US 2010O240622A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/024.0622 A1 Garvey (43) Pub. Date: Sep. 23, 2010

(54) NITRICOXIDE ENHANCING Publication Classification PROSTAGLANDIN COMPOUNDS, (51) Int. Cl. COMPOSITIONS AND METHODS OF USE A6II 3/56 (2006.01) C07D 271/08 (2006.01) A6II 3/42.45 (2006.01) (75) Inventor: David S. Garvey, Dover, MA (US) A6IP27/02 (2006.01) A6IPI3/08 (2006.01) A6IP 9/00 (2006.01) Correspondence Address: A6IPL/04 (2006.01) WILMERHALEANTROMED A6IP 5/04 (2006.01) 1875 PENNSYLVANIAAVE, NW C07D 413/04 (2006.01) WASHINGTON, DC 20006 (US) A 6LX 3/5.377 (2006.01) A63L/454 (2006.01) C07D 265/06 (2006.01) (73) Assignee: NITROMED, INC., Laxington, A 6LX 3/535 (2006.01) MA (US) A 6LX 3/55.75 (2006.01) CD7C 403/10 (2006.01) (52) U.S. Cl...... 514/171; 548/125; 514/364; 54.4/138: (21) Appl. No.: 12/294,642 514/236.2:546/210: 514/326; 544/97: 514/228.8; 514/573; 562/503 (22) PCT Fled: Mar. 19, 2007 (57) ABSTRACT The invention provides compositions and kits comprising at least one nitric oxide enhancing prostaglandin compound ora (86) PCT NO.: PCT/US2007/006749 pharmaceutically acceptable Salt thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one S371 (c)(1), therapeutic agent. The invention also provides methods for (2), (4) Date: Sep. 26, 2008 (a) treating ophthalmic disorders; (b) treating cerebrovascu lar disorders; (c) treating cardiovascular disorders; (d) treat ing benign prostatic hyperplasia (BPH); (e) treating peptic Related U.S. Application Data ulcers; (e) treating sexual dysfunctions and (f) inducing abor tions. The nitric oxide enhancing prostaglandin compounds (60) Provisional application No. 60/786,689, filed on Mar. comprise at least one heterocyclic nitric oxide donor group 29, 2006. and/or at least one nitroxide group. US 2010/024.0622 A1 Sep. 23, 2010

