Organic Nitric Oxide Donor Salts of Angiotensin Converting Enzyme Inhibitors, Compositions and Methods of Use

1 . A compound of Formula (I), (II) or (III), wherein the compound of Formula (I) is:

wherein:

X 6 is:

(1) —R 22 ; or

Y 6 is:

(1) —CH 2 —S—R 21 ;

W 6 is:

Z 7 is:

(1) hydrogen;

(2) methyl; or

(3) —(CH 2 ) 4 —NH 2 ;

R 19 and R 20 are a hydrogen; or

R 19 and R 20 taken together are an oxo; or

R 20 and W 6 taken together are:

R 21 is:

(1) —C(O)—CH 2 —CH 3 ;

(2) hydrogen; or

R 22 is —O—CH 2 —CH 3 or —OH.Z;

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 27 , —CN, —S(O) 2 —C 6 H 4 R 27 , —C(O)—N(R a )(R i ), —NO 2 or —C(O)—OR 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, 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 3 ;

Y 3 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 compounds 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 and/or phosphinic acid group in the compounds of Formula (I);

the compounds of Formula (II) is:

wherein:

B 6 is:

(2) a nitrogen;

G 6 is:

D 6 is:

or B 6 and D 6 taken together form a phenyl ring;

Q 6 is a hydrogen; or

B 6 is a nitrogen and Q 6 is CH 2 and taken together form the ring:

Z is as defined herein and is linked via a salt bridge (i.e., .) to at least one carboxylic acid group in the compounds of Formula (II);

the compound of Formula (III) is:

wherein:

X 7 is a hydrogen;

Y 7 is

or X 7 and Y 7 taken together are:

R 23 is a hydrogen or —OCH 3 ;

R 22 and Z are as defined herein; and

Z is linked via a salt bridge (i.e., .) to at least one carboxylic acid group in the compounds of Formula (III).

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 donor salt of alacepril, an organic nitric oxide donor salt of captopril, an organic nitric oxide donor salt of ceronapril, an organic nitric oxide donor salt of enalapril, an organic nitric oxide donor salt of enalaprilat, an organic nitric oxide donor salt of fosinopril, an organic nitric oxide donor salt of fosinoprilat, an organic nitric oxide donor salt of imidapril, an organic nitric oxide donor salt of lisinopril, an organic nitric oxide donor salt of moveltipril, an organic nitric oxide donor salt of perindopril, an organic nitric oxide donor salt of perindoprilat, an organic nitric oxide donor salt of ramipril, an organic nitric oxide donor salt of spirapril, an organic nitric oxide donor salt of trandolapril, or an organic nitric oxide donor salt of trandolaprilat; the compound of Formula (II) is an organic nitric oxide donor salt of benazepril, an organic nitric oxide donor salt of benazeprilat, an organic nitric oxide donor salt of cilazapril, or an organic nitric oxide donor salt of temocapril; the compound of Formula (III) is an organic nitric oxide donor salt of delapril, an organic nitric oxide donor salt of imidapril, an organic nitric oxide donor salt of moexipril, an organic nitric oxide donor salt of quinapril or an organic nitric oxide donor salt of quinaprilat.

4 . The compound of claim 1 , wherein the compound of Formula (I) is an organic nitric oxide donor salt of alacepril of Formula (IV), an organic nitric oxide donor salt of captopril of Formula (V), an organic nitric oxide donor salt of ceronapril of Formula (VI), an organic nitric oxide donor salt of enalapril of Formula (VII), an organic nitric oxide donor salt of enalaprilat of Formula (VIII), an organic nitric oxide donor salt of fosinopril of Formula (IX), an organic nitric oxide donor salt of lisinopril of Formula (X), an organic nitric oxide donor salt of moveltipril of Formula (XI), an organic nitric oxide donor salt of perindopril of Formula (XII), an organic nitric oxide donor salt of ramipril of Formula (XIII), an organic nitric oxide donor salt of spirapril of Formula (XIV), an organic nitric oxide donor salt of trandolapril of Formula (XV), or an organic nitric oxide donor salt of trandolaprilat of Formula (XVI); the organic nitric oxide donor salt of angiotensin converting enzyme inhibitor of Formula (II) is an organic nitric oxide donor salt of benazepril of Formula (XVII); an organic nitric oxide donor salt of cilazapril of Formula (XVIII); or an organic nitric oxide donor salt of temocapril of Formula (XIX); the organic nitric oxide donor salt of angiotensin converting enzyme inhibitor of Formula (III) is an organic nitric oxide donor salt of imidapril of Formula (XX); an organic nitric oxide donor salt of moexipril of Formula (XXI), or an organic nitric oxide donor salt of quinapril of Formula (XXII);

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:

Z 1 is:

wherein Z 1 is linked via a salt bridge (i.e., .) to at least one carboxylic acid group in the compounds of Formula (IV) to (XXII).

5 . 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 .

6 . The method of claim 5 , wherein the cardiovascular disease is heart failure, restenosis, hypertension, diastolic dysfunction, a coronary artery disease, myocardial infarction, cerebral infarction, arterial stiffness, 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, 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.

7 . The method of claim 6 , wherein the cardiovascular disease is hypertension, heart failure, arterial stiffness, postmyocardial infarction, stroke and/or diastolic dysfunction.

8 . 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 .

9 . The method of claim 8 , wherein the renovascular disease is renal failure, renal insufficiency, renal deterioration associated with severe hypertension or renovascular hypertension.

10 . A method for treating diabetes; treating diseases resulting from oxidative stress; treating endothelial dysfunctions; treating a disease caused by endothelial dysfunctions; treating cirrhosis; treating pre-eclampsia; treating osteoporosis; treating nephropathy; treating a peripheral vascular disease; treating portal hypertension; treating an ophthalmic disorder; treating metabolic syndrome; or treating hyperlipidemia in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2 .

11 . 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.

12 . The composition of claim 11 , wherein the therapeutic agent is an aldosterone antagonist, an α-adrenergic receptor agonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti-hyperlipidemic compound, an antimicrobial compound, an antioxidant, an antithrombotic and vasodilator compound, a β-adrenergic antagonist, a calcium channel blocker, a carbonic anhydrase inhibitor, 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 prostaglandin, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, a steroid, 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 (ACE) inhibitor, a β-adrenergic antagonist, a calcium channel blocker, a diuretic, a hydralazine compound and a renin inhibitor.

14 . The composition of claim 13 , wherein the aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan, candesartan cilexetil, eprosartan mesylate, irbesartan, losartan, medoxomil, telmisartan, 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, terlkiren, tonin or zankiren.

15 . The composition of claim 11 , 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 5 , 8 or 10 , 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.

17 . The method of claim 16 , wherein the therapeutic agent is an aldosterone antagonist, an α-adrenergic receptor agonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti-hyperlipidemic compound, an antimicrobial compound, an antioxidant, an antithrombotic and vasodilator compound, a β-adrenergic antagonist, a calcium channel blocker, a carbonic anhydrase inhibitor, a digitali, 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 prostaglandin, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, a steroid, or a combination of two or more thereof.

18 . The method of claim 16 , 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.

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

20 . The kit of claim 19 , 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.

21 . The kit of claim 20 , 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.