US 20090012057A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0012057 A1 Garvey (43) Pub. Date: Jan. 8, 2009

(54) CARDOVASCULAR COMPOUNDS Publication Classification COMPRISING NITRC OXDE ENHANCNG (51) Int. Cl. GROUPS, COMPOSITIONS AND METHODS A6II 3/554 (2006.01) OF USE A 6LX 3/5.377 (2006.01) C07D 417/04 (2006.01) C07D 409/06 (2006.01) (75) Inventor: David S. Garvey, Dover, MA (US) A6IP 9/10 (2006.01) A6IP 9/00 (2006.01) A6II 3/478 (2006.01) Correspondence Address: C07D 22.3/22 (2006.01) WILMERHALEADC A6II 3/55 (2006.01) 1875 PENNSYLVANIAAVE, NW (52) U.S. Cl...... 514/211.07: 54.4/138: 514/236.2: WASHINGTON, DC 20004 (US) 514/397: 548/315.1: 540/588: 514/217 (57) ABSTRACT Assignee: NitroMed, Inc., Lexington, MA (73) The invention describes compositions and kits comprising at (US) least one cardiovascular compound comprising at least one nitric oxide enhancing group, orpharmaceutically acceptable Appl. No.: 11/815,270 salts thereof, and, optionally, at least one nitric oxide enhanc (21) ing compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating cardiovascu (22) PCT Fled: Feb. 28, 2006 lar diseases; (b) treating renovascular diseases; (c) treating diabetes; (d) treating diseases resulting from oxidative stress; (e) treating endothelial dysfunctions; (f) treating diseases (86) PCT NO.: PCT/USO6/O6843 caused by endothelial dysfunctions; (g) treating cirrhosis: (h) treating pre-eclampsia; Q) treating osteoporosis; (k) treating S371 (c)(1), nephropathy: (1) treating peripheral vascular diseases; (m) treating portal hypertension; (n) treating ophthalmic disor (2), (4) Date: Mar. 24, 2008 ders; (o) treating metabolic syndrome; and (p) treating hyper lipidemia. The cardiovascular compounds are angiotensin II Related U.S. Application Data antagonists, aldosterone antagonists, endothelin antagonists, hydralazine compounds, neutral endopeptidase inhibitors (60) Provisional application No. 60/656,544, filed on Feb. and renin inhibitors. The nitric oxide enhancing groups are 28, 2005. nitroxides and/or heterocyclic nitric oxide donors. US 2009/0012057 A1 Jan. 8, 2009

CARDOVASCULAR COMPOUNDS more sites such as oxygen (hydroxyl condensation), Sulfur COMPRISING NITRC OXDE ENHANCNG (sulfhydryl condensation) and/or nitrogen via a bond or moi GROUPS, COMPOSITIONS AND METHODS ety that can be hydrolyzed. The heterocyclic nitric oxide OF USE donor groups are furoxans, Sydnonimines, oXatriazole-5- ones and/or oXatriazole-5-imines. The invention also pro RELATED APPLICATIONS vides compositions comprising the novel compounds 0001. This application claims priority under 35 USC S 119 described herein in a pharmaceutically acceptable carrier. to U.S. Application No. 60/656,544 filed Feb. 28, 2005. 0006. The invention is also based on the discovery that administering at least one cardiovascular compound compris FIELD OF THE INVENTION ing at least one nitric oxide enhancing group or a pharmaceu tically acceptable salt thereof, and, optionally, at least one 0002 The invention describes compositions and kits com nitric oxide enhancing compound improves the properties of prising at least one cardiovascular compound comprising at the cardiovascular compound. Nitric oxide enhancing com least one nitric oxide enhancing group, or pharmaceutically pounds include, for example, S-nitrosothiols, nitrites, acceptable salts thereof, and, optionally, at least one nitric nitrates, N-oxo-N-nitrosamines, furoxans, Sydnonimines, oxide enhancing compound and/or at least one therapeutic SPM3672, SPM 4757, SPM5185, SPM5186 and analogues agent. The invention also provides methods for (a) treating thereof, substrates of the various isozymes of nitric oxide cardiovascular diseases; (b) treating renovascular diseases; synthase, and nitroxides. Thus, another embodiment of the (c) treating diabetes; (d) treating diseases resulting from oxi invention provides compositions comprising at least one car dative stress; (e) treating endothelial dysfunctions; (f) treating diovascular compound comprising at least one nitric oxide diseases caused by endothelial dysfunctions; (g) treating cir enhancing group and at least one nitric oxide enhancing com rhosis: (h) treating pre-eclampsia; () treating osteoporosis: pound. The invention also provides for Such compositions in (k) treating nephropathy: (1) treating peripheral vascular dis a pharmaceutically acceptable carrier. eases; (m) treating portal hypertension, (n) treating oph 0007. The invention provides compositions comprising at thalmic disorders; (o) treating metabolic syndrome; and (p) least one cardiovascular compound comprising at least one treating hyperlipidemia. The cardiovascular compounds are nitric oxide enhancing group, and, optionally, at least one angiotensin II antagonists, aldosterone antagonists, endothe nitric oxide enhancing compound and/or at least one thera lin antagonists, hydralazine compounds, neutral endopepti peutic agent, including, but not limited to, aldosterone dase inhibitors and renin inhibitors. The nitric oxide enhanc antagonists, C-adrenergic receptor agonists, C.-adrenergic ing groups are nitroxides and/or heterocyclic nitric oxide receptor antagonists, angiotensin II antagonists, angiotensin donors. converting enzyme (ACE) inhibitors, antidiabetic com BACKGROUND OF THE INVENTION pounds, anti-hyperlipidemic compounds, antimicrobial com pounds, antioxidants, antithrombotic and vasodilator 0003. The decline in cardiovascular morbidity and mor compounds, B-adrenergic antagonists, calcium channel tality in the United States over the past three decades has been blockers, carbonic anhydrase inhibitors, digitalis, diuretics, the result of significant advances in research on cardiovascu endothelin antagonists, hydralazine compounds, H2 receptor lar disease mechanisms and therapeutic strategies. The inci antagonists, neutral endopeptidase inhibitors, nonsteroidal dence and prevalence of myocardial infarction and death antiinflammatory compounds (NSAIDs), phosphodiesterase from myocardial infarction, as well as that from cerebrovas inhibitors, potassium channel blockers, platelet reducing cular accident, have decreased significantly over this period agents, prostaglandins, proton pump inhibitors, renin inhibi largely owing to advances in prevention, early diagnosis, and tors, selective cyclooxygenase-2 (COX-2) inhibitors, ste treatment of these very common diseases. roids, and combinations of two or more thereof. In one 0004. The compounds administered for the treatment of embodiment the at least one therapeutic agent is selected diuresis, cardiovascular diseases, and diseases resulting from from the group consisting of an aldosterone antagonist, an oxidative and/or endothelial dysfunctions often result in angiotensin II antagonist, an angiotensin-converting enzyme toxic, chronic and/or debilitating side effects. Cardiovascular (ACE) inhibitor, a 3-adrenergic antagonist, a calcium channel compounds such as ACE inhibitors, beta-adrenergic blockers, blocker, a diuretic, a hydralazine compound and a renin antithrombotic and vasodilator compounds or anti-hyperlipi inhibitor. The invention also provides for such compositions demic compounds, show, for example, respiratory toxicity in a pharmaceutically acceptable carrier. resulting in asthma and/or bronchitis. Hence there is a need in 0008 Another embodiment of the invention provides the art for compounds that have improved efficacy, lower compositions comprising at least one cardiovascular com toxicity and that can be used at low dosages. The invention is pound of the invention comprising at least one nitric oxide directed to these, as well as other, important ends. enhancing group, and at least one therapeutic agentis selected from the group consisting of an aldosterone antagonist, an SUMMARY OF THE INVENTION angiotensin II antagonist, an angiotensin-converting enzyme 0005. The invention provides novel cardiovascular com (ACE) inhibitor, a 3-adrenergic antagonist, a calcium channel pounds comprising at least one nitric oxide enhancing group, blocker, a diuretic, a hydralazine compound and a renin and pharmaceutically acceptable salts thereof. The cardiovas inhibitor. The invention also provides for such compositions cular compounds can be, for example, aldosterone antago in a pharmaceutically acceptable carrier. nists, angiotensin II antagonists, endothelin antagonists, 0009. The invention provides methods for (a) treating car hydralazine compounds, neutral endopeptidase inhibitors diovascular diseases; (b) treating renovascular diseases; (c) and renin inhibitors. The nitric oxide enhancing groups are treating diabetes; (d) treating diseases resulting from oxida nitroxides and/or heterocyclic nitric oxide donor groups that tive stress; (e) treating endothelial dysfunctions, (f) treating are linked to the cardiovascular compounds through one or diseases caused by endothelial dysfunctions; (g) treating cir US 2009/0012057 A1 Jan. 8, 2009 rhosis: (h) treating pre-eclampsia; () treating osteoporosis: more thereof. The cardiovascular compound comprising at (k) treating nephropathy: (1) treating peripheral vascular dis least one nitric oxide enhancing group, the nitric oxide eases; (m) treating portal hypertension, (n) treating oph enhancing compound and/or therapeutic agent, can be sepa thalmic disorders; (o) treating metabolic syndrome; and (p) rate components in the kit or can be in the form of a compo treating hyperlipidemia in a patient in need thereof compris sition in one or more pharmaceutically acceptable carriers. ing administering to the patient a therapeutically effective 0011. These and other aspects of the invention are amount of at least one cardiovascular compound comprising described in detail herein. at least one nitric oxide enhancing group, and, optionally, at least one therapeutic agent, such as, for example, aldosterone DETAILED DESCRIPTION OF THE INVENTION antagonists, C.-adrenergic receptor agonists, C.-adrenergic 0012. As used throughout the disclosure, the following receptor antagonists, angiotensin II antagonists, angiotensin terms, unless otherwise indicated, shall be understood to have converting enzyme (ACE) inhibitors, antidiabetic com the following meanings. pounds, anti-hyperlipidemic compounds, antimicrobial com 0013 “Cardiovascular disease or disorder” refers to any pounds, antioxidants, antithrombotic and vasodilator cardiovascular disease or disorder known in the art, includ compounds, B-adrenergic antagonists, calcium channel ing, but not limited to, heart failure, restenosis, hypertension blockers, carbonic anhydrase inhibitors, digitalis, diuretics, (e.g. pulmonary hypertension, systolic hypertension, labile endothelin antagonists, hydralazine compounds. He receptor hypertension, idiopathic hypertension, low-renin hyperten antagonists, neutral endopeptidase inhibitors, nonsteroidal Sion, salt-sensitive hypertension, low-renin, salt-sensitive antiinflaminatory compounds (NSAIDs), phosphodiesterase hypertension, thromboembolic pulmonary hypertension; inhibitors, potassium channel blockers, platelet reducing pregnancy-induced hypertension; renovascular hyperten agents, prostaglandins, proton pump inhibitors, renin inhibi sion; hypertension-dependent end-stage renal disease, hyper tors, selective cyclooxygenase-2 (COX-2) inhibitors, ste tension associated with cardiovascular Surgical procedures, roids, and combinations of two or more thereof. The methods hypertension with left ventricular hypertrophy, and the like), can optionally further comprise the administration of at least diastolic dysfunction, coronary artery disease, myocardial one nitric oxide enhancing compound. In this embodiment of infarctions, cerebral infarctions, arterial stiffness, atheroscle the invention, the methods can involve (i) administering the rosis, atherogenesis, cerebrovascular disease, angina, (in cardiovascular compounds comprising at least one nitric cluding chronic, stable, unstable and variant (Prinzmetal) oxide enhancing group, (ii) administering the cardiovascular angina pectoris), aneurysm, ischemic heart disease, cerebral compounds comprising at least one nitric oxide enhancing ischemia, myocardial ischemia, thrombosis, platelet aggre group and nitric oxide enhancing compounds, (iii) adminis gation, platelet adhesion, Smooth muscle cell proliferation, tering the cardiovascular compounds comprising at least one vascular or non-vascular complications associated with the nitric oxide enhancing group and therapeutic agents, or (iv) use of medical devices, wounds associated with the use of administering the cardiovascular compounds comprising at medical devices, vascular or non-vascular wall damage, least one nitric oxide enhancing group, nitric oxide enhancing peripheral vascular disease, neointimal hyperplasia following compounds, and therapeutic agents. In one embodiment theat percutaneous transluminal coronary angiograph, vascular least one therapeutic agent is selected from the group consist grafting, coronary artery bypass Surgery, thromboembolic ing of analdosterone antagonist, an angiotensin II antagonist, events, post-angioplasty restenosis, coronary plaque inflam an angiotensin-converting enzyme (ACE) inhibitor, a B-adr mation, hypercholesterolemia, embolism, stroke, shock, energic antagonist, a calcium channel blocker, a diuretic, a arrhythmia, atrial fibrillation or atrial flutter, thrombotic hydralazine compound and a renin inhibitor. The cardiovas occlusion and reclusion cerebrovascular incidents, left ven cular compounds comprising at least one nitric oxide enhanc tricular dysfunction and hypertrophy, and the like. ing group, nitric oxide enhancing compounds, and/or thera 0014) “Heart failure' includes, but is not limited to con peutic agents can be administered separately or as gestive heart failure, compensated heart failure, decompen components of the same composition in one or more pharma sated heart failure, and the like. ceutically acceptable carriers. 0015. “Thromboembolic events' include, but are not lim 0010. Another embodiment of the invention provides kits ited to, ischemic stroke, transientischemic stroke, myocardial comprising at least one cardiovascular compound comprising infarction, angina pectoris, thrombosis (for example, resteno at least one nitric oxide enhancing group, and, optionally, at sis, arterial thrombosis, coronary thrombosis, heart Valve least one nitric oxide enhancing compound. The kit can fur thrombosis, coronary Stenosis, stent thrombosis, graft throm ther comprise at least one therapeutic agent, Such as, for bosis, and first and Subsequent thrombotic stroke, and the example, aldosterone antagonists, C.-adrenergic receptorago like), thromboembolism (for example, pulmonary throm nists, C.-adrenergic receptor antagonists, angiotensin II boembolism, cerebral thromboembolism, and the like), antagonists, angiotensin-converting enzyme (ACE) inhibi thrombophlebitis, thrombocytopenia, bleeding disorders, tors, antidiabetic compounds, anti-hyperlipidemic com thrombotic occlusion and reocclusion and acute vascular pounds, antimicrobial compounds, antioxidants, antithrom events. Patients who are at risk of developing thromboembo botic and vasodilator compounds, B-adrenergic antagonists, lic events, may include those with a familial history of, or calcium channel blockers, carbonic anhydrase inhibitors, genetically predisposed to, thromboembolic disorders, who digitalis, diuretics, endothelin antagonists, hydralazine com have had ischemic stroke, transientischemic stroke, myocar pounds, H2 receptor antagonists, neutral endopeptidase dial infarction, and those with unstable angina pectoris or inhibitors, nonsteroidal antiinflammatory compounds chronic stable angina pectoris and patients with altered pros (NSAIDs), phosphodiesterase inhibitors, potassium channel tacyclin/thromboxane A homeostasis or higher than normal blockers, platelet reducing agents, prostaglandins, proton thromboxane A levels leading to increase risk for throm pump inhibitors, renin inhibitors, selective cyclooxygenase-2 boembolism, including patients with diabetes and rheuma (COX-2) inhibitors, steroids, and combinations of two or toid arthritis. US 2009/0012057 A1 Jan. 8, 2009

0016 “Diseases resulting from oxidative stress' refers to 0022 "Metabolic syndrome' also known as “insulin-re any disease that involves the generation of free radicals or sistance syndrome' or “syndrome X' refers to a condition radical compounds, such as, for example, atherogenesis, characterized by an increased amount of adipose tissue inside atheromatosis, arteriosclerosis, atherosclerosis, vascular the abdominal cavity, insulin resistance with increased risk of hypertrophy associated with hypertension, hyperlipoprotein developing senile diabetes, i.e. diabetes type II, high levels of aemia, normal vascular degeneration through aging, parathy blood fats and high blood pressure. roidal reactive hyperplasia, renal disease (e.g., acute or 0023 “Therapeutic agent” includes any therapeutic agent chronic), neoplastic diseases, inflammatory diseases, neuro that can be used to treat or prevent the diseases described logical and acute bronchopulmonary disease, tumorigenesis, herein. "Therapeutic agents' include, for example, aldoster ischemia-reperfusion syndrome, arthritis, sepsis, cognitive one antagonists, C.-adrenergic receptor agonists, C.-adrener gic receptor antagonists, angiotensin II antagonists, angio dysfunction, endotoxic shock, endotoxin-induced organ fail tensin-converting enzyme (ACE) inhibitors, antidiabetic ure, and the like. compounds, anti-hyperlipidemic compounds, antimicrobial 0017 “Renovascular diseases” refers to any disease or compounds, antioxidants, antithrombotic and vasodilator dysfunction of the renal system including, but not limited to, compounds, B-adrenergic antagonists, calcium channel renal failure (e.g., acute or chronic), renal insufficiency, neph blockers, carbonic anhydrase inhibitors, digitalis, diuretics, rotic edema, acute glomerulonephritis, oliguric renal failure, endothelin antagonists, hydralazine compounds, H2 receptor renal deterioration associated with severe hypertension, uni antagonists, neutral endopeptidase inhibitors, nonsteroidal lateral perechymal renal disease, polycystic kidney disease, antiinflammatory compounds (NSAIDs), phosphodiesterase chronic pyelonephritis, renal diseases associated with renal inhibitors, potassium channel blockers, platelet reducing insufficiency, complications associated with dialysis or renal agents, prostaglandins, proton pump inhibitors, renin inhibi transplantation, renovascular hypertension, nephropathy, tors, selective cyclooxygenase-2 (COX-2) inhibitors, ste glomerulonephritis, Scleroderma, glomerular Sclerosis, renal roids, and the like. Therapeutic agent includes the pharma artery Stenosis, AIDS-associated nephropathy, immune-me ceutically acceptable salts thereof, pro-drugs, and diated renal disease, atheroembolic renal disease, pre-renal pharmaceutical derivatives thereof including, but not limited azotemia, and the like. to, the corresponding nitrosated and/or nitrosylated and/or 0018 “Endothelial dysfunction” refers to the impaired heterocyclic nitric oxide donor derivatives and/or nitroxide ability in any physiological processes carried out by the derivative. Although nitric oxide enhancing compounds have endothelium, in particular, production of nitric oxide regard therapeutic activity, the term “therapeutic agent” does not less of cause. It may be evaluated by, Such as, for example, include the nitric oxide enhancing compounds described invasive techniques, such as, for example, coronary artery herein, since nitric oxide enhancing compounds are sepa reactivity to acetylcholine or methacholine, and the like, or by rately defined. noninvasive techniques. Such as, for example, blood flow 0024 “Prodrug” refers to a compound that is made more measurements, brachial artery flow dilation using cuffocclu active in vivo. sion of the arm above or below the elbow, brachial artery 0025 Antioxidant’ refers to and includes any compound ultrasonography, imaging techniques, measurement of circu that can react and quench a free radical. lating biomarkers. Such as, asymmetric dimethylarginine 0026 Angiotensin converting enzyme (ACE) inhibitor (ADMA), and the like. For the latter measurement the endot refers to compounds that inhibit an enzyme which catalyzes helial-dependent flow-mediated dialation will be lower in the conversion of angiotensin I to angiotensin II. ACE inhibi patients diagnosed with an endothelial dysfunction. tors include, but are not limited to, amino acids and deriva 0019 “Methods for treating endothelial dysfunction” tives thereof, peptides, including di- and tri-peptides, and include, but are not limited to, treatment prior to the onset/ antibodies to ACE which intervene in the renin-angiotensin diagnosis of a disease that is caused by or could result from system by inhibiting the activity of ACE thereby reducing or endothelial dysfunction, such as, for example, atherosclero eliminating the formation of the pressor Substance angio sis, hypertension, diabetes, heart failure, and the like. tensin II. 0020 “Methods for treating diseases caused by endothe 0027 “Angiotensin II antagonists' refers to compounds lial dysfunction include, but are not limited to, the treatment which interfere with the function, synthesis or catabolism of of any disease resulting from the dysfunction of the endothe angiotensin II. Angiotensin II antagonists include peptide lium, Such as, for example, arteriosclerosis, heart failure, compounds and non-peptide compounds, including, but not hypertension, cardiovascular diseases, cerebrovascular dis limited to, angiotensin II antagonists, angiotensin II receptor eases, renovascular diseases, mesenteric vascular diseases, antagonists, agents that activate the catabolism of angiotensin pulmonary vascular diseases, ocular vascular diseases, II, and agents that prevent the synthesis of angiotensin I from peripheral vascular diseases, peripheral ischemic diseases, angiotensin II. The renin-angiotensin System is involved in and the like. the regulation of hemodynamics and water and electrolyte 0021 “Ophthalmic disorders' include, but are not limited balance. Factors that lower blood volume, renal perfusion to, ophthalmic infections, cataracts, glaucoma, elevated pressure, or the concentration of Sodium in plasma tend to intraocular pressure, ocular pain (e.g., following corneal Sur activate the system, while factors that increase these param gery), dry eye disorder, ocular hypertension, ocular bleeding, eters tend to Suppress its function. retinal diseases or disorders, presbyopia, macular degenera 0028 “Anti-hyperlipidemic compounds’ refers to any tion, choroidal neovascularization (CNV), retinopathies, compound or agent that has the effect of beneficially modi Such as for example, diabetic retinopathy, vitreoretinopathy, fying serum cholesterol levels such as, for example, lowering and the like, retinitis, such as for example, cytomegalovirus serum low density lipoprotein (LDL) cholesterol levels, or (CMV) retinitis, uveitis, macular edema, neuropathies and inhibiting oxidation of LDL cholesterol, whereas high den the like. sity lipoprotein (HDL) serum cholesterol levels may be low US 2009/0012057 A1 Jan. 8, 2009

ered, remain the same, or be increased. Preferably, the anti 0039. “Transmucosal” refers to delivery of a compound by hyperlipidemic compound brings the serum levels of LDL passage of the compound through the mucosal tissue and into cholesterol and HDL cholesterol (and, more preferably, trig the blood stream. lyceride levels) to normal or nearly normal levels. 0040) “Penetration enhancement” or “permeation 0029 “Diuretic compound” refers to and includes any enhancement” refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound or agent that increases the amount of urine compound Such that the rate at which the compound perme excreted by a patient. ates through the skin or mucosal tissue is increased. 0030 “Neutral endopeptidase inhibitors' refers to and 0041. “Carriers' or “vehicles' refers to carrier materials includes compounds that are antagonists of the renin angio Suitable for compound administration and include any Such tensin aldosterone system including compounds that are dual material known in the art such as, for example, any liquid, gel. inhibitors of neutral endopeptidases and angiotensin convert solvent, liquid diluent, solubilizer, or the like, which is non ing (ACE) enzymes. toxic and which does not interact with any components of the 0031) “Renin inhibitors’ refers to compounds which inter composition in a deleterious manner. fere with the activity of renin. 0042 “Sustained release' refers to the release of an active 0032 “Phosphodiesterase inhibitor” or “PDE inhibitor” compound and/or composition such that the blood levels of refers to any compound that inhibits the enzyme phosphodi the active compound are maintained within a desirable thera esterase. The term refers to selective or non-selective inhibi peutic range over a period of time. The Sustained release tors of cyclic guanosine 3',5'-monophosphate phosphodi formulation can be prepared using any conventional method esterases (cGMP-PDE) and cyclic adenosine 3',5'- known to one skilled in the art to obtain the desired release monophosphate phosphodiesterases (cAMP-PDE). characteristics. 0033 “Platelet reducing agents’ refers to compounds that 0043 "Nitric oxide enhancing refers to compounds and prevent the formation of a blood thrombus via any number of functional groups which, under physiological conditions can potential mechanisms. Platelet reducing agents include, but increase endogenous nitric oxide. Nitric oxide enhancing are not limited to, fibrinolytic agents, anti-coagulant agents compounds include, but are not limited to, nitric oxide releas and any inhibitors of platelet function. Inhibitors of platelet ing compounds, nitric oxide donating compounds, nitric function include agents that impair the ability of mature plate oxide donors, radical scavenging compounds and/or reactive lets to perform their normal physiological roles (i.e., their oxygen species scavenger compounds. In one embodiment normal function, such as, for example, adhesion to cellular the radical scavenging compound contains a nitroxide group. and non-cellular entities, aggregation, release of factors such 0044) "Nitroxide group' refers to compounds that have as growth factors) and the like. the ability to mimic Superoxide dimutase and catalase and act as radical scavengers, or react with Superoxide or other reac 0034) “Proton pump inhibitor refers to any compound tive oxygen species via a stable aminoxyl radical i.e. N-oxide. that reversibly or irreversibly blocks gastric acid secretion by 0045 “Nitric oxide adduct' or “NO adduct refers to com inhibiting the H/K-ATPase enzyme system at the secretory pounds and functional groups which, under physiological Surface of the gastric parietal cell. conditions, can donate, release and/or directly or indirectly 0035 “NSAID' refers to a nonsteroidal anti-inflamma transfer any of the three redox forms of nitrogen monoxide tory compound or a nonsteroidal anti-inflammatory drug. (NO", NO, NO.), such that the biological activity of the NSAIDs inhibit cyclooxygenase, the enzyme responsible for nitrogen monoxide species is expressed at the intended site of the biosyntheses of the prostaglandins and certain autocoid action. inhibitors, including inhibitors of the various isozymes of 0046 “Nitric oxide releasing or "nitric oxide donating cyclooxygenase (including but not limited to cyclooxyge refers to methods of donating, releasing and/or directly or nase-1 and -2), and as inhibitors of both cyclooxygenase and indirectly transferring any of the three redox forms of nitro lipoxygenase. gen monoxide (NO", NO, NO.), such that the biological 0036) “Cyclooxygenase-2 (COX-2) selective inhibitor” activity of the nitrogen monoxide species is expressed at the refers to a compound that selectively inhibits the cyclooxy intended site of action. genase-2 enzyme over the cyclooxygenase-1 enzyme. In one 0047. “Nitric oxide donor or “NO donor refers to com embodiment, the compound has a cyclooxygenase-2 ICso of pounds that donate, release and/or directly or indirectly trans less than about 2 LLM and a cyclooxygenase-1 ICs of greater fera nitrogen monoxide species, and/or stimulate the endog than about 5uM, in the human whole blood COX-2 assay (as enous production of nitric oxide or endothelium-derived described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) relaxing factor (EDRF) in vivo and/or elevate endogenous and also has a selectivity ratio of cyclooxygenase-2 inhibition levels of nitric oxide or EDRF in vivo and/or are oxidized to over cyclooxygenase-1 inhibition of at least 10, and prefer produce nitric oxide and/or are substrates for nitric oxide ably of at least 40. In another embodiment, the compound has synthase and/or cytochrome P450. "NO donor also includes a cyclooxygenase-1 ICso of greater than about 1 uM, and compounds that are precursors of L-arginine, inhibitors of the preferably of greater than 20 uM. The compound can also enzyme arginase and nitric oxide mediators. inhibit the enzyme, lipoxygenase. Such selectivity may indi 0048 “Heterocyclic nitric oxide donor refers to a trisub cate an ability to reduce the incidence of common NSAID stituted 5-membered ring comprising two or three nitrogen induced side effects. atoms and at least one oxygen atom. The heterocyclic nitric 0037 “Patient” refers to animals, preferably mammals, oxide donoris capable of donating and/or releasing a nitrogen most preferably humans, and includes males and females, and monoxide species upon decomposition of the heterocyclic children and adults. ring. Exemplary heterocyclic nitric oxide donors include 0038. “Transdermal refers to the delivery of a compound oXatriazol-5-ones, oXatriazol-5-imines, Sydnonimines, by passage through the skin and into the blood stream. furoxans, and the like. US 2009/0012057 A1 Jan. 8, 2009

