compound linked via a salt bridge (i.e., .) to at least one carboxylic acid group;

wherein the compound of Formula (II):

wherein:

R q is:

and Z is as defined herein; and

with the proviso that the compounds of Formula (II) must contain at least one organic nitric oxide enhancing compound linked via a salt bridge (i.e., .) to at least one carboxylic acid group.

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

3 . The compound of claim 1 , wherein the compound of Formula (I) is an organic nitric oxide enhancing salt of acemetacin, an organic nitric oxide enhancing salt of aceclofenac, an organic nitric oxide enhancing salt of alclofenac, an organic nitric oxide enhancing salt of alminoprofen, an organic nitric oxide enhancing salt of amfenac, an organic nitric oxide enhancing salt of bendazac, an organic nitric oxide enhancing salt of benoxaprofen, an organic nitric oxide enhancing salt of bromfenac, an organic nitric oxide enhancing salt of bucloxic acid, an organic nitric oxide enhancing salt of butibufen, an organic nitric oxide enhancing salt of carprofen, an organic nitric oxide enhancing salt of cinmetacin, an organic nitric oxide enhancing salt of clopirac, an organic nitric oxide enhancing salt of diclofenac, an organic nitric oxide enhancing salt of etodolac, an organic nitric oxide enhancing salt of felbinac, an organic nitric oxide enhancing salt of fenclozic acid, an organic nitric oxide enhancing salt of fenbufen, an organic nitric oxide enhancing salt of fenoprofen, an organic nitric oxide enhancing salt of fentiazac, an organic nitric oxide enhancing salt of flunoxaprofen, an organic nitric oxide enhancing salt of flurbiprofen, an organic nitric oxide enhancing salt of ibufenac, an organic nitric oxide enhancing salt of ibuprofen, an organic nitric oxide enhancing salt of indomethacin, an organic nitric oxide enhancing salt of isofezolac, an organic nitric oxide enhancing salt of isoxepac, an organic nitric oxide enhancing salt of indoprofen, an organic nitric oxide enhancing salt of ketoprofen, an organic nitric oxide enhancing salt of lonazolac, an organic nitric oxide enhancing salt of loxoprofen, an organic nitric oxide enhancing salt of metiazinic acid, an organic nitric oxide enhancing salt of mofezolac, an organic nitric oxide enhancing salt of miroprofen, an organic nitric oxide enhancing salt of naproxen, an organic nitric oxide enhancing salt of oxaprozin, an organic nitric oxide enhancing salt of pirozolac, an organic nitric oxide enhancing salt of pirprofen, an organic nitric oxide enhancing salt of pranoprofen, an organic nitric oxide enhancing salt of protizinic acid, an organic nitric oxide enhancing salt of salicylamide O-acetic acid, an organic nitric oxide enhancing salt of sulindac, an organic nitric oxide enhancing salt of suprofen, an organic nitric oxide enhancing salt of suxibuzone, an organic nitric oxide enhancing salt of tiaprofenic acid, an organic nitric oxide enhancing salt of tolmetin, an organic nitric oxide enhancing salt of xenbucin, an organic nitric oxide enhancing salt of ximoprofen, an organic nitric oxide enhancing salt of zaltoprofen or an organic nitric oxide enhancing salt of zomepirac; and the organic nitric oxide enhancing salt of NSAID of Formula II is an organic nitric oxide enhancing salt of aspirin, an organic nitric oxide enhancing salt of acemetcin, an organic nitric oxide enhancing salt of bumadizon, an organic nitric oxide enhancing salt of carprofenac, an organic nitric oxide enhancing salt of clidanac, an organic nitric oxide enhancing salt of diflunisal, an organic nitric oxide enhancing salt of enfenamic acid, an organic nitric oxide enhancing salt of fendosal, an organic nitric oxide enhancing salt of flufenamic acid, an organic nitric oxide enhancing salt of flunixin, an organic nitric oxide enhancing salt of gentisic acid, an organic nitric oxide enhancing salt of ketorolac, an organic nitric oxide enhancing salt of meclofenamic acid, an organic nitric oxide enhancing salt of mefenamic acid, an organic nitric oxide enhancing salt of mesalamine, an organic nitric oxide enhancing salt of niflumic acid, an organic nitric oxide enhancing salt of salsalate, an organic nitric oxide enhancing salt of tolfenamic acid or an organic nitric oxide enhancing salt of tropensin.

