Nitric Oxide Enhancing Glutamic Acid Compounds, Compositions and Methods of Use

1 . A nitric oxide enhancing glutamic acid compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein the compound of Formula (I) is:

wherein:

R b is a hydrogen or a lower alkyl group;

D is a hydrogen, V 4 or K;

U is oxygen, sulfur or —N(R a )R i ;

V 4 is V 3 or V 6 ;

V 3 is:

R 24 is —C 6 H 4 R 27 , —CN, —S(O) 2 —C 6 H 4 R 27 , 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 27 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 6 ;

R 6 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;

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

aa is an integer from 0 to 1

a, 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 —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 c )(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 4 , —(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 , —(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 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 tone 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 glutamic acid compound of Formula (I) must contain at least heterocyclic nitric oxide donor group and/or nitroxide group linked to the glutamic acid compound of Formula (I) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.

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

3 . A method for treating a cardiovascular disease in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2 .

4 . The method of claim 3 , wherein the cardiovascular disease is heart failure, restenosis, hypertension, diastolic dysfunction, a coronary artery disease, myocardial infarction, cerebral infarction, atherosclerosis, atherogenesis, cerebrovascular disease, angina, aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, a vascular or non-vascular complications associated with the use of a medical device, a wound associated with the use of a medical device, vascular or non-vascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiograph, vascular grafting, coronary artery bypass surgery, a thromboembolic events, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and reclusion cerebrovascular incidents, left ventricular dysfunction and hypertrophy,

5 . The method of claim 4 , wherein the cardiovascular disease is hypertension, heart failure and/or diastolic dysfunction.

6 . A method for treating a renovascular disease in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2 .

7 . The method of claim 6 , wherein the renovascular disease is renal failure, renal insufficiency, renal deterioration associated with severe hypertension or renovascular hypertension.

8 . A method for treating diabetes; treating diseases resulting from oxidative stress; treating endothelial dysfunctions; treating diseases caused by endothelial dysfunctions; treating cirrhosis; treating pre-eclampsia; treating osteoporosis; treating nephropathy; treating peripheral vascular diseases; treating portal hypertension; treating diseases resulting from elevated levels of gamma-glutamyl transpeptidase or targeting the delivery of compounds and nitric oxide to organs, cells or tissues that contain the enzyme gamma-glutamyl transpeptidase in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2 .

9 . 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.

10 . The composition of claim 9 , wherein the therapeutic agent is an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti-hyperlipidemic compound, an antioxidant, an antithrombotic and vasodilator compound, a β-adrenergic antagonist, a calcium channel blocker, a digitalis a diuretic, an endothelin antagonist, a hydralazine compound, a H 2 receptor antagonist, an neutral endopeptidase inhibitor, a nonsteroidal antiinflammatory compound, a phosphodiesterase inhibitor, a potassium channel blocker, a platelet reducing agent, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, or a combination of two or more thereof.

11 . The composition of claim 10 , wherein the therapeutic agent is at least one compound selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme (ACE) inhibitor, a β-adrenergic antagonist, a calcium channel blocker, a diuretic, a hydralazine compound and a renin inhibitor.

12 . The composition of claim 11 , wherein the aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan, candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisaltan, trandolapril, trandolaprilat or valsartan; the angiotensin-converting enzyme inhibitor is benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride, ramipril; the β-adrenergic antagonist is bisoprolol fumarate, carvedilol, metoprolol tartrate, propranolol hydrochloride or timolol maleate; the calcium channel blockers is amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil; the diuretic is amiloride hydrochloride, chlorthalidone, hydrochlorothiazide or triamterene; the hydralazine compound is hydralazine hydrochloride; and the renin inhibitor is aliskiren, ciprokiren, ditekiren, enalkrein, medullipin, remikiren, terikiren, tonin or zankiren.

13 . The composition of claim 9 , 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.

14 . The method of claims 3 , 6 or 8 , further comprising administering (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.

15 . The method of claim 14 , wherein the therapeutic agent is the therapeutic agent is an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti-hyperlipidemic compound, an antioxidant, an antithrombotic and vasodilator compound, a β-adrenergic antagonist, a calcium channel blocker, a digitali, a diuretic, an endothelin antagonist, a hydralazine compound, a H 2 receptor antagonist, an neutral endopeptidase inhibitor, a nonsteroidal antiinflammatory compound, a phosphodiesterase inhibitor, a potassium channel blocker, a platelet reducing agent, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, or a combination of two or more thereof.

16 . The method of claim 14 , wherein the nitric oxide donor 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 iuroxan or a nitroxide.

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.