0049 Alkyl refers to a lower alkyl group, a substituted tyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3.3.0) lower alkyl group, a haloalkyl group, a hydroxyalkyl group, octane, 7-Oxabicyclo(2.2.1)heptyl, 8-azabicyclo(3.2.1)oct-2- an alkenyl group, a Substituted alkenyl group, an alkynyl enyl and the like. group, a bridged cycloalkyl group, a cycloalkyl group or a 0.058 “Cycloalkyl refers to a saturated or unsaturated heterocyclic ring, as defined herein. An alkyl group may also cyclic hydrocarbon comprising from about 3 to about 10 comprise one or more radical species, such as, for example a carbon atoms. Cycloalkyl groups can be unsubstituted or cycloalkylalkyl group or a heterocyclicalkyl group. substituted with one, two or three substituents independently 0050 “Lower alkyl refers to branched or straight chain selected from alkyl, alkoxy, amino, alkylamino, dialky acyclic alkyl group comprising one to about ten carbonatoms lamino, arylamino, diarylamino, alkylarylamino, aryl, (preferably one to about eight carbon atoms, more preferably amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, one to about six carbonatoms). Exemplary lower alkyl groups alkylcarboxylic ester, carboxamido, alkylcarboxamido, OXo, include methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, alkylsulfinyl, and nitro. Exemplary cycloalkyl groups include sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex and the like. enyl, cyclohepta-1,3-dienyl, and the like. 0051. “Substituted lower alkyl refers to a lower alkyl 0059) “Heterocyclic ring or group' refers to a saturated or group, as defined herein, wherein one or more of the hydrogen unsaturated cyclic hydrocarbon group having about 2 to about atoms have been replaced with one or more R' groups, 10 carbon atoms (preferably about 4 to about 6 carbonatoms) wherein each R' is independently a hydroxy, an ester, an where 1 to about 4 carbon atoms are replaced by one or more amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a nitrogen, oxygen and/or Sulfur atoms. Sulfur may be in the nitrate, a nitrite, a thionitrate, a thionitrite oran amino group, thio, sulfinyl or sulfonyl oxidation state. The heterocyclic ring as defined herein. or group can be fused to an aromatic hydrocarbon group. Heterocyclic groups can be unsubstituted or substituted with 0052 “Haloalkyl refers to a lower alkyl group, an alkenyl one, two or three substituents independently selected from group, an alkynyl group, a bridged cycloalkyl group, a alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, cycloalkyl group or a heterocyclic ring, as defined herein, to hydroxy, OXO, thial, halo, carboxyl, carboxylic ester, alkyl which is appended one or more halogens, as defined herein. carboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic Exemplary haloalkyl groups include trifluoromethyl, chlo acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, aryl romethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the carbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, like. arylcarboxamido, Sulfonic acid, Sulfonic ester, Sulfonamide 0053 Alkenyl refers to a branched or straight chain nitrate and nitro. Exemplary heterocyclic groups include pyr C-Cohydrocarbon (preferably a C-Cs hydrocarbon, more rolyl, furyl, thienyl, 3-pyrrolinyl, 4.5,6-trihydro-2H-pyranyl, preferably a C-C hydrocarbon) that can comprise one or pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl pyrim more carbon-carbon double bonds. Exemplary alkenyl idinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, groups include propylenyl, buten-1-yl, isobutenyl, penten-1- thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl pyrrolinyl, y1, 2.2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, hepten-1-yl, octen-1-yl, and the like. imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, 0054 “Lower alkenyl refers to a branched or straight isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadia chain C-C hydrocarbon that can comprise one or two car Zolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl. bon-carbon double bonds. morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, pip 0055 “Substituted alkenyl refers to a branched or erazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophe straight chain C-C hydrocarbon (preferably a C-Cs nyl, benzimidazolyl, benzothiazolinyl, quinolinyl. 2,6-diox hydrocarbon, more preferably a C-C hydrocarbon) which abicyclo(3.3.0)octane, and the like. can comprise one or more carbon-carbon double bonds, 0060 “Heterocyclic compounds’ refer to mono- and poly wherein one or more of the hydrogen atoms have been cyclic compounds comprising at least one aryl or heterocyclic replaced with one or more R'groups, wherein each R" is ring. independently a hydroxy, an oxo, a carboxyl, a carboxamido, 0061 Aryl refers to a monocyclic, bicyclic, carbocyclic a halo, a cyano or an amino group, as defined herein. or heterocyclic ring system comprising one or two aromatic 0056 “Alkynyl refers to an unsaturated acyclic C-Co rings. Exemplary aryl groups include phenyl, pyridyl, hydrocarbon (preferably a C-C hydrocarbon, more prefer napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, inde ably a C-C hydrocarbon) that can comprise one or more nyl, indoyl, and the like. Aryl groups (including bicyclic aryl carbon-carbon triple bonds. Exemplary alkynyl groups groups) can be unsubstituted or Substituted with one, two or include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1- three substituents independently selected from alkyl, alkoxy, yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, alkylthio, amino, alkylamino, dialkylamino, arylamino, dia hexyl-3-yl, 3.3-dimethyl-butyn-1-yl, and the like. rylamino, alkylarylamino, halo, cyano, alkylsulfinyl, 0057. “Bridged cycloalkyl” refers to two or more hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, cycloalkyl groups, heterocyclic groups, or a combination alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxy thereof fused via adjacent or non-adjacent atoms. Bridged lic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxa cycloalkyl groups can be unsubstituted or Substituted with mido, alkylcarboxamido, carbomyl, Sulfonic acid, Sulfonic one, two or three substituents independently selected from ester, Sulfonamido and nitro. Exemplary Substituted aryl alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, groups include tetrafluorophenyl, pentafluorophenyl, Sul halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alky fonamide, alkylsulfonyl, arylsulfonyl, and the like. lcarboxylic ester, carboxamido, alkylcarboxamido, oxo and 0062 “Cycloalkenyl refers to an unsaturated cyclic nitro. Exemplary bridged cycloalkyl groups include adaman C-Cohydrocarbon (preferably a C-Cs hydrocarbon, more US 2009/0012057 A1 Jan. 8, 2009 preferably a C-C hydrocarbon) which can comprise one or 0079 Alkylthioalkyl refers to an alkylthio group, as more carbon-carbon double bonds. defined herein, to which is appended an alkyl group, as 0063 “Alkylaryl refers to an alkyl group, as defined defined herein. Exemplary alkylthioalkyl groups include herein, to which is appended an aryl group, as defined herein. allylthiomethyl, ethylthiomethyl, trifluoroethylthiomethyl, Exemplary alkylaryl groups include benzyl, phenylethyl, and the like. hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the 0080 “Alkoxyalkyl refers to an alkoxy group, as defined like. herein, appended to an alkyl group, as defined herein. Exem 0064 "Arylalkyl refers to an aryl radical, as defined plary alkoxyalkyl groups include methoxymethyl, methoxy herein, attached to an alkyl radical, as defined herein. Exem ethyl, isopropoxymethyl, and the like. plary arylalkyl groups include benzyl, phenylethyl, 4-hy I0081 “Alkoxyhaloalkyl refers to an alkoxy group, as droxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and the defined herein, appended to a haloalkyl group, as defined like. herein. Exemplary alkoxyhaloalkyl groups include 4-meth 0065 'Arylalkenyl refers to an aryl radical, as defined oxy-2-chlorobutyl and the like. herein, attached to an alkenyl radical, as defined herein. I0082 “Cycloalkoxy' refers to Rs.O—, wherein Rs is a Exemplary arylalkenyl groups include styryl, propenylphe cycloalkyl group or a bridged cycloalkyl group, as defined nyl, and the like. herein. Exemplary cycloalkoxy groups include cyclopropy 0066 “Cycloalkylalkyl refers to a cycloalkyl radical, as loxy, cyclopentyloxy, cyclohexyloxy, and the like. I0083) “Cycloalkylthio” refers to RS , wherein Rs is a defined herein, attached to an alkyl radical, as defined herein. cycloalkyl group or a bridged cycloalkyl group, as defined 0067 “Cycloalkylalkoxy' refers to a cycloalkyl radical, as herein. Exemplary cycloalkylthio groups include cyclopro defined herein, attached to an alkoxy radical, as defined pylthio, cyclopentylthio, cyclohexylthio, and the like. herein. I0084) “Haloalkoxy' refers to an alkoxy group, as defined 0068 “Cycloalkylalkylthio’ refers to a cycloalkyl radical, herein, in which one or more of the hydrogen atoms on the as defined herein, attached to an alkylthio radical, as defined alkoxy group are Substituted with halogens, as defined herein. herein. Exemplary haloalkoxy groups include 1,1,1-trichloroethoxy, 0069) “Heterocyclicalkyl refers to a heterocyclic ring 2-bromobutoxy, and the like. radical, as defined herein, attached to an alkyl radical, as I0085. “Hydroxy” refers to OH. defined herein. I0086) “Oxy” refers to - O - 0070 "Arylheterocyclic ring refers to a bi- or tricyclic 0087. “Oxo” refers to —O. ring comprised of an aryl ring, as defined herein, appended I0088 “Oxylate” refers to —OR," wherein R, is an via two adjacent carbon atoms of the aryl ring to a heterocy organic or inorganic cation. clic ring, as defined herein. Exemplary arylheterocyclic rings 0089. “Thiol” refers to SH. include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the 0090 “Thio” refers to - S - like. (0091 “Oxime” refers to —N ORs, wherein Rs is a 0071 Alkylheterocyclic ring refers to a heterocyclic hydrogen, an alkyl group, an aryl group, an alkylsulfonyl ring radical, as defined herein, attached to an alkyl radical, as group, an arylsulfonyl group, a carboxylic ester, an alkylcar defined herein. Exemplary alkylheterocyclic rings include bonyl group, an arylcarbonyl group, a carboxamido group, an 2-pyridylmethyl, 1-methylpiperidin-2-one-3-methyl, and the alkoxyalkyl group or an alkoxyaryl group. like. 0092 “Hydrazone” refers to —N N(Rs)(R's) wherein 0072 "Alkoxy' refers to Rs.O—, wherein Rs is an alkyl R's is independently selected from Rs, and Rs is as defined group, as defined herein (preferably a lower alkyl group or a herein. haloalkyl group, as defined herein). Exemplary alkoxy 0093. “Hydrazino” refers to HN N(H)–. groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, 0094 “Organic cation” refers to a positively charged trifluoromethoxy, and the like. organic ion. Exemplary organic cations include alkyl Substi 0073 "Aryloxy' refers to Rs.O. , wherein Rss is an aryl tuted ammonium cations, and the like. group, as defined herein. Exemplary arylkoxy groups include 0.095 “Inorganic cation” refers to a positively charged napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like. metalion. Exemplary inorganic cations include Group I metal 0074 Alkylthio’ refers to Rs.S. , wherein Rs is an cations such as for example, sodium, potassium, magnesium, alkyl group, as defined herein. calcium, and the like. 0075 "Lower alkylthio’ refers to a lower alkyl group, as 0096 “Hydroxyalkyl refers to a hydroxy group, as defined herein, appended to a thio group, as defined herein. defined herein, appended to an alkyl group, as defined herein. 0076 “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy 0097. “Nitrate” refers to —O NO, i.e. oxidized nitro group, as defined herein, to which is appended an aryl group, gen. as defined herein. Exemplary arylalkoxy groups include ben (0098 “Nitrite” refers to - O NO i.e. oxidized nitrogen. Zyloxy, phenylethoxy, chlorophenylethoxy, and the like. (0099. “Thionitrate” refers to S NO. 0077 Arylalklythio’ refers to an alkylthio group, as 0100 “Thionitrite” and “nitrosothiol refer to S NO. defined herein, to which is appended an aryl group, as defined 0101. “Nitro” refers to the group - NO, and “nitrosated” herein. Exemplary arylalklythio groups include benzylthio. refers to compounds that have been substituted therewith. phenylethylthio, chlorophenylethylthio, and the like. 0102) “Nitroso’ refers to the group - NO and “nitrosy 0078 “Arylalklythioalkyl refers to an arylalkylthio lated refers to compounds that have been substituted there group, as defined herein, to which is appended an alkyl group, with. as defined herein. Exemplary arylalkylthioalkyl groups (0103 "Nitrile” and “cyano” refer to CN. include benzylthiomethyl, phenylethylthiomethyl, chlo (0.104) “Halogen” or “halo” refers to iodine (I), bromine rophenylethylthioethyl, and the like. (Br), chlorine (Cl), and/or fluorine (F). US 2009/0012057 A1 Jan. 8, 2009

0105 “Imine” refers to —C(=N Rs)— wherein Rs is 0.124 Alkylsulfonamido” refers to a sulfonamido group, a hydrogen atom, an alkyl group, an aryl group or an arylhet as defined herein, appended to an alkyl group, as defined erocyclic ring, as defined herein “Amine” refers to any herein. organic compound that contains at least one basic nitrogen 0.125 "Arylsulfonamido” refers to a sulfonamido group, atOm. as defined herein, appended to an aryl group, as defined 0106 “Amino” refers to —NH, an alkylamino group, a herein. dialkylamino group, an arylamino group, a diarylamino I0126 “Alkylthio” refers to RS , wherein Rs is an group, an alkylarylamino group or a heterocyclic ring, as alkyl group, as defined herein (preferably a lower alkyl group, defined herein. as defined herein). 0107 “Alkylamino” refers to RsNH , wherein Rs is an I0127. 'Arylthio’ refers to RssS , wherein Rss is an aryl alkyl group, as defined herein. Exemplary alkylamino groups group, as defined herein. include methylamino, ethylamino, butylamino, cyclohexy I012.8 “Arylalkylthio’ refers to an aryl group, as defined lamino, and the like. herein, appended to an alkylthio group, as defined herein. 0108 "Arylamino” refers to RNH , wherein Rss is an I0129. “Alkylsulfinyl" refers to Rs. S(O) , wherein Rso aryl group, as defined herein. is an alkyl group, as defined herein. 0109) “Dialkylamino” refers to RsRsN—, wherein Rs. 0.130 Alkylsulfonyl refers to Rs S(O) , wherein and Rs are each independently an alkyl group, as defined Rs is an alkyl group, as defined herein. herein. Exemplary dialkylamino groups include dimethy I0131 “Alkylsulfonyloxy' refers to Rso S(O). O—, lamino, diethylamino, methyl propargylamino, and the like. wherein Rs is an alkyl group, as defined herein. 0110 “Diarylamino” refers to RssRN , wherein Rss I0132 Arylsulfinyl refers to Rss S(O)—, wherein Rss and Reo are each independently an aryl group, as defined is an aryl group, as defined herein. herein. I0133 "Arylsulfonyl” refers to Rss S(O) , wherein 0111 “Alkylarylamino” or “arylalkylamino” refers to Rss is an aryl group, as defined herein. RsRN—, wherein Rs is an alkyl group, as defined herein, 0.134 "Arylsulfonyloxy' refers to Rss S(O). O—, and Rss is an aryl group, as defined herein. wherein Rss is an aryl group, as defined herein. 0112 Alkylarylalkylamino” refers to Rs.R.N , I0135 “Amidyl” refers to RC(O)N(Rs.)— wherein Rs wherein Rs is an alkyl group, as defined herein, and R is an and Rs, are each independently a hydrogen atom, an alkyl arylalkyl group, as defined herein. group, an aryl group or an arylheterocyclic ring, as defined 0113 “Alkylcycloalkylamino” refers to RRsN , herein. wherein Rs is an alkyl group, as defined herein, and Rs is a I0136). “Ester” refers to RC(O)Rs— wherein Rs is a cycloalkyl group, as defined herein. hydrogen atom, an alkyl group, an aryl group or an arylhet 0114 “Aminoalkyl refers to an amino group, an alky erocyclic ring, as defined herein and Rs is oxygen or sulfur. lamino group, a dialkylamino group, an arylamino group, a I0137 “Carbamoyl refers to - O C(O)N(Rs)(Rs), diarylamino group, an alkylarylamino group or a heterocyclic wherein Rs and Rs, are each independently a hydrogen ring, as defined herein, to which is appended an alkyl group, atom, an alkyl group, an aryl group or an arylheterocyclic as defined herein. Exemplary aminoalkyl groups include dim ring, as defined herein, or Rs and Rs, taken together are a ethylaminopropyl, diphenylaminocyclopentyl, methylami heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl nomethyl, and the like. group, as defined herein. 0115 “Aminoaryl' refers to an aryl group to which is I0138 “Carboxyl refers to C(O)OR, wherein R is a appended an alkylamino group, an arylamino group or an hydrogen, an organic cation oran inorganic cation, as defined arylalkylamino group. Exemplary aminoaryl groups include herein. anilino, N-methylanilino, N-benzylanilino, and the like. (0.139. “Carbonyl refers to C(O)-. 0116. “Sulfinyl refers to S(O)-. 0140 Alkylcarbonyl refers to Rs C(O)—, wherein 0117 “Methanthial” refers to C(S)-. Rs is an alkyl group, as defined herein. 0118 “Thial” refers to -S. I0141 'Arylcarbonyl” refers to Rs. C(O)—, wherein 0119) “Sulfonyl refers to S(O), . Rss is an aryl group, as defined herein. 0120 "Sulfonic acid refers to —S(O)OR, wherein Rze 0.142 "Arylalkylcarbonyl refers to Rss-Rs C(O)—, is a hydrogen, an organic cation or an inorganic cation, as wherein Rss is an aryl group, as defined herein, and Rs is an defined herein. alkyl group, as defined herein. 0121 “Alkylsulfonic acid refers to a sulfonic acid group, 0.143 “Alkylarylcarbonyl refers to Rs-Rss C(O)—, as defined herein, appended to an alkyl group, as defined wherein Rss is an aryl group, as defined herein, and Rs is an herein. alkyl group, as defined herein. 0122 "Arylsulfonic acid refers to a sulfonic acid group, 0144) “Heterocyclicalkylcarbonyl refer to R7C(O)— as defined herein, appended to an aryl group, as defined herein wherein R-7s is a heterocyclicalkyl group, as defined herein. "Sulfonic ester refers to —S(O)ORss, wherein Rss is an (0145 “Carboxylic ester” refers to C(O)ORs, wherein alkyl group, an aryl group, or an aryl heterocyclic ring, as Rss is an alkyl group, an aryl group or an aryl heterocyclic defined herein. ring, as defined herein. 0123 "Sulfonamido” refers to —S(O), N(Rs)(Rs.), 0146 “Alkylcarboxylic acid” and “alkylcarboxyl refer to wherein Rs and Rs, are each independently a hydrogen an alkyl group, as defined herein, appended to a carboxyl atom, an alkyl group, an aryl group or an arylheterocyclic group, as defined herein. ring, as defined herein, or Rs and Rs, when taken together are 0147 “Alkylcarboxylic ester” refers to an alkyl group, as a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl defined herein, appended to a carboxylic ester group, as group, as defined herein. defined herein. US 2009/0012057 A1 Jan. 8, 2009

0148 Alkyl ester refers to an alkyl group, as defined HN-65021, HOE-720, HR-720, ICI-D6888, ICI-D7155, ICI herein, appended to an ester group, as defined herein. D8731, KRI-1177, KT3-671, KT-3579, KW-3433, 0149 Arylcarboxylic acid refers to an aryl group, as L-158809, L-158978, L-159282 (MK-996), L-159689, defined herein, appended to a carboxyl group, as defined L-159874, L-161177, L-162154, L-162234, L-162441, herein. L-163007, L-163017, LF-70156, LRB-057, LRB-081, LRB 0150 “Arylcarboxylic ester” and “arylcarboxyl refer to 087, LY-235656, LY-266099, LY-285.434, LY-301875, an aryl group, as defined herein, appended to a carboxylic LY-302289, LY-315995, ME-3221, MK-954, PD-123177, ester group, as defined herein. PD-1233.19, PD-126055, PD-150304, RG-13647, RWJ 0151. Aryl ester” refers to an aryl group, as defined 38970, RWJ-46458, S-8307, S-8308, SC-51757, SC-54629, herein, appended to an ester group, as defined herein. SC-52458, SC-52459, SK 1080, SL-910102, SR-47436, 0152 “Carboxamido” refers to C(O)N(Rs)(Rs), TAK-536, UP-2696, U-96849, U-97018, UK-77778, wherein Rs and Rs, are each independently a hydrogen UP-275-22, WAY-126227, WK-1260, WK-1360, WK-1492, atom, an alkyl group, an aryl group or an arylheterocyclic WY 126227, YH-1498, YM-358, YM-31472, X-6803, ring, as defined herein, or Rs and Rs, when taken together are XH-148, XR-510, ZD-6888, ZD-7155, ZD-8731, ZD 8.131, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl the compounds of ACS registry numbers 133240-46-7, group, as defined herein. 135070-05-2, 139958-16-0, 145160-84-5, 147403-03-0, 0153. Alkylcarboxamido” refers to an alkyl group, as 153806-29-2, 439904-54-8P 439904-55-9P, 439904-56-OP, defined herein, appended to a carboxamido group, as defined 439904-57-1P,439904-58-2P 155918-60-8P 155918-61-9P, herein. 272438-16-1P, 272446-75-0P, 223926-77-OP. 169281-89-4, 0154 "Arylcarboxamido” refers to an aryl group, as 165113-17-7P, 165113-18-8P, 165113-19-9P, 165113-20-2P defined herein, appended to a carboxamido group, as defined 165113-13-3P, 165113-14-4P 165113-15-5P, 165113-16-6P. herein. 165113-21-3P, 165113-22-4P 165113-23-5P, 165113-24-6P. (O155 “Urea” refers to N(Rs.) C(O)N(Rs)(Rs.) 165113-25-7P, 165113-26-8P, 165113-27-9P, 165113-28-OP, wherein Rs. Rs 7, and Rs are each independently a hydrogen 165113-29-1P, 165113-30-4P 165113-31-5P, 165113-32-6P. atom, an alkyl group, an aryl group or an arylheterocyclic 165113-33-7P, 165113-34-8P, 165113-35-9P, 165113-36-0P, ring, as defined herein, or Rs and Rs, taken together are a 165113-37-1P, 165113-38-2P 165113-39-3P, 165113-40-6P. heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl 165113-41-7P, 165113-42-8P, 165113-43-9P, 165113-44-OP, group, as defined herein. 165113-45-1P, 165113-46-2P 165113-47-3P, 165113-48-4P. 0156 "Phosphoryl” refers to P(R)(R)(R), 165113-49-5P, 165113-50-8P, 165113-51-9P, 165113-52-OP, wherein Rio is a lone pair of electrons, thial or oxo, and R7 165113-53-1P, 165113-54-2P 165113-55-3P, 165113-56-4P. and R are each independently a covalent bond, a hydrogen, 165113-57-5P, 165113-58-6P, 165113-59-7P 165113-60-0P, a lower alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or 165113-6.1-1P, 1651 13-62-2P 165113-63-3P, 165113-64-4P. an aryl, as defined herein. 165113-65-5P, 165113-66-6P, 165113-67-7P 165113-68-8P. 0157. “Phosphoric acid” refers to -P(O)(OR)OH 165113-69-9P, 165113-70-2P 165113-71-3P, 165113-72-4P. wherein Rs is a hydrogenatom, an alkyl group, an aryl group 165113-73-5P, 165113-74-6P, 114798-27-5, 114798-28-6, or an arylheterocyclic ring, as defined herein. 114798-29-7, 124749-82-2, 114798-28-6, 124749-84-4, 0158 “Phosphinic acid” refers to -P(O)(Rs)OH 124750-88-5, 124750-91-0, 124750-93-2, 161946-65-2P wherein Rs is a hydrogenatom, an alkyl group, an aryl group 161947-47-3P, 161947-48-4P 161947-51-9P, 161947-52-OP, or an arylheterocyclic ring, as defined herein. 161947-55-3P, 161947-56-4P 161947-60-0P 161947-61-1P 0159. “Silyl refers to —Si(R-7) (Ra)(R-7s), wherein Rz, 161947-68-8P 161947-69-9P, 161947-70-2P 161947-71-3P, R7 and Rs are each independently a covalent bond, a lower 161947-72-4P 161947-74-6P 161947-75-7P 161947-81-5P, alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein. 161947-82-6P 161947-83-7P 161947-84-8P 161947-85-9P, 0160 The cardiovascular compounds used in the com 161947-86-OP. 161947-87-1P 161947-88-2P 161947-89-3P, pounds and compositions of the invention are preferably 161947-90-6P 161947-91-7P 161947-92-8P 161947-93-9P, aldosterone antagonists, angiotensin II antagonists, endothe 161947-94-OP. 161947-95-1P 161947-96-2P 161947-97-3P, lin antagonists, hydralazine compounds, neutral endopepti 161947-98-4P 161947-99-5P, 161948-00-1P 161948-01-2P dase inhibitors and renin inhibitors. 161948-02-3P, 168686-32-6P, 167301-42-OP. 166813-82-7P. 0161 Suitable angiotensin II antagonists, include, but are 166961-56-4P, 166961-58-6P, 158872-96-9P, 158872-97-0P, not limited to, angiotensin, abitesartan, candesartan, cande 158807-14-8P, 158807-15-9P, 158807-16-0P, 158807-17-1P Sartan cilexetil, elisartan, embusartan, enoltaSosartan, epro 158807-18-2P, 158807-19-3P, 158807-20-6P, 155884-08-5P, Sartan, fonsartan, forasartan, glycylosartan, irbesartan, losa 154749-99-2, 167371-59-7P. 244126-99-6P, 177848-35-OP, rtan, olmesartan, milfasartan, medoxomil, ripisartan, 141309-82-2P, and the like. pomisartan, pratosartan, saprisartan, Saralasin, Sarnesin, 0162 Suitable endothelin antagonists include, but are not tasosartan, telmisartan, Valsartan, Zolasartan, 3-(2'(tetrazole limited to, atrasentan, bosentan, darusentan, endothelin, enra 5-yl)-1,1'-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imi sentan, Sitaxsentan, Sulfonamide endothelin antagonists, dazo[4,5-b]pyridine, antibodies to angiotensin II, A-81282, tezosentan, BMS 193884, BQ-123, SQ28.608, and the like. A-81988, BAY 106734, BIBR-363, BIBS-39, BIBS-222, 0163 Suitable hydralazine compounds include, but are BMS-180560, BMS-184698, BMS-346567, CGP-38560A, not limited to, compounds having the formula: CGP-42112A, CGP-48369, CGP-49870, CGP-63170, CI-996, CP-148130, CL-329167, CV-11194, CV-11974, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, DuP R4 R3 753, E-1477, E-4177, E-4188, EMD-66397, EMD-666R4, a b c EMD-73495, EMD-66684, EXP-063, EXP-929, EXP-3134, R1 NNR2 EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, EXP-9954, FK-739, FRI 153332, GA-0050, GA-0056, US 2009/0012057 A1 Jan. 8, 2009

0164 wherein a, b and c are independently a single or (0168. In another embodiment, the invention describes double bond; R and R are each independently a hydrogen, angiotensin II antagonists of Formula (I) and pharmaceuti an alkyl, an ester or a heterocyclic ring, wherein alkyl, ester cally acceptable salts thereof: and heterocyclic rind areas defined herein; R and Rare each independently alone pair of electrons or a hydrogen, with the (I) proviso that at least one of R. R. RandR is not a hydrogen. R10 X3 Exemplary hydralazine compounds include budralazine, Y Z3 cadralazine, dihydralazine, endralazine, hydralazine, / & pildralazine, todralazine, and the like. 0165 Suitable renin inhibitors include, but are not limited to, aldosterone, aliskiren (SPP-100), ditekiren, enalkrein (A-64662), medullipin, terlkiren, tonin, Zankiren, RO wherein: 42-5892 (remikiren), A 62198. A 64662, A 65317. A 69729, (0169 X is: A 72517 (Zankiren), A 74273, CP80794, CGP 29287, CGP 38560A, EMD 47942, ES 305, ES 1005, ES 8891, FK 906, (1) FK 744, H 113, H-142, KRI 1314, pepstatin A, RO 44-9375 (ciprokiren), RO 42-5892, RO 66-1132, RO 66-1168, SP500, SP 800, SR-43845, SQ 34017, U 71038, YM-21095, YM-26365, urea derivatives of peptides, amino acids con nected by nonpeptide bonds, di- and tri-peptide derivatives (2) (e.g., Act-A, Act-B, Act-C, ACT-D, and the like), amino acids and derivatives thereof, diol sulfonamides and sulfinyls, modified peptides, peptidyl beta-aminoacyl aminodiol car bamates, monoclonal antibodies to renin. Suitable renin inhibitors are described more fully in U.S. Pat. Nos. 5,116, 835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, (3) 5,098,924), 5,095,006, 5,089,471, 5,075451, 5,066,643, 5,063,208, 4,845,079, 5,055,466, 4,980,283, 4,885.292), 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, 5,036,053, 5,034,512, and 4,894,437, the disclosures of each of which are incorporated herein by reference in their entirety. (4) 0166 The contemplated cardiovascular compounds of the invention are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Thera peutics (9th Edition), McGraw-Hill, (1996); Merck Index on CD-ROM, 13" Edition; STN Express, file phar and file reg (5) istry, the disclosures of each of which are incorporated by reference herein in their entirety. 0167. In one embodiment the cardiovascular compounds of the invention are angiotensin II antagonists, aldosterone antagonists, endothelin antagonists, hydralazine compounds, (6) neutral endopeptidase inhibitors and renin inhibitors that (7) must contain one or more of the following functionalities: a carboxylic acid group (-COOH), a hydroxyl group (-OH), O a thiol group (-SH) and/or a primary or secondary amine S-N(D) \ N, group (-NH). The cardiovascular compounds are Substi O tuted with at least one nitric oxide enhancing group that is HC CH: linked to the cardiovascular compound through one or more sites Such as oxygen (hydroxyl condensation), Sulfur (sulfhy dryl condensation) and/or nitrogen via a bond or moiety that (0170 (8) —N(D)-C(O) N(D)-CH CH-CH: can be hydrolyzed. The cardiovascular compounds compris (0171 (9)-C(O) UD; ing at least one nitric oxide enhancing group are in accor (0172 (10) - C(O) CH NH(D): dance with the invention and/or are included in the composi (0173 (11) - S(O), N(D)-C(O)-CHs: tions of the invention can be any of those known in the art, (0174 (12) - S(O), N(D)-C(O)-ND-CH CH including those exemplified below. The nitric oxide enhanc CH; or ing groups are nitroxides and/or heterocyclic nitric oxide (0175 (13) - S(O), N(D)-OD; donor groups. The heterocyclic nitric oxide donor groups are (0176 D is D. —C(O)—CH NH(D) or —C(CHs): furoxans, Sydnonimines, oXatriazole-5-ones and/or oXatriaz 0177 Z is a carbon, —CH or a nitrogen atom; ole-5-imines. 0.178 Rio is a fluorine or a hydrogen atom; US 2009/0012057 A1 Jan. 8, 2009 10

