US 20080293702Al (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2008/0293702 A1 Garvey (43) Pub. Date: NOV. 27, 2008

(54) NITRIC OXIDE ENHANCING PYRUVATE A61K 31/4245 (2006.01) COMPOUNDS, COMPOSITIONS AND A61K 31/42 (2006.01) METHODS OF USE C07D 273/00 (2006.01) C07D 413/04 (2006.01) (75) Inventor: David S. Garvey, Dover, MA (U S) A61 K 31/53 77 (200601) A61P 9/00 (2006.01) Correspondence Address: A 61p 9/06 (200601) WILMERHALE/NITROMED A 611) 9/10 (200601) 1875 PENNSYLVANIA AVE, NW A611) 9/12 (200601) WASHINGTON, DC 20006 (US) _ _ (52) US. Cl...... 514/222.5; 548/125; 514/364; (73) Assrgnee: NITROMED, INC., Lexington, 514/361; 544/138; 514/2362 MA (U S) (21) Appl. N0.: 12/096,867 (57) ABSTRACT (22) PCT F 11 e d: D e c_ 19, 2006 The invention provides novel compositions and kits compris ing at least one nitric oxide enhancing pyruvate compound, or (86) PCT NO; PCT M52006 /0 4819 4 a pharmaceutically acceptable salt thereof, and, optionally, at least one nitric oxide enhancing compound and/ or at least one § 371 (OX1), therapeutic agent. The invention also provides methods for (2)’ (4) Date; Jun_ 10, 2008 (a) treating cardiovascular diseases; (b) treating renovascular diseases; (0) treating diabetes; (d) treating diseases resulting Related US. Application Data from oxidative stress; (e) treating endothelial dysfunctions; (f) treating diseases caused by endothelial dysfunctions; (g) (60) Provisional application No. 60/753,971, ?led on Dec. treating cirrhosis; (h) treating pre-eclampsia; (j) treating 22, 2005. osteoporosis; (k) treating nephropathy; (l) treating peripheral vascular diseases; (m) treating portal hypertension (n) treat Publication Classi?cation ing reperfusion injury following ischemia; and/or (m) pre (51) Int. Cl. serving tissues, organs, organ parts and/or limbs. The nitric A61K 31/546 (2006.01) oxide enhancing pyruvate compounds comprise at least one C07D 271/08 (2006.01) nitroxide group. US 2008/0293702 A1 Nov. 27, 2008

NITRIC OXIDE ENHANCING PYRUVATE tuted With at least one heterocyclic nitric oxide donor group COMPOUNDS, COMPOSITIONS AND and/or at least one nitroxide group and pharmaceutically METHODS OF USE acceptable salts thereof. The pyruvate compound can be sub stituted With the heterocyclic nitric oxide donor group and/ or RELATED APPLICATIONS the nitroxide group through one or more sites such as oxygen [0001] This application claims priority under 35 USC § 1 19 (hydroxyl condensation), sulfur (sulfhydryl condensation) to US. Application No. 60/753,971 ?led Dec. 22, 2005; the and/or nitrogen via a bond or moiety that can be hydrolyZed. disclosure of Which is incorporated by reference herein in its The heterocyclic nitric oxide donors are furoxans, sydnon entirety. imines, oxatriaZole-5-ones and/or oxatriaZole-5-imines. The invention also provides compositions comprising the novel FIELD OF THE INVENTION compounds described herein in a pharmaceutically accept [0002] The invention provides novel compositions and kits able carrier. comprising at least one nitric oxide enhancing pyruvate com [0006] The invention is also based on the discovery that pound, or a pharmaceutically acceptable salt thereof, and, administering at least one pyruvate compound, comprising at optionally, at least one nitric oxide enhancing compound least one nitric oxide enhancing group (i.e. heterocyclic nitric and/ or at least one therapeutic agent. The invention also pro oxide donor group and/ or nitroxide group), and, optionally, at vides methods for (a) treating cardiovascular diseases; (b) least one nitric oxide enhancing compound can be used for the treating renovascular diseases; (c) treating diabetes; (d) treat targeted delivery of the compounds to organs, cells or tissues ing diseases resulting from oxidative stress; (e) treating containing the enZyme gamma-glutamyl transpeptidase and endothelial dysfunctions; (f) treating diseases caused by for the delivery of nitric oxide at the targeted site. Nitric oxide endothelial dysfunctions; (g) treating cirrhosis; (h) treating enhancing compounds include, for example, S-nitrosothiols, pre-eclampsia; (j) treating osteoporosis; (k) treating nephr nitrates, nitrates, N-oxo-N-nitrosamines, furoxans, sydnon opathy; (l) treating peripheral vascular diseases; (m) treating imines, SPM 3672, SPM 4757, SPM 5185, SPM 5186 and portal hypertension; (n) treating reperfusion injury folloWing analogues thereof, substrates of the various isoZymes of nitric ischemia; and/or (m) preserving tissues, organs, organ parts oxide synthase, and nitroxides. Thus, another embodiment of and/or limbs. The nitric oxide enhancing pyruvate com the invention provides compositions comprising at least one pounds comprise at least one heterocyclic nitric oxide donor nitric oxide enhancing pyruvate compound and at least one group and/or at least one nitroxide group. nitric oxide enhancing compound. The invention also pro vides for such compositions in a pharmaceutically acceptable BACKGROUND OF THE INVENTION carrier. [0003] Normal metabolic processes in vascular cells are [0007] The invention provides compositions comprising at associated With the generation of reactive oxygen intermedi least one nitric oxide enhancing pyruvate compound, and, ates that must be neutraliZed in order to limit oxidative dam optionally, at least one nitric oxide enhancing compound age and cellular dysfunction. In the setting of common dis and/or at least one therapeutic agent, including, but not lim orders or in the presence of common risk factors for numerous ited to, aldosterone antagonists, alpha-adrenergic receptor diseases reactive oxygen species (ROS) are generated in antagonists, angiotensin II antagonists, angiotensin-convert abundance and their rate of synthesis and ?ux typically ing enZyme (ACE) inhibitors, antidiabetic compounds, anti exceeds the capacity of endogenous antioxidant mechanisms. hyperlipidemic compounds, antioxidants, antithrombotic and For example, hypercholesterolemia, hyperglycemia (Keaney vasodilator compounds, [3-adrenergic antagonists, calcium et al, Circulation, 99:189-191 (1999)), cigarette smoking, channel blockers, digitalis, diuretics, endothelin antagonists, hyperhomocysteinemia, hypertension, and atherosclerosis hydralaZine compounds, H2 receptor antagonists, neutral are all accompanied by an increase in plasma and tissue ROS endopeptidase inhibitors, nonsteroidal antiin?ammatory generation. Superoxide anion, hydrogen peroxide, hydroxyl compounds (NSAIDs), phosphodiesterase inhibitors, potas radical, peroxynitrite, and lipid peroxides all increase in dis sium channel blockers, platelet reducing agents, proton pump eases resulting from oxidative stress. inhibitors, renin inhibitors, selective cyclooxygenase-2 [0004] It is believed that oxidative damage is mediated by (COX-2) inhibitors, and combinations of tWo or more thereof. intracellular redox-active metal reactions catalyZed by highly In one embodiment the at least one therapeutic agent is reactive oxygen species (i.e. hydroxyl radicals). The genera selected from the group consisting of an aldosterone antago tion of such reactive oxygen species depends on the availabil nist, an angiotensin II antagonist, an angiotensin-converting ity of their common precursor, the superoxide anion. Mito enZyme (ACE) inhibitors, a [3-adrenergic antagonist, a cal chondria, microsomes and other various enZyme systems are cium channel blocker, a diuretic, a hydralaZine compound knoWn to produce superoxide anion that reacts With nitric and a renin inhibitor. The invention also provides for such oxide at or near diffusion controlled rates to form the poWer compositions in a pharmaceutically acceptable carrier. ful oxidant peroxynitrite. At pH 7.4, peroxynitrite protonates [0008] Another embodiment of the invention provides to form peroxynitrous acid (pKa 6.6) Which decays homolyti compositions comprising at least one at least one nitric oxide cally to form hydroxyl and nitrogen dioxide radicals in addi enhancing pyruvate compound, and at least one therapeutic tion to a host of other ions. The extent to Which these later agent is selected from the group consisting of an aldosterone reactive ions and radicals can cause cellular damage and antagonist, an angiotensin II antagonist, an angiotensin-con death depends on the rate of formation of their peroxynitrite verting enZyme (ACE) inhibitor, a [3-adrenergic antagonist, a precursor. calcium channel blocker, a diuretic, a hydralaZine compound and a renin inhibitor. The invention also provides for such SUMMARY OF THE INVENTION compositions in a pharmaceutically acceptable carrier. [0005] The invention provides novel nitric oxide enhancing [0009] The invention provides methods for (a) treating car pyruvate compounds and derivatives thereof that are substi diovascular diseases; (b) treating renovascular diseases; (c) US 2008/0293702 A1 Nov. 27, 2008

treating diabetes; (d) treating diseases resulting from oxida [0011] These and other aspects of the invention are tive stress; (e) treating endothelial dysfunctions; (f) treating described in detail herein. diseases caused by endothelial dysfunctions; (g) treating cir rhosis; (h) treating pre-eclampsia; (j) treating osteoporosis; DETAILED DESCRIPTION OF THE INVENTION (k) treating nephropathy; (l) treating peripheral vascular dis [0012] As used throughout the disclosure, the folloWing eases; (m) treating portal hypertension; (n) treating reperfu temms, unless otherWise indicated, shall be understood to sion injury folloWing ischemia; and/or (m) preserving tissues, have the folloWing meanings. organs, organ parts and/or limbs in a patient in need thereof [0013] “Pyruvate compound” refers to and includes deriva comprising administering to the patient an effective amount tives of pyruvic acid such as for example oximes, amides, of at least one nitric oxide enhancing pyruvate compound, pyruvate analogues, modi?ed pyruvate analogues, pyruvate and, optionally, at least one therapeutic agent, such as, for esters (for example polyol-pyruvate esters, pyruvate example, aldosterone antagonists, alpha-adrenergic receptor thioesters, glycerol-pyruvate esters, dihydroxyacetone pyru antagonists, angiotensin II antagonists, angiotensin-convert vate esters, and the like), pyruvyl-amino acids (for example ing enzyme (ACE) inhibitors, antidiabetic compounds, anti pyruvyl-glycine, pyruvyl-glutamic, pyruvyl-alanine, pyru hyperlipidemic compounds, antioxidants, antithrombotic and vyl-leucine, pyruvyl-valine, pyruvyl-isoleucine, pyruvyl vasodilator compounds, [3-adrenergic antagonists, calcium phenylalanine, pyruvyl-cysteine, pyruvyl-proline, pyruvyl channel blockers, digitalis, diuretics, endothelin antagonists, sarcosine, and their amides and esters the like); pyruvate di-, hydralaZine compounds, H2 receptor antagonists, neutral tri- or tetra peptides (such as for example glutamine-cysteine endopeptidase inhibitors, nonsteroidal antiin?ammatory pyruvate, glutamine-cysteine-glycine-pyruvate and the like). compounds (N SAIDs), phosphodiesterase inhibitors, potas [0014] “Cardiovascular disease or disorder” refers to any cardiovascular disease or disorder knoWn in the art, includ sium channel blockers, platelet reducing agents, proton pump ing, but not limited to, congestive heart failure, restenosis, inhibitors, renin inhibitors, selective cyclooxygenase-2 hypertension (e.g. pulmonary hypertension, systolic hyper (COX-2) inhibitors, and combinations of tWo or more thereof. tension, labile hypertension, idiopathic hypertension, loW The methods can optionally further comprise the administra renin hypertension, salt-sensitive hypertension, loW-renin, tion of at least one nitric oxide enhancing compound. In this salt-sensitive hypertension, thromboembolic pulmonary embodiment of the invention, the methods can involve (i) hypertension; pregnancy-induced hypertension; renovascu administering the nitric oxide enhancing pyruvate com lar hypertension; hypertension-dependent end-stage renal pounds, (ii) administering the nitric oxide enhancing pyru disease, hypertension associated With cardiovascular surgical vate compounds, and nitric oxide enhancing compounds, (iii) procedures, hypertension With left ventricular hypertrophy, administering the nitric oxide enhancing pyruvate com and the like), diastolic dysfunction, coronary artery disease, pounds and therapeutic agents, or (iv) administering the nitric myocardial infarctions, cerebral infarctions, arterial stiffness, oxide enhancing pyruvate compounds, nitric oxide enhancing atherosclerosis, atherogenesis, cerebrovascular disease, compounds, and therapeutic agents. In one embodiment the at angina, (including chronic, stable, unstable and variant (Prin least one therapeutic agent is selected from the group consist Zmetal) angina pectoris), aneurysm, ischemic heart disease, ing of an aldosterone antagonist, an angiotensin II antagonist, cerebral ischemia, myocardial ischemia, thrombosis, platelet an angiotensin-converting enzyme (ACE) inhibitor, a [3-adr aggregation, platelet adhesion, smooth muscle cell prolifera energic antagonist, a diuretic, and a hydralaZine compound. tion, vascular or non-vascular complications associated With The nitric oxide enhancing pyruvate compounds, nitric oxide the use of medical devices, Wounds associated With the use of enhancing compounds, and/or therapeutic agents can be medical devices, vascular or non-vascular Wall damage, administered separately or as components of the same com peripheral vascular disease, neointimal hyperplasia folloWing percutaneous transluminal coronary angiograph, vascular position in one or more pharmaceutically acceptable carriers. grafting, coronary artery bypass surgery, thromboembolic [0010] Another embodiment of the invention provides kits events, post-angioplasty restenosis, coronary plaque in?am comprising at least one nitric oxide enhancing pyruvate com mation, hypercholesterolemia, embolism, stroke, shock, pound, and, optionally, at least one nitric oxide enhancing arrhythmia, atrial ?brillation or atrial ?utter, thrombotic compound. The kit can further comprise at least one thera occlusion and reclusion cerebrovascular incidents, left ven peutic agent, such as, for example, aldosterone antagonists, tricular dysfunction and hypertrophy, and the like. alpha-adrenergic receptor antagonists, angiotensin II antago [0015] “Heart failure” includes, but is not limited to con nists, angiotensin-converting enZyme (ACE) inhibitors, gestive heart failure, compensated heart failure, decompen antidiabetic compounds, anti-hyperlipidemic compounds, sated heart failure, and the like. antioxidants, antithrombotic and vasodilator compounds, [0016] “Thromboembolic events” include, but are not lim [3-adrenergic antagonists, calcium channel blockers, digitalis, ited to, ischemic stroke, transient ischemic stroke, myocardial diuretics, endothelin antagonists, hydralaZine compounds, infarction, angina pectoris, thrombosis (for example, resteno H2 receptor antagonists, neutral endopeptidase inhibitors, sis, arterial thrombosis, coronary thrombosis, heart valve nonsteroidal antiin?ammatory compounds (N SAIDs), phos thrombosis, coronary stenosis, stent thrombosis, graft throm phodiesterase inhibitors, potassium channel blockers, plate bosis, and ?rst and subsequent thrombotic stroke, and the let reducing agents, proton pump inhibitors, renin inhibitors, like), thromboembolism (for example, pulmonary throm selective cyclooxygenase-2 (COX-2) inhibitors, and combi boembolism, cerebral thromboembolism, and the like), nations of tWo or more thereof. The nitric oxide enhancing thrombophlebitis, thrombocytopenia, bleeding disorders, pyruvate compound, the nitric oxide enhancing compound thrombotic occlusion and reocclusion and acute vascular and/ or therapeutic agent, can be separate components in the events. Patients Who are at risk of developing thromboembo kit or can be in the form of a composition in one or more lic events, may include those With a familial history of, or pharmaceutically acceptable carriers. genetically predisposed to, thromboembolic disorders, Who US 2008/0293702 A1 Nov. 27, 2008