4 . The compound of claim 1 , wherein the compound of Formula (I) is an organic nitric oxide enhancing salt of acemetacin, an organic nitric oxide enhancing salt of aceclofenac of Formula (III), an organic nitric oxide enhancing salt of alclofenac of Formula (IV), an organic nitric oxide enhancing salt of bromfenac of Formula (V), an organic nitric oxide enhancing salt of carprofen of Formula (VI), an organic nitric oxide enhancing salt of diclofenac of Formula (VII), an organic nitric oxide enhancing salt of etodolac of Formula (VIII), an organic nitric oxide enhancing salt of fenbufen of Formula (IX), an organic nitric oxide enhancing salt of fenoprofen of Formula (X), an organic nitric oxide enhancing salt of flurbiprofen of Formula (XI), an organic nitric oxide enhancing salt of ibuprofen of Formula (XII), an organic nitric oxide enhancing salt of indomethacin of Formula (XIII), an organic nitric oxide enhancing salt of ketoprofen of Formula (XIV), an organic nitric oxide enhancing salt of loxoprofen of Formula (XV), an organic nitric oxide enhancing salt of naproxen of Formula (XVI), an organic nitric oxide enhancing salt of oxaprozin of Formula (XVII), an organic nitric oxide enhancing salt of pirozolac of Formula (XVIII), an organic nitric oxide enhancing salt of sulindac of Formula (XIX), an organic nitric oxide enhancing salt of suprofen of Formula (XX), an organic nitric oxide enhancing salt of tolmetin of Formula (XXI); and the organic nitric oxide enhancing salt of NSAID of Formula II is an organic nitric oxide enhancing salt of aspirin of Formula (XXII), an organic nitric oxide enhancing salt of acemetcin of Formula (XXIII), an organic nitric oxide enhancing salt of diflunisal of Formula (XXIV), an organic nitric oxide enhancing salt of enfenamic acid of Formula (XXV), an organic nitric oxide enhancing salt of flufenamic acid of Formula (XXVI), an organic nitric oxide enhancing salt of gentisic acid of Formula (XXVII), an organic nitric oxide enhancing salt of ketorolac of Formula (XXVIII), an organic nitric oxide enhancing salt of meclofenamic acid of Formula (XXIX), an organic nitric oxide enhancing salt of mefenamic acid of Formula (XXX), an organic nitric oxide enhancing salt of mesalamine of Formula (XXXI), an organic nitric oxide enhancing salt of salsalate of Formula (XXXII) or an organic nitric oxide enhancing salt of tolfenamic acid of Formula (XXXIII);

and the compound of Formula (III) is:

and the compound of Formula (IV) is:

and the compound of Formula (V) is:

and the compound of Formula (VI) is:

and the compound of Formula (VII) is:

and the compound of Formula (VIII) is:

and the compound of Formula (IX) is:

and the compound of Formula (X) is:

and the compound of Formula (XI) is:

and the compound of Formula (XII) is:

and the compound of Formula (XIII) is:

and the compound of Formula (XIV) is:

and the compound of Formula (XV) is:

and the compound of Formula (XVI) is:

and the compound of Formula (XVII) is:

and the compound of Formula (XVIII) is:

and the compound of Formula (XIX) is:

and the compound of Formula (XX) is:

and the compound of Formula (XXI) is:

and the compound of Formula (XXII) is:

and the compound of Formula (XXIII) is:

and the compound of Formula (XXIV) is:

and the compound of Formula (XXV) is:

and the compound of Formula (XXVI) is:

and the compound of Formula (XXVII) is:

and the compound of Formula (XXVIII) is:

and the compound of Formula (XXIX) is:

and the compound of Formula (XXX) is:

and the compound of Formula (XXXI) is:

and the compound of Formula (XXXII) is:

and the compound of Formula (XXXIII) is:

Z 1 is:

with the proviso that the compounds of Formula (III) and (XXXIII) must contain at least one organic nitric oxide enhancing compound linked via a salt bridge (i.e., . or ▪) to at least one carboxylic acid group in the compounds of Formula (III) and (XXXIII).

5 . 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 .

6 . A method for treating a gastrointestinal disorder 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 gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, constipation, 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.

8 . 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 .

9 . The method of claim 8 , wherein the wound is an ulcer.

10 . A method for treating or reversing gastrointestinal, 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 .

11 . A method for treating an inflammatory disease in patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2 , wherein the inflammatory disease is a cardiovascular disorder, reperfusion injury to an ischemic organ, angiogenisis, arthritis, asthma, bronchitis, premature labor, tendinitis, bursitis, an autoimmune disease, an immunological disorder, a skin-related condition, neoplasia, an inflammatory process in a disease, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, a microbial infection, a bacterial-induced inflammation, a viral induced inflammation, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, a sexual dysfunction or activation, adhesion and infiltration of neutrophils at the site of inflammation.

12 . A method for treating an ophthalmic disorder; treating a peripheral vascular disease; treating a diseases resulting from oxidative stress; treating an endothelial dysfunction; or treating a disease caused by endothelial dysfunctions in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2 .

13 . The composition of claim 2 , further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.

14 . The composition of claim 13 , wherein the therapeutic agent is a steroid, a cyclooxygenase-2 inhibitor, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B 4 receptor antagonist, a leukotriene A 4 hydrolase inhibitor, a 5-HT agonist, an anti-hyperlipidemic compound, a H 2 antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a carbonic anhydrase inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, an Helicobacter pylori inhibitor, a phosphodiesterase inhibitor, a proton pump inhibitor, an isoprostane inhibitor, a compound used for the treatment of glaucoma, and combinations of two or more thereof.

15 . The composition of claim 13 , wherein the nitric oxide enhancing compound is selected from the group consisting of a S-nitrosothiol, a nitrite, a nitrate, a S-nitrothiol, a sydnonimine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a nitrosimine, a diazetine dioxide, an oxatriazole 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a hydroxyurea, a furoxan or a nitroxide.

16 . The method of claims 6 , 7 , 8 , 10 , 11 or 12 , further comprising administering (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.

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

18 . The kit of claim 17 , further comprising further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.

19 . The kit of claim 18 , wherein the (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound are in the form of separate components in the kit.