(0179 Y, is: -continued (8) (1) R12 N HC uS-N 3 / y-cis-ch, N R11 N

(2) (9) H3C CH3 O

les-- N U3D

N CH

(3)

(10) CH3 1. Y R33 (4) N N

Ho-Hsc.1S O

(11) O U3D (5)

H3C r N O O UD (6) H3C OD (12) CH3 ODI HC 3 W N za N DU \ CH-CH N H3C lsN N O O -- (7) CH (13) N \ 2NNX-R, US 2009/0012057 A1 Jan. 8, 2009 11

-continued -continued (14) 22 R16 O (22)

R16 R16 -(CH2)k N H3C e R32 / R16 N \ - NZ,

CH3O - N -circa

(15) (23) C N R11 n CH3 s \ HC3 21 S le X-CH-CH, N DIO R11 (16) RJC Z "nz, O s R34 (24)

/ -- (17) N\ |

D1 -- (25) (18) D O

(19) N 26 za y-n-n CH (26) N 1. -N N N X O S. R DU O HC-(CH1N N 28 (20) N R20

N (27) R51 CH3

(21) z1N US 2009/0012057 A1 Jan. 8, 2009 12

0188 Ra is a lower alkyl or a cycloalkyl: -continued (0189 Rs is: (28) (0190 (1) hydrogen: (0191 (2) a lower alkyl:

(3)

UlD1

O)--CH (29)

(4)

(0192 (5) –C(O) UD; 0193 R is a hydrogen, a lower alkyl, an alkoxy, —OD, a cyano. —C(O)—UD, NH(D) or an alkylcarbonyl: 0194 R, is an aryl or a cycloalkyl: (30) 0.195 Rs at each occurrence is independently selected from a lower alkyl, an alkoxyalkyl, an alkylcarboxylic acid, an hydroxyalkyl, an arylalkoxy, an arylalkyl or an aryl; (0196), R is a hydrogen or —C(O) UD; 0.197 Rao is a hydrogen, a lower alkyl or —C(O)—UD; (0198 R is:

(1)

(31) O

(2) DO

(32)

0199 R is a hydrogen, —C(O)—UD or D(HDN CH3 -N DU3|EC s 0180 Z is C R or a nitrogen; 0181 R is: 0182 (1) —CH OD: (0200 R is a lower alkyl or an alkoxyalkyl; 0183 (2) - C(O) UD; 0201 R, is a lower alkyl, an arylan arylalkyl or —(CH) (0.184 (3) - C(O) O CH(CH) O C(O) OR; O 0202 Rs is —OD —S(O), N(D)H, N(D)H, 0185 (4) —CH N(D)-C(O) OR; 0186 R is a chlorine. —SCH or a haloalkyl: 0203 R is a hydrogen, a lower alkyl or —C(O)UD; 0187 R is a lower alkyl or K: 0204 Rio is a lower alkyl or a haloalkyl: US 2009/0012057 A1 Jan. 8, 2009 13

0205 R is: (0219) K is —(W)-E,-(C(R)(R)).-E.-(C(R)(R))— (W), (C(R)(R)) (W), E-(W), (C(R)(R)). V. (1) 0220 a, b, c, d, g, i and are each independently an integer O U3D from 0 to 3: 0221 p. x,y and Zare each independently an integer from O to 10; O 0222 V is V. R. —U Vs or Ve: 0223 V is: UD (2) O 31 (1)

N NYNoN 0206 R is a hydrogen, an alkyl or an aryl; 0207 R is —(CH), OD or (2) R24 S y / -N- (3) O Me 0208 R is a hydrogen, a lower alkyl, a lower haloalkyl, an aryl or an arylalkyl; ? \N 0209 Rs is a hydrogen or a lower alkyl: No1 No 0210 R is an alkoxy, -Dean amino group or —N(R) (Rs); (4) 0211 Rao is a hydrogen, a lower alkyl, an alkoxyalkyl or Me —(C(R)R)), Va.; 0212 R is a hydrogen or a lower alkyl: f \ (0213 R2 is a lower alkyl or —(C(R)R)), Va.; O-NN -N 0214 Ras and R taken together are: O (5)

H3C CH3 (1) P.? \ N-O or No1 No Z5 (6) HC CH CN (2) H3C CH3 ( \ o1 N No1 N N-O; Zs (7)

0215 Z is —CH or oxygen; f \ 0216 o is an integer from 0 to 3: N-No 0217 k is an integer from 1 to 3: 0218 D is a hydrogen, V or K:

US 2009/0012057 A1 Jan. 8, 2009 15

-continued -continued (3) (5) H3C CH3 x - Re N-O or R-N Z5 Y. d T HC CH Yo 1 O (4) H3C CH3 21 (6) N-O; S " ;4. HC CH Re - Nt 0230 Z is —CH or nitrogen; 0231 W, at each occurrence is independently —C(O)—, N - —C(S)-, -T-, -(C(R)(R)), , – N(R)R, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, —(CH2CH2O)— or a heterocyclic nitric oxide donor; 0232 E at each occurrence is independently -T-, an alkyl 0234 T is a S(O) ; a carbonyl or a covalent bond; group, an aryl group, —(C(R)(R)), , a heterocyclic ring, 0235 o is an integer from 0 to 2: an arylheterocyclic ring, -(CH2CH2O) — orY.: (0236) R, and R are independently selected from an alkyl group, an aryl group, or R, and R taken together with the 0233 Y is: nitrogen atom to which they are attached are a heterocylic r1ng, (1) 0237 T at each occurrence is independently a covalent bond, a carbonyl, an oxygen, —S(O) - or —N(R)R. 0238 his an integer form 1 to 10; 0239) q is an integer from 1 to 5: (0240 R, and R, 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, (2) a cycloalkylthio, an arylalklythio, an arylalkylthioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky lamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul fonic 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, (3) an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar boxylic ester, an arylcarboxylic ester, a Sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, (4) a nitro, -U, Vs, V, -(C(R)(R)). U, Vs, -(C(R) (R)). Us V, -(C(R)(R)). U V —(C(R) (R)). Us—C(O)—Vs, or R, and R, 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, US 2009/0012057 A1 Jan. 8, 2009 16

0246 R, is a hydrogen, an alkyl, an aryl, an alkylcarboxy lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an (1) arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsul phonyloxy, a Sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH2—C-(U Vs)(R) (R), a bond to an adjacent atom creating a double bond to that atom or —(N2O ).M.", wherein M is an organic or inor (2) ganic cation; and 0247 with the proviso that the compound of Formula (I) must contain at least one nitric oxide enhancing group linked to the compound of Formula (I) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed. 0248. In cases where multiple designations of variables which reside in sequence are chosen as a “covalent bond' or the integer chosen is 0, the intent is to denote a single covalent 0241) R, and R are each independently a hydrogen, an bond connecting one radical to another. For example, Eo alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, would denote a covalent bond, while E. denotes (E-E) and an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an (C(R)(R)) denotes —C(R)(R)—C(R)(R)—. alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, 0249. In another embodiment, the invention describes a cycloalkylthio, an arylalklythio, an arylalkylthioalkyl, an angiotensin II antagonists of Formula (II) and pharmaceuti alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an cally acceptable salts thereof: alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky lamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul (II) fonic 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, N \ S an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an les-- 2 UD alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo N nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar boxylic ester, an arylcarboxylic ester, a Sulfonamido, an O alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U, Vs, Vs, or R, and R, taken together with the UlD1 carbons to which they are attached form a carbonyl, a meth anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, O an oxime, an imine, a hydraZone a bridged cycloalkyl group, wherein: 0250 U and D are as defined herein; and (1) 0251 with the proviso that the compounds of Formula (II) must contain at least one nitric oxide enhancing group linked to the compound of Formula (II) through an oxygen atom, a N-O O nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed. 0252. In another embodiment, the invention describes angiotensin II antagonists of Formula (III) and pharmaceuti (2) cally acceptable salts thereof:

(III) Y Br X3 HC CH

0242 U is an oxygen, Sulfur or —N(R)R. 0243 Vs is —NO or —NO (i.e. an oxidized nitrogen); 0244 k is an integer from 1 to 3: 0245 R is alone pair of electrons, a hydrogen oran alkyl 0253 wherein: group; 0254 X and Y are as defined herein; and US 2009/0012057 A1 Jan. 8, 2009

0255 with the proviso that the compounds of Formula 0265 wherein: (III) must contain at least one nitric oxide enhancing group 0266 X and Y are as defined herein; and linked to the compound of Formula (III) through an oxygen 0267 with the proviso that the compounds of Formula atom, a nitrogen atom or a Sulfur atom via a bond or moiety (III) must contain at least one nitric oxide enhancing group that can be hydrolyzed. linked to the compound of Formula (VI) through an oxygen 0256 In another embodiment, the invention describes angiotensin II antagonist compounds of Formula (IV) and atom, a nitrogen atom or a Sulfur atom via a bond or moiety pharmaceutically acceptable salts thereof: that can be hydrolyzed. 0268. In another embodiment, the invention describes angiotensin II antagonist compounds of Formula (VII) and (IV) pharmaceutically acceptable salts thereof: Y

(VII)

N X

wherein: 0257 wherein: 0269 Ra, is a lower alkyl group: 0258 X and Y are as defined herein; and (0270 X and Y as defined herein; and 0259 with the proviso that the compounds of Formula 0271 with the proviso that the compounds of Formula (IV) must contain at least one nitric oxide enhancing group (VII) must contain at least one nitric oxide enhancing group linked to the compound of Formula (IV) through an oxygen linked to the compound of Formula (VII) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or moiety atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed. that can be hydrolyzed. 0260. In another embodiment, the invention describes 0272. In another embodiment, the invention describes angiotensin II antagonist compounds of Formula (V) and angiotensin II antagonist compounds of Formula (VII) and pharmaceutically acceptable salts thereof: pharmaceutically acceptable salts thereof:

(V) (VIII) Ns 0273 wherein: 0261 wherein: 0274 X and Y are as defined herein; and 0262 X and Y are as defined herein; and 0275 with the proviso that the compounds of Formula 0263 with the proviso that the compounds of Formula (V) (VIII) must contain at least one nitric oxide enhancing group must contain at least one nitric oxide enhancing group linked linked to the compound of Formula (VIII) through an oxygen to the compound of Formula (V) through an oxygen atom, a atom, a nitrogen atom or a Sulfur atom via a bond or moiety nitrogen atom or a Sulfur atom via a bond or moiety that can that can be hydrolyzed. be hydrolyzed. 0276. In other embodiments of the invention the com 0264. In another embodiment, the invention describes pound of Formula (I) is a nitric oxide enhancing abitesartan, angiotensin II antagonist compounds of Formula (VI) and a nitric oxide enhancing candesartan, a nitric oxide enhancing pharmaceutically acceptable salts thereof: CV-1 1974, a nitric oxide enhancing elisartan analogue, a nitric oxide enhancing embusartan, a nitric oxide enhancing enoltaSosartan, a nitric oxide enhancing fonsartan, a nitric (VI) oxide enhancing forasartan, a nitric oxide enhancing glycyl X losartan, a nitric oxide enhancing irbesartan, a nitric oxide enhancing losartan, a nitric oxide enhancing olmesartan, a N nitric oxide enhancing milfasartan, a nitric oxide enhancing pomisartan, a nitric oxide enhancing ripisartan, a nitric oxide S-( ) enhancing tasosartan, a nitric oxide enhancing telmisartan, a 2 nitric oxide enhancing Valsartan, a nitric oxide enhancing CL-329167, a nitric oxide enhancing analogue related to EMD 66684, a nitric oxide enhancing EXP 3134, a nitric US 2009/0012057 A1 Jan. 8, 2009 oxide enhancing MK 996, a nitric oxide enhancing enhancing pomisartan of Formula (XXI), a nitric oxide SR-47436, a nitric oxide enhancingYM358, or a nitric oxide enhancing ripisartan of Formula (XXII), a nitric oxide enhancing compound of any of the following compounds of enhancing tasosartan of Formula (XXIII), a nitric oxide enhancing telmisartan of Formula (XXIV), a nitric oxide ACS registry number 124750-92-1, 133240-46-7, 135070 enhancing Valsartan of Formula (XXV); a nitric oxide 05-2, 139958-16-0, 145160-84-5, 147403-03-0, 153806-29 enhancing analogue related to EMD 66684 of Formula 2, 439904-54-8P 439904-55-9P 439904-56-0P 439904-57 (XXVI); a nitric oxide enhancing EXP 3134 of Formula 1P 439904-58-2P 155918-60-8P 155918-61-9P, 272438 (XXVII); a nitric oxide enhancing MK-996 of Formula (XX VIII); the compound of Formula (II) is a nitric oxide enhanc 16-1P 272446-75-0P, 223926-77-OP. 169281-89-4, 439904 ing of eprosartan of Formula (XXIX); and the compound of 65-1P 165113-01-9P, 165113-02-0P, 165113-03-1P Formula (III) is a nitric oxide enhancing analogue related to 165113-03-2P, 165113-05-3P, 165113-06-4P, 165113-07-5P, Saprisartan of Formula (XXX), a nitric oxide enhancing Zola 165113-08-6P, 165113-09-7P 165113-10-0P, 165113-11-1P sartan of Formula (XXXI), or a pharmaceutically acceptable 165113-12-2P, 165113-17-7P 165113-18-8P, 165113-19-9P, salt thereof, 165113-20-2P, 165113-13-3P, 165113-14-4P, 165113-15-5P, 0278 wherein the compound of Formula (IX) is: 165113-16-6P, 165113-21-3P, 165113-22-4P 165113-23-SP, 165113-24-6P, 165113-25-7P 165113-26-8P, 165113-27-9P, 165113-28-OP. 165113-29-1P, 165113-30-4P 165113-31-SP, (IX) 165113-32-6P, 165113-33-7P 165113-34-8P, 165113-35-9P, 165113-36-0P, 165113-37-1P, 165113-38-2P, 165113-39-3P, T nBu O Rn N 165113-40-6P, 165113-41-7P 165113-42-8P, 165113-43-9P, O n NR1 2 165113-44-OP. 165113-45-1P 165113-46-2P, 165113-47-3P, 165113-48-4P, 165113-49-5P, 165113-50-8P, 165113-51-9P, CH2 -N-CH 165113-52-OP. 165113-53-1P, 165113-54-2P, 165113-55-3P, 165113-56-4P, 165113-57-5P, 165113-58-6P, 165113-59-7P. 165113-60-0P, 165113-6.1-1P, 165113-62-2P, 165113-63-3P, 165113-64-4P, 165113-65-5P, 165113-66-6P, 165113-67-7P. 0279 and the compound of Formula (X) is: 165113-68-8P, 165113-69-9P, 165113-70-2P, 165113-71-3P, 165113-72-4P, 165113-73-5P, 165113-74-6P, 114798-27-5, 114798-28-6, 114798-29-7, 124749-82-2, 114798-28-6, (X) 124749-84-4, 124750-88-5, 124750-91-0, 124750-93-2, 161946-65-2P, 161947-47-3P, 161947-48-4P 161947-51-9P, 161947-52-OP. 161947-55-3P, 161947-56-4P 161947-60-0P, 161947-61-1P 161947-68-8P 161947-69-9P, 161947-70-2P 161947-71-3P, 161947-72-4P 161947-74-6P, 161947-75-7P. 161947-81-5P, 161947-82-6P 161947-83-7P 161947-84-8P. 161947-85-9P, 161947-86-OP. 161947-87-1P, 161947-88-2P 161947-89-3P, 161947-90-6P 161947-91-7P 161947-92-8P. 161947-93-9P, 161947-94-OP. 161947-95-1P, 161947-96-2P 161947-97-3P, 161947-98-4P 161947-99-5P, 161948-00-1P 0280 and the compound of Formula (XI) is: 161948-01-2P, 161948-02-3P, 168686-32-6P, 167301-42-OP, 166813-82-7P, 166961-56-4P 166961-58-6P, 158872-96-9P, (XI) 158872-97-0P, 158807-14-8P, 158807-15-9P, 158807-16-0P, NN 158807-17-1P, 158807-18-2P, 158807-19-3P, 158807-20-6P. 155884-08-5P, 154749-99-2, 167371-59-7P. 244126-99-6P. 177848-35-OP and 141309-82-2P; the compound of Formula (II) is a nitric oxide enhancing eprosartan; the compound of Formula (III) is a nitric oxide enhancing saprisartan, a nitric oxide enhancing Zalasartan, the compound of Formula (IV) is a nitric oxide enhancing BMS 180560; the compound of Formula (V) is a nitric oxide enhancing KW 3433; the com C pound of Formula (VI) is a nitric oxide enhancing GA 0056; O and the compound of Formula (VII) is a nitric oxide enhanc ing L 158,809; and pharmaceutically acceptable salts thereof. 0281 and the compound of Formula (XII) is: 0277. In other embodiments of the invention, the com pound of Formula (I) is a nitric oxide enhancing abitesartan of Formula (IX), a nitric oxide enhancing candesartan cilexetil (XII) of Formula (X), a nitric oxide enhancing elisartan analogue of Formula (XI), a nitric oxide enhancing embusartan of For mula (XII), a nitric oxide enhancing enoltaSosartan of For mula (XIII), a nitric oxide enhancing fonsartan of Formula (XIV), a nitric oxide enhancing forasartan of Formula (XV), a nitric oxide enhancing glycyllosartan of Formula (XVI), a nitric oxide enhancing irbesartan of Formula (XVII), a nitric oxide enhancing losartan of Formula (XVIII), a nitric oxide enhancing olmesartan metabolite of Formula (XIX), a nitric oxide enhancing milfasartan of Formula (XX), a nitric oxide US 2009/0012057 A1 Jan. 8, 2009 19

0282 and the compound of Formula (XIII) is: 0286 and the compound of Formula (XVII) is:

(XIII) (XVII) N O / RN / Rn NR, N Na O Rn NR1 Na O N CH H3C / \ N es.e

CH 0287 and the compound of Formula (XVIII) is: 0283 and the compound of Formula (XIV) is: (XVIII) (XIV) O 1. NR1 Rin-Rm ls Pr 2 1-12CH NN N1 N N nBu ON21 Sa 2 O )= 1. -v-f-12CH SRn C CH-O N 2 N V Rn

HC-S O T-Rn 0288 and the compound of Formula (XIX) is: 0284 and the compound of Formula (XV) is: XIX

XV N=N NN (XV) Pr Rn, 1 N 2 N Rn \ 1. CH Rim NR, Na %N1 nBu NS-" N HC o

b= nBu N 2 He YRn O VRn

0285 and the compound of Formula (XVI) is: 0289 and the compound of Formula (XX) is:

(XVI) R O (XX) Rm NHS ul fNN \ N=N 1.nBu CH N 2 N O "S-N 2N % -CH: S CH2 CH o \ / N C CH-O HC N nBu V O Rn T-Rn US 2009/0012057 A1 Jan. 8, 2009 20

0290 and the compound of Formula (XXI) is: 0294 and the compound of Formula (XXV) is:

(XXI) (XXV) NN

O R. . . us NR1 Na 1N1"CH O O Rn iPr

sersO

0295) and the compound of Formula (XXVI) is:

0291 and the compound of Formula (XXII) is: (XXVI) O 21 N nBu NN NN (XXII) Rn N / \ f NT, N R"n-N 2N nPr Rn N N N NR1 Na O CH2

to-yoN . OO \, Rn-Rm1 Y 0296 and the compound of Formula (XXVII) is:

O (XXVII) 0292 and the compound of Formula (XXIII) is: N =N. nBu1. Rn NR1 N Na N III CH

o '-Rn C

O

0297 and the compound of Formula (XXVIII) is:

(XXVIII) 0293 and the compound of Formula (XXIV) is: CH3

21 (XXIV) N /CH3 H3C N N W O T-Rn

% CH N1 2

N2. Pr C US 2009/0012057 A1 Jan. 8, 2009

0298 and the compound of Formula (XXIX) is: 0309 wherein 0310 R-R, taken together are a hydrogen atom; or (XXIX) 0311 R is: 0312 (i) —C-(O)—;

S 0313 (ii) —C (O) NR; 0314) (iii) —C(O)—O—: W N Rn-T N > 0315 (iv) —C(O)—S: N nBu 0316 (v) —CH2—O—; O 1. 0317 (vi) —CH(CH)—O—; 0318 (vii) —N C(O)—S—: T-Rn 0319 (viii) —N—C(O)—CH2—, 0320 (ix) —N C(O)—O—: O 0321 (X) a covalent bond; 0322 (xi) —(C-(R)(R)) is ; or 0299 and the compound of Formula (XXX) is: 0323 (xii) —(C-(R)(R)).s-T-C(O)–: 0324 R, is: a hydrogen or: (XXX) 0325) O (1) Rn FC3C in Rim-Rn O NH-RnW ON1 a N1 CH 2 O O/ O NF ( Br (2) Et

0300 and the compound of Formula (XXXI) is: (3) (XXXI) NN R.NR1 . Na. (4)

nBu (5)

0301 wherein 0302) T is oxygen, sulfur or NR; 0303 Et is the lower alkyl group CH-CH : 0304 nBu is the lower alkyl group CH, CH, CH2— (6) CH2—, CN 0305 nPr is the lower alkyl group CH, CH, CH : 0306 iPr is the lower alkyl group (CH) CH : 0307 OEt is the alkoxy group —OCH CH: 0308 R is a hydrogen, a lower alkyl group, an aryl group; US 2009/0012057 A1 Jan. 8, 2009 22

-continued -continued (15) (7) N-N- x - | \N (16) (8) j, x - N (17) O ls N (9) T 2 i. N N-R-T-Rs

(10) - c. n{y Nt Yo N-R -T-Rs or (19)

(11) N *.../ N Yo > O;

0326 R is —CHR 7, -CN. —S(O). CHR, —C(O)—N(R)(R), NO. —C(O)—ORs or —S(O)— (12) R2s: 0327 R-2s is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group; 0328 R is C(O)—or —S(O) ; 0329 R, is a hydrogen, —CN, —S(O) Rs —C(O)— N(R)(R), NO, or —C(O)—ORs: (13) 0330 T is oxygen, sulfur or NR; 0331 R is a hydrogen, a lower alkyl group, or an aryl group; 10332 R, and R are independently selected from an alkyl group, an aryl group, or R, and R taken together with the nitrogen atom to which they are attached are a heterocylic ring; and 0333 with the proviso that the compounds of Formula (14) (IX) to Formula (XXXI) must contain at least one nitric oxide enhancing group linked to the compound through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed. 0334. In other embodiments of the invention, the com pound of Formula (I) is a nitric oxide enhancing abitesartan of Formula (XXXII), a nitric oxide enhancing candesartan cilexetil of Formula (XXXIII), a nitric oxide enhancing US 2009/0012057 A1 Jan. 8, 2009

elisartan analogue of Formula (XXXIV), a nitric oxide 0338 and the compound of Formula (XXXV) is: enhancing embusartan of Formula (XXXV), a nitric oxide enhancing enoltasosartan of Formula (XXXVI), a nitric oxide enhancing fonsartan of Formula (XXXVII), a nitric oxide (XXXV) enhancing forasartan of Formula (XXXVIII), a nitric oxide NN enhancing glycyllosartan of Formula (XXIX), a nitric oxide O / \ enhancing irbesartan of Formula (XL), a nitric oxide enhanc HN 2 N ing losartan of Formula (XLI), a nitric oxide enhancing olm esartan metabolite of Formula (XLII), a nitric oxide enhanc ing milfasartan of Formula (XLIII), a nitric oxide enhancing CH2 R45 pomisartan of Formula (XLIV), a nitric oxide enhancing rip nBu isartan of Formula (XLV), a nitric oxide enhancing tasosartan F of Formula (XLVI), a nitric oxide enhancing telmisartan of O Formula (XLVII), a nitric oxide enhancing Valsartan of For mula (XLVIII); a nitric oxide enhancing analogue related to EMD 66684 of Formula (XLIX); a nitric oxide enhancing EXP3134 of Formula (L); a nitric oxide enhancing MK-996 0339 and the compound of Formula (XXXVI) is: of Formula (LI); the compound of Formula (II) is a nitric oxide enhancing of eprosartan of Formula (LII); and com pound of Formula (III) is a nitric oxide enhancing analogue (XXXVI) related to saprisartan of Formula (LII), a nitric oxide enhanc NN ing Zolasartan of Formula (LIV), or a pharmaceutically O / \ acceptable salt thereof, R4 / HN 2 N 0335 wherein the compound of Formula (XXXII) is: 6 No NS (XXXII) HC / \ NN O nBu / V O R45 n HN 2 N CH3 N

(0340 and the compound of Formula (XXXVII) is:

0336 and the compound of Formula (XXXIIII) is: (XXXVII) O (XXXIII) NN B sists, N in \ 2 1. Oseo X-OE "OO O R45 HC-S O R45 0337 and the compound of Formula (XXXIV) is: 0341 and the compound of Formula (XXXVIII) is: (XXXIV) NN / \ (XXXVIII) NN nBu HN 2 N / V 1. R-N 2 N B N N N-CH O O l "ne YN-CH, N

= N 2 nBu US 2009/0012057 A1 Jan. 8, 2009 24

0342 and the compound of Formula (XXXIX) is: 0347 and the compound of Formula (XLIV) is: (XXXIX) O NN (XLIV)

nBn H2NN ? \ 1. CH2 NNeN 2 N /N SCH, O R45 Cl H.é. ON 0343 and the compound of Formula (XL) is: (XL) N=N R46 N.NeN 0348 and the compound of Formula (XLV) is: N1 CH2 (XLV) als Pr NN N nBn N in \ 0344 and the compound of Formula (XLI) is: HC W \ 2 N CH (XLI) R- \N C N NN Y R4 W \ in \ O No N nBn a Y-h 2 O O 0349 and the compound of Formula (XLVI) is:

0345 and the compound of Formula (XLII) is: (XLVI)

(XLII) N21 NE

HN 1. 2 H3C N N O N N nCH CH2 H3C o

0350 and the compound of Formula (XLVII) is: 0346 and the compound of Formula (XLIII) is:

(XLVII) (XLIII) CH US 2009/0012057 A1 Jan. 8, 2009 25

0351) and the compound of Formula (XLVIII) is: 0356 and the compound of Formula (LIII) is:

O NN (XLVIII) (LIII) O in \ O -- ill "Se Fic3C a R45 Y-H, O R45 I NH iPr O a NS 0352 and the compound of Formula (LIX) is: \= CH / (LIX) Et Br NN 1 \ O 21 N HNNeN 0357 and the compound of Formula (LIV) is:

N N-CHX-B, R45 CH 2 O O (LIV) O NN 0353 and the compound of Formula (L) is: in - O R45

C (L) C O 4N f N=N NF YCH, / Ris-5 N > nBn, 's-2 nBn Br V O CH

O O wherein:0358 Et is the lower alkyl group CH-CH : 0354 and the compound of Formula (LI) is: 0359 nBu is the lower alkyl group CH CH-CH CH2—, (LI) 0360 nPr is the lower alkyl group CH CH-CH : CH 0361 iPr is the lower alkyl group (CH) CH : 3 O 0362 OEt is the alkoxy group —OCH CH: 21 N R46 0363 Rs is: y Et O N Sa N SS1 H3C N V 2 (1) CH O R48