have had ischemic stroke, transient ischemic stroke, myocar angiotensin II antagonists, angiotensin-converting enZyme dial infarction, and those With unstable angina pectoris or (ACE) inhibitors, antidiabetic compounds, anti-hyperlipi chronic stable angina pectoris and patients With altered pros demic compounds, antioxidants, antithrombotic and vasodi tacyclin/thromboxane A2 homeostasis or higher than normal lator compounds, P-adrenergic antagonists, calcium channel thromboxane A2 levels leading to increase risk for throm blockers, digitalis, diuretics, endothelin antagonists, hydrala boembolism, including patients With diabetes and rheuma Zine compounds, H2 receptor antagonists, neutral endopepti toid arthritis. dase inhibitors, nonsteroidal antiin?ammatory compounds [0017] “Diseases resulting from oxidative stress” refers to (N SAlDs), phosphodiesterase inhibitors, potassium channel any disease that involves the generation of free radicals or blockers, platelet reducing agents, proton pump inhibitors, radical compounds, such as, for example, atherogenesis, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibi atheromatosis, arteriosclerosis, atherosclerosis, vascular tors, and the like. Therapeutic agent includes the pharmaceu hypertrophy associated With hypertension, hyperlipopro tically acceptable salts thereof, pro-drugs, and pharmaceuti teinemia, normal vascular degeneration through aging, par cal derivatives thereof including, but not limited to, the athyioidal reactive hyperplasia, renal disease (e.g., acute or corresponding nitrosated and/or nitrosylated and/ or hetero chronic), neoplastic diseases, in?ammatory diseases, neuro cyclic nitric oxide donor derivatives and/or nitroxide deriva logical and acute bronchopulmonary disease, tumorigenesis, tive. Although nitric oxide enhancing compounds have thera ischemia-reperfusion syndrome, arthritis, sepsis, cognitive peutic activity, the term “therapeutic agent” does not include dysfunction, endotoxic shock, endotoxin-induced organ fail the nitric oxide enhancing compounds described herein, since ure, and the like. nitric oxide enhancing compounds are separately de?ned. [0018] “Renovascular diseases” refers to any disease or [0023] “Prodrug” refers to a compound that is made more dysfunction of the renal system including, but not limited to, active in vivo. renal failure (e. g., acute or chronic), renal insu?iciency, neph [0024] “Antioxidant” refers to and includes any compound rotic edema, acute glomerulonephritis, oliguric renal failure, that can react and quench a free radical. renal deterioration associated With severe hypertension, uni lateral perechymal renal disease, polycystic kidney disease, [0025] “Angiotensin converting enZyme (ACE) inhibitor” chronic pyelonephritis, renal diseases associated With renal refers to compounds that inhibit an enZyme Which catalyZes insuf?ciency, complications associated With dialysis or renal the conversion of angiotensin I to angiotensin II. ACE inhibi transplantation, renovascular hypertension, nephropathy, tors include, but are not limited to, amino acids and deriva glomerulonephritis, scleroder'ma, glomerular sclerosis, renal tives thereof, peptides, including di- and tri-peptides, and artery stenosis, AIDS-associated nephropathy, immune-me antibodies to ACE Which intervene in the renin-angiotensin diated renal disease, atheroembolic renal disease, pre-renal system by inhibiting the activity of ACE thereby reducing or aZotemia, and the like. eliminating the formation of the pressor substance angio [0019] “Endothelial dysfunction” refers to the impaired tensin H. ability in any physiological processes carried out by the [0026] “Angiotensin II antagonists” refers to compounds endothelium, in particular, production of nitric oxide regard Which interfere With the function, synthesis or catabolism of less of cause. It may be evaluated by, such as, for example, angiotensin II. Angiotensin II antagonists include peptide invasive techniques, such as, for example, coronary artery compounds and non-peptide compounds, including, but not reactivity to acetylcholine or methacholine, and the like, or by limited to, angiotensin II antagonists, angiotensin II receptor noninvasive techniques, such as, for example, blood ?oW antagonists, agents that activate the catabolism of angiotensin measurements, brachial artery ?oW dilation using cuff occlu II, and agents that prevent the synthesis of angiotensin I from sion of the arm above or beloW the elboW, brachial artery angiotensin II. The renin-angiotensin system is involved in ultrasonography, imaging techniques, measurement of circu the regulation of hemodynamics and Water and electrolyte lating biomarkers, such as, asymmetric dimethylarginine balance. Factors that loWer blood volume, renal perfusion (ADMA), and the like. For the latter measurement the endot pressure, or the concentration of sodium in plasma tend to helial-dependent ?oW-mediated dilation Will be loWer in activate the system, While factors that increase these param patients diagnosed With an endothelial dysfunction. eters tend to suppress its function. [0020] “Methods for treating endothelial dysfunction” [0027] “Anti-hyperlipidemic compounds” refers to any include, but are not limited to, treatment prior to the onset/ compound or agent that has the effect of bene?cially modi diagnosis of a disease that is caused by or could result from fying serum cholesterol levels such as, for example, loWering endothelial dysfunction, such as, for example, atherosclero serum loW density lipoprotein (LDL) cholesterol levels, or sis, hypertension, diabetes, heart failure, and the like. inhibiting oxidation of LDL cholesterol, Whereas high den [0021] “Methods for treating diseases caused by endothe sity lipoprotein (HDL) serum cholesterol levels may be loW lial dysfunction” include, but are not limited to, the treatment ered, remain the same, or be increased. Preferably, the anti of any disease resulting from the dysfunction of the endothe hyperlipidemic compound brings the serum levels of LDL lium, such as, for example, arteriosclerosis, congestive heart cholesterol and HDL cholesterol (and, more preferably, trig failure, hypertension, cardiovascular diseases, cerebrovascu lyceride levels) to normal or nearly normal levels. lar diseases, renovascular diseases, mesenteric vascular dis [0028] “Diuretic compound” refers to and includes any eases, pulmonary vascular diseases, ocular vascular diseases, compound or agent that increases the amount of urine peripheral vascular diseases, peripheral ischemic diseases, excreted by a patient. and the like. [0029] “Neutral endopeptidase inhibitors” refers to and [0022] “Therapeutic agent” includes any therapeutic agent includes compounds that are antagonists of the renin angio that can be used to treat or prevent the diseases described tensin aldosterone system including compounds that are dual herein. “Therapeutic agents” include, for example, aldoster inhibitors of neutral endopeptidases and angiotensin convert one antagonists, alpha-adrenergic receptor antagonists, ing (ACE) enZymes. US 2008/0293702 A1 Nov. 27, 2008

[0030] “Renin inhibitors” refers to compounds Which inter [0041] “Sustained release” refers to the release of an active fere With the activity of renin. compound and/or composition such that the blood levels of [0031] “Phosphodiesterase inhibitor” or “PDE inhibitor” the therapeutically active compound are maintained Within a refers to any compound that inhibits the enzyme phosphodi desirable therapeutic range over a period of time. The sus esterase. The term refers to selective or non-selective inhibi tained release formulation can be prepared using any conven tors of cyclic guanosine 3',5'-monophosphate phosphodi tional method knoWn to one skilled in the art to obtain the esterases (cGMP-PDE) and cyclic adenosine 3',5' desired release characteristics. monophosphate phosphodiesterases (cAMP-PDE). [0042] “Nitric oxide enhancing” refers to compounds and [0032] “Platelet reducing agents” refers to compounds that functional groups Which, under physiological conditions can prevent the formation of a blood thrombus via any number of increase endogenous nitric oxide. Nitric oxide enhancing potential mechanisms. Platelet reducing agents include, but compounds include, but are not limited to, nitric oxide releas are not limited to, ?brinolytic agents, anti-coagulant agents ing compounds, nitric oxide donating compounds, nitric and any inhibitors of platelet function. Inhibitors of platelet oxide donors, radical scavenging compounds and/ or reactive function include agents that impair the ability of mature plate oxygen species scavenger compounds. In one embodiment lets to perform their normal physiological roles (i.e., their the radical scavenging compound contains a nitroxide group. normal function, such as, for example, adhesion to cellular [0043] “Nitroxide group” refers to compounds that have and non-cellular entities, aggregation, release of factors such the ability to mimic superoxide dimutase and catalase and act as groWth factors) and the like. as radical scavengers, or react With superoxide or other reac [0033] “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 [0044] “Nitric oxide adduct” or “NO adduct” refers to com inhibiting the H+/K+-ATP ase enzyme system at the secretory pounds and functional groups Which, tinder physiological surface of the gastric parietal cell. conditions, can donate, release and/or directly or indirectly [0034] “NSAID” refers to a nonsteroidal anti-in?amma transfer any of the three redox forms of nitrogen monoxide tory compound or a nonsteroidal anti-in?ammatory 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 [0045] “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-l and -2), and as inhibitors of both cyclooxygenase and indirectly transferring any of the three redox forms of nitro lipoxygenase. gen monoxide (NO+, NOi, NO~), such that the biological [0035] “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-l enzyme. In one [0046] “Nitric oxide donor” or “NO donor” refers to com embodiment, the compound has a cyclooxygenase-2 IC5O of pounds that donate, release and/ or directly or indirectly trans less than about 2 [1M and a cyclooxygenase-l IC5O of greater fer a nitrogen monoxide species, and/or stimulate the endog than about 5 uM, in the human Whole blood COX-2 assay (as enous production of nitric oxide or endothelium-derived described in Brideau et al., In?amm 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-l 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-l IC5O of greater than about 1 [1M, and compounds that are precursors of L-arginine, inhibitors of the preferably of greater than 20 [1M. The compound can also enzyme arginase and nitric oxide mediators. inhibit the enzyme, lipoxygenase. Such selectivity may indi [0047] “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 [0036] “Patient” refers to animals, preferably mammals, oxide donor is capable of donating and/or releasing a nitrogen mo st 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 [0037] “Transdermal” refers to the delivery of a compound oxatriazole-5-ones, oxatriazole-5-imines, sydnonimines, by passage through the skin and into the blood stream. furoxans, and the like. [0038] “Transmucosal” refers to delivery of a compound by [0048] “Alkyl” refers to a loWer alkyl group, a substituted passage of the compound through the mucosal tissue and into loWer alkyl group, a haloalkyl group, a hydroxyalkyl group, the blood stream. an alkenyl group, a substituted alkenyl group, an alkynyl [0039] “Penetration enhancement” or “permeation group, a bridged cycloalkyl group, a cycloalkyl group or a enhancement” refers to an increase in the permeability of the heterocyclic ring, as de?ned herein. An alkyl group may also skin or mucosal tissue to a selected pharmacologically active comprise one or more radical species, such as, for example a compound such that the rate at Which the compound perme cycloalkylalkyl group or a heterocyclicalkyl group. ates through the skin or mucosal tissue is increased. [0049] “LoWer alkyl” refers to branched or straight chain [0040] “Carriers” or “vehicles” refers to carrier materials acyclic alkyl group comprising one to about ten carbon atoms suitable for compound administration and include any such (preferably one to about eight carbon atoms, more preferably material knoWn in the art such as, for example, any liquid, gel, one to about six carbon atoms). Exemplary loWer alkyl groups solvent, liquid diluent, solubilizer, or the like, Which is non include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, toxic and Which does not interact With any components of the sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, composition in a deleterious manner. and the like. US 2008/0293702 A1 Nov. 27, 2008

