NITRIC OXIDE RELEASING AMINO ACID ESTER COMPOUND, COMPOSITION AND METHOD OF USE

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

wherein,

n=1-2, and

R 1 =an amino acid side chain group (D or L configuration), and pharmaceutically acceptable salts thereof.

2 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is:

wherein n=7-10, and

R 1 =an amino acid side chain group (D or L configuration), and pharmaceutically acceptable salts thereof.

3 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is:

wherein n=3 to 6; and

R 1 =an amino acid side chain group (D or L configuration and pharmaceutically acceptable salts thereof, and wherein R 1 is different than lysine, arginine, methionine, phenylalanine, cystine or glycine.

4 . The compound of claim 1 , wherein said compound is:

5 . The compound of claim 2 , wherein said compound is:

6 . The compound of claim 2 , wherein said compound is:

7 . A compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is:

wherein,

n=1 to 10;

R 1 ═—CH 2 CH 3 ;

R 2 =an amino acid side chain group (D or L configuration), or pharmaceutically acceptable salts thereof.

8 . The compound of claim 1 , wherein R 1 is selected from the group consisting of:

Originating

Amino acid

formula

R 1

Alanine

CH 3

CH 3

Valine

CH(CH 3 ) 2

Leucine

CH 2 CH(CH 3 ) 2

Isoleucine

CH(CH 3 )CH 2 CH 3

Tyrosine

CH 2 C 6 H 4 OH

Tryptophane

C 9 H 8 N

Serine

CH 2 OH

H 2 C—OH

Threonine

CH(OH)CH 3

Cysteine

CH 2 SH

H 2 C—SH

Proline

C 5 H 9 NO 2

Asparagine

CH 2 COCH 2

Glutamine

CH 2 CH 2 CONH 2

Aspartic acid

CH 2 COOH

CH 2 —COOH

Glutamic acid

CH 2 CH 2 COOH

H 2 C—CH 2 —COOH

Histidine

CH 3 C 3 N 2 H 3

Hydroxyproline

ε-N-methyllysine

CH 2 CH 2 CH 2 CH 2 NHCH 3

β-alanine

NH 2 CH 2 CH 2 COOH

diiodotyrosine

CH 2 C 6 H 2 I 2 OH

homocysteine

CH 2 CH 2 SH

H 2 C—CH 2 —SH

ornithine

CH 2 CH 2 CH 2 NH 2

Norvaline

CH 2 —CH 2 —CH 3

CH 2 —CH 2 —CH 3

selenocysteine

CH 2 —SeH

CH 2 —SeH

Hypusine

CH 2 CH 2 CH 2 CH 2 NHCH 2 CH(OH)CH 2 CH 2 NH 2

Dehydroalanine

CH 2

9 . The compound of claim 7 , wherein R 2 is selected from the group consisting of:

Originating

Amino acid

formula

R 2

Glycine

H

H

Alanine

CH 3

CH 3

Valine

CH(CH 3 ) 2

Leucine

CH 2 CH(CH 3 ) 2

Isoleucine

CH(CH 3 )CH 2 CH 3

Phenylalanine

CH 2 C 6 H 5

Tyrosine

CH 2 C 6 H 4 OH

Tryptophane

C 9 H 8 N

Serine

CH 2 OH

H 2 C—OH

Threonine

CH(OH)CH 3

Cysteine

CH 2 SH

H 2 C—SH

Methionine

CH 2 CH 2 SCH 3

Proline

C 5 H 9 NO 2

Asparagine

CH 2 COCH 2

Glutamine

CH 2 CH 2 CONH 2

Aspartic acid

CH 2 COOH

CH 2 —COOH

Glutamic acid

CH 2 CH 2 COOH

H 2 C—CH 2 —COOH

Lysine

CH 2 CH 2 CH 2 CH 2 NH 2

Histidine

CH 3 C 3 N 2 H 3

Arginine

(CH 2 ) 3 CN 3 H 4

Cystine

CH 2 S 2 CH 2 CHNH 2 COOH

Hydroxyproline

ε-N- methyllysine

CH 2 CH 2 CH 2 CH 2 NHCH 3

β-alanine

NH 2 CH 2 CH 2 COOH

diiodotyrosine

CH 2 C 6 H 2 I 2 OH

homocysteine

CH 2 CH 2 SH

H 2 C—CH 2 —SH

ornithine

CH 2 CH 2 CH 2 NH 2

Norvaline

CH 2 —CH 2 —CH 3

CH 2 —CH 2 —CH 3

selenocysteine

CH 2 —SeH

CH 2 —SeH

Hypusine

CH 2 CH 2 CH 2 CH 2 NHCH 2 CH(OH)CH 2 CH 2 NH 2

Dehydroalanine

CH 2

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

11 . The composition of claim 10 , further comprising (i) at least one other therapeutic agent; (ii) at least one other nitric oxide donor compound; or (iii) at least one other therapeutic agent and at least one other nitric oxide donor compound.

12 . The composition of claim 11 , wherein the therapeutic agent is an aldosterone antagonist, an alpha-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, a 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.

13 . The composition of claim 12 , 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 inhibitor, a β-adrenergic antagonist, a diuretic and a hydralazine compound.

14 . The composition of claim 13 , wherein the aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisartan, trandolapril, trandolaprilat or valsartan; the angiotensin-converting enzyme inhibitor is benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride; the β-adrenergic antagonist is bisoprolol fumarate, carvedilol, metoprolol tartrate, propranolol hydrochloride or timolol maleate; the diuretic is amiloride hydrochloride, chlorthalidone, hydrochlorothiazide or triamterene; and the hydralazine compound is hydralazine hydrochloride.

15 . The composition of claim 11 , 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 oxatriazole-5-one, an oxime, a hydroxylamine, a N-hydroxyguanidine, a hydroxyurea and/or a furoxan.

16 . A method for treating a disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 9 .

17 . The method according to claim 16 , wherein said disease is a vascular disease.

18 . The method of claim 17 , wherein the vascular disease is congestive 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 complication associated with the use of a medical device, a wound associated with the use of a medical device, vascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiograph, vascular grafting, coronary artery bypass surgery, a thromboembolic event, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, or thrombotic occlusion and reclusion cerebrovascular incident.

19 . The method of claim 16 , wherein said disease is a non-vascular complication associated with the use of a medical device, and a non-vascular wall damage.

20 . The method of claim 17 , wherein the vascular disease is congestive heart failure, hypertension or diastolic dysfunction.

21 . A method for treating a renovascular disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 10 .

22 . The method of claim 21 , wherein the renovascular disease is renal failure or renal insufficiency.

23 . A method for treating diabetes; treating a disease resulting from oxidative stress; treating an endothelial dysfunction; treating a disease caused by endothelial dysfunction; treating cirrhosis; treating pre-eclampsia; treating osteoporosis; treating nephropathy; reperfusing injury following ischemia and/or preserving a tissue, an organ, an organ part and/or a limb in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 9 .

24 . The method of claim 16 , further comprising administering:

(i) at least one other therapeutic agent;

(ii) at least one other nitric oxide donor compound; or

(iii) at least one other therapeutic agent and at least one other nitric oxide donor compound.

25 . The method of claim 24 , wherein the therapeutic agent is an aldosterone antagonist, an alpha-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, a 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.

26 . The method of claim 25 , 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 oxatriazole-5-one, an oxime, a hydroxylamine, a N-hydroxyguanidine, a hydroxyurea and/or a furoxan.

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