0355 and the compound of Formula (LII) is: N-No (2) (LII) O R4s

/ S \ N or - 4. {N sus- > o1No1 N nBu (3)

O HC -NO R45 N C.o1 US 2009/0012057 A1 Jan. 8, 2009 26

-continued -continued (7) (4) O R67 N-N ( \ No1 No N 4 o1 5 (8) O (5) -OH: R67 ( \, 0364 Ras is —S(O). CHs: —CN, C(O) NH or o1 No1 —C(O)CCH, and (9) 0365 R is a hydrogen or chlorine; 0366 Rs is a hydrogen or a methyl group: r O N-1 Nu 0367 R is: ( \, N o1 (1) r (10) O N-1 Nu ( \, (2) N o1 O (11)

O N-N (3) f \ R N o1 65

(12)

(4) O W Nt\ R49 N - R65

O (13) (5)

O O N-N

N ( O1\ .65 (6)

0368 wherein: 0369 R is —(CH), O C(O)—CH or —(CH) NH C(O)-CH: 0370 R, is –CN, -C(O) NH or C(O) OCH: 0371 Rao and Rs are as defined herein; and US 2009/0012057 A1 Jan. 8, 2009 27

0372 with the proviso that the compounds of Formula the reactions may not be applicable as described to each (XXXII) to (LIV) must contain at least one nitric oxide compound included within the disclosed scope. The com enhancing group linked to the compound through an oxygen pounds for which this occurs will be readily recognized by atom, a nitrogen atom or a Sulfur atom via a bond or moiety one skilled in the art. In all such cases, either the reactions can that can be hydrolyzed. be successfully performed by conventional modifications 0373 The invention describes cardiovascular compounds known to one skilled in the art, e.g., by appropriate protection that are aldosterone antagonists comprising a nitric oxide of interfering groups, by changing to alternative conventional enhancing group, endothelin antagonists comprising a nitric reagents, by routine modification of reaction conditions, and oxide enhancing group, hydralazine compounds comprising the like, or other reactions disclosed herein or otherwise con a nitric oxide enhancing group, neutral endopeptidase inhibi ventional, will be applicable to the preparation of the corre tors comprising a nitric oxide enhancing group and renin sponding compounds of this invention. In all preparative inhibitors comprising a nitric oxide enhancing group, methods, all starting materials are known or readily prepared wherein the aldosterone antagonists, endothelin antagonists, from known starting materials. hydralazine compounds, neutral endopeptidase inhibitors 0379 The compounds of Formulas (I) to (LIV) can be and renin inhibitors of the invention must have least one synthesized by one skilled in the art using conventional meth carboxylic acid group (-CO)K), hydroxyl group (-OK), ods. Some of the parent cardiovascular compounds (i.e. car thiol group (—SK) and/or primary or secondary amine group diovascular compounds that do not contain a nitric oxide ( NK); wherein K is as defined herein. enhancing group) are commercially available or their synthe 0374. In another embodiment, the invention describes car sis has been reported in the scientific literature. The cardio diovascular compounds of the invention comprising a nitric vascular compounds that are Substituted to contain a nitric oxide enhancing group and pharmaceutically acceptable salts oxide enhancing group linked to the cardiovascular com thereof. In one embodiment, the pharmaceutically acceptable pound through one or more sites such as oxygen, Sulfur and/or salts do not include the nitrate salt. nitrogen can be synthesized using conventional methods 0375 Compounds of the invention that have one or more known to one skilled in the art. Known methods for linking asymmetric carbon atoms may exist as the optically pure the nitric oxide enhancing groups to compounds are enantiomers, pure diastereomers, mixtures of enantiomers, described in WO99/64417, WO 94/01422: EP 0574726A1, mixtures of diastereomers, racemic mixtures of enantiomers, EP 0 683 159 A1; and in J. Med. Chem., 47: 2688-2693 diastereomeric racemates or mixtures of diastereomeric race (2004); J. Med. Chem., 47: 1840-1846 (2004); J. Med. Chem., mates. It is to be understood that the invention anticipates and 46: 3762-3765 (2003); J. Med. Chem., 46: 747-754 (2003); includes within its scope all such isomers and mixtures Chem Rev., 102: 1091-1134 (2002); J. Med. Chem., 42: 1941 thereof. 1950 (1999); J. Med. Chem., 41: 5393-5401 (1998); J. Med. 0376 Another embodiment of the invention describes the Chem., 38: 4944-4949 (1995): Arzneim. Forsch. Drug Res., metabolites of the cardiovascular compounds comprising at 47 (II): 847-854 (1997); the disclosures of each of which are least one nitric oxide enhancing group and pharmaceutically incorporated by reference herein in their entirety. The meth acceptable salts thereof. These metabolites, include but are ods of linking the nitric oxide enhancing group to compounds not limited to, the non-nitric oxide enhancing derivatives, described in these references can be applied by one skilled in degradation products, hydrolysis products, and the like, of the the art to produce any of the cardiovascular compounds com cardiovascular compounds comprising at least one nitric prising at least one nitric oxide enhancing group described oxide enhancing group and pharmaceutically acceptable salts herein. The cardiovascular compounds comprising at least thereof. one nitric oxide enhancing group of the invention donate or 0377 Another embodiment of the invention provides pro transfera biologically active form of nitrogen monoxide (i.e., cesses for making the novel compounds of the invention and nitric oxide). to the intermediates useful in Such processes. The reactions 0380 Compounds contemplated for use in the invention, are performed in solvents appropriate to the reagents and e.g., cardiovascular compounds that contain at least one nitric materials used are suitable for the transformations being oxide enhancing group, linked through one or more sites Such effected. It is understood by one skilled in the art of organic as oxygen (hydroxyl condensation), Sulfur (sulfhydryl con synthesis that the functionality present in the molecule must densation) and/or nitrogen, are, optionally, used in combina be consistent with the chemical transformation proposed. tion with nitric oxide enhancing compounds that release nitric This will, on occasion, necessitate judgment by the routineer oxide, increase endogeneous levels of nitric oxide or other as to the order of synthetic steps, protecting groups required, wise directly or indirectly deliver or transfer a biologically and deprotection conditions. Substituents on the starting active form of nitrogen monoxide to a site of its intended materials may be incompatible with some of the reaction activity, Such as on a cell membrane in vivo. conditions required in some of the methods described, but 0381 Nitrogen monoxide can exist in three forms: NO alternative methods and substituents compatible with the (nitroxyl), NO. (nitric oxide) and NO" (nitrosonium). NO. is reaction conditions will be readily apparent to one skilled in a highly reactive short-lived species that is potentially toxic to the art. The use of sulfur and oxygen protecting groups is well cells. This is critical because the pharmacological efficacy of known for protecting thiol and alcohol groups against unde NO depends upon the form in which it is delivered. In contrast sirable reactions during a synthetic procedure and many Such to the nitric oxide radical (NO.), nitrosonium (NO") does not protecting groups are known and described by, for example, react with O. or O - species, and functionalities capable of Greene and Wuts, Protective Groups in Organic Synthesis, transferring and/or releasing NO" and NO are also resistant Third Edition, John Wiley & Sons, New York (1999). to decomposition in the presence of many redox metals. Con 0378. The chemical reactions described herein are gener sequently, administration of charged NO equivalents (posi ally disclosed in terms of their broadest application to the tive and/or negative) does not result in the generation of toxic preparation of the compounds of this invention. Occasionally, by-products or the elimination of the active NO group. US 2009/0012057 A1 Jan. 8, 2009 28

0382. The term "nitric oxide encompasses uncharged otides (preferably of at least 5, and more preferably 5-200 nitric oxide (NO.) and charged nitrogen monoxide species, nucleotides); Straight or branched, Saturated or unsaturated, preferably charged nitrogen monoxide species, such as aliphatic or aromatic, Substituted or unsubstituted S-nitrosy nitrosonium ion (NO") and nitroxyl ion (NO ). The reactive lated hydrocarbons; and S-nitroso heterocyclic compounds. form of nitric oxide can be provided by gaseous nitric oxide. S-nitrosothiols and methods for preparing them are described The nitrogen monoxide releasing, delivering or transferring in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; compounds have the structure F NO, wherein F is a nitrogen monoxide releasing, delivering or transferring group, and WO 98/19672; and Oae et al. Org. Prep. Proc. Int., 15(3): include any and all Such compounds which provide nitrogen 165-198 (1983), the disclosures of each of which are incor monoxide to its intended site of action in a form active for its porated by reference herein in their entirety. intended purpose. 0389. Another embodiment of the invention is S-nitroso 0383. The term “NO adducts’ encompasses any nitrogen amino acids where the nitroso group is linked to a Sulfur monoxide releasing, delivering or transferring compounds, group of a Sulfur-containing amino acid orderivative thereof. including, for example, S-nitrosothiols, nitrites, nitrates, Such compounds include, for example, S-nitroso-N-acetyl S-nitrothiols, Sydnonimines, 2-hydroxy-2-nitroSohydra cysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicil zines, (NONOates), (E)-alkyl-2-((E)-hydroxyimino)-5-ni lamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-ni tro-3-hexeneamide (FK-409), (E)-alkyl-2-(E)-hydroxy troso-glutathione, S-nitroso-cysteinyl-glycine, and the like. imino)-5-nitro-3-hexeneamines, N-((2Z.3E)-4-ethyl-2- 0390 Suitable S-nitrosylated proteins include thiol-con (hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3- taining proteins (where the NO group is attached to one or pyridinecarboxamide (FR 146801), N-nitrosoamines, more Sulfur groups on an amino acid oramino acid derivative N-hydroxyl nitrosamines, nitrosimines, diazetine dioxides, thereof) from various functional classes including enzymes, oXatriazole 5-imines, OXimes, hydroxylamines, N-hydrox Such as tissue-type plasminogen activator (TPA) and cathep yguanidines, hydroxyureas, benzofuroxanes, furoxans as sin B; transport proteins, such as lipoproteins; heme proteins, well as Substrates for the endogenous enzymes which synthe Such as hemoglobin and serum albumin; and biologically size nitric oxide. protective proteins, such as immunoglobulins, antibodies and 0384 Suitable NONOates include, but are not limited to, (Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino)) cytokines. Such nitrosylated proteins are described in WO diazen-1-ium-1,2-diolate (“MAHMA/NO”), (Z)-1-(N-(3- 93/09806, the disclosure of which is incorporated by refer ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-di ence herein in its entirety. Examples include polynitrosylated olate (“PAPA/NO”), (Z)-1-(N-(3-aminopropyl)-N-(4-(3- albumin where one or more thiol or other nucleophilic centers aminopropylammonio)butyl)-amino)diazen-1-ium-1,2- in the protein are modified. diolate (spermine NONOate or “SPER/NO”) and sodium(Z)- 0391. Other examples of suitable S-nitrosothiols include: 1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamine (0392 (i) HS(C(R)(R)), SNO; NONOate or “DEA/NO”) and derivatives thereof. NON Oates are also described in U.S. Pat. Nos. 6,232,336, 5,910, (0393 (ii) ONS(C(R)(R)), R.; or 316 and 5,650,447, the disclosures of which are incorporated 0394 (iii) HN CH(COH)–(CH), C(O)NH-CH herein by reference in their entirety. The “NO adducts’ can be (CHSNO) C(O)N H CH-COH: mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/ 0395 wherein m is an integer from 2 to 20; or poly-nitrosated at a variety of naturally susceptible or 0396 R and R, are each independently a hydrogen, an artificially provided binding sites for biologically active alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, forms of nitrogen monoxide. an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an 0385 Suitable furoxanes include, but are not limited to, alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, CAS1609, C93-4759, C92-4678, S35b, CHF 2206, CHF a cycloalkylthio, an arylalklythio, an arylalkylthioalkyl, an 2363, and the like. alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an 0386 Suitable sydnonimines include, but are not limited alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky to, molsidomine (N-ethoxycarbonyl-3-morpholinosydnon lamino, an arylamino, a diarylamino, an alkylarylamino, an imine), SIN-1 (3-morpholinosydnonimine) CAS 936 (3-(cis 2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnon alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul imine, pirsidomine), C87-3754 (3-(cis-2,6- fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio. dimethylpiperidino)sydnonimine, linsidomine, C4144 (3-(3. an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an 3-dimethyl-1,4-thiazane-4-yl)sydnonimine hydrochloride), arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, C89-4095 (3-(3.3-dimethyl-1,1-dioxo-1,4-thiazane-4-yl) an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an sydnonimine hydrochloride, and the like. alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo 0387 Suitable oximes, include, but are not limited to, nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar NOR-1, NOR-3, NOR-4, and the like. boxylic ester, an arylcarboxylic ester, a Sulfonamido, an 0388 One group of NO adducts is the S-nitrosothiols, alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an which are compounds that include at least one —S NO alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul group. These compounds include S-nitroso-polypeptides (the fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, term “polypeptide' includes proteins and polyamino acids a nitro, -U, Vs, V, -(C(R)(R)). U, Vs, -(C(R) that do not possess an ascertained biological function, and (R)). U V —(C(R)(R)). Us—C(O)—Vs, or R. derivatives thereof); S-nitrosylated amino acids (including and R, taken together with the carbons to which they are natural and synthetic amino acids and their stereoisomers and attached form a carbonyl, a methanthial, a heterocyclic ring, racemic mixtures and derivatives thereof); S-nitrosylated a cycloalkyl group, an aryl group, an oxime, a hydraZone, a Sugars; S-nitrosylated, modified and unmodified, oligonucle bridged cycloalkyl group, US 2009/0012057 A1 Jan. 8, 2009 29

04.01 R is a lone pair of electrons, a hydrogen or an alkyl group; (1) 0402 R, is a hydrogen, an alkyl, an aryl, an alkylcarboxy H3C CH3 lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an N-O O alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulpho nyloxy, a Sulfonamido, a carboxamido, a carboxylic ester, an 2-7(H3C CH3 aminoalkyl, an aminoaryl, -CH C(Us Vs)(R)(R), a (2) bond to an adjacent atom creating a double bond to that atom or —(N.O. ).M.", wherein M is an organic or inorganic H3C CH3 cation. (0403. In cases where R and Rare independently a het N-O; erocyclic ring or taken together R, and Rare a heterocyclic ring, then R, can be a Substituent on any disubstituted nitrogen contained within the radical wherein R, is as defined herein. HC CH 0404 Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the 10397) R, and R are each independently a hydrogen, an thiol group with NaNO under acidic conditions (pH is about alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, 2.5) which yields the S-nitroso derivative. Acids which can be an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an used for this purpose include aqueous Sulfuric, acetic and alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, hydrochloric acids. The thiol precursor can also be nitrosy a cycloalkylthio, an arylalklythio, an arylalkylthioalkyl, an lated by reaction with an organic nitrite Such as tert-butyl alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an nitrite, or a nitrosonium salt Such as nitrosonium tetrafluo alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky roborate in an inert solvent. lamino, an arylamino, a diarylamino, an alkylarylamino, an 04.05 Another group of NO adducts for use in the inven alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul tion, where the NO adduct is a compound that donates, trans fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, fers or releases nitric oxide, include compounds comprising an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an at least one ON O— or ON N— group. The compounds arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, that include at least one ON O— or ON N— group are an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an preferably ON O— or ON N-polypeptides (the term alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo "polypeptide' includes proteins and polyamino acids that do nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar not possess an ascertained biological function, and deriva boxylic ester, an arylcarboxylic ester, a Sulfonamido, an tives thereof); ON O - or ON N-amino acids (including alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an natural and synthetic amino acids and their stereoisomers and alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul racemic mixtures); ON O - or ON N-sugars; ON O— fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, or —ON N— modified or unmodified oligonucleotides a nitro, -U, Vs, V, or R, and R taken together with the (comprising at least 5 nucleotides, preferably 5-200 nucle carbons to which they are attached form a carbonyl, a meth otides); ON O— or ON N straight or branched, satu anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, rated or unsaturated, aliphatic or aromatic, Substituted or an oxime, an imine, a hydraZone, a bridged cycloalkyl group, unsubstituted hydrocarbons; and ON O—, ON N— or ON C-heterocyclic compounds. Examples of compounds comprising at least one ON O— or ON N group (1) include butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite, N-nitrosamines, N-nitrosamides, N-nitrosourea, N-nitrosoguanidines, N-nitrosocarbamates, N-acyl-N-nitroso compounds (such as, N-methyl-N-ni N-O or trosourea); N-hydroxy-N-nitrosamines, cupferron, alanosine, dopastin, 1.3-disubstituted nitrosiminobenzimida 2-7(HC CH Zoles, 1,3,4-thiadiazole-2-nitrosimines, benzothiazole-2 (3H)-nitrosimines, thiazole-2-nitrosimines, oligonitroso Syd (2) nonimines, 3-alkyl-N-nitroso-Sydnonimines, 2H-1,3,4- thiadiazine nitrosimines. 0406 Another group of NO adducts for use in the inven tion include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one ON O—, ON.—N— or ON S-group. Among these com pounds are ON O—, ON N or ON. S. polypep tides (the term “polypeptide' includes proteins and also polyamino acids that do not possess an ascertained biological 0398 k is an integer form 1 to 3: function, and derivatives thereof); ON O—, ON N— or 0399 U is an oxygen, sulfur- or N(R)R.; ON-S-amino acids (including natural and synthetic 0400 Vs is —NO or - NO (i.e. an oxidized nitrogen); amino acids and their stereoisomers and racemic mixtures); US 2009/0012057 A1 Jan. 8, 2009 30

ON O ON N— or ON S sugars; ON O , thereof, including, for example, citrulline, ornithine, ON N or ON S modified and unmodified oligo glutamine, lysine, polypeptides comprising at least one of nucleotides (comprising at least 5 nucleotides, preferably these amino acids, inhibitors of the enzyme arginase (e.g., 5-200 nucleotides); O.N. O. , ON N- or ON S N-hydroxy-L-arginine and 2CS)-amino-6-boronohexanoic straight or branched, saturated or unsaturated, aliphatic or acid), nitric oxide mediators and/or physiologically accept aromatic, Substituted or unsubstituted hydrocarbons; and able salts thereof, including, for example, pyruvate, pyruvate ON O—, ON N or ON. S. heterocyclic com precursors, C.-keto acids having four or more carbon atoms, pounds. Examples of compounds comprising at least one precursors of C-keto acids having four or more carbon atoms ON O ON N or ON S group include isosor (as disclosed in WO 03/017996, the disclosure of which is bide dinitrate, isosorbide mononitrate, clonitrate, erythrityl incorporated herein in its entirety), and the substrates for tetranitrate, mannitol hexanitrate, nitroglycerin, pentaeryth nitric oxide synthase, cytokines, adenosin, bradykinin, cal ritoltetranitrate, pentrinitrol, propatylnitrate and organic reticulin, bisacodyl, and phenolphthalein. EDRF is a vascular nitrates with a sulfhydryl-containing amino acid Such as, for relaxing factor secreted by the endothelium, and has been example SPM 3672, SPM 4757, SPM 5185, SPM 5186 and identified as nitric oxide (NO) or a closely related derivative those disclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661, thereof (Palmeretal, Nature, 327:524-526 (1987); Ignarro et 129, 5,807,847 and 5,883,122 and in WO 97/46521, WO al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)). 00/54756 and in WO 03/013432, the disclosures of each of 04.09. The invention is also directed to nitric oxide enhanc which are incorporated by reference herein in their entirety. ing compounds that can increase endogenous nitric oxide. 0407 Another group of NO adducts are N-oxo-N-ni Such compounds, include for example, nitroxide containing troSoamines that donate, transfer or release nitric oxide and compounds, include, but are not limited to, Substituted 2.2.6. are represented by the formula: R"R.N. N(O-M')-NO, 6-tetramethyl-1-piperidinyloxy compounds, Substituted 2.2, where R, and R are each independently a polypeptide, an 5.5-tetramethyl-3-pyrroline-1-oxyl compounds, substituted amino acid, a Sugar, a modified or unmodified oligonucle 2.2.5.5-tetramethyl-1-pyrrolidinyloxyl compounds, Substi otide, a straight or branched, saturated or unsaturated, ali tuted 1,1,3,3-tetramethylisoindolin-2-yloxyl compounds, phatic or aromatic, Substituted or unsubstituted hydrocarbon, substituted 2,2,4,4-tetramethyl-1-oxazolidinyl-3-oxyl com or a heterocyclic group, and where M is an organic or pounds, Substituted 3-imidazolin-1-yloxy, 2.2.5.5-tetram inorganic cation, such, as for example, an alkyl Substituted ethyl-3-imidazolin-1-yloxyl compounds, OT-551, 4-hy ammonium cation or a Group I metal cation. droxy-2.2.6.6-tetramethyl-1-piperidinyloxy (tempol), and 0408. The invention is also directed to compounds that the like. Suitable substituents, include, but are not limited to, stimulate endogenous NO or elevate levels of endogenous aminomethyl, benzoyl 2-bromoacetamido. 2-(2-(2-bro endothelium-derived relaxing factor (EDRF) in vivo or are moacetamido)ethoxy)ethylcarbamoyl, carbamoyl carboxy, oxidized to produce nitric oxide and/or are substrates for cyano, 5-(dimethylamino)-1-naphthalenesulfonamido, nitric oxide synthase and/or cytochrome P450. Such com ethoxyfluorophosphinyloxy, ethyl, 5-fluoro-2,4-dinitroa pounds include, for example, L-arginine, L-homoarginine, nilino, hydroxy, 2-iodoacetamido, isothiocyanato, isothiocy and N-hydroxy-L-arginine, N-hydroxy-L-homoarginine, anatomethyl, methyl, maleimido, maleimidoethyl 2-(2-ma N-hydroxydebrisoquine, N-hydroxypentamidine including leimidoethoxy)ethylcarbamoyl, maleimidomethyl, their nitrosated and/or nitrosylated analogs (e.g., nitrosated maleimido, Oxo, phosphonooxy, and the like. L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L- 0410 The invention is also based on the discovery that arginine, nitrosylated N-hydroxy-L-arginine, nitrosated and compounds and compositions of the invention may be used in nitrosylated L-homoarginine), N-hydroxyguanidine com conjunction with other therapeutic agents for co-therapies, pounds, amidoxime, ketoximes, aldoxime compounds, that partially or completely, in place of other therapeutic agents, can be oxidized in vivo to produce nitric oxide. Compounds Such as, for example, aldosterone antagonists, C.-adrenergic that may be substrates for a cytochrome P450, include, for receptor agonists, C.-adrenergic receptor antagonists, angio example, imino(benzylamino)methylhydroxylamine, imino tensin II antagonists, angiotensin-converting enzyme (ACE) (((4-methylphenyl)methyl)amino)methylhydroxylamine, inhibitors, antidiabetic compounds, anti-hyperlipidemic imino(((4-methoxyphenyl)methyl)amino)methylhydroxy compounds, antimicrobial compounds, antioxidants, anti lamine, imino(((4-(trifluoromethyl)phenyl)methyl)amino) thrombotic and vasodilator compounds, B-adrenergic antago methylhydroxylamine, imino(((4-nitrophenyl)methyl) nists, calcium channel blockers, carbonic anhydrase inhibi amino)methylhydroxylamine, (butylamino) tors, digitalis, diuretics, endothelin antagonists, hydralazine iminomethylhydroxylamine, imino(propylamino) compounds, H receptor antagonists, neutral endopeptidase methylhydroxylamine, imino(pentylamino) inhibitors, nonsteroidal antiinflammatory compounds methylhydroxylamine, imino(propylamino) (NSAIDs), phosphodiesterase inhibitors, potassium channel methylhydroxylamine, imino ((methylethyl)amino) blockers, platelet reducing agents, prostaglandins, proton methylhydroxylamine, (cyclopropylamino) pump inhibitors, renin inhibitors, selective cyclooxygenase-2 iminomethylhydroxylamine, imino-2-1,2,3,4- (COX-2) inhibitors, steroids, and combinations of two or tetrahydroisoquinolyl methylhydroxylamine, imino(1- more thereof. The therapeutic agent may optionally be nitro methyl(2-1,2,3,4-tetrahydroisoquinolyl)) sated and/or nitrosylated and/or contain at least one hetero methylhydroxylamine, (1,3-dimethyl(2-1,2,3,4- cyclic nitric oxide donor group and/or at lest one nitroxide. tetrahydroisoquinolyl)) iminomethylhydroxylamine, (((4- 0411 Suitable aldosterone antagonists include, but are not chlorophenyl)methyl)amino)iminomethylhydroxylamine, limited to, canrenone, potassium canrenoate, drospirenone, ((4-chlorophenyl)amino)iminomethylhydroxylamine, spironolactone, eplerenone (INSPRAR), epoxymexrenone, (4-chlorophenyl)(hydroxyimino)methylamine, and 1-(4- fadrozole, pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy chlorophenyl)-1-(hydroxyimino)ethane, and the like, precur 17-hydroxy-3-oxo, y-actone, methyl ester, (7C.11C. 17 B.)-; sors of L-arginine and/or physiologically acceptable salts pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hy US 2009/0012057 A1 Jan. 8, 2009 droxy-3-oxo-dimethyl ester, (7C.11C. 17 B.)-; 3'H-cyclopropa 0415 Suitable C.-adrenergic receptor antagonists receptor (6.7)pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7- antagonists include, but are not limited to, phentolamine, dihydro-17-hydroxy-3-oxo-, y-lactone, (6?.7f8,11C. 17(3)-; tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408, pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hy BRL 44409, BAM 1303, labetelol, ifenprodil, rauwolscine, droxy-3-oxo-, 7-(1-methylethyl)ester, monopotassium salt, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, (7C.11C. 17 B.)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11 akuammigine, B-yohimbine, yohimbol, yohimbine, epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium pseudoyohimbine, epi-3C-yohimbine, 10-hydroxy-yohim salt, (7C,11C. 17 B.)-; 3'H-cyclopropa(6.7) pregna-1,4,6- triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hy bine, 11-hydroxy-yohimbine, tamsulosin, benoxathian, ati droxy-3-oxo-, y-lactone, (6,3,7,8,11C.)-; 3'H-cyclopropa(6.7) pamezole, BE 2254, WB 4101, HU-723, tedisamil, mir pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7- taZipine, Setiptiline, reboxitine, deleguamine, naftopil, dihydro-17-hydroxy-3-oxo-, methyl ester, (6?.7f8,11C. 17(3)-; saterinone, SL 89.0591, ARC 239, urapidil, 5-methylurapi 3'H-cyclopropa (6.7)pregna-4,6-diene-21-carboxylic acid, dil, monatepi, haloperidol, indoramin, SB 216469, moxisy 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotas lyte, trazodone, dapiprozole, efaroxan, Recordati 15/2739, sium salt, (6?.7f8,11C, 17(3)-;3H-cyclopropa(6.7)pregna-1,4, SNAP 1069, SNAP 5089, SNAP 5272, RS 17053, SL 6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hy 89.0591, KMD 3213, spiperone, AH 11110A, chloroethyl droxy-3-oxo-, y-lactone, (63.7B...11C. 17B)-; pregn-4-ene-7, clonidine, BMY 7378, niguldipine, and the like. Suitable 21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-. alpha-adrenergic receptor antagonists are described more y-lactone, ethyl ester, (7C,11C. 17B)-; pregn-4-ene-7,21-di fully in the literature, such as in Goodman and Gilman, The carboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, y-lactone, Pharmacological Basis of Therapeutics (9th Edition), 1-methylethyl ester, (7C,11C. 17 B)-; RU-28318, and the like. McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir Suitable aldosterone antagonists are described more fully in teenth Edition; and on STN Express, file phar and file registry. the literature, such as in Goodman and Gilman, The Pharma 0416) Suitable angiotensin II antagonists, include, but are cological Basis of Therapeutics (9th Edition), McGraw-Hill, not limited to, angiotensin, abitesartan, candesartan, cande 1995; and the Merck Index on CD-ROM, 13 hEdition; and on Sartan cilexetil, elisartan, embusartan, enoltaSosartan, epro STN Express, file phar and file registry. Sartan, fonsartan, forasartan, glycylosartan, irbesartan, losa rtan, olmesartan, milfasartan, medoxomil, ripisartan, 0412. In some embodiments the aldosterone antagonists is pomisartan, pratosartan, Saprisartan, Saralasin, Sarmesin, eplerenone or spironolactone (a potassium sparing diuretic tasosartan, telmisartan, Valsartan, Zolasartan, 3-(2'(tetrazole that acts like an aldosterone antagonist). In more particular 5-yl)-1,1'-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imi embodiments eplerenone is administered in an amount of dazo[4,5-b]pyridine, antibodies to angiotensin II, A-81282, about 25 milligrams to about 300 milligrams as a single dose A-81988, BAY 106734, BIBR-363, BIBS-39, BIBS-222, or as multiple doses per day; the spironolactone is adminis BMS-180560, BMS-184698, BMS-346567, CGP-38560A, tered in an amount of about 25 milligrams to about 150 CGP-42112A, CGP-48369, CGP-49870, CGP-63170, milligrams as a single dose or as multiple doses per day. CI-996, CP-148130, CL-329167, CV-11194, CV-11974, 0413 Suitable C-adrenergic receptor agonists, including, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, DuP but are not limited to, agnatine, p-aminoclonidine, apracloni 753, E-1477, E-4177, E-4188, EMD-66397, EMD-666R4, dine (IOPIDINE(R), 2-(arylamino)imidazolidine derivatives, EMD-73495, EMD-66684, EXP-063, EXP-929, EXP-3134, aZepexole, azepin derivatives, such as for example, 2-amino EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, 6-alkyl-4,5,7,8-tetrahydro-6H-thiazolo-(5.4.d) aZepine, EXP-9954, FK-739, FRI 153332, GA-0050, GA-0056, 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-thiazolo-(5.4.d) HN-65021, HOE-720, HR-720, ICI-D6888, ICI-D7155, ICI azepine, 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-(5. D8731, KRI-1177, KT3-671, KT-3579, KW-3433, 4.d) azepine, and the like; brimonidine, clonidine, clonidine L-158809, L-158978, L-159282 (MK-996), L-159689, derivatives, detomidine, dexmedetomidine, diplivefrin, L-159874, L-161177, L-162154, L-162234, L-162441, dipivalylepinephrine, epinephrine, guanabenz, guanfacine, L-163007, L-163017, LF-70156, LRB-057, LRB-081, LRB imidazolidine derivatives, such as, for example, 5-bromo-6- 087, LY-235656, LY-266099, LY-285.434, LY-301875, (2-imidazolidine-2-ylamino)cquinoxaline, and the like; p-io LY-302289, LY-315995, ME-3221, MK-954, PD-123177, doclonidine, medetomidine, methoxamine (VASOXYL(R), PD-1233.19, PD-126055, PD-150304, RG-13647, RWJ mephentermine, metaraminol (ARAMINE(R), methyldopa, 38970, RWJ-46458, S-8307, S-8308, SC-51757, SC-54629, mitodrine, naphazoline (PRIVINE(R), NAPHCONR), norepi SC-52458, SC-52459, SK 1080, SL-910102, SR-47436, nephrine, oxymetazoline (AFRINR, OCUCLEAR(R), phe TAK-536, UP-2696, U-96849, U-97018, UK-77778, nylepinephrine (NEOSYNEPHRINE(R), rilmenidine, tet UP-275-22, WAY-126227, WK-1260, WK-1360, WK-1492, rahydrozoline (TYZINE(R), VISINE(R), tramazoline, WY 126227, YH-1498, YM-358, YM-31472, X-6803, xylazine, xylometazoline (OTRIVINR), B-HT 920 (6-allyl XH-148, XR-510, ZD-6888, ZD-7155, ZD-8731, ZD 8.131, 2-amino-5,6,7,8-tetrahydro-4H-thiazolo(4.5-d)-azepine, the compounds of ACS registry numbers 133240-46-7, B-HT933 and UK 14.304, and the like. Suitable C.-adrenergic 135070-05-2, 139958-16-0, 145160-84-5, 147403-03-0, receptor agonists are described more fully in the literature, 153806-29-2, 439904-54-8P 439904-55-9P, 439904-56-OP, Such as in Goodman and Gilman, The Pharmacological Basis 439904-57-1P,439904-58-2P 155918-60-8P 155918-61-9P, of Therapeutics (9th Edition), McGraw-Hill, (1996); Merck 272438-16-1P, 272446-75-0P, 223926-77-OP. 169281-89-4, Index on CD-ROM, 13" Edition; STN Express, file phar and 165113-17-7P, 165113-18-8P, 165113-19-9P, 165113-20-2P file registry, the disclosures of each of which are incorporated 165113-13-3P, 165113-14-4P 165113-15-5P, 165113-16-6P. by reference herein in their entirety. 165113-21-3P, 165113-22-4P 165113-23-5P, 165113-24-6P. 0414. In some embodiments the O.-adrenergic receptor 165113-25-7P, 165113-26-8P, 165113-27-9P, 165113-28-OP, agonists are aminoclonidine, apraclonidine (IOPIDINE), 165113-29-1P, 165113-30-4P 165113-31-5P, 165113-32-6P. brimonidine, clonidine and clonidine derivatives. 165113-33-7P, 165113-34-8P, 165113-35-9P, 165113-36-0P, US 2009/0012057 A1 Jan. 8, 2009 32