[0050] “Substituted lower alkyl” refers to a loWer alkyl 10 carbon atoms (preferably about 4 to about 6 carbon atoms) group, as de?ned herein, Wherein one or more of the hydrogen Where 1 to about 4 carbon atoms are replaced by one or more atoms have been replaced With one or more R100 groups, nitrogen, oxygen and/or sulfur atoms. Sulfur maybe in the Wherein each R100 is independently a hydroxy, an ester, an thio, sul?nyl or sulfonyl oxidation state. The heterocyclic ring amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a or group can be fused to an aromatic hydrocarbon group. nitrate, a nitrite, a thionitrate, a thionitrite or an amino group, Heterocyclic groups can be unsubstituted or substituted With as de?ned herein. one, tWo or three substituents independently selected from [0051] “Haloalkyl” refers to a loWer alkyl group, an alkenyl alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, group, an alkynyl group, a bridged cycloalkyl group, a hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkyl cycloalkyl group or a heterocyclic ring, as de?ned herein, to carboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic Which is appended one or more halogens, as de?ned herein. acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, aryl Exemplary haloalkyl groups include tri?uoromethyl, chlo carbonyl, alkylsul?nyl, carboxamido, alkylcarboxamido, romethyl, 2-bromobutyl, l-bromo-2-chloro-pentyl, and the arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamide like. nitrate and nitro. Exemplary heterocyclic groups include pyr [0052] “Alkenyl” refers to a branched or straight chain rolyl, furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, CZ-C1O hydrocarbon (preferably a C2-C8 hydrocarbon, more pyridinyl, l,4-dihydropyridinyl, pyraZolyl, triaZolyl, pyrim preferably a C2-C6 hydrocarbon) that can comprise one or idinyl, pyridaZinyl, oxaZolyl, thiaZolyl, imidaZolyl, indolyl, more carbon-carbon double bonds. Exemplary alkenyl thiophenyl, furanyl, tetrahydrofuranyl, tetraZolyl, pyrrolinyl, groups include propylenyl, buten- l -yl, isobutenyl, penten-l - pyrrolidinyl, oxaZolidinyl 1,3-dioxolanyl, imidaZolinyl, imi yl, 2,2-methylbutene-l-yl, 3-methylbutene-l-yl, hexane-l daZolidinyl, pyraZolinyl, pyraZolidinyl, isoxaZolyl, isothiaZ yl, hepten-l -yl, octene-l -yl, and the like. olyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, [0053] “LoWer alkenyl” refers to a branched or straight 2H-pyranyl, 4H-pyranyl, piperidinyl, l,4-dioxanyl, mor chain C2-C4 hydrocarbon that can comprise one or tWo car pholinyl, l,4-dithianyl, thiomorpholinyl, pyraZinyl, piperaZi bon-carbon double bonds. nyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benZo(b)thiophenyl, [0054] “Substituted alkenyl” refers to a branched or benZimidaZolyl, benZothiaZolinyl, quinolinyl, 2,6-dioxabicy straight chain C2-Cl0 hydrocarbon (preferably a C2-C8 clo(3.3.0)octane, and the like. hydrocarbon, more preferably a C2-C6 hydrocarbon) Which [0059] “Heterocyclic compounds” refer to mono- andpoly can comprise one or more carbon-carbon double bonds, cyclic compounds comprising at least one aryl or heterocyclic Wherein one or more of the hydrogen atoms have been ring. replaced With one or more R100 groups, Wherein each R100 is independently a hydroxy, an oxo, a carboxyl, a carboxamido, [0060] “Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or tWo aromatic a halo, a cyano or an amino group, as de?ned herein. rings. Exemplary aryl groups include phenyl, pyridyl, [0055] “Alkynyl” refers to an unsaturated acyclic C2-Cl0 napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, inde hydrocarbon (preferably a C2-C8 hydrocarbon, more prefer nyl, indoyl, and the like. Aryl groups (including bicyclic aryl ably a C2-C6 hydrocarbon) that can comprise one or more groups) can be unsubstituted or substituted With one, tWo or carbon-carbon triple bonds. Exemplary alkynyl groups three sub stituents independently selected from alkyl, alkoxy, include ethynyl, propynyl, butyne-l-yl, butyne-2-yl, pentyl alkylthio, amino, alkylamino, dialkylamino, arylamino, dia l-yl, pentyl-2-yl, 3-methylbutyn-l-yl, hexyl-l-yl, hexyl-2 rylamino, alkylarylamino, halo, cyano, alkylsul?nyl, yl, hexyl-3-yl, 3,3-dimethyl-butyne-l-yl, and the like. hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, [0056] “Bridged cycloalkyl” refers to tWo or more alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxy cycloalkyl groups, heterocyclic groups, or a combination lic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxa thereof fused Via adjacent or non-adjacent atoms. Bridged mido, alkylcarboxamido, carbonyl, sulfonic acid, sulfonic cycloalkyl groups can be unsubstituted or substituted With ester, sulfonamido and nitro. Exemplary substituted aryl one, tWo or three substituents independently selected from groups include tetra?uorophenyl, penta?uorophenyl, sul alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, fonamide, alkylsulfonyl, arylsulfonyl, and the like. halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alky lcarboxylic ester, carboxamido, alkylcarboxamido, oxo and [0061] “Cycloalkenyl” refers to an unsaturated cyclic nitro. Exemplary bridged cycloalkyl groups include adaman CZ-C1O hydrocarbon (preferably a C2-C8 hydrocarbon, more tyl, decahydronaphthyl, quinuclidyl, 2,6-dioxabicyclo(3.3.0) preferably a C2-C6 hydrocarbon) Which can comprise one or octane, 7-oxabicyclo(2.2. l)heptyl, 8-aZabicyclo(3,2, l )oct-2 more carbon-carbon double bonds. enyl and the like. [0062] “Alkylaryl” refers to an alkyl group, as de?ned [0057] “Cycloalkyl” refers to a saturated or unsaturated herein, to Which is appended an aryl group, as de?ned herein. cyclic hydrocarbon comprising from about 3 to about 10 Exemplary alkylaryl groups include benZyl, phenylethyl, carbon atoms. Cycloalkyl groups can be unsubstituted or hydroxybenZyl, ?uorobenZyl, ?uorophenylethyl, and the substituted With one, tWo or three sub stituents independently like. selected from alkyl, alkoxy, amino, alkylamino, dialky [0063] “Arylalkyl” refers to an aryl radical, as de?ned lamino, arylamino, diarylamino, alkylarylamino, aryl, herein, attached to an alkyl radical, as de?ned herein. Exem amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, plary arylalkyl groups include benZyl, phenylethyl, 4-hy alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo, droxybenZyl, 3-?uorobenZyl, 2-?uorophenylethyl, and the alkylsul?nyl, and nitro. Exemplary cycloalkyl groups include like. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex [0064] “Arylalkenyl” refers to an aryl radical, as de?ned enyl, cyclohepta-l,3-dienyl, and the like. herein, attached to an alkenyl radical, as de?ned herein. [0058] “Heterocyclic ring or group” refers to a saturated or Exemplary arylalkenyl groups include styryl, propenylphe unsaturated cyclic hydrocarbon group having about 2 to about nyl, and the like. US 2008/0293702 A1 Nov. 27, 2008

[0065] “Cycloalkylalkyl” refers to a cycloalkyl radical, as [0082] “Cycloalkylthio” refers to R54Si, Wherein R54 is a de?ned herein, attached to an alkyl radical, as de?ned herein. cycloalkyl group or a bridged cycloalkyl group, as de?ned [0066] “Cycloalkylalkoxy” refers to a cycloalkyl radical, as herein. Exemplary cycloalkylthio groups include cyclopro de?ned herein, attached to an alkoxy radical, as de?ned pylthio, cyclopentylthio, cyclohexylthio, and the like. herein. [0083] “Haloalkoxy” refers to an alkoxy group, as de?ned [0067] “Cycloalkylalkylthio” refers to a cycloalkyl radical, herein, in Which one or more of the hydrogen atoms on the as de?ned herein, attached to an alkylthio radical, as de?ned alkoxy group are substituted With halogens, as de?ned herein. herein. Exemplary haloalkoxy groups include l,l,l-trichloroethoxy, [0068] “Heterocyclicalkyl” refers to a heterocyclic ring 2-bromobutoxy, and the like. radical, as de?ned herein, attached to an alkyl radical, as [0084] “Hydroxy” refers to ‘OH. de?ned herein. [0085] “Oxy” refers to iOi [0069] “Arylheterocyclic ring” refers to a bi- or tricyclic [0086] “Oxo” refers to :O. ring comprised of an aryl ring, as de?ned herein, appended [0087] “Oxylate” refers to iO_R77+ Wherein R77 is an via tWo adjacent carbon atoms of the aryl ring to a heterocy organic or inorganic cation. clic ring, as de?ned herein. Exemplary arylheterocyclic rings [0088] “Thiol” refers to iSH. include dihydroindole, l,2,3,4-tetra-hydroquinoline, and the [0089] “Thio” refers to iSi. like. [0090] “Oxime” refers to :NiOR81 Wherein R81 is a [0070] “Alkylheterocyclic ring” refers to a heterocyclic hydrogen, an alkyl group, an aryl group, an alkylsulfonyl ring radical, as de?ned herein, attached to an alkyl radical, as group, an arylsulfonyl group, a carboxylic ester, an alkylcar de?ned herein. Exemplary alkylheterocyclic rings include bonyl group, an arylcarbonyl group, a carboxamido group, an 2-pyridylmethyl, l -methylpiperidin-2 -one-3-methyl, and the alkoxyalkyl group or an alkoxyaryl group. like. [0091] “HydraZone” refers to :NiN(R8l)(R'81) Wherein [0071] “Alkoxy” refers to RSOOi, Wherein R50 is an alkyl R'81 is independently selected from R81, and R81 is as de?ned group, as de?ned herein (preferably a loWer alkyl group or a herein. haloalkyl group, as de?ned herein). Exemplary alkoxy [0092] “HydraZino” refers to H2NiN(H)i. groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, [0093] “Organic cation” refers to a positively charged tri?uoromethoxy, and the like. organic ion. Exemplary organic cations include alkyl substi [0072] “Aryloxy” refers to RSSOi, Wherein R55 is an aryl tuted ammonium cations, and the like. group, as de?ned herein. Exemplary aryloxy groups include [0094] “Inorganic cation” refers to a positively charged naphthyloxy, quinolyloxy, isoquinoliZinyloxy, and the like. metal ion. Exemplary inorganic cations include Group I metal [0073] “Alkylthio” refers to RSOSi, Wherein R50 is an cations such as for example, sodium, potassium, magnesium, alkyl group, as de?ned herein. calcium, and the like. [0074] “LoWer alkylthio” refers to a loWer alkyl group, as [0095] “Hydroxyalkyl” refers to a hydroxy group, as de?ned herein, appended to a thio group, as de?ned herein. de?ned herein, appended to an alkyl group, as de?ned herein. [0075] “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy [0096] “Nitrate” refers to iOiNOZ i.e. oxidiZed nitro group, as de?ned herein, to Which is appended an aryl group, gen. as de?ned herein. Exemplary arylalkoxy groups include ben [0097] “Nitrite” refers to 4OiNO i.e. oxidiZed nitrogen. Zyloxy, phenylethoxy, chlorophenylethoxy, and the like. [0098] “Thionitrate” refers to isiNOz. [0076] “Arylalklythio” refers to an alkylthio group, as [0099] “Thionitrite” and “nitrosothiol” refer to iSiNO. de?ned herein, to Which is appended an aryl group, as de?ned [0100] “Nitro” refers to the group iNOZ and “nitrosated” herein. Exemplary arylalkylthio groups include benZylthio, refers to compounds that have been substituted thereWith. phenylethylthio, chlorophenylethylthio, and the like. [0101] “Nitroso” refers to the group iNO and “nitrosy [0077] “Arylalklythioalkyl” refers to an arylalkylthio lated” refers to compounds that have been substituted there group, as de?ned herein, to Which is appended an alkyl group, With. as de?ned herein. Exemplary arylalkylthioalkyl groups [0102] “Nitrile” and “cyano” refer to 4CN. include benZylthiomethyl, phenylethylthiomethyl, chlo [0103] “Halogen” or “halo” refers to iodine (I), bromine rophenylethylthioethyl, and the like. (Br), chlorine (Cl), and/or ?uorine (F). [0078] “Alkylthioalkyl” refers to an alkylthio group, as [0104] “lmine” refers to 4C(:NiR5 l)i Wherein R5 1 is de?ned herein, to Which is appended an alkyl group, as a hydrogen atom, an alkyl group, an aryl group or an arylhet de?ned herein. Exemplary alkylthioalkyl groups include erocyclic ring, as de?ned herein allylthiomethyl, ethylthiomethyl, tri?uoroethylthiomethyl, [0105] “Amine” refers to any organic compound that con and the like. tains at least one basic nitrogen atom. [0079] “Alkoxyalkyl” refers to an alkoxy group, as de?ned [0106] “Amino” refers to iNHZ, an alkylamino group, a herein, appended to an alkyl group, as de?ned herein. Exem dialkylamino group, an arylamino group, a diarylamino plary alkoxyalkyl groups include methoxymethyl, methoxy group, an alkylarylamino group or a heterocyclic ring, as ethyl, isopropoxymethyl, and the like. de?ned herein. [0080] “Alkoxyhaloalkyl” refers to an alkoxy group, as [0107] “Alkylamino” refers to RSONHi, Wherein R50 is an de?ned herein, appended to a haloalkyl group, as de?ned alkyl group, as de?ned herein. Exemplary alkylamino groups herein. Exemplary alkoxyhaloalkyl groups include 4-meth include methylamino, ethylamino, butylamino, cyclohexy oxy-2-chlorobutyl and the like. lamino, and the like. [0081] “Cycloalkoxy” refers to R54Oi, Wherein R54 is a [0108] “Arylamino” refers to RSSNHi, Wherein R55 is an cycloalkyl group or a bridged cycloalkyl group, as de?ned aryl group, as de?ned herein. herein. Exemplary cycloalkoxy groups include cyclopropy [0109] “Dialkylamino” refers to R52R53Ni, Wherein R52 loxy, cyclopentyloxy, cyclohexyloxy, and the like. and R53 are each independently an alkyl group, as de?ned US 2008/0293702 A1 Nov. 27, 2008