165113-37-1P, 165113-38-2P 165113-39-3P, 165113-40-6P. alkyl dipeptide, phosphinylalkanoyl pralines, registry no. 165113-41-7P, 165113-42-8P, 165113-43-9P, 165113-44-OP, 796406, AVE 7688, BP1.137, CHF 1514, E 4030, ER 3295, 165113-45-1P, 165113-46-2P 165113-47-3P, 165113-48-4P. FPL-66564, MDL 100240, RL 6134, RL 6207, RL 6893, SA 165113-49-5P, 165113-50-8P, 165113-51-9P, 165113-52-OP, 760, S-5590, Z 13752A, and the like. Suitable angiotensin 165113-53-1P, 165113-54-2P 165113-55-3P, 165113-56-4P. converting enzyme inhibitors are described more fully in the 165113-57-5P, 165113-58-6P, 165113-59-7P, 165113-60-0P, literature. Such as in Goodman and Gilman, The Pharmaco 165113-6.1-1P, 1651 13-62-2P 165113-63-3P, 165113-64-4P. logical Basis of Therapeutics (9th Edition), McGraw-Hill, 165113-65-5P, 165113-66-6P, 165113-67-7P, 165113-68-8P. 1995; and the Merck Index on CD-ROM, Twelfth Edition, 165113-69-9P, 165113-70-2P 165113-71-3P, 165113-72-4P. Version 12:1, 1996; and on STN Express, file phar and file 165113-73-5P, 165113-74-6P, 114798-27-5, 114798-28-6, registry. 114798-29-7, 124749-82-2, 114798-28-6, 124749-84-4, 0419. In some embodiments the angiotensin-converting 124750-88-5, 124750-91-0, 124750-93-2, 161946-65-2P enzyme inhibitors are benazepril, captopril, enalapril, fosino 161947-47-3P, 161947-48-4P 161947-51-9P, 161947-52 pril, lisinopril, moexipril, quinapril, ramipril, trandolapril or OP. 161947-55-3P, 161947-56-4P 161947-60-0P 161947 trandolaprilat. In more particular embodiments the 61-1P 161947-68-8P 161947-69-9P, 161947-70-2P benazepril is administered as benazepril hydrochloride in an 161947-71-3P, 161947-72-4P 161947-74-6P, 161947-75-7P. amount of about 5 milligrams to about 80 milligrams as a 161947-81-5P, 161947-82-6P 161947-83-7P 161947-84-8P. single dose or as multiple doses per day; the captopril is 161947-85-9P, 161947-86-OP 161947-87-IP, 161947-88-2P administered in an amount of about 12.5 milligrams to about 161947-89-3P, 161947-90-6P 161947-91-7P 161947-92-8P. 450 milligrams as a single dose or as multiple doses per day; 161947-93-9P, 161947-94-OP. 161947-95-1P, 161947-96-2P the enalapril is administered as enalapril maleate in an 161947-97-3P, 161947-98-4P 161947-99-5P, 161948-00-1P amount of about 2.5 milligrams to about 40 milligrams as a 161948-01-2P, 161948-02-3P, 168686-32-6P, 167301-42-OP, single dose or as multiple doses per day; the fosinopril is 166813-82-7P, 166961-56-4P 166961-58-6P, 158872-96-9P, administered as fosinopril sodium in an amount of about 5 158872-97-0P, 158807-14-8P, 158807-15-9P, 158807-16-0P, milligrams to about 60 milligrams as a single dose or as 158807-17-1P, 158807-18-2P, 158807-19-3P, 158807-20-6P. multiple doses per day; the lisinopril is administered in an 155884-08-5P, 154749-99-2, 167371-59-7P. 244126-99-6P. amount of about 2.5 milligrams to about 75 milligrams as a 177848-35-OP. 141309-82-2P, and the like. Suitable angio single dose or as multiple doses per day; the moexipril is tensin II antagonists are described more fully in the literature, administered as moexipril hydrochloride in an amount of such as in Goodman and Gilman, The Pharmacological Basis about 7.5 milligrams to about 45 milligrams as a single dose of Therapeutics (9th Edition), McGraw-Hill, 1995; and the or as multiple doses per day; the quinapril is administered as Merck Index on CD-ROM, 13° Edition; and on STN Express, quinapril hydrochloride in an amount of about 5 milligrams to file phar and file registry. about 40 milligrams as single or multiple doses per day; the 0417. In some embodiments the angiotensin II antagonists ramipril hydrochloride in an amount of about 1.25 milligrams are candesartan, eprosartan, irbesartan, losartan, omlesartan, to about 40 milligrams as single or multiple doses per day; the telmisartan or Valsartan. In more particular embodiments the trandolapril is administered as in an amount of about 0.5 candesartan is administered as candesartan cilexetil in an milligrams to about 4 milligrams as single or multiple doses amount of about 15 milligrams to about 100 milligrams as a per day; the trandolaprilat is administered as in an amount of single dose or as multiple doses per day; the eprosartan, is about 0.5 milligrams to about 4 milligrams as single or mul administered as eprosartan mesylate in an amount of about tiple doses per day. 400 milligrams to about 1600 milligrams as a single dose or as 0420 Suitable antidiabetic compounds include but are not multiple doses per day; the irbesartan is administered in an limited to, acarbose, acetohexamide, buformin, carbutamide, amount of about 75 milligrams to about 1200 milligrams as a chlorpropamide, glibornuride, gliclazide, glimepiride, glip single dose or as multiple doses per day; the losartan is admin izide, gliquidone, glisoxepid, glyburide, glybuthiazol(e), gly istered as losartan potassium in an amount of about 25 milli buzole, glyhexamide, glymidine, glypinamide, insulin, met grams to about 100 milligrams as a single dose or as multiple formin, miglitol, nateglinide, phenbutamide, phenformin, doses per day; the omlesartan is administered as omlesartan pioglitaZone, repaglinide, rosiglitaZone, tolaZamide, tolbuta medoxomil in an amount of about 5 milligrams to about 40 mide, tolcyclamide, troglitaZone, Voglibose, and the like. milligrams as a single dose or as multiple doses per day; the Suitable antidiabetic compounds are described more fully in telmisartan is administered in an amount of about 20 milli the literature, such as in Goodman and Gilman, The Pharma grams to about 80 milligrams as a single dose or as multiple cological Basis of Therapeutics (9th Edition), McGraw-Hill, doses per day; the Valsartan is administered in an amount of 1995; and the Merck Index on CD-ROM, Thirteenth Edition; about 80 milligrams to about 320 milligrams as a single dose and on STN Express, file phar and file registry. or as multiple doses per day. 0421 Suitable anti-hyperlipidemic compounds include, 0418 Suitable angiotensin-converting enzyme inhibitors but are not limited to, statins or HMG-CoA reductase inhibi (ACE inhibitors) include, but are not limited to, alacepril, tors, such as, for example, atorvastatin (LIPITORR), bervas benazepril (LOTENSINR), CIBACENR), benazeprilat, cap tatin, cerivastatin (BAYCOLR), dalvastatin, fluindostatin topril, ceronapril, cilaZapril, delapril, duinapril, enalapril, (Sandoz XU-62-320), fluvastatin, glenvastatin, lovastatin enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, (MEVACORR), mevastatin, pravastatin (PRAVACHOL(R), glycopril, idrapril, imidapril, lisinopril, moexipril, movel rosuvastatin (CRESTROR), simvastatin (ZOCORR), tipril, naphthopidil, omapatrilat, pentopril, perindopril, per Velostatin (also known as synvinolin), VYTORN (ezetimibe/ indoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rent simvastatin), GR-95030, SQ 33,600, BMY 22089, BMY ipril, Saralasin acetate, spirapril, temocapril, trandolapril, 22,566, CI-980, and the like; gemfibrozil, cholystyramine, trandolaprilat, urapidil, Zofenopril, acylmercapto and mer colestipol, niacin, nicotinic acid, bile acid sequestrants. Such captoalkanoyl pralines, carboxyalkyl dipeptides, carboxy as, for example, cholestyramine, colesevelam, colestipol, US 2009/0012057 A1 Jan. 8, 2009 poly(methyl-(3-trimethylaminopropyl)imino-trimethylene niazide, gramicidin, grepafloxacin, guamecycline, halofugi dihalide) and the like; probucol; fibric acid agents or fibrates, none, hetacillin, homidium, hydroxyl-Stilbamidine, such as, for example, bezafibrate (BezalipTM), beclobrate, ibostamycin, inidocarb, imipenam, ipronidazole, isoniazide, binifibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, josamycin, inosine, kanamycin, lauroguadine, lenampicillin, fenofibrate (LipidilTM, Lipidil MicroTM), gemfibrozil lincomycin, lomefloxacin, loracarbef, lymecyclin, mafenide, (LopidTM.), nicofibrate, pirifibrate, ronifibrate, simfibrate, mebendazole, meclocyclin, meropenem, metampicillin, met theofibrate and the like; cholesterol ester transfer protein acicline, methacycline, methicillin sodium, metronidazole, (CETP) inhibitors, such as for example, CGS 25159, 4'-(methylsulfamoyl)sulfanilanilide, mezlocillin, meziocil CP-529414 (torcetrapid), JTT-705, substituted N-3-(1,1,2,2- lin, micronomycin, midecamycin A, minocycline, mioca tetrafluoroethoxy)benzyl-N-(3-phenoxyphenyl)-trifluoro mycin, miokamycin, morfaZinamide, moxalactam, mupiro 3-amino-2-propanols, N,N-disubstituted trifluoro-3-amino cin, myxin, nadifloxacin, nalidixic acid, negamycin, 2-propanols, PD 140195 (4-phenyl-5-tridecyl-4H-1,2,4- neomycin, netliniycin, nifurfoline, nifurpirinol, nifurprazine, triazole-3-thiol), SC-794, SC-795, SCH 58149, and the like. nimorazole, nitroxoline, norfloxacin, novobiocin, ofloxacin, 0422. In some embodiments the anti-hyperlipidemic com oleandomycin, opiniazide, oxacillin, oxophenarsine, OXo pounds are atorvastatin, fluvastatin, lovastatin, pravastatin, linic acid, oxytetracycline, panipenam, paromycin, paZu rosuvastatin or simvastatin. In more particular embodiments floxacin, pefloxacin, penicillin G potassium salt, penicillinN, the atorvastatin is administered in an amount of about 10 penicillin O, penicillin V, penethamate hydroiodide, pentami milligrams to about 80 milligrams as a single dose or as dine, phenamidine, phenethicillin potassium salt, phenyl multiple doses per day; the fluvastatin is administered in an aminosalicyclate, pipacycline, pipemidic acid, piperacillin, amount of about 20 milligrams to about 80 milligrams as a pirlimycin, piromidic acid, pivampicillin, piveefalexin, poly single dose or as multiple doses per day; the lovastatin is myxin B, profiromycin, propamidine, propicillin, protiona administered in an amount of about 10 milligrams to about 80 mide, puraltadone, puromycin, pyrazinamide, milligrams as a single dose or as multiple doses per day; the pyrimethamine, quinacillin, quinacrine, quinapyramine, pravastatin is administered in an amount of about 10 milli quintine, ribostamycin, rifabutine, rifamide, rifampin, rifa grams to about 80 milligrams as a single dose or as multiple mycin, rifanpin, rifapentine, rifaxymine, ritipenem, rokita doses per day; the rosuvastatin is administered in an amount mycin, rollitetracycline, rosamycin, rufloxacin, Salazosulfadi of about 5 milligrams to about 40 milligrams as a single dose midine, salinazid, sancycline, Sarafloxacin, Sedacamycin, or as multiple doses per day; the simvastatin is administered secnidazole, Sisomycin, sparfloxacin, spectinomycin, spira in an amount of about 5 milligrams to about 80 milligrams as mycin, spiramycin I, spiramycin II, spiramycin III, stilbami a single dose or as multiple doses per day. dine, Streptomycin, Streptonicizid, Sulbactam, Sulbenicillin, 0423 Suitable antimicrobial compounds, include, but are Succisulfone, Sulfanilamide, Sulfabenzamide, Sulfacetamide, not limited to, acediasulfone, aceturate, acetyl Sulfameto Sulfachloropyridazine, Sulfachrysoidine, Sulfacytine, Sulfadi ssipirazine, acetyl sulfamethoxypyrazine, acranil, albenda azine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sul Zole, alexidine, amatadine, ambazone, amdinocillin, amika fadrazine, Sulfaetidol, Sulfafenazol, Sulfaguanidine, Sulfagua cin, p-aminosalicylic acid, p-aminosalicylic acid hydrazine, nole, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, amoxicillin, amplicillin, anisomycin, apalcillin, apicyclin, Sulfamethizole, Sulfamethomidine, Sulfamethoxazole, Sul apramycin, arbekacin, argininsa, aspoxicillin, azidamfenicol, famethoxypyridazine, sulfamethylthiazol, sulfamethylthiaz azidocillin, azithromycin, azlocillin, aztreonam, bacampicil ole, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfa lin, bacitracin, benzoylpas, benzylpenicillin acid, benzyl Sul nilamide, 4-Sulfanilamido salicylic acid, 4-4'- famide, bicoZamycin, bipenam, brodimoprim, capreomycin, Sulfanilylbenzylamine, p-sulfanilylbenzylamine, 2-p- carbenicillin, carbomycin, cafaZedone, carindacillin, caru Sulfinylanilinoethanol, Sulfanily lurea, Sulfoniazide, monam, cefcapene pivoxil, cefaclor, cefadroxil, cefafroxil, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, cefamandole, cefatamet, cefatrizine, cefazedone, cefazolin, sulfapyridine, sulfathiazole, sulfaethidole, sulfathiourea, cefbuperaZone, cefclidin, cefdinir, cefditoren, cefixime, Sulfisomidine, Sulfasomizole, Sulfasymazine, Sulfisoxazole, cefinenoXime, cefinetazole, cefiminox, cefodizime, cefonicid, 4,4'-sulfinyldianiline, N-sulfanilylsulfanilamide, N-sulfa cefoperaZone, ceforanide, cefotaxime, cefotetan, cefotiam, nillyl-3,4-Xylamide, Sultamicillin, talampicillin, tambutol, cefoxitin, cefoZopran, cefpimizole, cefpiramide, ce?pirome, taurolidine, teiclplanin, temocillin, tetracycline, tetroxoprim, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, thiabendazole, thiazolsulfone, tibeZonium iodide, ticarcillin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, cefti tigemonam, timidazole, tobramycin, toSufloxacin, trimetho Zoxime, ceftriaxone, cefuroxime, cefuZonam, cephacetrile prim, troleandromycin, trospectomycin, trovafloxacin, tuber Sodium, cephadrine, cephalexin, cephaloglycin, cephalori cidine, miokamycin, oleandomycin, troleandromycin, van dine, cephalosporin C, cephalothin, cephapirin Sodium, ceph comycin, Verazide, Viomycin, Virginiamycin, Zalcitabine, radine, chibrorifamycin, chloramphenicol, chlorotetracy PA-1806 and PA-2794, and the like. Suitable antimicrobial cline, cinoxacin, ciprofloxacin, claritromycin, clavulanic compounds are described more fully in the literature, Such as acid, clinafloxacin, clindamycin, clofazimine, clofoctal, in Goodman and Gilman, The Pharmacological Basis of clometocillin, clomocycline, cloxacillin, cloxyquin, colistin, Therapeutics (9th Edition), McGraw-Hill, (1996); Merck cyclacilline, cycloserine, danoflaxcin, dapsone, deoxycy Index on CD-ROM, 13' Edition; STN Express, file phar and cline, deoxydihydrostreptomycin, dibekacin, dicloxacillin, file registry, the disclosures of each of which are incorporated difloxacin, dihydrostreptomycin, dimetridazole, diminaZene, by reference herein in their entirety. dirirtomycin, duramycin, eflomithine, enrofloxacin, envio 0424. In some embodiments the antimicrobial compound mycin, epicillin, erythromycin, etacillin, ethambutol, amikacin, azithromycin, azetreonam, bacitracin, carbenicil ethionamide, famcyclovir, fenbecillin, fleroxacin, flomoxef, lin, cefazolin, cefoxitin, cephaloridine, chibrorifamycin, floxacillin, flumequine, n-formamidoylthienamycin, furona chloramphenicol, colistin, duramycin, n-formamidoylthiena Zide, fortimycin, furazolium chloride, gentamycin, glyco mycin, gentamycin, gramicidin, kanamycin, neomycin, peni US 2009/0012057 A1 Jan. 8, 2009 34 cillin G, polymyxin B, Sisomicin, tetracyclines, tigecycline, 0429 Suitable f3-adrenergic antagonists include, but are tobramycin, Vancomycin, PA-1806 and PA-2794. not limited to, acebutolol, alprenolol, amoSulalol, arotinolol. 0425. In other embodiments the antimicrobial compound atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopin is an antiviral compound, including but not limited to, acy dolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, clovir, amatadine, cidofovir, cytarabine, didanosine, bupranolol, butofilolol, carazolol, capsinolol, carteolol. dideoxyadenosine, edoxudine, famciclovir, floXuridine, gan carvedilol (COREGR), celiprolol, cetamolol, cindolol, clo cyclovir, idoxuridine, indanavir, kethoxal, lamivudine, ranolol, dilevalol, diprafenone, epanolol, ersentilide, MADU, penciclovir, podophyllotoxin, ribavirine, rimanta esmolol, esprolol, hydroxalol, indenolol, labetalol, landiolol, laniolol, levobunolol, mepindolol, methylpranol, metindol, dine, saquinavir, Sorivudine, stavudine, trifluridine, Valacy metipranolol, metrizoranolol, metoprolol, moprolol, nadolol. clovir, Vidarabine, Xenazoic acid, Zalcitabine, Zidovudine, nadoxolol, nebivolol, nifenalol, nipradillol, oXprenolol, pen and the like. butolol, pindolol, practolol, pronethalol, propranolol, Sotalol, 0426 Suitable antioxidants include, but are not limited to, Sotalolnadolol, sulfinalol, taliprolol, talinolol, tertatolol, til Small-molecule antioxidants and antioxidant enzymes. Suit isolol, timolol, toliprolol, tomalolol, trimepranol, Xamoterol, able small-molecule antioxidants include, but are not limited xibenolol, 2-(3-(1,1-dimethylethyl)-amino-2-hydroxypro to, hydralazine compounds, glutathione, Vitamin C, Vitamin poxy)-3-pyridenecarbonitrilHCl, 1-butylamino-3-(2,5- E. cysteine, N-acetyl-cysteine, B-carotene, ubiquinone, dichlorophenoxy)-2-propanol. 1-isopropylamino-3-(4-(2- ubiquinol-10, tocopherols, coenzyme Q, Superoxide dismu cyclopropylmethoxyethyl)phenoxy)-2-propanol, tase mimetics, such as, for example, 2.2.6.6-tetramethyl-1- 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide 2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl compounds; 4-hydroxy-2.2.6,6-tetramethyl-1-piperidiny 2-thienyl)thiazol, 7-(2-hydroxy-3-t-butylaminpropoxy)ph loxy (Tempol), M-40401, M-40403, M-40407, M-40419, thalide, Acc 9369, AMO-140, BIB-16S, CP-331684, M-40484, M-40587, M-40588, and the like. Suitable antioxi Fr-172516, ISV-208, L-653328, LM-2616, SB-226552, dant enzymes include, but are not limited to, Superoxide SR-58894A, SR-59230A, TZC-5665, UK-1745, YM-430, dismutase, catalase, glutathione peroxidase, NADPH oxidase and the like. Suitable f3-adrenergic antagonists are described inhibitors, such as, for example, apocynin, aminoguanidine, more fully in the literature, such as in Goodman and Gilman, ONO 1714, S17834 (benzo(b)pyran-4-one derivative), and The Pharmacological Basis of Therapeutics (9th Edition), the like; Xanthine oxidase inhibitors, such as, for example, McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, Edition; and on STN Express, file phar and file registry. 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, 0430. In some embodiments the B-adrenergic antagonists myricetin, isorhamnetin, benzophenones such as 2.2',4,4'- are atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxyben propranolol or timolol. In more particular embodiments the Zophenone and 4,4'-dihydroxybenzophenone; benzothiazi atenolol is administered in an amount of about 50 milligrams none analogues such as 2-amino-4H-1,3-benzothiazine-4- to about 200 milligrams as a single dose or as multiple doses one, 2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine; per day; the bisoprolol is administered as bisoprolol fumarate N-hydroxyguanidine derivative such as, PR5 (1-(3,4- in an amount of about 2.5 milligrams to about 30 milligrams dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguani as a single dose or as multiple doses per day; the carvedilol is dine); 6-formylpterin, and the like. The antioxidant enzymes administered in an amount of about 3.125 milligrams to about can be delivered by gene therapy as a viral vertor and/or a 200 milligrams as a single dose or as multiple doses per day; non-viral vector. Suitable antioxidants are described more the metoprolol is administered as metoprolol tartarate or fully in the literature, such as in Goodman and Gilman, The metoprolol Succinate in an amount of about 25 milligrams to Pharmacological Basis of Therapeutics (9th Edition), about 300 milligrams as a single dose or as multiple doses per McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir day; the nebivolol is administered as nebivolol hydrochloride teenth Edition; and on STN Express, file phar and file registry. in an amount of about 2.5 milligrams to about 20 milligrams 0427. In some embodiments the antioxidants are apocy as a single dose or as multiple doses per day; the propranolol nin, hydralazine compounds and Superoxide dimutase is administered as propranolol hydrochloride in an amount of mimetics. about 40 milligrams to about 240 milligrams as a single dose 0428 Suitable antithrombotic and vasodilator compounds or as multiple doses per day; the timolol is administered as include, but are not limited to, abciximab, acetorphan, ace timolol maleate in an amount of about 10 milligrams to about tylsalicylic acid, argatroban, bamethan, benfurodil, benzio 30 milligrams as a single dose or as multiple doses per day. darone, betahistine, bisaramil, brovincamine, bufeniode, citi 0431 Suitable calcium channel blockers include, but are coline, clobenfurol, clopidogrel, cyclandelate, dalteparin, not limited to, amlodipine (NORVASCR), anipamil, aranid dipyridamol, droprenilamine, enoxaparin, fendiline, ifen ipine, aminone, azelnidipine, barnidipine, bencyclane, beni prodil, iloprost, indobufen, isobogrel, isoxSuprine, heparin, dipine, bepridil, cilnidipine, cinnarizine, clentiazem, dilt lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylid iazem, dotarizine, efonidipine. elgodipine, fantofarone, rin, OZagrel, perhexyline, phenylpropanolamine, preny felodipine, fendiline, flunarizine, fluspirilene, furnidipine, lamine, papaveroline, reviparin Sodium salt, ridogrel, Suloc gallopamil, ipenoxazone, isradipine, lacidipine, lemildipine, tidil, tinofedrine, tinzaparin, trifusal, Vintoperol, Xanthinal lercanidipine, lomerizine, manidipine, mibefradil, niacinate, and the like. Suitable antithrombotic and vasodila monatepil, nicardipine, nifedipine, niguldipine, niludipine, tor compounds are described more fully in the literature, such nilvadipine, nimodipine, nisoldipine, nitrendipine, nival as in Goodman and Gilman, The Pharmacological Basis of dipine, Oxodipine, perhexylene, phenyloin, phenylpreny Therapeutics (9th Edition), McGraw-Hill, 1995; and the lamine, pranidipine, ranolazine, ryosidine, semotiadil, tamo Merck Index on CD-ROM, Thirteenth Edition; and on STN larizine, temiverine hydrochloride, terodiline, tiapamil, Express, file phar and file registry. Vatanidipine hydrochloride, Verapamil, Ziconotide, AE-0047. US 2009/0012057 A1 Jan. 8, 2009

CAI, JTV-519, CHF-1521, L-651582, NS-7, NW-1015, The method of administration of these compounds is RO-2933, SB-237376, SL-34.0829-08, S-312d, SD-3212, described in further detail in U.S. Pat. No. 4,868,179, the TA-993, YM-430, and the like. Suitable calcium channel disclosure of which is incorporated by reference herein in its blockers are described more fully in the literature, such as in entirety. Goodman and Gilman, The Pharmacological Basis of Thera peutics (9th Edition), McGraw-Hill, 1995; and the Merck 0438. In some embodiments the diuretics are amiloride, Index on CD-ROM. Thirteenth Edition; and on STN Express, furosemide, chlorthalidone, hydrochlorothiazide or triam file phar and file registry. terene. In more particular embodiments the amiloride is 0432. In some embodiments the calcium channel blockers administered as amiloride hydrochloride in an amount of are amlodipine, diltiazem, isradipine, nicardipine, nifedipine, about 5 milligrams to about 15 milligrams as a single dose or nimodipine, nisoldipine, nitrendipine, Verapamil. as multiple doses per day; the furosemide is administered in 0433 Suitable carbonic anhydrase inhibitors, include, but an amount of about 10 milligrams to about 600 milligrams as are not limited to, acetazolamide, brinzolamide, dorzolamide, a single dose or as multiple doses per day; the chlorthalidone ethoXZolamide, 6-hydroxy-2-benzothiazolesulfonamide, is administered in an amount of about 15 milligrams to about methazolamide, thiophene Sulfonamide, an aromatic Sulfona 150 milligrams as a single dose or as multiple doses per day; mide, an ester of 6-hydroxy-2-benzothiazolesulfonamide, an the hydrochlorothiazide is administered in an amount of ester of 5-hydroxy-2-benzothiazolesulfonamide, and the like. about 12.5 milligrams to about 300 milligrams as a single Suitable carbonic anhydrase inhibitors are described more dose or as multiple doses per day; the triamterene is admin fully in the literature, such as in Goodman and Gilman, The istered in an amount of about 35 milligrams to about 225 Pharmacological Basis of Therapeutics (9th Edition), milligrams as a single dose or as multiple doses per day. McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' 0439 Suitable endothelin antagonists include, but are not Edition; and on STN Express, file phar and file registry. limited to, atrasentan, bosentan, darusentan, endothelin, enra 0434 In some embodiments the carbonic anhydrase sentan, Sitaxsentan, Sulfonamide endothelin antagonists, inhibitors are brinzolamide and dorzolamide. tezosentan, BMS 193884, BQ-123, SQ 28.608, and the like. 0435 Suitable digitals include but are not limited to Suitable endothelin antagonists are described more fully in digoxin and digoxitin. In some embodiments the digoxin is the literature, such as in Goodman and Gilman, The Pharma administered to achieve a steady state blood serum concen cological Basis of Therapeutics (9th Edition), McGraw-Hill, tration of at least about 0.7 nanograms per ml to about 2.0 1995; and the Merck Index on CD-ROM, Thirteenth Edition; nanograms per ml. and on STN Express, file phar and file registry. 0436 Suitable diuretics include but are not limited to, 0440 Suitable hydralazine compounds include, but are thiazides (such as, for example, althiazide, bendroflumethi not limited to, compounds having the formula: azide, benzclortriazide, benzhydrochlorothiazide, benzthiaz ide, buthiazide, chlorothiazide, cyclopenethiazide, R4 R3 cyclothiazide, epithiazide, ethiazide, hydrobenzthiazide, 3. b C hydrochlorothiazide, hydroflumethiazide, methylclothiaz RNNR2 ide, methylcyclothiazide, penflutazide, polythiazide, teclothiazide, trichlormethiazide, triflumethazide, and the like); allilusem, ambuside, amiloride, aminometradine, whereina, b and c are independently a single or double bond; aZosemide, bemetizide, bumetanide, butazolamide, butizide, R and R2 are each independently a hydrogen, an alkyl, an canrenone, carperitide, chloraminophenamide, chlorazanil, ester or a heterocyclic ring, wherein alkyl, ester and hetero chlormerodrin, chlorthalidone, cicletanide, clofenamide, clo cyclic rind are as defined herein; R and Rare each indepen pamide, clorexolone, conivaptan, daglutril, dichlorophena dently alone pair of electrons or a hydrogen, with the proviso mide, disulfamide, ethacrynic acid, ethoXZolamide, etoZolon, that at least one of R. R. R. and R is not a hydrogen. fenoldopam, fenguizone, furosemide, indapamide, mebutiz Exemplary hydralazine compounds include budralazine, ide, mefruside, meralluride, mercaptomerin Sodium, mercu cadralazine, dihydralazine, endralazine, hydralazine, mallylic acid, mersalyl, methazolamide, meticane, metola pildralazine, todralazine, and the like. Suitable hydralazine Zone, moZavaptan, muZolimine, N-(5-1,3,4-thiadiazol-2-yl) compounds are described more fully in the literature, Such as acetamide, nesiritide, pamabrom, paraflutizide, piretanide, in Goodman and Gilman, The Pharmacological Basis of protheobromine, quinethaZone, scoparius, Spironolactone, Therapeutics (9th Edition), McGraw-Hill, 1995; and the theobromine, ticrynafen, torsemide, torvaptan, triamterene, Merck Index on CD-ROM, Thirteenth Edition; and on STN tripamide, ularitide, Xipamide or potassium, AT 189000, AY Express, file phar and file registry. 31906, BG 9928, BG 9791, C2921, DTI 0017, JDL961, KW 0441. In some embodiments the hydralazine compound is 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP hydralazine or a pharmaceutically acceptable salt thereof 120, and the like. Suitable diuretics are described more fully Such as hydralazine hydrochloride. In more particular in the literature, such as in Goodman and Gilman, The Phar embodiments the hydralazine is administered as hydralazine macological Basis of Therapeutics (9th Edition), McGraw hydrochloride in an amount of about 10 milligrams to about Hill, 1995; and the Merck Index on CD-ROM, 13" Edition; 300 milligrams as a single dose or as multiple doses per day. and on STN Express, file phar and file registry. 0442 Suitable H receptor antagonists include, but are not 0437 Depending on the diuretic employed, potassium limited to, burimamide, cimetidine, ebrotidin, famotidine, may also be administered to the patient in order to optimize nizatidine, roXatidine, rantidine, tiotidine, and the like. Suit the fluid balance while avoiding hypokalemic alkalosis. The able H receptor antagonists are described more fully in the administration of potassium can be in the form of potassium literature. Such as in Goodman and Gilman, The Pharmaco chloride or by the daily ingestion of foods with high potas logical Basis of Therapeutics (9th Edition), McGraw-Hill, sium content such as, for example, bananas or orange juice. 1995, Pgs. 901-915; the Merck Index on CD-ROM, 13' US 2009/0012057 A1 Jan. 8, 2009 36

Edition; and in WO 00/28988 assigned to NitroMed Inc., the bafylline, theophylline, nanterinone, pentoxofylline, disclosures of which are incorporated herein by reference in proxyphylline, cilostazol, cilostamide, MS 857, piroximone, their entirety. milrinone, aminone, tolafentrine, dipyridamole, papavero 0443) Suitable neutral endopeptidase inhibitors include, line, E4021, thienopyrimidine derivatives, triflusal, ICOS but are not limited to, atrial natriuretic peptides, diazapins, 351, tetrahydropiperazino(1.2-b)beta-carboline-1,4-dione azepinones, ecadotril, fasidotril, fasidotrilat, omapatrilat, derivatives, carboline derivatives, 2-pyrazolin-5-one deriva sampatrilat, BMS 189,921, Z 13752A, and the like. Neutral tives, fused pyridazine derivatives, quinazoline derivatives, endopeptidase inhibitors are described more fully in the lit anthranilic acid derivatives, imidazoquinazoline derivatives, erature, such as in Goodman and Gilman, The Pharmacologi tadalafil. Vardenafil, and in Goodman and Gilman, The Phar cal Basis of Therapeutics (9th Edition), McGraw-Hill, 1995: macological Basis of Therapeutics (9th Ed.), McGraw-Hill, and the Merck Index on CD-ROM, Thirteenth Edition; and on Inc. (1995), The Physician's Desk Reference (49th Ed.), STN Express, file phar and file registry. Medical Economics (1995), Drug Facts and Comparisons 0444 Suitable NSAIDs include, but are not limited to, (1993 Ed), Facts and Comparisons (1993), and the Merck acetaminophen, acemetacin, aceclofenac, alminoprofen, Index on CD-ROM, 13 Edition; and the like. Phosphodi amfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, esterase inhibitors and their nitrosated and/or nitrosylated butibufen, carprofen, cinmetacin, clopirac, diclofenac, etod derivatives are also disclosed in U.S. Pat. Nos. 5,932,538, olac, felbinac, fenclozic acid, fenbufen, fenoprofen, fen 5,994,294, 5,874,437, 5,958,926 reissued as U.S. Pat. No. RE tiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, 03772346,172,060, U.S. Pat. Nos. 6,197,778, 6,177,428, indomethacin, isofeZolac, isoxepac, indoprofen, ketoprofen, 6,172,068, 6,221,881, 6,232,321, 6,197,782, 6,133,272, lonazolac, loxoprofen, metiazinic acid, mofeZolac, miropro 6,211,179, 6,316,457 and 6,331,542, the disclosures of each fen, naproxen, oxaprozin, piroZolac, pirprofen, pranoprofen, of which are incorporated herein by reference in their entirety. protizinic acid, Salicylamide, Sulindac, Suprofen, SuXibuZone, 0447 Suitable potassium channel blockers include but are tiaprofenic acid, tolmetin, Xenbucin, Ximoprofen, Zaltopro not limited to, nicorandil, pinacidil, cromakalim (BRL fen, Zomepirac, aspirin, acemetcin, bumadizon, carprofenac, 34915), aprikalim, bimakalim, emakalim, lemakalim, clidanac, diflunisal, enfenamic acid, fendosal, flufenamic minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-py acid, fluniXin, gentisic acid, ketorolac, meclofenamic acid, rimido(5,4-d)(2)-benzazepine, Ribi, CPG-1 1952, CGS mefenamic acid, mesalamine, prodrugs thereof, and the like. 9896, ZD6169, diazixide, Bay X 9227, P1075, Bay X 9228, Suitable NSAIDs are described more fully in the literature, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, such as in Goodman and Gilman, The Pharmacological Basis SR 44869, BRL38226, S 0121, SR 46142A, CGP42500, SR of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 44994, artilide fumarate, lorazepam, temazepam, ril 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. maZafone, nimetazepam, midazolam, lormetazepam, lopra Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed Inc., Zolam, ibutilide fumarate, haloxazolam, flunitrazepam, esta the disclosures of which are incorporated herein by reference Zolam, doxefazepam, clonazepam, cinolazepam, brotizolam, in their entirety. and the like. Suitable potassium channel blockers are 0445. In some embodiments the NSAIDs are acetami described more fully in the literature, such as in Goodman and nophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, Gilman, The Pharmacological Basis of Therapeutics (9th ketoprofen, naproxen or aspirin. In more particular embodi Edition), McGraw-Hill, 1995; and the Merck Index on CD ments the acetaminophen is administered in an amount of ROM. Thirteenth Edition; and on STN Express, file phar and about 325 milligrams to about 4 grams as a single dose or as file registry. multiple doses per day; the diclofenac is administered in an 0448 Suitable platelet reducing agents include but are not amount of about 50 milligrams to about 250 milligrams as a limited to, fibrinolytic agents such as for example, ancrod, single dose or as multiple doses per day; the flurbiprofen is anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e. administered in an amount of about 100 milligrams to about factor XII) fragments, plasminogen activators such as, for 300 milligrams as a single dose or as multiple doses per day; example, Streptokinase, tissue plasminogen activators (TPA), the ibuprofen is administered in an amount of about 400 urokinase, pro-Urokinase, recombinant TPA, plasmin, plas milligrams to about 3.2 grams as a single dose or as multiple minogen, and the like; anti-coagulantagents including but are doses per day; the indomethacin is administered in an amount not limited to, inhibitors of factor Xa, factor TFPI, factor of about 25 milligrams to about 200 milligrams as a single VIIa, factor IXc, factor Va., factor VIIIa, inhibitors of other dose or as multiple doses per day; the ketoprofen is adminis coagulation factors, and the like; Vitamin Kantagonists. Such tered in an amount of about 50 milligrams to about 300 as, for example, coumarin, coumarin derivatives (e.g., war milligrams as a single dose or as multiple doses per day; the farin Sodium); glycoSoaminoglycans Such as, for example, naproxen is administered in an amount of about 250 milli heparins both in unfractionated form and in low molecular grams to about 1.5 grams as a single dose or as multiple doses weight form; ardeparin Sodium, bivalirudin, bromindione, per day; the aspirin is administered in an amount of about 10 coumarin, dalteparin Sodium, danaparoid sodium; daZOXiben milligrams to about 2 grams as a single dose or as multiple hydrochloride, desirudin, dicumarol, efegatran Sulfate, enox doses per day. aparin Sodium, ifetroban, ifetroban Sodium, lyapolate 0446 Suitable phosphodiesterase inhibitors, include but Sodium, nafamoStat mesylate, phenprocoumon, Sulfatide, tin are not limited to, filaminast, piclaimilast, rolipram, Org Zaparin Sodium, retaplase; trifenagrel, warfarin, dextrans and 20241, MCI-154, roflumilast, toborinone, posicar, lixazi the like; abciximab, acadesine, anipamil, argatroban, aspirin, none, Zaprinast, sildenafil, pyrazolopyrimidinones, motapi clopidogrel, diadenosine 5'5"-P1-P4-tetraphosphate Zone, pimobendan, Zardaverine, siguaZodan, CI-930, EMD (Ap4A) analogs, difibrotide, dilazep dihydrochloride, dipy 53998, imazodan, saterinone, loprinone hydrochloride, 3-py ridamole, dopamine, 3-methoxytyramine, glucagon, glyco ridinecarbonitrile derivatives, acefylline, albifylline, bami protein IIb/IIIa antagonists, such as, for example, Ro-43 fylline, denbufyllene, diphylline, doxofylline, etofylline, tor 8857, L-700.462, iloprost, isocarbacyclin methyl ester, US 2009/0012057 A1 Jan. 8, 2009 37 itazigrel, ketanserin, BM-13.177, lamifiban, lifarizine, mol A 72517 (Zankiren), A 74273, CP80794, CGP 29287, CGP sidomine, nifedipine, OXagrelate, prostaglandins, platelet 38560A, EMD 47942, ES 305, ES 1005, ES 8891, FK 906, activating factor antagonists Such as, for example, lexipafant, FK 744, H 113, H-142, KRI 1314, pepstatin A, RO 44-9375 prostacyclins, pyrazines, pyridinol carbamate, ReoPro (i.e., (ciprokiren), RO 42-5892, RO 66-1132, RO 66-1 168, SP500, abciximab), Sulfinpyrazone, synthetic compounds SP 800, SR-43845, SQ 34017, U 71038, YM-21095, BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, YM-26365, urea derivatives of peptides, amino acids con KB-2796, KBT-3022, KC-404, KF-4939, OP-41483, TRK nected by nonpeptide bonds, di- and tri-peptide derivatives 100, TA-3090, TFC-612, ZK-36374,2,4,5,7-tetrathiaoctane, (e.g., Act-A, Act-B, Act-C, ACT-D, and the like), amino acids 2,4,5,7-tetrathiaoctane 2,2-dioxide, 2,4,5-trithiahexane, and derivatives thereof, diol sulfonamides and sulfinyls, theophyllin pentoxifyllin, thromboxane and thromboxane modified peptides, peptidyl beta-aminoacyl aminodiol car synthetase inhibitors such as, for example, picotamide, bamates, monoclonal antibodies to renin. Suitable renin Sulotroban, ticlopidine, tirofiban, trapidil, ticlopidine, inhibitors are described more fully in U.S. Pat. Nos. 5,116, trifenagrel, trilinolein, 3-substituted 5,6-bis(4-methoxyphe 835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, nyl)-1,2,4-triazines; antibodies to glycoprotein IIb/IIIa, anti 5,098,924), 5,095,006, 5,089,471, 5,075,451, 5,066,643, serotonin drugs, such as, for example, clopridogrel, Sulfin 5,063,208, 4,845,079, 5,055,466, 4,980,283, 4,885.292), pyrazone and the like; aspirin; dipyridamole; clofibrate; 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, pyridinol carbamate; glucagon, caffeine; theophyllin pen 5,036,053, 5,034,512, and 4,894,437, the disclosures of each toxifyllin: ticlopidine, and the like. of which are incorporated herein by reference in their 0449 Suitable prostaglandins, include but are not limited entirety; and in the literature. Such as in Goodman and Gil to, naturally occurring prostaglandins such as, for example, man, The Pharmacological Basis of Therapeutics (9th Edi arbaprostil, alprostadil, beraprost, carboprost, cloprostenol, tion), McGraw-Hill, 1995; and the Merck Index on dimoxaprost, emprostil, enisoprost, fluprostenol, fenprostal CD-ROM. Thirteenth Edition; and on STN Express, file phar ene, gemeprost, latanaprost, limaprost, meteneprost, mex and file registry. iprostil, misoprostol, misoprost, misoprostol acid, noclo 0453 Suitable COX-2 inhibitors include, but are not lim prost, omoprostil, prostalene, PGE, PGE PGF, PGF ited to, nimeSulide, celecoxib (CELEBREXR), etoricoxib rioprostil, rosaprostol, remiprostol, Sulprostone, trimoprostil, (ARCOXIAR), flosulide, lumiracoxib (PREXIG(R), COX tiprostanide, travoprost, unoprostone, Viprostol, Viprostol. 189), parecoxib (DYNSTATR), rofecoxib (VIOXX(R), tira Suitable prostaglandins are described more fully in the litera coxib (JTE-522), valdecoxib (BEXTRAR), ABT 963, BMS ture, such as in Goodman and Gilman, The Pharmacological 347070, CS502, DuP 697, GW-406381, NS-386, SC-57666, Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and SC-58125, SC-58635, and the like, and mixtures of two or the Merck Index on CD-ROM, 13" Edition; and on STN more thereof. Suitable COX-2 inhibitors are in U.S. Pat. Nos. Express, file phar and file registry. 5,344.991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, 0450. In some embodiments the prostaglandins are clo 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, prostenol, fluprostenol and travoprost. 5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 0451 Suitable proton pump inhibitors include, but are not 5,932,598 and 6,633,272, and in WO 94/03387, WO limited to, disulprazole, esomeprazole, lanSoprazole, lemino 94/15723, WO 94/20480, WO 94/26731, WO 94/27980, WO prazole, omeprazole, pantoprazole, rabeprazole, timopra 95/00501, WO95/15316, WO 96/03387, WO 96/03388, WO Zole, tenatoprazole, 2-(2-benzimidazolyl)-pyridine, tricyclic 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO imidazole, thienopydidine benzimidazole, fluoroalkoxy sub 97/14691, WO 97/16435, WO 01/45703 and WO 01/87343, stituted benzimidazole, dialkoxy benzimidazole, N-substi the disclosures of each of which are incorporated herein by tuted 2-(pyridylalkenesulfinyl)benzimidazole, cyclohep reference in their entirety; and in the literature, such as in tenepyridine, 5-pyrrolyl-2-pyridylmethylsulfinyl Goodman and Gilman, The Pharmacological Basis of Thera benzimidazole, alkylsulfinyl benzimidazole, fluoro-pyridyl peutics (9th Edition), McGraw-Hill, 1995; and the Merck methylsulfinyl benzimidazole, imidazo[4,5-b]pydridine, RO Index on CD-ROM. Thirteenth Edition; and on STN Express, 18-5362, IY 81149, 4-amino-3-carbonyl quinoline, 4-amino file phar and file registry. 3-acylnaphthyride, 4-aminoquinoline, 4-amino-3-acylquino 0454. In some embodiments the COX-2 inhibitors are line, 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or ethoxy)guinoline, quinazoline, tetrahydroisoquinolin-2-yl Valdecoxib. In more particular embodiments the celecoxib is pyrimidine, YH 1885, 3-substituted 1,2,4-thiadiazolo(4.5-a) administered in an amount of about 100 milligrams to about benzimidazole, 3-substituted imidazo(1,2-d)-thiadiazole, 800 milligrams as a single dose or as multiple doses per day; 2-sulfinylnicotinamide, pyridylsulfinylbenz, imidazole, the etoricoxib is administered in an amount of about 50 mil pyridylsulfinyl thieno imidazole, theinoimidazole-toluidine, ligrams to about 200 milligrams as a single dose or as multiple 4,5-dihydrooxazole, thienoimidazole-toluidine, Hoe-731, doses per day; the lumiracoxib is administered in an amount imidazol-2-alpyridine, pyrrolo2,3-bipyridine, and the like. of about 40 milligrams to about 1200 milligrams as a single Suitable proton pump inhibitors are described more fully in dose or as multiple doses per day; the paracoxib is adminis the literature, such as in Goodman and Gilman, The Pharma tered in an amount of about 20 milligrams to about 100 cological Basis of Therapeutics (9th Edition), McGraw-Hill, milligrams as a single dose or as multiple doses per day; the 1995; the Merck Index on CD-ROM, 13" Edition; and in WO rofecoxib is administered in an amount of about 12.5 milli 00/50037 assigned to NitroMed Inc., the disclosures of which grams to about 50 milligrams as a single dose or as multiple are incorporated herein by reference in their entirety. doses per day; the Valdecoxib is administered in an amount of 0452 Suitable renin inhibitors include, but are not limited about 10 milligrams to about 40 milligrams as a single dose or to, aldosterone, aliskiren (SPP-100), ditekiren, enalkrein as multiple doses per day. (A-64662), medullipin, terlkiren, tonin, Zankiren, RO 0455 Suitable steroids include, but are not limited to, 42-5892 (remikiren), A 62198. A 64662, A 65317. A 69729, 21-acetoxypregnenolone, alcolometaSone, algestone, amci US 2009/0012057 A1 Jan. 8, 2009