herein. Exemplary dialkylamino groups include dimethy [0132] “Alkylsulfonyloxy” refers to R5OiS(O)24Oi, lamino, diethylamino, methyl propargylamino, and the like. Wherein R50 is an alkyl group, as de?ned herein. [0110] “Diarylamino” refers to R51R6ONi, Wherein R55 [0133] “Arylsul?nyl” refers to R55iS(O)i, Wherein R55 and R60 are each independently an aryl group, as de?ned is an aryl group, as de?ned herein. herein. [0134] “Arylsulfonyl” refers to R55iS(O)2i, Wherein [0111] “Alkylarylamino or arylalkylamino” refers to R55 is an aryl group, as de?ned herein. R52R55Ni, Wherein R52 is an alkyl group, as de?ned herein, [0135] “Arylsulfonyloxy” refers to R55iS(O)24Oi, and R55 is an aryl group, as de?ned herein. Wherein R55 is an aryl group, as de?ned herein. [0112] “Alkylarylalkylamino” refers to R52R79Ni, [0136] “Amidyl” refers to R5lC(O)N(R57)i Wherein R51 Wherein R52 is an alkyl group, as de?ned herein, and R79 is an and R57 are each independently a hydrogen atom, an alkyl arylalkyl group, as de?ned herein. group, an aryl group or an arylheterocyclic ring, as de?ned [0113] “Alkylcycloalkylamino” refers to R52R5ONi, herein. Wherein R52 is an alkyl group, as de?ned herein, and R80 is a [0137] “Ester” refers to R5 1C(O)R82i Wherein R51 is a cycloalkyl group, as de?ned herein. hydrogen atom, an alkyl group, an aryl group or an arylhet [0114] “Aminoalkyl” refers to an amino group, an alky erocyclic ring, as de?ned herein and R82 is oxygen or sulfur. lamino group, a dialkylamino group, an arylamino group, a [0138] “Carbamoyl” refers to iO4C(O)N(R51)(R57), diarylamino group, an alkylarylamino group or a heterocyclic Wherein R51 and R57 are each independently a hydrogen ring, as de?ned herein, to Which is appended an alkyl group, atom, an alkyl group, an aryl group or an arylheterocyclic as de?ned herein. Exemplary aminoalkyl groups include dim ring, as de?ned herein, or R51 and R57 taken together are a ethylaminopropyl, diphenylaminocyclopentyl, methylami heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl nomethyl, and the like. group, as de?ned herein. [0115] “Aminoaryl” refers to an aryl group to Which is [0139] “Carboxyl” refers to 4C(O)OR76, Wherein R76 is a appended an alkylamino group, an arylamino group or an hydrogen, an organic cation or an inorganic cation, as de?ned arylalkylamino group. Exemplary aminoaryl groups include herein. anilino, N-methylanilino, N-benZylanilino, and the like. [0140] “Carbonyl” refers to iC(O)i. [0116] “Sul?nyl” refers to iS(O)i. [0141] “Alkylcarbonyl” refers to R52iC(O)i, Wherein [0117] “Methanthial” refers to 4C(S)i. R52 is an alkyl group, as de?ned herein. [0118] “Thial” refers to :S. [0142] “Arylcarbonyl” refers to R554C(O)i, Wherein [0119] “Sulfonyl” refers to iS(O)2_. R55 is an aryl group, as de?ned herein. [0120] “Sulfonic acid” refers to iS(O)2OR76, Wherein R76 is a hydrogen, an organic cation or an inorganic cation, as [0143] “Arylalkylcarbonyl” refers to R55iR524C(O)i, de?ned herein. Wherein R55 is an aryl group, as de?ned herein, and R52 is an alkyl group, as de?ned herein. [0121] “Alkylsulfonic acid” refers to a sulfonic acid group, as de?ned herein, appended to an alkyl group, as de?ned [0144] “Alkylarylcarbonyl” refers to R52iR554C(O)i, herein. Wherein R55 is an aryl group, as de?ned herein, and R52 is an alkyl group, as de?ned herein. [0122] “Arylsulfonic acid” refers to a sulfonic acid group, as de?ned herein, appended to an aryl group, as de?ned herein [0145] “Heterocyclicalkylcarbonyl” refer to R78C(O)i [0123] “Sulfonic ester” refers to iS(O)2OR58, Wherein Wherein R78 is a heterocyclicalkyl group, as de?ned herein. R58 is an alkyl group, an aryl group, or an aryl heterocyclic [0146] “Carboxylic ester” refers to 4C(O)OR58, Wherein ring, as de?ned herein. R58 is an alkyl group, an aryl group or an aryl heterocyclic ring, [0124] “Sulfonamido” refers to iS(O)2iN(R5l)(R57), as de?ned herein. Wherein R51 and R57 are each independently a hydrogen [0147] “Alkylcarboxylic acid” and “alkylcarboxyl” refer to atom, an alkyl group, an aryl group or an arylheterocyclic an alkyl group, as de?ned herein, appended to a carboxyl ring, as de?ned herein, or R5 1 and R57 When taken together are group, as de?ned herein. a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl [0148] “Alkylcarboxylic ester” refers to an alkyl group, as group, as de?ned herein. de?ned herein, appended to a carboxylic ester group, as [0125] “Alkylsulfonamido” refers to a sulfonamido group, de?ned herein. as de?ned herein, appended to an alkyl group, as de?ned [0149] “Alkyl ester” refers to an alkyl group, as de?ned herein. herein, appended to an ester group, as de?ned herein. [0126] “Arylsulfonamido” refers to a sulfonamido group, [0150] “Arylcarboxylic acid” refers to an aryl group, as as de?ned herein, appended to an aryl group, as de?ned de?ned herein, appended to a carboxyl group, as de?ned herein. herein. [0127] “Alkylthio” refers to RSOSi, Wherein R50 is an [0151] “Arylcarboxylic ester” and “arylcarboxyl” refer to alkyl group, as de?ned herein (preferably a loWer alkyl group, an aryl group, as de?ned herein, appended to a carboxylic as de?ned herein). ester group, as de?ned herein. [0128] “Arylthio” refers to RSSSi, Wherein R55 is an aryl [0152] “Aryl ester” refers to an aryl group, as de?ned group, as de?ned herein. herein, appended to an ester group, as de?ned herein. [0129] “Arylalkylthio” refers to an aryl group, as de?ned [0153] “Carboxamido” refers to 4C(O)N(R51)(R57), herein, appended to an alkylthio group, as de?ned herein. Wherein R51 and R57 are each independently a hydrogen [0130] “Alkylsul?nyl” refers to R5OiS(O)i, Wherein R50 atom, an alkyl group, an aryl group or an arylheterocyclic is an alkyl group, as de?ned herein. ring, as de?ned herein, or R5 1 and R57 When taken together are [0131] “Alkylsulfonyl” refers to R5OiS(O)2i, Wherein a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl R50 is an alkyl group, as de?ned herein. group, as de?ned herein. US 2008/0293702 A1 Nov. 27, 2008

[0154] “Alkylcarboxamido” refers to an alkyl group, as Wherein: de?ned herein, appended to a carboxamido group, as de?ned [0163] R1 is K' or i(C(Re)(Rf))aa-T3-A; herein. [0164] R2 is K, K' or [0155] “Arylcarboxamido” refers to an aryl group, as de?ned herein, appended to a carboxamido group, as de?ned herein. A [0156] “Urea” refers to iN(R59)4C(O)N(R5l)(R57) T? Wherein R5 1, R57, and R59 are each independently a hydrogen | atom, an alkyl group, an aryl group or an arylheterocyclic (C(ReXRfDW ring, as de?ned herein, or R51 and R57 taken together are a (C(Re)(Rf))aa_CH T3\ heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as de?ned herein. \H/ K; O [0157] “Phosphoryl” refers to iP(R7O)(R71)(R72), Wherein R70 is a tone pair of electrons, thial or oxo, and RM and R72 are each independently a covalent bond, a hydrogen, [0165] A is a hydrogen, K, K', a loWer alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or an aryl, as de?ned herein. [0158] “Phosphoric acid” refers to iP(O)(OR5l)OH Wherein R5 1 is a hydrogen atom, an alkyl group, an aryl group O or an arylheterocyclic ring, as de?ned herein. [0159] “Phosphinic acid” refers to iP(O)(R5l)OH Wherein R5 1 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as de?ned herein. U3\ [0160] “Silyl” refers to iSi(R73)(R74)(R75), Wherein R73, Rb—NH D or R74 and R75 are each independently a covalent bond, a loWer alkyl, an alkoxy, an aryl or an arylalkoxy, as de?ned herein. O [0161] The invention is directed to methods for (a) treating cardiovascular diseases; (b) treating renovascular diseases; O O (c) treating diabetes; (d) treating diseases resulting from oxi dative stress; (e) treating endothelial dysfunctions; (f) treating Rb—NH NHA diseases caused by endothelial dysfunctions; (g) treating cir NH o— RC; rhosis; (h) treating pre-eclampsia; (j) treating osteoporosis; O (k) treating nephropathy; (l) treating peripheral vascular dis O O—Rc eases; (m) treating portal hypertension; (n) treating reperfu sion injury folloWing ischemia; and/or (m) preserving tissues, organs, organ parts and/or limbs by administering one or [0166] Rb is a hydrogen, a loWer alkyl group or 4COCH3; more pyruvate compounds of the invention, that are linked [0167] RC is a hydrogen or a loWer alkyl group; (directly or indirectly) to one or more nitric oxide enhancing [0168] D is a hydrogen, V4, K or K'; moieties via a bond or moiety that can be hydrolyZed. The nitric oxide enhancing pyruvate compounds of the invention [0169] Z is an oxo, an oxime, a hydroZone, :N4O-A, are substituted With at least one heterocyclic nitric oxide donor group and/or the nitroxide group through one or more [0170] R82 is a hydrogen, K, K', an alkyl group, an aryl sites such as oxygen (hydroxyl condensation), sulfur (sulfhy group, an alkylsulfonyl group, an arylsulfonyl group, a car dryl condensation) and/or nitrogen via a bond or moiety that boxylic ester, an alkylcarbonyl group, an arylcarbonyl group, can be hydrolyZed. The heterocyclic nitric oxide donors are a carboxamido group, an alkoxyalkyl group or an alkoxyaryl preferably furoxans, sydnonimines, oxatriaZole-5-ones and/ group; or oxatriaZole-5-imines. The novel compounds and novel compositions of the invention are described in more detail herein. [0162] In one embodiment, the invention describes pyru vate compounds comprising at least one nitric oxide enhanc ing group and pharmaceutically acceptable salts thereof, of Formula (I),

(1) (1) US 2008/0293702 A1 Nov. 27, 2008

-continued -continued (2) (4) H3C CH3

I N—O 26% H3C CH3 (3) (5) H3C CH3 Z57< —0 or H3C CH3 (4) (6) H3C CH3 / I N—o, N+ \ T I \\N H3C CH3 g \ N_ 0/

[0174] Z5 is iCHZ or oxygen; [0183] T is a iS(O)0i; a carbonyl or a covalent bond; [0175] Z6 is iCH or nitrogen; [0184] o is an integer from 0 to 2; [0176] aa is an integer from 0 to 5; [0177] bb is an integer from 0 to l; [0185] R]. and Rk are independently selected from an alkyl [0178] a, b, c, d, g, i and j are each independently an integer group, an aryl group, or Rj and Rk taken together With the from 0 to 3; nitrogen atom to Which they are attached are a heterocylic [0179] p, x, y and Z are each independently an integer from 1mg; 0 to 10; [0186] T3 at each occurrence is independently a covalent [0180] W at each occurrence is independently iC(O)i, bond, a carbonyl, an oxygen, iS(O)Oi or iN(Ra)Ri; *C(S)*, -T3-, *(C(Re)(Rf))h< *N(Ra)Rl-, an alkyl [0187] h is an integer form 1 to 10; group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, i(CH2CH2O)qZi or a heterocyclic nitric oxide donor; [0188] ql is an integer from 1 to 5; [0181] E at each occurrence is independently -T3-, an alkyl [0189] Re and Rf are each independently a hydrogen, an group, an aryl group, i(C(Re)(Rf))hi, a heterocyclic ring, alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an arylheterocyclic ring, i(CH2CH2O)q,i or Y4: an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an [0182] Y4 is: alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalkylthio, an arylalkylthioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an (1) alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky lamino, an arylamino, a diarylamino, an alkylaZylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsul fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, W an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, (Z) 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 W alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsuliphonyloxy, a sul fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitros iU3ivss V6’ i(C(RO)(RP))kZiU3iVS5 *(C(RO) (RQHHJFVH *(C(RO)(RP))WUFC(O)*V6, or R8 and Rf 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 2008/0293702 A1 Nov. 27, 2008 10