nonide, beclomethasone, betamethasone, budesonide, chlor (such as hydralazine hydrochloride). In one embodiment, the prednisone, clobetasol, clobentaSone, clocortolone, clopred hydralazine hydrochloride can be administered in an amount nol, corticosterone, cortisine, corticaZol (cortivatol), of about 30 milligrams per day to about 400 milligrams per deflazacort, desonide, desoximetaSone, dexamethasone, day; the isosorbide dinitrate can be administered in an amount diflorasone, diflucortolone, difluprednate, enoxolone, fluza of about 10 milligrams per day to about 200 milligrams per cort, flucloronide, flumethasone, flunisolide, flucinolone day; or the isosorbide mononitrate can be administered in an acetonide, fluocininide, fluocortin butyl, fluocortolone, fluo amount of about 5 milligrams per day to about 120 milligrams rometholone, fluperolone acetate, fluprednidene acetate, flu per day. In another embodiment, the hydralazine hydrochlo prednisolone, flurandrenolide, fluticasone propionate, fluti ride can be administered in an amount of about 50 milligrams casone propionate, formocortal, halcinonide, halobetasol per day to about 300 milligrams per day; the isosorbide dini propionate, halometaSone, haloprednone acetate, hydrocor trate can be administered in an amount of about 20 milligrams tamate, hydrocortisone and its derivatives (such as phosphate, per day to about 160 milligrams per day; or the isosorbide 21-sodium Succinate and the like), hydrocortisone terbutate, mononitrate can be administered in an amount of about 15 isoflupredone, loteprednol etabonate, maZipredone, milligrams per day to about 100 milligrams per day. In yet medrysone, meprednisone, methylprednisolone, mometa another embodiment, the hydralazine hydrochloride can be Sone furoate, paremethasone, prednicarbate, prednisolone administered in an amount of about 37.5 milligrams to about and its derivatives (such as 21-stearoylglycolate, sodium 75 milligrams one to four times per day; the isosorbide dini phosphate and the like), prednisone, prednival, prednylidene trate can be administered in an amount of about 20 milligrams and its derivatives (such as 21-diethylaminoactetate and the to about 40 milligrams one to four times per day; or the like), rimexolone, tiXocortol, trimcinolone and its derivatives isosorbide mononitrate can be administered in an amount of (such as acetonide, benetonide and the like), and the like. about 10 milligrams to about 20 milligrams one to four times Suitable NSAIDs are described more fully in the literature, per day. In another embodiment of the methods of the inven Such as in Goodman and Gilman, The Pharmacological Basis tion, the patient can be administered a composition compris of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 ing about 225 mg hydralazine hydrochloride and about 120 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. mg isosorbide dinitrate once per day (i.e., q.d.). In another Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed Inc., embodiment of the methods of the invention, the patient can the disclosures of which are incorporated herein by reference be administered a composition comprising about 112.5 mg in their entirety. hydralazine hydrochloride and about 60 mg isosorbide dini 0456. In some embodiments the steroids are dexametha trate twice per day (i.e., b.i.d.). In another embodiment of the Sone, fluorometholone, hydrocortisone, and prednisolone. methods of the invention, the patient can be administered a 0457. The invention provides compositions comprising (i) composition comprising about 56.25 mg hydralazine hydro cardiovascular compounds of the invention comprising a chloride and about 30 mg isosorbide dinitrate twice per day nitric oxide enhancing group or pharmaceutically acceptable (i.e., b.i.d.). In another embodiment of the methods of the salt thereof, and (ii) at least one compound is selected from invention, the patient can be administered a composition the group consisting of an aldosterone antagonist, an angio comprising about 75 mg hydralazine hydrochloride and about tensin II antagonist, an angiotensin-converting enzyme 40 mg isosorbide dinitrate three times per day (i.e., t.i.d.). In (ACE) inhibitor, a B-adrenergic antagonist, a calcium channel another embodiment of the methods of the invention, the blocker, a diuretic, a hydralazine compound and a renin patient can be administered a composition comprising about inhibitorin one or more pharmaceutically acceptable carriers. 37.5 mg hydralazine hydrochloride and about 20 mg isosor In other embodiments of the invention the aldosterone bide dinitrate three times per day (i.e., t.i.d.). The particular antagonist is eplerenone or spironolactone; the angiotensin II amounts of hydralazine and isosorbide dinitrate or isosorbide antagonist is candesartan, candesartan cilexetil, eprosartan mononitrate can be administered as a single dose once a day; mesylate, irbesartan, losartan potassium, medoxomil, telmis or in multiple doses several times throughout the day; or as a artan, trandolapril, trandolaprilat or Valsartan; the angio Sustained-release oral formulation, or as an injectable formu tensin-converting enzyme inhibitor is benazepril hydrochlo lation. In one embodiment of the invention the cardiovascular ride, captopril, enalapril maleate, fosinopril Sodium, compound is an angiotensin II antagonist. lisinopril, moexipril hydrochloride, quinapril hydrochloride, 0459. The invention provides methods for treating cardio ramipril; the B-adrenergic antagonist is bisoprolol fumarate, vascular disorders by administering to the patient in need carvedilol, metoprolol tartrate, propranolol hydrochloride or thereof a therapeutically effective amount of the compounds timolol maleate; the calcium channel blockers is amlodipine, and/or compositions described herein. For example, the diltiazem, isradipine, nicardipine, nifedipine, nimodipine, patient can be administered a therapeutically effective nisoldipine, nitrendipine, Verapamil; the diuretic is amiloride amount of at least one cardiovascular compound comprising hydrochloride, chlorthalidone, hydrochlorothiazide or triam at least one nitric oxide enhancing group. In another embodi terene; the hydralazine compound is hydralazine hydrochlo ment, the patient can be administered a therapeutically effec ride; and the renin inhibitor is aliskiren, ciprokiren, ditekiren, tive amount of at least one cardiovascular compound com enalkrein, medullipin, remikiren, terlkiren, tonin or Zankiren. prising at least one nitric oxide enhancing group, and at least In one embodiment of the invention the cardiovascular com one nitric oxide enhancing compound. In yet another embodi pound is an angiotensin II antagonist. ment, the patient can be administered a therapeutically effec 0458. The invention provides compositions comprising (i) tive amount of at least one cardiovascular compound com cardiovascular compounds of the invention comprising a prising at least one nitric oxide enhancing group, and, at least nitric oxide enhancing group or pharmaceutically acceptable one therapeutic agent, including but not limited to, such as, salt thereof, (ii) a nitric oxide enhancing compound, Such as, for example, aldosterone antagonists, C.-adrenergic receptor isosorbide dinitrate and/or isosorbide mononitrate (prefer agonists, C.-adrenergic receptor antagonists, angiotensin II ably isosorbide dinitrate), and (i) a hydralazine compound antagonists, angiotensin-converting enzyme (ACE) inhibi US 2009/0012057 A1 Jan. 8, 2009 39 tors, antidiabetic compounds, anti-hyperlipidemic com cardiovascular compounds comprising at least one nitric pounds, antimicrobial compounds, antioxidants, antithrom oxide enhancing group, nitric oxide enhancing compounds, botic and vasodilator compounds, B-adrenergic antagonists, and/ortherapeutic agents can be administered separately or as calcium channel blockers, carbonic anhydrase inhibitors, components of the same composition in one or more pharma digitalis, diuretics, endothelin antagonists, hydralazine com ceutically acceptable carriers. pounds, H2 receptor antagonists, neutral endopeptidase 0461 The invention provides methods for treating diabe inhibitors, nonsteroidal antiinflammatory compounds tes; treating diseases resulting from oxidative stress; treating (NSAIDs), phosphodiesterase inhibitors, potassium channel endothelial dysfunctions; treating diseases caused by endot blockers, platelet reducing agents, prostaglandins, proton helial dysfunctions; treating cirrhosis; treating pre-eclamp pump inhibitors, renin inhibitors, selective cyclooxygenase-2 sia; treating osteoporosis; treating nephropathy; treating (COX-2) inhibitors, steroids, and combinations of two or peripheral vascular diseases; treating portal hypertension; more thereof. In another embodiment, the patient can be treating metabolic syndrome; and treating hyperlipidemia by administered a therapeutically effective amount of at least administering to the patient in need thereofatherapeutically one cardiovascular compound comprising at least one nitric effective amount of the compounds and/or compositions oxide enhancing group, and, at least one therapeutic agent, described herein. For example, the patient can be adminis and, at least one nitric oxide enhancing compound. In one tered a therapeutically effective amount of at least one car embodiment the cardiovascular disorder is hypertension, diovascular compound comprising at least one nitric oxide heart failure and/or diastolic dysfunction. In one embodiment enhancing group. In another embodiment, the patient can be of the invention the cardiovascular compound is an angio administered a therapeutically effective amount of at least tensin II antagonist. The cardiovascular compounds compris one cardiovascular compound comprising at least one nitric ing at least one nitric oxide enhancing group, nitric oxide oxide enhancing group, and at least one nitric oxide enhanc enhancing compounds, and/or therapeutic agents can be ing compound. In yet another embodiment, the patient can be administered separately or as components of the same com administered a therapeutically effective amount of at least position in one or more pharmaceutically acceptable carriers. one cardiovascular compound comprising at least one nitric 0460. The invention provides methods for treating ren oxide enhancing group, and, at least one therapeutic agent, ovascular diseases by administering to the patient in need including but not limited to, such as, for example, aldosterone thereof a therapeutically effective amount of the compounds antagonists, C.-adrenergic receptor agonists, C.-adrenergic and/or compositions described herein. For example, the receptor antagonists, angiotensin II antagonists, angiotensin patient can be administered a therapeutically effective converting enzyme (ACE) inhibitors, antidiabetic com amount of at least one cardiovascular compound comprising pounds, anti-hyperlipidemic compounds, antimicrobial com at least one nitric oxide enhancing group. In another embodi pounds, antioxidants, antithrombotic and vasodilator ment, the patient can be administered a therapeutically effec compounds, B-adrenergic antagonists, calcium channel tive amount of at least one cardiovascular compound com blockers, carbonic anhydrase inhibitors, digitalis, diuretics, prising at least one nitric oxide enhancing group, and at least endothelin antagonists, hydralazine compounds. He receptor one nitric oxide enhancing compound. In yet another embodi antagonists, neutral endopeptidase inhibitors, nonsteroidal ment, the patient can be administered a therapeutically effec antiinflammatory compounds (NSAIDs), phosphodiesterase tive amount of at least one cardiovascular compound com inhibitors, potassium channel blockers, platelet reducing prising at least one nitric oxide enhancing group, and, at least agents, prostaglandins, proton pump inhibitors, renin inhibi one therapeutic agent, including but not limited to, such as, tors, selective cyclooxygenase-2 (COX-2) inhibitors, ste for example, aldosterone antagonists, C.-adrenergic receptor roids, and combinations of two or more thereof. In another agonists, C.-adrenergic receptor antagonists, angiotensin II embodiment, the patient can be administered a therapeuti antagonists, angiotensin-converting enzyme (ACE) inhibi cally effective amount of at least one cardiovascular com tors, antidiabetic compounds, anti-hyperlipidemic com pound comprising at least one nitric oxide enhancing group, pounds, antimicrobial compounds, antioxidants, antithrom and, at least one therapeutic agent, and, at least one nitric botic and vasodilator compounds, B-adrenergic antagonists, oxide enhancing compound. In one embodiment of the inven calcium channel blockers, carbonic anhydrase inhibitors, tion the cardiovascular compound is an angiotensin II antago digitalis, diuretics, endothelin antagonists, hydralazine com nist. The cardiovascular compounds comprising at least one pounds, H2 receptor antagonists, neutral endopeptidase nitric oxide enhancing group, nitric oxide enhancing com inhibitors, nonsteroidal antiinflammatory compounds pounds, and/or therapeutic agents can be administered sepa (NSAIDs), phosphodiesterase inhibitors, potassium channel rately or as components of the same composition in one or blockers, platelet reducing agents, prostaglandins, proton more pharmaceutically acceptable carriers. pump inhibitors, renin inhibitors, selective cyclooxygenase-2 0462. The invention provides methods for treating oph (COX-2) inhibitors, steroids, and combinations of two or thalmic disorders in a patient in need thereof comprising more thereof. In another embodiment, the patient can be administering to the patient a therapeutically effective administered a therapeutically effective amount of at least amount of at least one cardiovascular compound comprising one cardiovascular compound comprising at least one nitric at least one nitric oxide enhancing group, and, optionally, at oxide enhancing group, and, at least one therapeutic agent, least one therapeutic agent, such as, for example, C.-adrener and, at least one nitric oxide enhancing compound. In one gic receptoragonists, angiotensin-converting enzyme (ACE) embodiment of the invention the cardiovascular compound is inhibitors, antimicrobial compounds, 3-adrenergic antago an angiotensin II antagonist. In one embodiment the renovas nists, carbonic anhydrase inhibitors, nonsteroidal antiinflam cular disease is renal failure, renal insufficiency, renal dete matory compounds, prostaglandins, selective cyclooxyge rioration associated with severe hypertension or renovascular nase-2 (COX-2) inhibitors, steroids and combinations of two hypertension. In another embodiment of the invention the or more thereof. The methods can optionally further comprise cardiovascular compound is an angiotensin II antagonist. The the administration of at least one nitric oxide enhancing com US 2009/0012057 A1 Jan. 8, 2009 40 pound. In this embodiment of the invention, the methods can cardiovascular compound comprising at least one nitric oxide involve (i) administering the cardiovascular compounds com enhancing group is administered orally, parentally or by inha prising at least one nitric oxide enhancing group, (ii) admin lation. istering the cardiovascular compounds comprising at least 0466 Transdermal compound administration, which is one nitric oxide enhancing group and nitric oxide enhancing known to one skilled in the art, involves the delivery of phar compounds, (iii) administering the cardiovascular com maceutical compounds via percutaneous passage of the com pounds comprising at least one nitric oxide enhancing group pound into the systemic circulation of the patient. Topical and therapeutic agents, or (iv) administering the cardiovas administration can also involve the use of transdermal admin cular compounds comprising at least one nitric oxide enhanc istration Such as transdermal patches or iontophoresis ing group, nitric oxide enhancing compounds, and therapeu devices. Other components can be incorporated into the trans tic agents. In one embodiment the at least one therapeutic dermal patches as well. For example, compositions and/or agentis selected from the group consisting of an O-adrenergic transdermal patches can be formulated with one or more receptor agonist, an angiotensin-converting enzyme (ACE) preservatives or bacteriostatic agents including, but not lim inhibitor, an antimicrobial compound, a B-adrenergic antago ited to, methyl hydroxybenzoate, propyl hydroxybenzoate, nist, a carbonic anhydrase inhibitor, a nonsteroidal antiin chlorocresol, benzalkonium chloride, and the like. Dosage flammatory compound, a prostaglandin, a selective forms for topical administration of the compounds and com cyclooxygenase-2 (COX-2) inhibitor, and a steroid. In one positions can include creams, sprays, lotions, gels, ointments, embodiment the ophthalmic disorder is ophthalmic infection, eye drops, nose drops, ear drops, and the like. In Such dosage glaucoma, elevated intraocular pressure, ocular pain follow forms, the compositions of the invention can be mixed to form ing corneal Surgery, dry eye disorder, ocular hypertension, white, Smooth, homogeneous, opaque cream or lotion with, ocular bleeding, retinal diseases or disorders. In another for example, benzyl alcohol 1% or 2% (wit/wt) as a preserva embodiment of the invention the cardiovascular compound is tive, emulsifying wax, glycerin, isopropyl palmitate, lactic an angiotensin II antagonist. The cardiovascular compounds acid, purified water and sorbitol solution. In addition, the of the invention, nitric oxide enhancing compounds, and/or compositions can contain polyethylene glycol 400. They can therapeutic agents can be administered separately or as com be mixed to form ointments with, for example, benzyl alcohol ponents of the same composition in one or more pharmaceu 2% (wt/wt) as preservative, white petrolatum, emulsifying tically acceptable carriers. wax, and tenox II (butylated hydroxyanisole, propyl gallate, 0463 When administered separately, the cardiovascular citric acid, propylene glycol). Woven pads or rolls of bandag compound comprising at least one nitric oxide enhancing ing material, e.g., gauze, can be impregnated with the com group, nitric oxide enhancing compound and/or therapeutic positions in solution, lotion, cream, ointment or other Such agent can be administered about the same time as part of the form can also be used for topical application. The composi overall treatment regimen, i.e., as a combination therapy. tions can also be applied topically using a transdermal sys About the same time' includes administering the cardiovas tem, such as one of an acrylic-based polymer adhesive with a cular compound comprising at least one nitric oxide enhanc resinous crosslinking agent impregnated with the composi ing group, simultaneously, sequentially, at the same time, at tion and laminated to an impermeable backing. different times on the same day, or on different days, as long 0467. The compositions can also be applied topically as they are administered as part of an overall treatment regi using a transdermal system, Such as one of an acrylic-based men, i.e., combination therapy or a therapeutic cocktail. polymer adhesive with a resinous crosslinking agent impreg 0464 When administered in vivo, the compounds and nated with the composition and laminated to an impermeable compositions of the invention can be administered in combi backing. In a particular embodiment, the compositions of the nation with pharmaceutically acceptable carriers and in dos invention are administered as a transdermal patch, more par ages described herein. When the compounds and composi ticularly as a Sustained-release transdermal patch. The trans tions of the invention are administered as a combination of at dermal patches of the invention can include any conventional least one cardiovascular compound comprising at least one form such as, for example, adhesive matrix, polymeric nitric oxide enhancing group and/or at least one nitric oxide matrix, reservoir patch, matrix or monolithic-type laminated enhancing compound and/or therapeutic agent, they can also structure, and are generally comprised of one or more backing be used in combination with one or more additional com layers, adhesives, penetration enhancers, an optional rate pounds which are known to be effective against the specific controlling membrane and a release liner which is removed to disease state targeted for treatment. The nitric oxide enhanc expose the adhesives prior to application. Polymeric matrix ing compounds, therapeutic agents and/or other additional patches also comprise a polymeric-matrix forming material. compounds can be administered simultaneously with, Subse Suitable transdermal patches are described in more detail in, quently to, or prior to administration of the cardiovascular for example, U.S. Pat. Nos. 5,262,165, 5.948,433, 6,010,715 compound comprising at least one nitric oxide enhancing and 6,071,531, the disclosure of each of which are incorpo group. rated herein in their entirety. 0465. The compounds and compositions of the invention 0468 Solid dosage forms for oral administration can can be administered by any available and effective delivery include capsules, Sustained-release capsules, tablets, Sus system including, but not limited to, orally, bucally, parenter tained release tablets, chewable tablets, sublingual tablets, ally, by inhalation, by topical application, by injection, trans effervescent tablets, pills, powders, granules and gels. In Such dermally, or rectally (e.g., by the use of Suppositories) in Solid dosage forms, the active compounds can be admixed dosage unit formulations containing conventional nontoxic with at least one inert diluent such as Sucrose, lactose or pharmaceutically acceptable carriers, adjuvants, and starch. Such dosage forms can also comprise, as in normal vehicles, as desired. Parenteral includes subcutaneous injec practice, additional Substances other than inert diluents, e.g., tions, intravenous, intramuscular, intrasternal injection, or lubricating agents such as magnesium Stearate. In the case of infusion techniques. In one embodiment of the invention the capsules, tablets, effervescent tablets, and pills, the dosage US 2009/0012057 A1 Jan. 8, 2009 forms can also comprise buffering agents. Soft gelatin cap Such as pharmaceutical grades of mannitol, lactose, starch, Sules can be prepared to contain a mixture of the active magnesium Stearate, sodium saccharine, cellulose, magne compounds or compositions of the invention and vegetable sium carbonate, and the like. oil. Hard gelatin capsules can contain granules of the active 0474 The compounds of the invention, can be incorpo compound in combination with a solid, pulverulent carrier rated into various types of pharmaceutical compositions, such Such as lactose, Saccharose, Sorbitol, mannitol, potato starch, as, for example, ophthalmic formulations for delivery to the corn starch, amylopectin, cellulose derivatives of gelatin. eye (e.g., topically, intracamerally, or via an implant). The Tablets and pills can be prepared with enteric coatings. compounds are preferably incorporated into topical oph 0469 Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, Solutions, thalmic formulations, such as for example, Solutions, Suspen Suspensions, syrups, and elixirs containing inert diluents sions, gels, ointments, implants, and the like. The compounds commonly used in the art, Such as water. Such compositions of the invention may be combined with opthalmologically can also comprise adjuvants, such as wetting agents, emulsi acceptable preservatives, viscosity enhancers, penetration fying and Suspending agents, and Sweetening, flavoring, and enhancers, buffers, Sodium chloride, water to form an aque perfuming agents. ous, sterile ophthalmic Suspensions or solutions, and the like. 0470 Suppositories for vaginal or rectal administration of 0475 Suitable preservatives include, but are not limited the compounds and compositions of the invention, such as for to, benzalkonium chloride, thimerosal, chlorobutanol, methyl treating pediatric fever and the like, can be prepared by mix paraben, propyl paraben, phenylethyl alcohol, edetate diso ing the compounds or compositions with a suitable nonirri dium, sorbic acid, ONAMER(R), and the like. The preserva tating excipient Such as cocoa butter and polyethylene glycols tives are typically employed at a concentration between about which are solid at room temperature but liquid at rectal tem 0.001% and about 1.0% by weight. Appropriate co-solvents perature, such that they will melt in the rectum and release the include, but are not limited to, Polysorbate 20, 60 and 80; drug. Pluronic F-68, F-84 and P-103; TyloxapolR); Cremophor(R) 0471 Injectable preparations, for example, sterile inject EL: sodium dodecyl sulfate; glycerol; PEG 400; propylene able aqueous or oleaginous Suspensions can be formulated glycol, cyclodextrins, and the like. The co-solvents are typi according to the known art using Suitable dispersing agents, cally employed at a concentration between about 0.01% and wetting agents and/or Suspending agents. The sterile inject about 2% by weight. Viscosity enhancers are required as a able preparation can also be a sterile injectable solution or Viscosity greater than that of simple aqueous Solutions may be suspension in a nontoxic parenterally acceptable diluent or desirable to increase ocular absorption of the active com Solvent, for example, as a solution in 1,3-butanediol. Among pound, to decrease variability in dispensing the formulations, the acceptable vehicles and solvents that can be used are to decrease physical separation of components of a Suspen water, Ringer's Solution, and isotonic sodium chloride solu sion or emulsion of formulation and/or otherwise to improve tion. Sterile fixed oils are also conventionally used as a sol the ophthalmic formulation. Suitable viscosity enhancers, vent or Suspending medium. include, but are not limited to, polyvinyl alcohol, methyl 0472. The compositions of this invention can further cellulose, hydroxy propyl carboxymethyl cellulose, include conventional excipients, i.e., pharmaceutically hydroxymethylcellulose, hydroxyethylcellulose, hydrox acceptable organic or inorganic carrier Substances Suitable for ypropylmethylcellulose, methylcellulose, polyvinylpyrroli parenteral application which do not deleteriously react with done, and the like. Gelling agents can also be used, including, the active compounds. Suitable pharmaceutically acceptable but not limited to, gellan and Xanthan gum, and the like. carriers include, for example, water, salt Solutions, alcohol, Viscosity enhancers are typically employed at a concentra Vegetable oils, polyethylene glycols, gelatin, lactose, amy tion between about 0.01% and about 2% by weight. lose, magnesium Stearate, talc, Surfactants, silicic acid, vis 0476 Ophthalmic solution formulations may be prepared cous paraffin, perfume oil, fatty acid monoglycerides and by dissolving a compound in a physiologically acceptable diglycerides, petroethral fatty acid esters, hydroxymethyl isotonic aqueous buffer. Alternatively, the ophthalmic solu cellulose, polyvinylpyrrolidone, and the like. The pharma tion may include an opthalmologically acceptable surfactant ceutical preparations can be sterilized and if desired, mixed to assist in dissolving the compound. Additionally for sterile with auxiliary agents, e.g., lubricants, preservatives, stabiliz ophthalmic ointment formulations, the compounds of the ers, wetting agents, emulsifiers, salts for influencing osmotic invention may be combined with a preservative in an appro pressure, buffers, colorings, flavoring and/or aromatic Sub priate vehicle, such as, mineral oil, liquid lanolin, or white stances and the like which do not deleteriously react with the petrolatum. Sterile ophthalmic gel formulations may be pre active compounds. For parenteral application, particularly pared by Suspending the active ingredient in a hydrophilic Suitable vehicles consist of solutions, preferably oily or aque base prepared from the combination of for example, car ous solutions, as well as Suspensions, emulsions, or implants. bopol-974, and the like. Aqueous Suspensions may contain Substances which increase 0477 Various delivery systems are known and can be used the viscosity of the Suspension and include, for example, to administer the compounds or compositions of the inven sodium carboxymethyl cellulose, sorbitol and/or dextran. tion, including, for example, encapsulation in liposomes, Optionally, the Suspension may also contain stabilizers. microbubbles, emulsions, microparticles, microcapsules and 0473. The composition, if desired, can also contain minor the like. The required dosage can be administered as a single amounts of wetting agents, emulsifying agents and/or pH unit or in a Sustained release form. buffering agents. The composition can be a liquid solution, 0478. The bioavailability of the compositions can be Suspension, emulsion, tablet, pill, capsule, Sustained release enhanced by micronization of the formulations using conven formulation, or powder. The composition can be formulated tional techniques such as grinding, milling, spray drying and as a Suppository, with traditional binders and carriers such as the like in the presence of suitable excipients or agents such as triglycerides. Oral formulations can include standard carriers phospholipids or Surfactants. US 2009/0012057 A1 Jan. 8, 2009 42

0479. Sustained release dosage forms of the invention may Sulfonic, benzenesulfonic, pantothenic, toluenesulfonic, comprise microparticles and/or nanoparticles having a thera 2-hydroxyethanesulfonic, Sulfanilic, Stearic, algenic, C.-hy peutic agent dispersed therein or may comprise the therapeu droxybutyric, cyclohexylaminosulfonic, galactaric and tic agent in pure, crystalline, Solid form. The therapeutic galacturonic acid and the like. Suitable pharmaceutically dosage forms of this aspect of the invention may be of any acceptable base addition salts include, but are not limited to, configuration Suitable for Sustained release. metallic salts made from aluminum, calcium, lithium, mag 0480 Nanoparticle sustained release therapeutic dosage nesium, potassium, Sodium and Zinc or organic salts made forms are preferably biodegradable and, optionally, bind to from primary, secondary and tertiary amines, cyclic amines, the vascular Smooth muscle cells and enter those cells, pri N,N'-dibenzylethylenediamine, chloroprocaine, choline, marily by endocytosis. The biodegradation of the nanopar diethanolamine, ethylenediamine, meglumine (N-methylglu ticles occurs over time (e.g., 30 to 120 days; or 10 to 21 days) camine) and procaine and the like. All of these salts may be in prelysosomic vesicles and lysosomes. Larger microparticle prepared by conventional means from the corresponding therapeutic dosage forms of the invention release the thera compound by reacting, for example, the appropriate acid or peutic agents for Subsequent target cell uptake with only a few base with the compound. In one embodiment, the pharma of the Smaller microparticles entering the cell by phagocyto ceutically acceptable salts of the compounds of the invention sis. A practitioner in the art will appreciate that the precise do not include the nitrate salt. mechanism by which a target cell assimilates and metabolizes 0484 While individual needs may vary, determination of a dosage form of the invention depends on the morphology, optimal ranges for effective amounts of the compounds and/ physiology and metabolic processes of those cells. The size of or compositions is within the skill of the art. Generally, the the particle Sustained release therapeutic dosage forms is also dosage required to provide an effective amount of the com important with respect to the mode of cellular assimilation. pounds and compositions, which can be adjusted by one of For example, the smaller nanoparticles can flow with the ordinary skill in the art, will vary depending on the age, interstitial fluid between cells and penetrate the infused tis health, physical condition, sex, diet, weight, extent of the Sue. The larger microparticles tend to be more easily trapped dysfunction of the recipient, frequency of treatment and the interstitially in the infused primary tissue, and thus are useful nature and scope of the dysfunction or disease, medical con to deliver anti-proliferative therapeutic agents. dition of the patient, the route of administration, pharmaco 0481 Particular sustained release dosage forms of the logical considerations such as the activity, efficacy, pharma invention comprise biodegradable microparticles or nanopar cokinetic and toxicology profiles of the particular compound ticles. More particularly, biodegradable microparticles or used, whether a drug delivery system is used, and whether the nanoparticles are formed of a polymer containing matrix that compound is administered as part of a drug combination. biodegrades by random, nonenzymatic, hydrolytic Scission 0485 The amount of a given cardiovascular compound of ing to release therapeutic agent, thereby forming pores within the invention compound comprising at least one nitric oxide the particulate structure. enhancing group that will be effective in the treatment of a 0482 In a particular embodiment, the compositions of the particular disorder or condition will depend on the nature of invention are orally administered as a Sustained release tablet the disorder or condition, and can be determined by standard or a Sustained release capsule. For example, the Sustained clinical techniques, including reference to Goodman and Gil release formulations can comprise a therapeutically effective man, supra: The Physician's Desk Reference, Medical Eco amount of at least one cardiovascular compound comprising nomics Company, Inc., Oradell, N.J., 1995; and Drug Facts at least one nitric oxide enhancing group or a pharmaceuti and Comparisons, Inc., St. Louis, Mo., 1993. The precise cally acceptable salt thereof, and, optionally at least one nitric dose to be used in the formulation will also depend on the oxide enhancing compound, or the Sustained release formu route of administration, and the seriousness of the disease or lations can comprise a therapeutically effective amount of at disorder, and should be decided by the physician and the least one cardiovascular compound comprising at least one patient's circumstances. nitric oxide enhancing group or a pharmaceutically accept 0486 The invention also provides pharmaceutical kits able salt thereof, and at least one nitric oxide enhancing comprising one or more containers filled with one or more of compound, and, optionally at least one therapeutic agent the ingredients of the pharmaceutical compounds and/or 0483 The compounds and compositions of the invention compositions of the invention, including, at least, one or more can be formulated as pharmaceutically acceptable salt forms. of the novel cardiovascular compound comprising at least one Pharmaceutically acceptable salts include, for example, nitric oxide enhancing group, and one or more of the NO alkali metal salts and addition salts of free acids or free bases. donors described herein. Associated with such kits can be The nature of the salt is not critical, provided that it is phar additional therapeutic agents or compositions (e.g., aldoster maceutically-acceptable. Suitable pharmaceutically-accept one antagonists, C.-adrenergic receptor agonists, C.-adrener able acid addition salts may be prepared from an inorganic gic receptor antagonists, angiotensin II antagonists, angio acid or from an organic acid. Examples of Such inorganic tensin-converting enzyme (ACE) inhibitors, antidiabetic acids include, but are not limited to, hydrochloric, hydrobro compounds, anti-hyperlipidemic compounds, antimicrobial mic, hydroiodic, nitric, carbonic, Sulfuric and phosphoric compounds, antioxidants, antithrombotic and vasodilator acid and the like. Appropriate organic acids include, but are compounds, B-adrenergic antagonists, calcium channel not limited to, aliphatic, cycloaliphatic, aromatic, heterocy blockers, carbonic anhydrase inhibitors, digitalis, diuretics, clic, carboxylic and Sulfonic classes of organic acids, such as, endothelin antagonists, hydralazine compounds, H2 receptor for example, formic, acetic, propionic, succinic, glycolic, antagonists, neutral endopeptidase inhibitors, nonsteroidal gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, antiinflammatory compounds (NSAIDs), phosphodiesterase maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthra inhibitors, potassium channel blockers, platelet reducing nilic, mesylic, Salicylic, p-hydroxybenzoic, phenylacetic, agents, prostaglandins, proton pump inhibitors, renin inhibi mandelic, embonic (pamoic), methanesulfonic, ethane tors, selective cyclooxygenase-2 (COX-2) inhibitors, ste US 2009/0012057 A1 Jan. 8, 2009

roids, and the like, and combinations of two or more thereof), devices for administering the compositions, and notices in the -continued form prescribed by a governmental agency regulating the (7) manufacture, use or sale of pharmaceuticals or biological O products which reflects approval by the agency of manufac o N(D) 'N ture, use or sale for humans. \ | 0487. The disclosure of each patent, patent application O and publication cited or described in the present specification H3C CH3: is hereby incorporated by reference herein in its entirety. 0488 Although the invention has been set forth in detail, one skilled in the art will appreciate that numerous changes (8) —N(D)-C(O)—N(D)-CH CH, CH: and modifications can be made to the invention, and that Such (9) —C(O)—UD; changes and modifications can be made without departing from the spirit and scope of the invention. (10) –C(O) CH-NH(D): (11)—S(O), N(D)-C(O) CHs: What is claimed is: (12) —S(O), N(D)-C(O) ND-CH, CH, CH; or 1. A compound of Formula (I), (II), (III), (IV), (V), (VI), (13) - S(O), N(D)-OD; (VII) or a pharmaceutically acceptable salt thereof: D is D. —C(O)—CH NH(D) or —C(CHs): wherein the compound of Formula (I) is: Z is a carbon, —CH or a nitrogen atom; Ro is a fluorine or a hydrogen atom; (I) Y is: R10 X3 Y Z3 (1) / & R12 / Ny-ch-ch wherein: R11 N X is:

(2) (1) HC CH O

les-N- N UD (2) -- O (3) les---O O UD (3) -- (4) (4) >N O --N (C(R)(R)) V4 (5) y (5) (6) x -N(D)-S(O)-CF, or O UD US 2009/0012057 A1 Jan. 8, 2009 44

-continued -continued (6) (12) CH ODI za N

HC lsN N O

(13) (7)

(8) (14) R16 R16 R16

R16 N \ CH3 - - CH2-), CH3 O N (9)

(15) C N n CH CH3 HC 21

DO (16) R22 Z4 (10) CH JC Nz, N211.- NN1 O --, N HC-(HC), O (17)

(11) O UD

N (18) HC -- O US 2009/0012057 A1 Jan. 8, 2009

-continued -continued (19) (26) za N CH 1. -N N N N N N S. R28 O HC-(CH) N DU O

(20) N R20 (27)

(21)

(28) R16 N

R19 X N N (22) R30 O 2N/ HC1 (CH2) U3D N1 NNA O

(29) -- CH3 (23) R11 f S O

N YN > N ls R31

(30) (24) R35 R36 N 21 N-is?