(1)

(1)

fl51 3O

(Z) (Z)

(3)

fl5

O [0190] R0 and RP are each independently a hydrogen, an (4) alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an 0 alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalkylthio, an arylalkylthioalkyl, an / alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an f alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky (5) 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, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo (6) nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar CN boxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sul Z fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, iU3iV5, V6, or R0 and RP, taken together With the (7) carbons to Which they are attached form a carbonyl, a meth anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydraZone a bridged cycloalkyl group,

(1) H3C CH3 (3)

Z5 CH3 (Z) (9) US 2008/0293702 A1 Nov. 27, 2008

(10)

(11)

(12)

(13)

(14)

(15)

(16)

group, a hydroxyalkyl group or an arylalkyl group;

[0196] R27 is a hydrogen, iCN, iS(O)2iR25, iC(O)i (17) N(Ra)(Rl-), *NOZ 0r %(O)*OR25; [0197] T' is oxygen, sulfur or NR6; [0198] R6 is a hydrogen, a loWer alkyl group, an aryl group; [0199] U3 is an oxygen, sulfur or iN(Ra)Rl-; [0200] V5 is iNO or iNOZ (ie an oxidized nitrogen); [0201] k1 is an integer from 1 to 3; [0202] Ra is a lone pair of electrons, a hydrogen or an alkyl group; [0203] Rl- is a hydrogen, an alkyl, an aryl, an alkylcarboxy lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an US 2008/0293702 A1 Nov. 27, 2008

arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa [0211] Another embodiment of the invention provides pro mido, an alkylaryl, an alkylsul?nyl, an alkylsulfonyl, an cesses for making the novel compounds of the invention and alkylsulfonyloxy, an arylsul?nyl, an arylsulfonyl, an arylsul to the intermediates useful in such processes. The reactions phonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, are performed in solvents appropriate to the reagents and an aminoalkyl, an aminoaryl, iCHziCi?hiVsxRe) materials used are suitable for the transformations being (R), a bond to an adjacent atom creating a double bond to that effected. It is understood by one skilled in the art of organic atom or i(N 2O2i)~M 1", wherein Ml+ is an organic or inor synthesis that the functionality present in the molecule must ganic cation; and be consistent With the chemical transformation proposed. [0204] With the proviso that the pyruvate compounds of This Will, on occasion, necessitate judgment by the routineer Formula (I) must contain at least heterocyclic nitric oxide as to the order of synthetic steps, protecting groups required, donor group and/or nitroxide group linked to the pyruvate and deprotection conditions. Substituents on the starting compound of Formula (I) through an oxygen atom, a nitrogen materials may be incompatible With some of the reaction atom or a sulfur atom via a bond or moiety that can be conditions required in some of the methods described, but hydrolyZed. alternative methods and substituents compatible With the reaction conditions Will be readily apparent to one skilled in [0205] In cases Where multiple designations of variables the art. The use of sulfur and oxygen protecting groups is Well Which reside in sequence are chosen as a “covalent bond” or knoWn for protecting thiol and alcohol groups against unde the integer chosen is 0, the intent is to denote a single covalent sirable reactions during a synthetic procedure and many such bond connecting one radical to another. For example, Eo protecting groups are knoWn and described by, for example, Would denote a covalent bond, While E2 denotes (E-E) and Greene and Wuts, Protective Groups in Organic Synthesis, (C(R4)(R4))2 denotes *C(R4)(R4)*C(R4)(R4)*~ Third Edition, John Wiley & Sons, NeW York (1999). [0206] Compounds of the invention that have one or more [0212] The chemical reactions described herein are gener asymmetric carbon atoms may exist as the optically pure ally disclosed in terms of their broadest application to the enantiomers, pure diastereomers, mixtures of enantiomers, preparation of the compounds of this invention. Occasionally, mixtures of diastereomers, racemic mixtures of enantiomers, the reactions may not be applicable as described to each diastereomeric racemates or mixtures of diastereomeric race compound included Within the disclosed scope. The com mates. It is to be understood that the invention anticipates and pounds for Which this occurs Will be readily recogniZed by includes Within its scope all such isomers and mixtures one skilled in the art. In all such cases, either the reactions can thereof. be successfully performed by conventional modi?cations [0207] In another embodiment the pyruvate compounds knoWn to one skilled in the art, e.g., by appropriate protection comprising at least one nitric oxide releasing group, and of interfering groups, by changing to alternative conventional pharmaceutically acceptable salts thereof, of Formula (II) are reagents, by routine modi?cation of reaction conditions, and the compounds of Formula (II): the like, or other reactions disclosed herein or otherWise con ventional, Will be applicable to the preparation of the corre sponding compounds of this invention. In all preparative (II) methods, all starting materials are knoWn or readily prepared from knoWn starting materials. [0213] The pyruvate compounds are substituted to contain a nitric oxide enhancing group linked to the pyruvate com pound through one or more sites such as oxygen, sulfur and/ or nitrogen via a bond or moiety that can be hydrolyZed using conventional methods knoWn to one skilled in the art. Known Wherein Z, T3 and R2 are as de?ned herein, and methods of linking the nitroxide group to compounds are [0208] With the proviso that the pyruvate compounds of described in Us. Pat. Nos. 6,448,267, 6,455,542, 6,759,430, Formula (II) must contain at least heterocyclic nitric oxide and in WO 2004/050084, WO 03/088961, the disclosures of donor group and/or nitroxide group linked to the pyruvate each of Which are incorporated by reference herein in their compound of Formula (II) through an oxygen atom, a nitro entirety. gen atom or a sulfur atom via a bond or moiety that can be [0214] Compounds contemplated for use in the invention, hydrolyZed. e.g., nitric oxide enhancing pyruvate compounds comprising [0209] The compounds of Formula (I) and (II) that contains at least one nitric oxide enhancing group selected from a at least one nitric oxide enhancing group linked to the com heterocyclic nitric oxide donor group and a nitroxide group; pound of Formula (I) or (II) through an oxygen atom, a Where the nitric oxide enhancing group is directly or indi nitrogen atom or a sulfur atom via a bond or moiety that can rectly linked to the pyruvate compound through one or more be hydrolyZed are prodrugs of the parent pyruvate compound sites such as oxygen, nitrogen and/or sulfur via a bond or and can be hydrolyZed to give the parent pyruvate compound moiety that can be hydrolyZed are, optionally, used in com and a moiety that contains the nitric oxide enhancing group. bination With nitric oxide enhancing compounds that release [0210] Another embodiment of the invention describes the nitric oxide, increase endogeneous levels of nitric oxide or metabolites of the nitric oxide enhancing pyruvate com otherWise directly or indirectly deliver or transfer a biologi pounds and pharmaceutically acceptable salts thereof. These cally active form of nitrogen monoxide to a site of its intended metabolites, include but are not limited to, degradation prod activity, such as on a cell membrane in vivo. ucts, hydrolysis products, gluconoride adducts and the like, of [0215] Nitrogen monoxide can exist in three forms: NOi the nitric oxide enhancing pyruvate compounds and pharma (nitroxyl), NO~ (nitric oxide) and NO+ (nitrosonium). NO is ceutically acceptable salts thereof, of the pyruvate com a highly reactive short-lived species that is potentially toxic to pounds. cells. This is critical because the pharmacological e?icacy of US 2008/0293702 A1 Nov. 27, 2008

NO depends upon the form in Which it is delivered. In contrast [0222] One group of NO adducts is the S-nitrosothiols, to the nitric oxide radical (N O), nitrosonium (N O") does not Which are compounds that include at least one iSiNO react With O2 or Ozi species, and functionalities capable of group. These compounds include S-nitroso-polypeptides (the transferring and/or releasing NO+ and NOi are also resistant term “polypeptide” includes proteins and polyamino acids to decomposition in the presence of many redox metals. Con that do not possess an ascertained biological function, and sequently, administration of charged NO equivalents (posi derivatives thereof); S-nitrosylated amino acids (including tive and/or negative) does not result in the generation of toxic natural and synthetic amino acids and their stereoisomers and by-products or the elimination of the active NO group. racemic mixtures and derivatives thereof); S-nitrosylated [0216] The term “nitric oxide” encompasses uncharged sugars; S-nitrosylated, modi?ed and unmodi?ed, oligonucle nitric oxide (NO) and charged nitrogen monoxide species, otides (preferably of at least 5, and more preferably 5-200 preferably charged nitrogen monoxide species, such as nucleotides); straight or branched, saturated or unsaturated, nitro sonium ion (NO") and nitroxyl ion (N Of). The reactive aliphatic or aromatic, substituted or unsubstituted S-nitrosy form of nitric oxide can be provided by gaseous nitric oxide. lated hydrocarbons; and S-nitroso heterocyclic compounds. The nitrogen monoxide releasing, delivering or transferring S-nitro sothiols and methods for preparing them are described compounds have the structure FiNO, Wherein F is a nitrogen in US. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; monoxide releasing, delivering or transferring group, and WO 98/19672; and Oae et al, Org. Prep. Proc. 1112., 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. [0223] Another embodiment of the invention is S-nitroso [0217] 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 or derivative thereof. including, for example, S-nitrosothiols, nitrites, nitrates, S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydra Such compounds include, for example, S-nitroso-N-acetyl Zines, (NONOates), (E)-alkyl-2-((E)-hydroxyimino)-5-ni cysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicil tro-3-hexeneamide (PK-409), (E)-alkyl-2-((E)-hydroxy lamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-ni imino)-5-nitro-3-hexeneamines, N-((2Z, 3 E)-4-ethyl-2 troso-glutathione, S-nitroso-cysteinyl-glycine, and the like. (hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3 [0224] Suitable S-nitrosylated proteins include thiol-con pyridinecarboxamide (FR 146801), N-nitrosamines, taining proteins (Where the NO group is attached to one or N-hydroxyl nitrosamines, nitrosamines, diaZetine dioxides, more sulfur groups on an amino acid or amino acid derivative oxatriaZole 5-imines, oximes, hydroxylamines, N-hydrox thereof) from various functional classes including enZymes, yguanidines, hydroxyureas, benZofuroxanes, furoxans as such as tissue-type plasminogen activator (TPA) and cathep Well as substrates for the endogenous enZymes Which synthe sin B; transport proteins, such as lipoproteins; heme proteins, siZe nitric oxide. such as hemoglobin and serum albumin; and biologically [0218] Suitable NONOates include, but are not limited to, protective proteins, such as immunoglobulins, antibodies and (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/N O”), (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 modi?ed. diolate (spermine NONOate or “SPEIVNO”) and sodium(Z) 1 -(N,N-diethylamino)diaZenium-1,2-diolate (diethylamine [0225] Other examples of suitable S-nitrosothiols include: NONOate or “DEA/ NO”) and derivatives thereof. NON [0226] (i) HS(C(Re)(Rf))mSNO; Oates are also described in US. Pat. Nos. 6,232,336, 5,910, [0227] (ii) ONS(C(Re)(Rf))mRe; or 316 and 5,650,447, the disclosures of Which are incorporated herein by reference in their entirety. The “NO adducts” can be mono-nitrosylated, poly-nitro sylated, mono -nitro sated and/ Wherein m is an integer from 2 to 20; or poly-nitrosated at a variety of naturally susceptible or arti?cially provided binding sites for biologically active [0230] Re and Rf are each independently a hydrogen, an forms of nitrogen monoxide. alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an [0219] Suitable furoxanes include, but are not limited to, alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, CAS 1609, C93-4759, C92-4678, S35b, CHF 2206, CHF a cycloalkylthio, an arylalkylthio, an arylalkylthioalkyl, an 2363, and the like. alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an [0220] 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 alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsul 2,6-dimethylpiperidino)-N-(4-methoxybenZoyl)-sydnon fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, imine, pirsidomine), C87-3754 (3-(cis-2,6 an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an dimethylpiperidino)sydnonimine, linsidomine, C4144 (3-(3, arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, 3 -dimethyl-1,4-thiaZane-4-yl)sydnonimine hydrochloride), an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an C89-4095 (3-(3,3-dimethyl-1,1-dioxo-1,4-thiaZane-4-yl) alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo sydnonimine hydrochloride, and the like. nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar [0221] Suitable oximes, include, but are not limited to, boxylic ester, an arylcarboxylic ester, a sulfonamido, an NOR-1, NOR-3, NOR-4, and the like. alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an US 2008/0293702 A1 Nov. 27, 2008

alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sul fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, -continued a nitro, iU3ivss V6: i(C(R0)(Rp))kliU3iV5$ *(C(R0) (2) (RPHFUFVQ *(QRO)(Ruuillfqmiva or R. H30 CH3 and Rf taken together With the carbons to Which they are attached form a carbonyl, a methanthial, a heterocyclic ring, N—O; a cycloalkyl group, an aryl group, an oxime, a hydraZone, a bridged cycloalkyl group, H3c CH3