(25) (31) R44 R43 N

O > R42

US 2009/0012057 A1 Jan. 8, 2009 47

Ras and R taken together are: -continued (5) (1) PS CN n N / O (6) (2) ^ (7)

Zs is —CH2 or oxygen; XCN NN o is an integer from 0 to 3: Yo / O k is an integer from 1 to 3: D is a hydrogen, V or K, K is —(W)-E,-(C(R)(R)).-E.-(C(R)(R)), (W) (8) (C(R)(R)), (W), E-(W), (C(R)(R)). Va: a, b, c, d, g, i and j are each independently an integer from O to 3: p. x, y and Z are each independently an integer from 0 to XCN 10: -N / O No V is V. R. —U Vs or V: (9) V is:

(1)

N

(10) (2)

N -N. / O Yo (3) (11)

(4) (12)

US 2009/0012057 A1 Jan. 8, 2009 49

ester, an aryl ester, aurea, a phosphoryl, a nitro. —U - -continued Vs, V, -(C(R)(R)). U, Vs, -(C(R)(R)) — (3) Us V, -(C(R)(R)). U V —(C(R)(R)) Us C(O) V, or RandR, 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, (4) (1)

(5) (2)

(6)

R, and R 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 cycloalky lalkyl, a cycloalkylthio, an arylalklythio, an arylalkylth ioalkyl, an alkylthioalkyla cycloalkenyl, an heterocycli calkyl, an alkoxy, a haloalkoxy, an amino, an T is a —S(O) ; a carbonyl or a covalent bond; alkylamino, a dialkylamino, an arylamino, a diary o is an integer from 0 to 2; lamino, an alkylarylamino, an alkoxyhaloalkyl, a Sul R, and R are independently selected from an alkyl group, an aryl group, or R, and R taken together with the nitro fonic acid, a Sulfonic ester, an alkylsulfonic acid, an gen atom to which they are attached are a heterocylic arylsulfonic acid, an arylalkoxy, an alkylthio, an ring: arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcar Ts at each occurrence is independently a covalent bond, a boxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbonyl, an oxygen, —S(O)O— or —N(R)R. carbamoyl, an alkylcarboxylic acid, an arylcarboxylic his an integer form 1 to 10; acid, an alkylcarbonyl, an arylcarbonyl, an ester, a car q is an integer from 1 to 5: boxylic ester, an alkylcarboxylic ester, an arylcarboxylic R, and R, are each independently a hydrogen, an alkyl, a ester, a Sulfonamido, an alkylsulfonamido, an arylsul cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an fonamido, an alkylsulfonyl, an alkylsulfonyloxy, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalky arylsulfonyl, arylsulphonyloxy, a Sulfonic ester, an alkyl lalkyl, a cycloalkylthio, an arylalklythio, an arylalkylth ester, an aryl ester, a urea, a phosphoryl, a nitro. —U— ioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocy Vs, Vs, or R, and R, taken together with the carbons to clicalkyl, an alkoxy, a haloalkoxy, an amino, an which they are attached form a carbonyl, a methanthial, alkylamino, a dialkylamino, an arylamino, a diary a heterocyclic ring, a cycloalkyl group, an aryl group, an lamino, an alkylarylamino, an alkoxyhaloalkyl, a Sul Oxime, an imine, a hydrazone a bridged cycloalkyl fonic acid, a Sulfonic ester, an alkylsulfonic acid, an grOup, arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcar (1) boxamido, an arylcarboxamido, an amidyl, a carboxyl, a H3C CH3 carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a car N-O or boxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a Sulfonamido, an alkylsulfonamido, an arylsul fonamido, an alkylsulfonyl, an alkylsulfonyloxy, an 2-7( arylsulfonyl, arylsulphonyloxy, a Sulfonic ester, an alkyl US 2009/0012057 A1 Jan. 8, 2009 50

wherein: -continued X and Y are as defined herein; and (2) with the proviso that the compounds of Formula (III) must contain at least one nitric oxide enhancing group linked H3C CH3 to the compound of Formula (III) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or N-O moiety that can be hydrolyzed: Z5 wherein the compound of Formula (IV) is:

H3C CH3 (IV) Us is an oxygen, Sulfur or —N(R)R, Vs is NO or - NO, (i.e. an oxidized nitrogen); k is an integer from 1 to 3: R is alone pair of electrons, a hydrogen oran alkyl group; R, is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an aryl carboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a Sulfonamido, a carboxamido, a car boxylic ester, an aminoalkyl, an aminoaryl, —CH2— C (Us Vs)(R)(R), a bond to an adjacent atom cre ating a double bond to that atom or —(N2O ).M. wherein: wherein M is an organic or inorganic cation; and X and Y are as defined herein; and with the proviso that the compound of Formula (I) must with the proviso that the compounds of Formula (IV) must contain at least one nitric oxide enhancing group linked contain at least one nitric oxide enhancing group linked to the compound of Formula (I) through an oxygen to the compound of Formula (IV) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed: moiety that can be hydrolyzed: wherein the compound of Formula (E) is: wherein the compound of Formula (V) is:

(II) (V)

wherein: X and Y are as defined herein; and with the proviso that the compounds of Formula (V) must contain at least one nitric oxide enhancing group linked to the compound of Formula (V) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed: wherein: wherein the compound of Formula (VI) is: U and D are as defined herein; and with the proviso that the compounds of Formula (II) must contain at least one nitric oxide enhancing group linked (VI) to the compound of Formula (II) through an oxygen X atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed: wherein the compound of Formula (III) is: NS-( ) Y 2 (III) Br wherein: X and Y are as defined herein; and with the proviso that the compounds of Formula (VI) must contain at least one nitric oxide enhancing group linked to the compound of Formula (VI) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed: US 2009/0012057 A1 Jan. 8, 2009 51

wherein the compound of Formula (VII) is: 165113-09-7P, 165113-10-0P, 165113-11-1P, 165113-12-2P 165113-17-7P, 165113-18-8P, 165113-19-9P, 165113-20-2P 165113-13-3P, 165113-14-4P 165113-15-5P, 165113-16-6P. (VII) 165113-21-3P, 165113-22-4P 165113-23-5P, 165113-24-6P. R47 X 165113-25-7P, 165113-26-8P, 165113-27-9P, 165113-28-OP, Y 165113-29-1P, 165113-30-4P 165113-31-5P, 165113-32-6P. O 165113-33-7P, 165113-34-8P, 165113-35-9P, 165113-36 OP. 165113-37-1P, 165113-38-2P, 165113-39-3P, 16511340 6P 165113-41-7P 165113-42-8P 165113-43-9P, 165113 R47 44-OP. 165113-45-1P, 165113-46-2P, 165113-47-3P, 165113-48-4P, 165113-49-5P, 165113-50-8P, 165113-51-9P, wherein: 165113-52-OP. 165113-53-1P, 165113-54-2P 165113-55-3P, Raz is a lower alkyl group; 165113-56-4P, 165113-57-5P, 165113-58-6P, 165113-59-7P. X and Y as defined herein; and 165113-60-OP. 165113-6.1-1P, 1651 13-62-2P, 165113-63 with the proviso that the compounds of Formula (VII) must 3P, 165113-64-4P 165113-65-5P, 165113-66-6P, 165113 contain at least one nitric oxide enhancing group linked 67-7P 165113-68-8P, 165113-69-9P, 165113-70-2P to the compound of Formula (VII) through an oxygen 165113-71-3P, 165113-72-4P 165113-73-5P, 165113-74-6P. atom, a nitrogen atom or a Sulfur atom via a bond or 114798-27-5, 114798-28-6, 114798-29-7, 124749-82-2, moiety that can be hydrolyzed: 114798-28-6, 124749-84-4, 124750-88-5, 124750-91-0, 124750-93-2, 161946-65-2P 161947-47-3P, 161947-48-4P. wherein the compound of Formula (VIII) is: 161947-51-9P, 161947-52-0P 161947-55-3P, 161947-56-4P. 161947-60-0P, 161947-61-1P 161947-68-8P 161947-69-9P, (VIII) 161947-70-2P 161947-71-3P, 161947-72-4P 161947-74-6P. 161947-75-7P 161947-81-5P, 161947-82-6P 161947-83-7P. 161947-84-8P 161947-85-9P, 161947-86-OP. 161947-87-1P 161947-88-2P 161947-89-3P, 161947-90-6P 161947-91-7P. 161947-92-8P 161947-93-9P, 161947-94-OP. 161947-95-1P 161947-96-2P 161947-97-3P, 161947-98-4P 161947-99-5P, 161948-00-1P 161948-01-2P 161948-02-3P, 168686-32-6P. 167301-42-OP. 166813-82-7P 166961-56-4P 166961-58-6P. wherein: 158872-96-9P, 158872-97-0P, 158807-14-8P, 158807-15-9P, X and Y are as defined herein; and 158807-16-0P, 158807-17-1P, 158807-18-2P 158807-19-3P, with the proviso that the compounds of Formula (VIII) 158807-20-6P, 155884-08-5P, 154749-99-2, 167371-59-7P. must contain at least one nitric oxide enhancing group 244126-99-6P, 177848-35-OP and 141309-82-2P; the com linked to the compound of Formula (VIII) through an pound of Formula (II) is a nitric oxide enhancing eprosartan; oxygenatom, a nitrogenatom or a Sulfur atom via a bond the compound of Formula (III) is a nitric oxide enhancing or moiety that can be hydrolyzed. Saprisartan, a nitric oxide enhancing Zalasartan, the com 2. A composition comprising the compound of claim 1 and pound of Formula (IV) is a nitric oxide enhancing BMS a pharmaceutically acceptable carrier. 180560; the compound of Formula (V) is a nitric oxide 3. The compound of claim 1, wherein the compound of enhancing KW 3433; the compound of Formula (VI) is a Formula (I) is a nitric oxide enhancing abitesartan, a nitric nitric oxide enhancing GA 0056; and the compound of For oxide enhancing candesartan, a nitric oxide enhancing can mula (VII) is a nitric oxide enhancing L 158,809; and phar desartancilexetil, a nitric oxide enhancing elisartan analogue, maceutically acceptable salts thereof. a nitric oxide enhancing embusartan, a nitric oxide enhancing 4. The compound of claim 1, wherein the compound of enoltaSosartan, a nitric oxide enhancing fonsartan, a nitric Formula (I) is a nitric oxide enhancing abitesartan of Formula oxide enhancing forasartan, a nitric oxide enhancing glycyl (IX), a nitric oxide enhancing candesartan cilexetil of For losartan, a nitric oxide enhancing irbesartan, a nitric oxide mula (X), a nitric oxide enhancing elisartan analogue of For enhancing losartan, a nitric oxide enhancing olmesartan, a mula (XI), a nitric oxide enhancing embusartan of Formula nitric oxide enhancing milfasartan, a nitric oxide enhancing (XII), a nitric oxide enhancing enoltaSosartan of Formula pomisartan, a nitric oxide enhancing ripisartan, a nitric oxide (XIII), a nitric oxide enhancing fonsartan of Formula (XIV), enhancing tasosartan, a nitric oxide enhancing telmisartan, a a nitric oxide enhancing forasartan of Formula (XV), a nitric nitric oxide enhancing Valsartan, a nitric oxide enhancing oxide enhancing glycyllosartan of Formula (XVI), a nitric CL-329167, a nitric oxide enhancing analogue related to oxide enhancing irbesartan of Formula (XVII), a nitric oxide EMD 66684, a nitric oxide enhancing EXP 3134, a nitric enhancing losartan of Formula (XVIII), a nitric oxide enhanc oxide enhancing MK 996, a nitric oxide enhancing ing olmesartan metabolite of Formula (XIX), a nitric oxide SR-47436, a nitric oxide enhancingYM358, or a nitric oxide enhancing milfasartan of Formula (XX), a nitric oxide enhancing any of the following compounds of ACS registry enhancing pomisartan of Formula (XXI), a nitric oxide number 124750-92-1, 133240-46-7, 135070-05-2, 139958 enhancing ripisartan of Formula (XXII), a nitric oxide 16-0, 145160-84-5, 147403-03-0, 153806-29-2, 439904-54 enhancing tasosartan of Formula (XXIII), a nitric oxide 8P 439904-55-9P 439904-56-OP 439904-57-1P 439904 enhancing telmisartan of Formula (XXIV), a nitric oxide 58-2P 155918-60-8P 155918-61-9P, 272438-16-1P enhancing Valsartan of Formula (XXV); a nitric oxide 272446-75-0P, 223926-77-OP. 169281-89-4, 439904-65-1P enhancing EMD 66684 of Formula (XXVI); a nitric oxide 165113-01-9P, 165113-02-0P, 165113-03-1P, 165113-03-2P enhancing EXP 3134 of Formula (XXVII); a nitric oxide 165113-05-3P, 165113-06-4P 165113-07-5P, 165113-08-6P. enhancing MK-996 of Formula (XXVII); the compound of US 2009/0012057 A1 Jan. 8, 2009 52

Formula (II) is a nitric oxide enhancing of eprosartan of and the compound of Formula (XIII) is: Formula (XXIX); and the compound of Formula (II) is a nitric oxide enhancing analogue related to saprisartan of Formula (XXX), a nitric oxide enhancing Zolasartan of Formula (XIII) (XXXI), or a pharmaceutically acceptable salt thereof, NN wherein the compound of Formula (IX) is: Rn * R a 1- 2 \ Y / NS Rim (IX) CH H3C } ("ON C

CH

and the compound of Formula (XIV) is:

and the compound of Formula (X) is: (XIV) O (X) Rin-Rn ls Pr NN N N1 nBu O O N R. . . KS OEt YR1 2 1. CH2 Nié Rm Rn N N% N1

HC-S O T-Rn T Rn

and the compound of Formula (XV) is:

(XI) (XV) NN R. NR1. Na. nBu N'S -CH2 N N= 2 N nBu

and the compound of Formula (XVI) is:

(XVI) Rn O VRim-NH ls /NN \ nBu CH, N 2N 1. -CH2

CSOC CH-O V Rn US 2009/0012057 A1 Jan. 8, 2009

and the compound of Formula (XVII) is: and the compound of Formula (XXI) is:

(XVII) (XXI)

T-Rn

(XVIII)

(XXII) NN Pr Rn \ N nRNa CH C CH-O N \, Rn-R? Y O

and the compound of Formula (XXIII) is: (XIX)

l P Rn (XXIII) 1. a 1 2 CH HC N% N1 2 N21 ty) O O ls NN HC N O / \ HC "a Na

and the compound of Formula (XX) is:

and the compound of Formula (XXIV) is:

(XXIV) US 2009/0012057 A1 Jan. 8, 2009 54

and the compound of Formula (XXV) is: and the compound of Formula (XXIX) is:

(XXV) (XXIX) NN

O R. . . W \

CH nBu ul-in-CN1 2 Rn-T S S-NW > N nBu Rn n T iPr O H O T-Rn

and the compound of Formula (XXVI) is: O

(XXVI) and the compound of Formula (XXX) is: O 21 N nBu NN Rn N I \ (XXX) NT Rn. R1 2 N O O CH2 Rn F c– Rim-Rn O NH-Rn O

CH and the compound of Formula (XXVII) is: a N 1. 2 O O/ O NF ( Br Et (XXVII) NN

illB R. Y. . 1. R1 2 and the compound of Formula (XXXI) is: CH N 2 N1 2

o (XXXI) T-Rn C NN / V O Rina-N-NaN and the compound of Formula (XXVIII) is: O O C a N1 CH2 O / (XXVIII) NF Br CH3 nBu

wherein T is oxygen, sulfur or NR; Et is the lower alkyl group CH-CH : nBu is the lower alkyl group CH-CH CH2—CH2—, nPr is the lower alkyl group CH, CH, CH : iPr is the lower alkyl group (CH) CH : OEt is the alkoxy group —OCH CH: R is a hydrogen, a lower alkyl group, an aryl group; US 2009/0012057 A1 Jan. 8, 2009 55

wherein R-R, taken together are a hydrogen atom; or -continued

(8)

(viii) —N C(O)—CH2—, (ix) —N C(O)—O—: (X) a covalent bond; (9) (xii) —(C-(R)( R is: a hydrogen or:

(1)

(10)

(2)

(11)

(3)

(12)

(4)

(13) (5)

(6) (14)

(7)

(15) US 2009/0012057 A1 Jan. 8, 2009 56

Formula (XLII), a nitric oxide enhancing milfasartan of For -continued mula (XLIII), a nitric oxide enhancing pomisartan of Formula (16) (XLIV), a nitric oxide enhancing ripisartan of Formula (XLV), a nitric oxide enhancing tasosartan of Formula (XLVI), a nitric oxide enhancing telmisartan of Formula (XLVII), a nitric oxide enhancing Valsartan of Formula (XLVIII); a nitric oxide enhancing analogue related to EMD 66684 of Formula (XLIX); a nitric oxide enhancing EXP 3134 of Formula (L); a nitric oxide enhancing MK-996 of N - o1 \ Formula (LI); the compound of Formula (II) is a nitric oxide (17) enhancing eprosartan of Formula (LII); and compound of Formula (III) is a nitric oxide enhancing analogue related to O Saprisartan of Formula (LIII), a nitric oxide enhancing Zola Sartan of Formula (LIV), or a pharmaceutically acceptable T salt thereof, -- ls N wherein the compound of Formula (XXXII) is: 2 jR (XXXII) O > N-R-T-Rs (18) NN O nBu / \ O O R45 N HNNeN N - n Nf \ and the compound of Formula (XXXIIII) is: Yo N-R-T-Rs or (19) (XXXIII) NN N in \ * - 2 N-CHX-OE, Ra is —CHR-7, —CN. —S(O). CHR-7, —C(O)— N(R)(R), —NO. —C(O)—ORs or —S(O) Rs: Rs is an aryl group, a lower alkyl group, a haloalkyl group, O R45 a hydroxyalkyl group or an arylalkyl group; and the compound of Formula (XXXIV) is: Reis —C(O)— or —S(O) ; Rs7 is a hydrogen, —CN. —S(O) Rs. —C(O)—N(R) (XXXIV) (R), NO, or —C(O)—ORs: NN T is oxygen, sulfur or NR; / \ R is a hydrogen, a lower alkyl group, or an aryl group; R, and R are independently selected from an alkyl group, 1. HN 2 N an aryl group, or R, and R taken together with the nitro gen atom to which they are attached are a heterocylic ring; and % - C with the proviso that the compounds of Formula (IX) to Formula (XXXI) must contain at least one nitric oxide 2.O R4s enhancing group linked to the compound through an oxygenatom, a nitrogenatom or a Sulfur atom via a bond or moiety that can be hydrolyzed. and the compound of Formula (XXXV) is: 5. The compound of claim 1, wherein the Formula (I) is a nitric oxide enhancing abitesartan of Formula (XXXII), a (XXXV) nitric oxide enhancing candesartan cilexetil of Formula (XXXIII), a nitric oxide enhancing elisartan analogue of For O 7 mula (XXXIV), a nitric oxide enhancing embusartan of For HN N mula (XXXV), a nitric oxide enhancing enoltaSosartan of 2 Formula (XXXVI), a nitric oxide enhancing fonsartan of CH Formula (XXXVII), a nitric oxide enhancing forasartan of R45 Formula (XXXVIII), a nitric oxide enhancing glycylosartan nBu of Formula (XXXIX), a nitric oxide enhancing irbesartan of F Formula (XL), a nitric oxide enhancing losartan of Formula O (XLI), a nitric oxide enhancing olmesartan metabolite of US 2009/0012057 A1 Jan. 8, 2009 57

and the compound of Formula (XXXVI) is: and the compound of Formula (XL) is:

(XXXVI) (XL) NN NN / \ O 1 \ O R46 NNeN R46 / HNNeN Yo NS CH2

HC / \ N

CH3

and the compound of Formula (XXVII) is: (XLI) C N NN (XXXVII) W \ in \ O R4 No nBn 2 s NH-nPr V 1. Oseo N 2 N-CH O O HC-S and the compound of Formula (XLII) is: O R45

(XLII) and the compound of Formula (XXXVIII) is: NN Pr / \

(XXXVIII) N 2 N "NY NN / \ HC o R46 N.NeN nBu N Hdi OH SOCO R45 n YN- CH2 N

b- N 2 and the compound of Formula (XLIII) is: nBu

and the compound of Formula (XXXIX) is: (XLIII) NEN (XXXIX) O in \ O 2 NN nBu H2NN / \ S CH2 CH2

Sa H3C N nBn O US 2009/0012057 A1 Jan. 8, 2009

and the compound of Formula (XLIV) is: and the compound of Formula (XLVIII) is:

(XLIV) (XLVIII) NN O / \ O ls HNNeN O R45 . N YCH, nBn iPr

and the compound of Formula (XLV) is: and the compound of Formula (LIX) is:

(XLV) (LIX) NN Pr f V NN N HN 2 N / \ O 21 \ HN 2 N

HC-(N \ CH2 ls N X-Bu f \ R45 CH1 N-CH '-- O O and the compound of Formula (L) is: and the compound of Formula (XLVI) is:

(XLVI) (L) CH C

21 NN N t \ HC usulN N O Q V

and the compound of Formula (XLVII) is: and the compound of Formula (LI) is:

(XLVII) (LI) CH H3C CH3 21 N R4 | Sa X-Fi O S1R N N2 > nPr O R45 N N O2 HC O O CH O US 2009/0012057 A1 Jan. 8, 2009 59

and the compound of Formula (LII) is: -continued (2) / \ (LII) 1N1 O (R4s S N ? N 1N1 R45, 1S ( ) O YO (3) N nBu O O HC NO Nt R45 W WN N- o1 O (4)

and the compound of Formula (LIII) is: N-N 9 or

(LIII) N -ko1 \ R65 O (5) F3CN -OH: O R45 inYNH O O Ras is —S(O). CHs: —CN, —C(O) NH or —C(O) 2 OCH and Yeh, / Rao is a hydrogen or chlorine; \= Ros is a hydrogen or a methyl group; Rao is: Et Br (1) and the compound of Formula (LIV) is: O V O S (LIV) x- y ( VO NN N- N. O R4 HN 2 N O O 5 V

YCH, O O N (3) nBn Br O O O \, M wherein: W \ \, Et is the lower alkyl group CH, CH : R66 NS-NN nBu is the lower alkyl group CH-CH CH-CH -: O O 4 nPr is the lower alkyl group CH, CH, CH : O O (4) iPr is the lower alkyl group (CH) CH-: O \, OEt is the alkoxy group —OCH CH: y \ V R is: R66 d \ O o1 NY (1) O (5) y1n-1 "y { R4s " . R67 US 2009/0012057 A1 Jan. 8, 2009 60

-continued -continued (6) (13) O

( \, O O N-N R49 o1 N/ N ( o1\ .65 (7) O R67 wherein: ? \ Reis —(CH), O—C(O)—CH or —(CH). NH-C No1 No. (O)—CH: R, is —CN, —C(O) NH or —C(O)—OCH: Rao and Res are as defined herein; and (8) with the proviso that the compounds of Formula (XXXII) O to (LIV) must contain at least one nitric oxide enhancing group linked to the compound through an oxygen atom, R67 a nitrogenatom or a Sulfur atom via a bond or moiety that can be hydrolyzed. ( \, 6. A method for treating a cardiovascular disease in a o1 NY patient in need thereof comprising administering to the (9) patient an effective amount of the composition of claim 2. 7. The method of claim 6, wherein the cardiovascular dis ease is heart failure, restenosis, hypertension, diastolic dys r function, a coronary artery disease, myocardial infarction, O N-1 Nu cerebral infarction, atherosclerosis, atherogenesis, cere ( \, brovascular disease, angina, aneurysm, ischemic heart dis N O1 ease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, Smooth muscle cell proliferation, a vascular or non-vascular complications asso (10) ciated with the use of a medical device, a wound associated with the use of a medical device, vascular or non-vascular r wall damage, peripheral vascular disease, neointimal hyper O N-1 N plasia following percutaneous transluminal coronary angio ( \, graph, vascular grafting, coronary artery bypass Surgery, a N O1 thromboembolic events, post-angioplasty restenosis, coro nary plaque inflammation, hypercholesterolemia, embolism, O stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and reclusion cerebrovascular inci dents, left ventricular dysfunction and hypertrophy, (11) 8. The method of claim 7, wherein the cardiovascular dis ease is hypertension, heart failure and/or diastolic dysfunc tion. 9. A method for treating a renovascular disease in a patient O N-N R49 in need thereof comprising administering to the patient an f \ R effective amount of the composition of claim 2. N O1. 65 10. The method of claim 9, wherein the renovascular dis ease is renal failure, renal insufficiency, renal deterioration associated with severe hypertension or renovascular hyper tension. 11. A method for treating diabetes; treating diseases result (12) ing from oxidative stress; treating endothelial dysfunctions; treating a disease caused by endothelial dysfunctions; treat ing cirrhosis; treating pre-eclampsia; treating osteoporosis: treating nephropathy; treating a peripheral vascular disease; O Nt R49 treating portal hypertension; treating an ophthalmic disorder; treating metabolic syndrome; or treating hyperlipidemia in a N ( o1\, . 5 patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2. O 12. The composition of claim 2, further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide US 2009/0012057 A1 Jan. 8, 2009

enhancing compound; or (iii) at least one therapeutic agent imine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitro and at least one nitric oxide enhancing compound. samine, a nitrosimine, a diazetine dioxide, an oXatriazole 13. The composition of claim 12, wherein the therapeutic 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, agent is an aldosterone antagonist, an O-adrenergic receptor a hydroxyurea, a furoxan or a nitroxide. agonist, an O-adrenergic receptor antagonist, an angiotensin 17. The method of claims 6, 9 or 11, further comprising II antagonist, an angiotensin-converting enzyme inhibitor, an administering (i) at least one therapeutic agent; (ii) at least antidiabetic compound, an anti-hyperlipidemic compound, one nitric oxide enhancing compound (iii) at least one thera an antimicrobial compound, an antioxidant, an antithrom peutic agent and at least one nitric oxide enhancing com botic and vasodilator compound, a B-adrenergic antagonist, a pound. calcium channel blocker, a carbonic anhydrase inhibitor, a 18. The method of claim 17, wherein the therapeutic agent digitali, a diuretic, an endothelin antagonist, a hydralazine is an aldosterone antagonist, an O-adrenergic receptor ago compound, a H2 receptor antagonist, an neutral endopepti nist, an O-adrenergic receptor antagonist, an angiotensin II dase inhibitor, a nonsteroidal antiinflammatory compound, a antagonist, an angiotensin-converting enzyme inhibitor, an phosphodiesterase inhibitor, a potassium channel blocker, a antidiabetic compound, an anti-hyperlipidemic compound, platelet reducing agent, a prostaglandin, a proton pump an antimicrobial compound, an antioxidant, an antithrom inhibitor, a renin inhibitor, a selective cyclooxygenase-2 botic and vasodilator compound, a B-adrenergic antagonist, a inhibitor, a steroid, or a combination of two or more thereof. calcium channel blocker, a carbonic anhydrase inhibitor, a 14. The composition of claim 13, wherein the therapeutic digitali, a diuretic, an endothelin antagonist, a hydralazine agent is at least one compound selected from the group con compound, a H2 receptor antagonist, an neutral endopepti sisting of analdosterone antagonist, an angiotensin II antago dase inhibitor, a nonsteroidal antiinflammatory compound, a nist, an angiotensin-converting enzyme (ACE) inhibitor, a phosphodiesterase inhibitor, a potassium channel blocker, a B-adrenergic antagonist, a calcium channel blocker, a platelet reducing agent, a prostaglandin, a proton pump diuretic, a hydralazine compound and a renin inhibitor. inhibitor, a renin inhibitor, a selective cyclooxygenase-2 15. The composition of claim 14, wherein the aldosterone inhibitor, a steroid, or a combination of two or more thereof. antagonist is eplerenone or spironolactone; the angiotensin II 19. The method of claim 17, wherein the nitric oxide donor antagonist is candesartan, candesartan cilexetil, eprosartan compound is selected from the group consisting of a S-nitro mesylate, irbesartan, losartan potassium, medoxomil, telmis Sothiol, a nitrite, a nitrate, a S-nitrothiol, a Sydnonimine, a artan, trandolapril, trandolaprilat or Valsartan; the angio NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a tensin-converting enzyme inhibitor is benazepril hydrochlo nitrosimine, a diazetine dioxide, an oXatriazole 5-imine, an ride, captopril, enalapril maleate, fosinopril Sodium, Oxime, a hydroxylamine, a N-hydroxyguanidine, a hydrox lisinopril, moexipril hydrochloride, quinapril hydrochloride, yurea, a furoxan or a nitroxide. ramipril; the C.-adrenergic antagonist is bisoprolol fumarate, 20. A kit comprising at least one compound of claim 1. carvedilol, metoprolol tartrate, propranolol hydrochloride or 21. The kit of claim 20, further comprising further com timolol maleate; the calcium channel blockers is amlodipine, prising (i) at least one therapeutic agent; (ii) at least one nitric diltiazem, isradipine, nicardipine, nifedipine, nimodipine, oxide enhancing compound; or (iii) at least one therapeutic nisoldipine, nitrendipine, Verapamil; the diuretic is amiloride agent and at least one nitric oxide enhancing compound. hydrochloride, chlorthalidone, hydrochlorothiazide or triam 22. The kit of claim 21, wherein the (i) at least one thera terene; the hydralazine compound is hydralazine hydrochlo peutic agent; (ii) at least one nitric oxide enhancing com ride; and the renin inhibitor is aliskiren, ciprokiren, ditekiren, pound; or (iii) at least one therapeutic agent and at least one enalkrein, medullipin, remikiren, terlkiren, tonin or Zankiren. nitric oxide enhancing compound are in the form of separate 16. The composition of claim 12, wherein the nitric oxide components in the kit. enhancing compound is selected from the group consisting of a S-nitrosothiol, a nitrite, a nitrate, a S-nitrothiol, a Sydnon c c c c c