(1) H30 cH3 [0232] k1 is an integer form 1 to 3; [0233] U3 is an oxygen, sulfur- or iN(Ra)R1-; [0234] V5 is iNO or iNOZ (i.e. an oxidized nitrogen); [0235] Ra is a lone pair of electrons, a hydrogen or an alkyl Z5 group; CH3 [0236] R1. is a hydrogen, an alkyl, an aryl, an alkylcarboxy H30 lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an (2) arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsul?nyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsul?nyl, an arylsulfonyl, arylsulpho nyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, iCH24C(U3iV5)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or i(N2O2i)_~M1+, Wherein Ml+ is an organic or inorganic H30 cH3 cation. [0237] In cases Where Re and Rf are independently a het erocyclic ring or taken together Re and Rf are a heterocyclic [0231] R0 and RP are each independently a hydrogen, an ring, then R. can be a sub stituent on any disubstituted nitrogen alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, contained Within the radical Wherein R,- is as de?ned herein. an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an [0238] Nitrosothiols can be prepared by various methods of alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, synthesis. In general, the thiol precursor is prepared ?rst, then a cycloalkylthio, an arylalkylthio, an arylalkylthioalkyl, an converted to the S-nitrosothiol derivative by nitrosation of the alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an thiol group With NaNO2 under acidic conditions (pH is about 2.5) Which yields the S-nitroso derivative. Acids Which can be alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky used for this purpose include aqueous sulfuric, acetic and lamino, an arylamino, a diarylamino, an alkylarylamino, an hydrochloric acids. The thiol precursor can also be nitrosy alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsul lated by reaction With an organic nitrite such as tert-butyl fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, nitrite, or a nitrosonium salt such as nitrosonium tetra?uo an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an roborate in an inert solvent. arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, [0239] Another group of NO adducts for use in the inven an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an tion, Where the NO adduct is a compound that donates, trans alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo fers or releases nitric oxide, include compounds comprising nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar at least one ONiOi or ONiNi group. The compounds boxylic ester, an arylcarboxylic ester, a sulfonamido, an that include at least one ON4Oi or ONiN-group are preferably ONiOi or ONiN-polypeptides (the term alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an “polypeptide” includes proteins and polyamino acids that do alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sul not possess an ascertained biological function, and deriva fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, tives thereof); ONiOi or ONiN-amino acids (including a nitro, iU3iV5, V6, or R0 and RP taken together With the natural and synthetic amino acids and their stereoisomers and carbons to Which they are attached form a carbonyl, a meth racemic mixtures); ON4Oi or ONiN-sugars; ONiOi anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, or iONiNi modi?ed or unmodi?ed oligonucleotides an oxime, an imine, a hydraZone, a bridged cycloalkyl group, (comprising at least 5 nucleotides, preferably 5-200 nucle otides); ON4Oi or ONiNi straight or branched, satu rated or unsaturated, aliphatic or aromatic, substituted or (1) unsubstituted hydrocarbons; and ONiOi, ONiNi or H30 cH3 ON4C-heterocyclic compounds. Examples of compounds comprising at least one ON4Oi or ONiN-group include butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite, N-nitrosamines, N-nitrosamides, N-ni Z5 trosourea, N-nitrosoguanidines, N-nitrosocarbamates, CH3 N-acyl-N-nitroso compounds (such as, N-methyl-N-ni trosourea); N-hydroxy-N-nitrosamines, cup ferron, alanosine, dopastin, l ,3 -disubstituted nitrosiminobenZimida US 2008/0293702 A1 Nov. 27, 2008

Zoles, 1,3,4-thiadiaZole-2-nitrosimines, benZothiaZole-2 imino(pentylamino)methylhydroxylamine, imino (propy (3H)-nitrosimines, thiaZole-2-nitrosimines, oligonitroso syd lamino)methylhydroxylamine, imino ((methylethyl)amino) nonimines, 3-alkyl-N-nitroso-sydnonimines, 2H-1,3,4 methylhydroxylamine, (cyclopropylamino) iminomethylhy thiadiaZine nitrosimines. droxylamine, imino-2-1,2,3,4-tetrahydroisoquinolyl [0240] Another group of NO adducts for use in the inven methylhydroxylamine, imino(1 -methyl(2-1,2,3,4-tetrahy tion include nitrates that donate, transfer or release nitric droisoquinolyl))methylhydroxylamine, (1 ,3 -dimethyl(2-1 ,2, oxide, such as compounds comprising at least one OzNi 3,4-tetrahydroisoquinolyl)) iminomethylhydroxylamine, Oi, OzNiNi or OZNiSi group. Among these com (((4-chlorophenyl)methyl)amino)iminomethylhydroxy pounds are OZNiOi, OzNiNi or O2NiS-polypeptides lamine, ((4-chlorophenyl)amino)iminomethylhydroxy (the term “polypeptide” includes proteins and also polyamino lamine, (4-chlorophenyl)(hydroxyimino) methylamine, and acids that do not possess an ascertained biological function, 1-(4-chlorophenyl)-1-(hydroxyimino)ethane, and the like, and derivatives thereof); O2N4Oi, OzNiNi or OzNi precursors of L-arginine and/or physiologically acceptable Si amino acids (including natural and synthetic amino acids salts thereof, including, for example, citrulline, ornithine, and their stereoisomers and racemic mixtures); OZNiOi, glutamine, lysine, polypeptides comprising at least one of OzNiNi or OZNiSi sugars; OZNiOi, OzNiNi or these amino acids, inhibitors of the enZyme arginase (e.g., OZNiSi modi?ed and unmodi?ed oligonucleotides (com N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic prising at least 5 nucleotides, preferably 5-200 nucleotides); acid), nitric oxide mediators and/or physiologically accept O2N4Oi, OzNiNi or OZNiSi straight or branched, able salts thereof, including, for example, pyruvate, pyruvate saturated or unsaturated, aliphatic or aromatic, substituted or precursors, ot-keto acids having four or more carbon atoms, unsubstituted hydrocarbons; and O2N4Oi, OzNiNi or precursors of ot-keto acids having four or more carbon atoms OZNiSi heterocyclic compounds. Examples of com (as disclosed in WO 03/017996, the disclosure of Which is pounds comprising at least one O2N4Oi, OzNiNi or incorporated herein in its entirety), and the substrates for OZNiSi group include isosorbide dinitrate, isosorbide nitric oxide synthase, cytokines, adenosine, bradykinin, cal mononitrate, clonitrate, erythrityl tetranitrate, mannitol hex reticulin, bisacodyl, and phenolphthalein. EDRF is a vascular anitrate, nitroglycerin, pentaeiythritoltetranitrate, pentrini relaxing factor secreted by the endothelium, and has been trol, propatylnitrate and organic nitrates With a sulfhydryl identi?ed as nitric oxide (NO) or a closely related derivative containing amino acid such as, for example SPM 3672, SPM thereof (Palmer et al, Nature, 327:524-526 (1987); lgnarro et 4757, SPM 5185, SPM 5186 and those disclosed in US. Pat. al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)). Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847 and 5,883, [0243] The invention is also directed to nitric oxide enhanc 122 and in WO 97/46521, WO 00/54756 and in WO ing compounds that can increase endogenous nitric oxide. 03/013432, the disclosures of each of Which are incorporated Such compounds, include for example, nitroxide containing by reference herein in their entirety. compounds, include, but are not limited to, substituted 2,2,6, [0241] Another group of NO adducts are N-oxo-N-nitro 6-tetramethyl-1-piperidinyloxy compounds, substituted 2,2, samines that donate, transfer or release nitric oxide and are 5,5-tetramethyl-3-pyrroline-1-oxyl compounds, substituted represented by the formula: Rl"R2"NiN(O-M+)iNO, 2,2,5,5-tetramethyl-1-pyrrolidinyloxy compounds, substi Where R1" and R2" are each independently a polypeptide, an tuted 1 ,1 ,3,3-tetramethylisoindolin-2-yloxyl compounds, amino acid, a sugar, a modi?ed or unmodi?ed oligonucle substituted 2,2,4,4-tetramethyl-1-oxaZolidinyl-3-oxyl com otide, a straight or branched, saturated or unsaturated, ali pounds, substituted 3-imidaZolin-1-yloxy, 2,2,5,5-tetram phatic or aromatic, substituted or unsubstituted hydrocarbon, ethyl-3 -imidaZolin-1-yloxyl compounds, OT-551, 4-hy or a heterocyclic group, and Where Ml+ is an organic or droxy-2,2,6,6-tetramethyl-1-piperidinyloxy (tempol), and inorganic cation, such, as for example, an alkyl substituted the like. Suitable substituents, include, but are not limited to, ammonium cation or a Group I metal cation. aminomethyl, benZoyl, 2-bromoacetamido, 2-(2-(2-bro [0242] The invention is also directed to compounds that moacetamido)ethoxy)ethylcarbamoyl, carbamoyl, carboxy, stimulate endogenous NO or elevate levels of endogenous cyano, 5 -(dimethylamino)- 1 -naphthalenesulfonamido, endothelium-derived relaxing factor (EDRF) in vivo or are ethoxy?uorophosphinyloxy, ethyl, 5-?uoro-2,4-dinitroa oxidiZed to produce nitric oxide and/or are substrates for nilino, hydroxy, 2-iodoacetamido, isothiocyanato, isothiocy nitric oxide synthase and/or cytochrome P450. Such com anatomethyl, methyl, maleimido, maleimidoethyl, 2-(2-ma pounds include, for example, L-arginine, L-homoarginine, leimidoethoxy)ethylcarbamoyl, maleimidomethyl, and N-hydroxy-L-arginine, N-hydroxy-L-homoarginine, maleimido, oxo, phosphonooxy, and the like. N-hydroxydebrisoquine, N-hydroxypentamidine including [0244] The invention is also based on the discovery that their nitrosated and/or nitrosylated analogs (e.g., nitrosated compounds and compositions of the invention may be used in L-arginine, nitro sylated L-arginine, nitrosated N-hydroxy-L conjunction With other therapeutic agents for co-therapies, arginine, nitrosylated N-hydroxy-L-arginine, nitrosated and partially or completely, in place of other therapeutic agents, nitrosylated L-homoarginine), N-hydroxyguanidine com such as, for example, aldosterone antagonists, alpha-adren pounds, amidoxime, ketoximes, aldoxime compounds, that ergic receptor antagonists, angiotensin II antagonists, angio can be oxidiZed in vivo to produce nitric oxide. Compounds tensin-converting enZyme (ACE) inhibitors, antidiabetic that may be substrates for a cytochrome P450, include, for compounds, anti-hyperlipidemic compounds, antioxidants, example, imino(benZylamino)methylhydroxylamine, imino antithrombotic and vasodilator compounds, P-adrenergic (((4-methylphenyl)methyl)amino)methylhydroxylamine, antagonists, calcium channel blockers, digitalis, diuretics, imino(((4-methoxyphenyl)methyl)amino) methylhydroxy endothelin antagonists, hydralaZine compounds, H2 receptor lamine, imino(((4-(tri?uoromethyl)phenyl)methyl)amino) antagonists, neutral endopeptidase inhibitors, nonsteroidal methylhydroxylamine, imino(((4-nitrophenyl)methyl) antiin?ammatory compounds (N SAlDs), phosphodiesterase amino)methylhydroxylamine, (butylamino) iminomethylhy inhibitors, potassium channel blockers, platelet reducing droxylamine, imino (propylamino) methylhydroxylamine, agents, proton pump inhibitors, renin inhibitors, selective US 2008/0293702 A1 Nov. 27, 2008

cyclooxygenase-2 (COX-2) inhibitors, and combinations of Edition), McGraW-Hill, 1995; and the Merck Index on CD tWo or more thereof. The therapeutic agent may optionally be ROM, Thirteenth Edition; and on STN Express, ?le phar and nitrosated and/or nitrosylated and/ or contain at least one het ?le registry. erocyclic nitric oxide donor group and/or at least one nitrox [0248] Suitable angiotensin II antagonists include, but are ide group. not limited to, angiotensin, abitesartan, candesartan, cande [0245] Suitable aldosterone antagonists include, but are not sartan cilexetil, elisartan, embusartan, enoltasosartan, epro limited to, canrenone, potassium canrenoate, drospirenone, sartan, fonsartan, forasartan, glycyllosartan, irbesartan, losa spironolactone, eplemone (INSIPRA®), epoxymexrenone, rtan, olmesartan, milfasartan, medoxomil, ripisartan, fadroZole, pregn-4-ene-7,2,1-dicarboxylic acid, 9,11-epoxy pomisartan, pratosartan, saprisartan, saralasin, sarmesin, 17-hydroxy-3 -oxo, y-lactone, methyl ester, (7a, 1 10., 1 76)-; tasosartan, telmisartan, Valsartan, Zolasartan, 3-(2'(tetraZole pregn-4-ene-7,21-dicarboxylic acid, 9,1 1-epoxy-17-hy 5 -yl)-1,1'-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imi droxy-3 -oxo-dimethyl ester, (70.,1 10., 17 6)-; 3'H-cyclopropa daZo[4,5-b]pyridine, antibodies to angiotensin 11, A-81282, (6,7)pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7 A-81988, BAY 106734, BIBR-363, BIBS-39, BIBS-222, dihydro-17-hydroxy-3-oxo-, y-lactone, (66,76,110t,176)-; BMS-180560, BMS-184698, BMS-346567, CGP-38560A, pregn-4-ene-7,21-dicarboxylic acid, 9,1 1-epoxy-17-hy CGP-42112A, CGP-48369, CGP-49870, CGP-63170, droxy-3-oxo-, 7-(1-methylethyl)ester, monopotassium salt, CI-996, CP-148130, CL-329167, CV-11194, CV-11974, (70.,1 10,176), pregn-4-ene-7,21-dicarboxylic acid, 9,11, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, DuP epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium 753, E-1477, E-4177, E-4188, EMD-66397, EMD-666R4, salt, (70.,1 16,176)-; 3'H-cyclopropa(6,7) pregna-1,4,6 EMD-73495, EMD-66684, EXP-063, EXP-929, EXP-3134, triene-21-carboxylic acid, 9,1 1-epoxy-6,7-dihydro-17-hy EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, EXP-9954, FK-739, FRI 153332, GA-0050, GA-0056, droxy-3-oxo-, y-lactone, (66,76,11 0t)-; 3'H-cyclopropa(6,7) HN-65021, HOE-720, HR-720, ICI-D6888, ICI-D7155, ICI pregna-4,6-diene-21-carboxylic acid, 9,1 1-epoxy-6,7 D8731, KRI-1177, KT3-671, KT-3579, KW-3433, dihydro-17-hydroxy-3-oxo-, methyl ester, (66,76,110t,176)-; L-158809, L-158978, L-159282 (MK-996), L-159689, 3'H-cyclopropa (6,7)pregna-4,6-diene-21-carboxylic acid, L-159874, L-161177, L-162154, L-162234, L-162441, 9,1 1 -epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotas L-163007, L-163017, LF-70156, LRB-057, LRB-081, LRB sium salt, (66,76,110t,176)-; 3'H-1-cyclopropa(6,7)pregna 087, LY-235656, LY-266099, LY-285434, LY-301875, 1 ,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17 LY-302289, LY-315995, ME-3221, MK-954, PD-123177, hydroxy-3 -oxo-, y-lactone, (66,76,110t,176)-; pregn-4-ene PD-123319, PD-126055, PD-150304, RG-13647, RWJ 7,21 -dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, 38970, RWJ-46458, S-8307, S-8308, SC-51757, SC-54629, y-lactone, ethyl ester, (7(>t,110t,176)-; pregn-4-ene-7,2,1-di SC-52458, SC-52459, SK 1080, SL-910102, SR-47436, carboxylic acid, 9,1 1-epoxy-17-hydroxy-3-oxo-, y-lactone, TAK-536, UP-2696, U-96849, U-97018, UK-77778, 1 -methylethyl ester, (7a, 1 10., 1 76)-; RU-28318, and the like. UP-275-22, WAY-126227, WK-1260, WK-1360, WK-1492, Suitable aldosterone antagonists are described more fully in WY 126227, YH-1498, YM-358, YM-31472, X-6803, the literature, such as in Goodman and Gilman, The Pharma XH-148, XR-510, ZD-6888, ZD-7155, ZD-8731, ZD 8131, cological Basis of Therapeutics (9th Edition), McGraW-Hill, the compounds of ACS registry numbers 133240-46-7, 1995; and the Merck Index on CD-ROM, 13th Edition; and on 135070-05-2, 139958-16-0, 145160-84-5, 147403-03-0, STN Express, ?le phar and ?le registry. 153806-29-2, 439904-54-8P, 439904-55-9P, 439904-56-01), [0246] In some embodiments the aldosterone antagonists is 439904-57-1P, 439904-58-2P, 155918-60-8P, 155918-61-9P, eplernone or spironolactone (a potassium sparing diuretic 272438-16-1P, 272446-75-0P, 223926-77-0P, 169281-89-4, that acts like an aldosterone antagonist). In more particular 165113-17-7P, 165113-18-8P, 165113-19-91P, 165113-20 embodiments eplemone is administered in an amount of 2P, 165113-13-3P, 165113-14-4P, 165113-15-5P, 165113 about 25 milligrams to about 300 milligrams as a single dose 16-6P, 165113-21-3P, 165113-22-4P, 165113-23-5P, or as multiple doses per day; the spironolactone is adminis 165113-24-6P,165113-25-7R165113-26-8R165113-27-9P, tered in an amount of about 25 milligrams to about 150 165113-28-0P,165113-29-1R165113-30-4R165113-31-5P, milligrams as a single dose or as multiple doses per day. 165113-32-6P,165113-33-7R165113-34-8R165113-35-9P, [0247] Suitable alpha-adrenergic receptor antagonists 165113-36-0P,165113-37-1R165113-38-2R165113-39-3P, include but are not limited to, phentolamine, tolaZoline, ida 165113-40-6P,165113-41-7R165113-42-8R165113-43-9P, Zoxan, deriglidole, RX 821002, BRL 44408, BRL 44409, 165113-44-0P,165113-45-1R165113-46-2R165113-47-3P, BAM 1303, labetalol, ifenprodil, rauWolscine, corynathine, 165113-48-4P,165113-49-SP,165113-50-8P,165113-51-9P, raubascine, tetrahydroalstonine, apoyohimbine, akuam 165113-52-0P,165113-53-1R165113-54-2R165113-55-3P, migine, 6-yohimbine, yohimbol, yohimbine, pseudoyohim 165113-56-4P,165113-57-5R165113-58-6R165113-59-7P, bine, epi-30t-yohimbine, 10-hydroxy-yohimbine, 11-hy 165113-60-0P,165113-61-1R165113-62-2R165113-63-3P, droxy-yohimbine, tamsulosin, benoxathian, atipameZole, BE 165113-64-4P,165113-65-5R165113-66-6R165113-67-7P, 2254, WB 4101, HU-723, tedisamil, mirtaZapine, setiptiline, 165113-68-8P,165113-69-9R165113-70-2R165113-71-3P, reboxetine, delequamine, naftopil, saterinone, SL 89.0591, 165113-72-4P, 165113-73-5P, 165113-74-6P, 114798-27-5, ARC 23 9, urapidil, 5 -methylurapidil, monatepi, haloperidol, 114798-28-6, 114798-29-7, 124749-82-2, 114798-28-6, indoramin, SB 216469, moxisylyte, traZodone, dapiproZole, 124749-84-4, 124750-88-5, 124750-91-0, 124750-93-2, efaroxan, Recordati 15/2739, SNAP 1069, SNAP 5089, 161946-65-2P, 161947-47-3P, 161947-48-4P, 161947-51-9P, SNAP 5272, RS 17053, SL 89.0591, KMD 3213, spiperone, 161947-52-0P, 161947-55-3P, 161947-56-4P, 161947-60-0P, AH 11110A, chloroethylclonidine, BMY 7378, niguldipine, 161947-61-1P,161947-68-8R161947-69-9R 161947-70-2P, and the like. Suitable alpha-adrenergic receptor antagonists 161947-71-3P, 161947-72-4P, 161947-74-6P, 161947-75-7P, are described more fully in the literature, such as in Goodman 161947-81-5P, 161947-82-6P, 161947-83-7P, 161947-84-8P, and Gilman, The Pharmacological Basis of Therapeutics (9th 161947-85-9P,161947-86-0R161947-87-1R 161947-88-2P, US 2008/0293702 A1 Nov. 27, 2008

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, 161947-94-0P, 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 -42-0P, 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 177848-35-0P, 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, 13th Edition; and on STN Express, quinapril hydrochloride in an amount of about 5 milligrams to ?le phar and ?le registry. about 40 milligrams as single or multiple doses per day; the [0249] 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 in 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 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 [0252] Suitable antidiabetic compounds include but are not multiple doses per day; the irbesartan is administered in an limited to, acarbose, acetohexamide, bulomlin, carbutamide, amount of about 75 milligrams to about 1200 milligrams as a chlorpropamide, glibomuride, gliclaZide, glimepiride, glipiZ single dose or as multiple doses per day; the losartan is admin ide, gliquidone, glisoxepide, 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, mi glitol, 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, ?le phar and ?le registry. or as multiple doses per day. [0253] Suitable anti-hyperlipidemic compounds include, [0250] 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 (LIPITOR®), bervas benaZepril (LOTENSIN®, CIBACEN®), benaZeprilat, cap tatin, cerivastatin (BAYCOL®), dalvastatin, ?uindostatin topril, ccronapril, cilaZapril, delapril, duinapril, enalapril, (SandoZ XU-62-320), ?uvastatin, glenvastatin, lovastatin enelaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, (MEVACOR®), mevastatin, pravastatin (PRAVACHOL®), glycopril, idrapril, imidapril, lisinopril, inoexipril, movel rosuvastatin (CRESTRO®), simvastatin (ZOCOR®), tipril, naphthopidil, omapatrilat, pentopril, perindopril, per Velostatin (also knoWn as synvinolin), VYTORINTM indoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rent (eZetimibe/simVastatin), GR-95030, SQ 33,600, BMY ipril, saralasin acetate, spirapril, temocapril, trandolapiil, 22089, BMY 22,566, CI-980, and the like; gem?broZil, trandolapiilat, urapidil, Zofenopril, acylmercapto and mer cholestyramine, colestipol, niacin, nicotinic acid, bile acid captoalkanoyl pralines, carboxyalkyl dipeptides, carboxy sequestrants, such as, for example, cholestyramine, coleseVe alkyl dipeptide, phosphinylalkanoyl pralines, registry no. lam, colestipol, poly(methyl-(3-trimethylaminopropyl) 796406, AVE 7688, B1.137, CHF 1514, E 4030, ER 3295, imino-trimethylene dihalide) and the like; probucol; ?bric FPL-66564, MDL 100240, RL 6134, RL 6207, RL 6893, SA acid agents or ?brates, such as, for example, beZa?brate 760, S-5590, Z 13752A, and the like. Suitable angiotensin (BeZalipTM), beclobrate, bini?brate, cipro?brate, clino?brate, converting enZyme inhibitors are described more fully in the clo?brate, eto?brate, feno?brate (LipidilTM, Lipidil literature, such as in Goodman and Gilman, The Pharmaco MicroTM), gem?broZil (LopidTM), nico?brate, piri?brate, logical Basis of Therapeutics (9th Edition), McGraW-Hill, roni?brate, sim?brate, theo?brate and the like; cholesterol 1995; and the Merck Index on CD-ROM, Twelfth Edition, ester transfer protein (CETP) inhibitors, such as for example, Version 12:1, 1996; and on STN Express, ?le phar and ?le CGS 25159, CP-529414 (torcetrapid), JTT-705, substituted registry. N-[3 -(1, 1 ,2,2-tetra?uoroethoxy)benZyl] -N-(3 -phenoxyphe [0251] In some embodiments the angiotensin-converting nyl)-tri?uoro-3-amino-2-propanols, N,N-disubstituted trif enZyme inhibitors are benaZepril, captopril, enalapril, fosino luoro-3-amino-2-propanols, PD 140195 (4-phenyl-5-tride pril, lisinopril, moexipril, quinapril, ramipril, trandolapril or cyl-4H-1,2,4-triaZole-3-thiol), SC-794, SC-795, SCH trandolaprilat. In more particular embodiments the 58149, and the like. benaZepril is administered as benaZepril hydrochloride in an [0254] In some embodiments the anti-hyperlipidemic com amount of about 5 milligrams to about 80 milligrams as a pounds are atorvastatin, ?uvastatin, lovastatin, pravastatin, single dose or as multiple doses per day; the captopril is rosuvastatin or simvastatin. In more particular embodiments administered in an amount of about 12.5 milligrams to about the atorvastatin is administered in an amount of about 10 US 2008/0293702 A1 Nov. 27, 2008

milligrams to about 80 milligrams as a single dose or as Merck Index on CD-ROM, Thirteenth Edition; and on STN multiple doses per day; the ?uvastatin is administered in an Express, ?le phar and ?le registry. amount of about 20 milligrams to about 80 milligrams as a [0258] Suitable calcium channel blockers include, but are single dose or as multiple doses per day; the lovastatin is not limited to, amlodipine (NORVASC®), anipamil, aranid administered in an amount of about 10 milligrams to about 80 ipine, aminone, aZelnidipine, bamidipine, bencyclane, beni milligrams as a single dose or as multiple doses per day; the dipine, bepridil, cilnidipine, cinnariZine, clentiaZem, dilt pravastatin is administered in an amount of about 10 milli iaZem, dotariZine, efonidipine, elgodipine, fantofarone, grams to about 80 milligrams as a single dose or as multiple felodipine, fendiline, IMunarizine, ?uspirilene, fumidipine, doses per day; the rosuvastatin is administered in an amount gallopamil, ipenoxaZone, isradipinc, lacidipine, lmildipine, of about 5 milligrams to about 40 milligrams as a single dose Iercanidipine, lomeriZine, manidipine, mibefradil, or as multiple doses per day; the simvastatin is administered monatepil, nicardipine, nifedipine, niguldipine, niludipine, in an amount of about 5 milligrams to about 80 milligrams as nilvadipine, nimodipine, nisoldipine, nitrendipine, nival a single dose or as multiple doses per day. dipine, oxodipine, perhexylene, phenyloin, phenylpreny [0255] Suitable antioxidants include, but are not limited to, lamine, pranidipine, ranolaZine, ryosidine, semotiadil, tamo small-molecule antioxidants and antioxidant enzymes. Suit lariZine, temiverine hydrochloride, terodiline, tiapamil, able small-molecule antioxidants include, but are not limited vatanidipine hydrochloride, verapamil, Ziconotide, AE-0047, to, hydralaZine compounds, glutathione, vitamin C, vitamin CAI, JTV-519, CHE-1521, L-651582, NS-7, NW-1015, E, cysteine, N-acetyl-cysteine, [3-carotene, ubiquinone, RO-2933, SB-237376, SL-34.0829-08, S-312d, SD-3212, ubiquinol-10, tocopherols, coenZyme Q, superoxide dismu TA-993, YM-430, and the like. Suitable calcium channel tase mimetics, such as, for example, 2,2,6,6-tetramethyl-1 blockers are described more fully in the literature, such as in piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide Goodman and Gilman, The Pharmacological Basis of Thera compounds; 4-hydroxy-2,2,6,6-tetramethyl-1-piperidiny peutics (9th Edition), McGraW-Hill, 1995; and the Merck loxy (Tempol), M-40401, M-40403, M-40407, M-40419, Index on CD-ROM, Thirteenth Edition; and on STN Express, M-40484, M-40587, M-40588, and the like. Suitable antioxi ?le phar and ?le registry. dant enzymes include, but are not limited to, superoxide [0259] In some embodiments the calcium channel blockers dismutase, catalase, glutathione peroxidase, NADPH oxidase are amlodipine, diltiaZem, isradipine, nicardipine, nifedipine, inhibitors, such as, for example, apocynin, aminoguanidine, nimodipine, nisoldipine, nitrendipine, verapamil. ONO 1714, S17834 (benZo(b)pyran-4-one derivative), and [0260] Suitable digitals include but are not limited to the like; xanthine oxidase inhibitors, such as, for example, digoxin and digoxitin. In some embodiments the digoxin is allopurinol, oxypurinol, am?lutiZole, diethyldithiocarbam administered to achieve a steady state blood serum concen ate, 2-styrylchromones, chrysin, luteolin, kaempferol, quer tration of at least about 0.7 nanograms per ml to about 2.0 cetin, myricetin, isorhamnetin, benZophenones such as 2,2‘, nanograms per ml. 4,4'-tetrahydroxybenZophenone, 3,4,5,2',3',4' [0261] Suitable diuretics include but are not limited to, hexahydroxybenZophenone and 4,4' thiaZides (such as, for example, althiaZide, bendro?umethi dihydroxybenZophenone; benZothiaZinone analogues such as aZide, benZclortriaZide, benZhydrochlorothiaZide, benZthiaZ 2-amino-41-1-1,3-benZothiaZine-4-one, 2-guanidino-41-1 ide, buthiaZide, chlorothiaZide, cyclopenethiaZide, 1,3-benZothiaZin-4-one and rhodanine; N-hydroxyguanidine cyclothiaZide, epithiaZide, ethiaZide, hydrobenZthiaZide, derivative such as, PR5 (1-(3,4-dimethoxy-2-chloroben hydrochlorothiaZide, hydro?umethiaZide, methylclothiaZ Zylideneamino)-3-hydroxyguanidine); 6-formylpterin, and ide, methylcyclothiaZide, pen?utaZide, polythiaZide, the like. The antioxidant enZymes can be delivered by gene teclothiaZide, trichlonrethiaZide, tri?umethaZide, and the therapy as a viral vertor and/or a non-viral vector. Suitable like); alilusem, ambuside, amiloride, aminometradine, antioxidants are described more fully in the literature, such as aZosemide, bemetiZide, bumetanide, butaZolamide, butiZide, in Goodman and Gilman, The Pharmacological Basis of canrenone, carperitide, chloraminophenamide, chloraZanil, Therapeutics (9th Edition), McGraW-Hill, 1995; and the chlormerodrin, chlorthalidone, cicletanide, clofenamide, clo Merck Index on CD-ROM, Thirteenth Edition; and on STN pamide, clorexolone, conivaptan, daglutril, dichlorophena Express, ?le phar and ?le registry. mide, disulfamide, ethaciynic acid, ethoxZolamide, etoZolon, [0256] In some embodiments the antioxidants are apocy fenoldopam, fenquiZone, furosemide, indapamide, mebutiZ nin, hydralaZine compounds and superoxide dimutase ide, mefruside, meralluride, mercaptomerin sodium, mercu mimetics. mallylic acid, mersalyl, methaZolamide, meticane, metola [0257] Suitable antithrombotic and vasodilator compounds Zone, moZavaptan, muZolimine, N-(5-1,3,4-thiadiaZol-2-yl) include, but are not limited to, abciximab, acetoiphan, acetyl acetamide, nesiritide, pamabrom, para?utiZide, piretanide, salicylic acid, argatroban, bamethan, ben?rodil, benZio protheobromine, quinethaZone, scoparius, spironolactone, darone, betahistine, bisaramil, brovincamine, bufeniode, citi theobromine, ticrynafen, torsemide, torvaptan, triamterene, coline, clobenfurol, clopidogrel, cyclandelate, dalteparin, tripamide, ularitide, xipamide or potassium, AT 189000, AY dipyridamol, droprenilamine, enoxaparin, fendiline, ifen 31906, BG 9928, BG 9791, C 2921, DTI 0017, JDL 961, KW prodil, iloprost, indobufen, isobogrel, isoxsuprine, heparin, 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP lami?ban, midrodine, nadroparin, nicotinoyl alcohol, nylid 120, and the like. Suitable diuretics are described more fully rin, oZagrel, perhexyline, phenylpropanolamine, preny in the literature, such as in Goodman and Gilman, The Phar lamine, papaveroline, reviparin sodium salt, ridogrel, suloc macological Basis of Therapeutics (9th Edition), McGraW tidil, tinofedrine, tinZaparin, trifusal, vintoperol, xanthinal Hill, 1995; and the Merck Index on CD-ROM, 13th Edition; niacinate, and the like. Suitable antithrombotic and vasodila and on STN Express, ?le phar and ?le registry. tor compounds are described more fully in the literature, such [0262] Depending on the diuretic employed, potassium as in Goodman and Gilman, The Pharmacological Basis of may also be administered to the patient in order to optimiZe Therapeutics (9th Edition), McGraW-Hill, 1995; and the the ?uid balance While avoiding hypokalemic alkalosis. The US 2008/0293702 A1 Nov. 27, 2008

administration of potassium can be in the form of potassium logical Basis of Therapeutics (9th Edition), McGraW-Hill, chloride or by the daily ingestion of foods With high potas 1995, Pgs. 901-915; the Merck Index on CD-ROM, 13th sium content such as, for example, bananas or orange juice. Edition; and in WO 00/28988 assigned to NitroMed Inc., the The method of administration of these compounds is disclosures of Which are incorporated herein by reference in described in further detail in US. Pat. No. 4,868,179, the their entirety. disclosure of Which is incorporated by reference herein in its [0269] Suitable neutral endopeptidase inhibitors include, entirety. but are not limited to, atrial natriuretic peptides, diaZapins, [0263] In some embodiments the diuretics are amiloride, aZepinones, ecadotril, fasidotril, fasidotritat, omapatriilat, furosemide, chlorthalidone, hydrochlorothiaZide or triam sampatrilat, BMS 189,921, Z 13752 A, and the like. Neutral terene. In more particular embodiments the amiloride is endopeptidase inhibitors are described more fully in the lit administered as amiloride hydrochloride in an amount of erature, such as in Goodman and Gilman, The Pharmacologi about 5 milligrams to about 15 milligrams as a single dose or cal Basis of Therapeutics (9th Edition), McGraW-Hill, 1995; as multiple doses per day; the furosemide is administered in and the Merck Index on CD-ROM, Thirteenth Edition; and on an amount of about 10 milligrams to about 600 milligrams as STN Express, ?le phar and ?le registry. a single dose or as multiple doses per day; the chlorthalidone [0270] Suitable NSAIDs include, but are not limited to, is administered in an amount of about 15 milligrams to about acetaminophen, acemetacin, aceclofenac, alminoprofen, 150 milligrams as a single dose or as multiple doses per day; amfenac, bendaZac, benoxaprofen, bromfenac, bucloxic acid, the hydrochlorothiaZide is administered in an amount of butibufen, caiprofen, cinmetacin, clopirac, diclofenac, etod about 12.5 milligrams to about 300 milligrams as a single olac, felbinac, fencloZic acid, fenblufen, fenoprofen, fen dose or as multiple doses per day; the triamterene is admin tiaZac, ?unoxaprofen, ?urbiprofen, ibufenac, ibuprofen, istered in an amount of about 35 milligrams to about 225 indomethacin, isofeZolac, isoxepac, indoprofen, ketoprofen, milligrams as a single dose or as multiple doses per day. lonaZolac, loxoprofen, metiaZinic acid, mofeZolac, miropro [0264] Suitable endothelin antagonists include, but are not fen, naproxen, oxaproZin, piroZolac, pirprofen, pranoprofen, limited to, atrasentan, bosentan, darusentan, endothelin, enra protiZinic acid, salicylamide, sulindac, suprofen, suxibuZone, sentan, sitaxsentan, sulfonamide endothelin antagonists, tiaprofenic acid, tolmetin, xenbucin, ximoprofen, Zaltopro teZosentan, BMS 193884, BQ-123, SQ 28608, and the like. fen, Zomepirac, aspirin, acemetcin, bumadiZon, carprofenac, Suitable endothelin antagonists are described more fully in clidanac, di?unisal, enfenamic acid, fendosal, ?ufenamic the literature, such as in Goodman and Gilman, The Pharma acid, ?unixin, gentisic acid, ketorolac, meclofenamic acid, cological Basis of Therapeutics (9th Edition), McGraW-Hill, mefenamic acid, mesalamine, prodrugs thereof, and the like. 1995; and the Merck Index on CD-ROM, Thirteenth Edition; Suitable NSAIDs are described more fully in the literature, and on STN Express, ?le phar and ?le registry. such as in Goodman and Gilman, The Pharmacological Basis [0265] Suitable hydralaZine compounds include, but are of Therapeutics (9th Edition), McGraW-Hill, 1995, Pgs. 617 not limited to, compounds having the formula: 657; the Merck Index on CD-ROM, 13th Edition; and in US. Pat. Nos. 6,057,347 and 6,297,260 assigned to NitroMed Inc., the disclosures of Which are incorporated herein by reference R4 R3 in their entirety. a bl c [0271] In some embodiments the NSAIDs are acetami nophen, diclofenac, ?urbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin. In more particular embodi [0266] Wherein a, b and c are independently a single or ments the acetaminophen is administered in an amount of double bond; R1 and R2 are each independently a hydrogen, about 325 milligrams to about 4 grams as a single dose or as an alkyl, an ester or a heterocyclic ring, Wherein alkyl, ester multiple doses per day; the diclofenac is administered in an and heterocyclic rind are as de?ned herein; R3 and R4 are each amount of about 50 milligrams to about 250 milligrams as a independently a lone pair of electrons or a hydrogen, With the single dose or as multiple doses per day; the ?urbiprofen is proviso that at least one of R1, R2, R3 and R4 is not a hydrogen. administered in an amount of about 100 milligrams to about Exemplary hydralaZine compounds include budralaZine, 300 milligrams as a single dose or as multiple doses per day; cadralaZine, dihydralaZine, endralaZine, hydralaZine, the ibuprofen is administered in an amount of about 400 pildralaZine, todralaZine, and the like. Suitable hydralaZine milligrams to about 3.2 grams as a single dose or as multiple compounds are described more fully in the literature, such as doses per day; the indomethacin is administered in an amount in Goodman and Gilman, The Pharmacological Basis of of about 25 milligrams to about 200 milligrams as a single Therapeutics (9th Edition), McGraW-Hill, 1995; and the dose or as multiple doses per day; the ketoprofen is adminis Merck Index on CD-ROM, Thirteenth Edition; and on STN tered in an amount of about 50 milligrams to about 300 Express, ?le phar and ?le registry. milligrams as a single dose or as multiple doses per day; the [0267] In some embodiments the hydralaZine compound is naproxen is administered in an amount of about 250 milli hydralaZine or a pharmaceutically acceptable salt thereof grams to about 1.5 grams as a single dose or as multiple doses such as hydralaZine hydrochloride. In more particular per day; the aspirin is administered in an amount of about 10 embodiments the hydralaZine is administered as hydralaZine milligrams to about 2 grams as a single dose or as multiple hydrochloride in an amount of about 10 milligrams to about doses per day. 300 milligrams as a single dose or as multiple doses per day. [0272] Suitable phosphodiesterase inhibitors, include but [0268] Suitable H2 receptor antagonists include, but are not are not limited to, ?laminast, piclamilast, rolipram, Org limited to, burimamide, cimetidine, ebrotidine, famotidine, 20241, MCI-154, ro?umilast, toborinone, posicar, lixaZi niZatidine, roxatidine, rantidine, tiotidine, and the like. Suit none, Zaprinast, sildena?l, pyraZolopyrimidinones, motapi able H2 receptor antagonists are described more fully in the Zone, pimobendan, ZardaVerine, siguaZodan, CI-930, EMD literature, such as in Goodman and Gilman, The Pharmaco 53998, imaZodan, saterinone, loprinone hydrochloride, 3-py