NITRC OXDE ENHANCING example, S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitro PROSTAGLANDIN COMPOUNDS, samines, furoxans, sydnonimines, SPM 3672, SPM 4757, COMPOSITIONS AND METHODS OF USE SPM 5185, SPM 5186 and analogues thereof, substrates of the various isozymes of nitric oxide synthase, and nitroxides. RELATED APPLICATIONS Thus, another embodiment of the invention provides compo 0001. This application claims priority under 35 USC S119 sitions comprising at least one nitric oxide enhancing pros to U.S. Application No. 60/786,689 filed Mar. 29, 2006; the taglandin compound and at least one nitric oxide enhancing disclosure of which is incorporated by reference herein in its compound. The invention also provides for Such composi entirety. tions in a pharmaceutically acceptable carrier. 0006. The invention provides compositions comprising at FIELD OF THE INVENTION least one nitric oxide enhancing prostaglandin compound, and, optionally, at least one nitric oxide enhancing compound 0002 The invention describes compositions and kits com and/or at least one therapeutic agent, including, but not lim prising at least one nitric oxide enhancing prostaglandin com ited to, aldosterone antagonists, C.-adrenergic receptor ago pound or a pharmaceutically acceptable salt thereof, and, nists, C.-adrenergic receptor antagonists, B-adrenergic ago optionally, at least one nitric oxide enhancing compound nists, antidiabetic compounds, antimicrobial compounds, and/or at least one therapeutic agent. The invention also pro antihyperlipidemic drugs, angiotensin II antagonists, angio vides methods for (a) treating ophthalmic disorders; (b) treat tensin-converting enzyme (ACE) inhibitors, antioxidants, ing cerebrovascular disorders; (c) treating cardiovascular dis antithrombotic and vasodilator drugs, B-adrenergic antago orders; (d) treating benign prostatic hyperplasia (BPH); (e) nists, calcium channel blockers, carbonic anhydrase inhibi treating peptic ulcers; (e) treating sexual dysfunctions and (f) tors, diuretics, endothelin antagonists, hydralazine com inducing abortions. The nitric oxide enhancing prostaglandin pounds, H2 receptor antagonists, neutral endopeptidase compounds comprise at least one heterocyclic nitric oxide inhibitors, nonsteroidal antiinflammatory compounds donor group and/or at least one nitroxide group. (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, prostaglandins, proton BACKGROUND OF THE INVENTION pump inhibitors, renin inhibitors, selective cyclooxygenase-2 0003 Most drugs conventionally used to treat ophthalmic (COX-2) inhibitors, steroids, compounds used for the treat disorders have potentially serious side effects Such as blurring ment of glaucoma, and combinations of two or more thereof. of vision and other visual side effects which may lead either The invention also provides for such compositions in a phar to decreased patient compliance or to the termination of maceutically acceptable carrier. therapy. Occasionally systemically administered drugs can 0007 Another embodiment of the invention provides also cause serious side effects, such as nausea, dyspepsia, compositions comprising at least one nitric oxide enhancing fatigue, and metabolic acidosis, which affect patient compli prostaglandin compound, and at least one therapeutic agent ance and/or necessitate the termination of treatment. Addi selected from the group consisting of an O-adrenergic recep tionally, Some B-adrenergic antagonists have increasingly tor antagonist, a B-adrenergic agonist, an antimicrobial com become associated with serious pulmonary side effects attrib pound, a B-adrenergic antagonist, a calcium channel blocker, utable to their effects on B-2 receptors in pulmonary tissue. a carbonic anhydrase inhibitor, a nonsteroidal antiinflamma Hence there is a need in the art for compounds that have tory compound (NSAID), a phosphodiesterase inhibitor, a improved efficacy, lower toxicity and/or fewer side effects potassium channel blocker, a prostaglandin, a proton pump and that can be used at low dosages. The invention is directed inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitor, a to these, as well as other, important ends. steroid, a compound used for the treatment of glaucoma, and combinations of two or more thereof. The invention also SUMMARY OF THE INVENTION provides for Such compositions in a pharmaceutically accept 0004. The invention provides novel nitric oxide enhancing able carrier. prostaglandin compounds that are Substituted with at least 0008. The invention provides methods for(a)treating oph one heterocyclic nitric oxide donor group and/or at least one thalmic disorders; (b) treating cerebrovascular disorders; (c) nitroxide group and pharmaceutically acceptable salts treating cardiovascular disorders; (d) treating benign pros thereof. The prostaglandin compound can be substituted with tatic hyperplasia (BPH); (e) treating peptic ulcers; (e) treating the heterocyclic nitric oxide donor group and/or the nitroxide sexual dysfunctions and (f) inducing abortions in a patient in group through one or more sites Such as oxygen (hydroxyl need thereof comprising administering to the patient an effec condensation), Sulfur (sulfhydryl condensation) and/or nitro tive amount of at least one nitric oxide enhancing prostaglan gen via a bond or moiety that can be hydrolyzed. The hetero din compound, and, optionally, at least one therapeutic agent, cyclic nitric oxide donors are furoxans, Sydnonimines, Such as, for example, aldosterone antagonists, B-adrenergic oXatriazole-5-ones and/or oxatriazole-5-imines. The inven receptor agonists, C.-adrenergic receptor antagonists, B-adr tion also provides compositions comprising the novel com energic agonists, antidiabetic compounds, antimicrobial pounds described herein in a pharmaceutically acceptable compounds, anti-hyperlipidemic drugs, angiotensin II carrier. antagonists, angiotensin-converting enzyme (ACE) inhibi 0005. The invention is also based on the discovery that tors, antioxidants, antithrombotic and vasodilator drugs, administering at least one nitric oxide enhancing prostaglan B-adrenergic antagonists, calcium channel blockers, carbonic din compound (i.e. heterocyclic nitric oxide donor group anhydrase inhibitors, diuretics, endothelin antagonists, and/or nitroxide group), or a pharmaceutically acceptable salt hydralazine compounds. He receptor antagonists, neutral thereof, and, optionally, at least one nitric oxide enhancing endopeptidase inhibitors, nonsteroidal antiinflammatory compound improves the properties of the prostaglandin com compounds (NSAIDs), phosphodiesterase inhibitors, potas pound. Nitric oxide enhancing compounds include, for sium channel blockers, platelet reducing agents, prostaglan US 2010/024.0622 A1 Sep. 23, 2010

dins, proton pump inhibitors, renin inhibitors, selective dry eye disorder, ocular hypertension, ocular bleeding, retinal cyclooxygenase-2 (COX-2) inhibitors, Steroids, compounds diseases or disorders, presbyopia, macular degeneration, cho used for the treatment of glaucoma, and combinations of two roidal neovascularization (CNV), retinopathies, such as for or more thereof. The methods can optionally further com example, diabetic retinopathy, vitreoretinopathy, and the like, prises the administration of at least one nitric oxide enhancing retinitis, such as for example, cytomegalovirus (CMV) retini compound. In this embodiment of the invention, the methods tis, uveitis, macular edema, neuropathies and the like. can involve (i) administering the nitric oxide enhancing pros 0013 “Ophthalmic infections' include, but are not limited taglandin compounds, (ii) administering the nitric oxide to an inflammation of the conjunctiva (conjunctivitis), enhancing prostaglandin compounds and nitric oxide inflammation of the cornea (keratitis), corneal ulcers, and the enhancing compounds, (iii) administering the nitric oxide like, caused by an organisms such as, for example, Staphylo enhancing prostaglandin compounds and therapeutic agents, cocci, Streptococci, Enterococci, Bacillus, Corynebacte or (iv) administering the nitric oxide enhancing prostaglandin rium, Chlamydia, Neisseria, and the like, including important compounds, nitric oxide enhancing compounds, and thera species of these genus Such as, for example, Staphyloccus peutic agents. In one embodiment the at least one therapeutic aureus, Streptococcus viridans, Staphloccus epidermidis, agentis selected from the group consisting of an O-adrenergic Streptococcus pneumoniae, staphylococci, Streptococci, receptor antagonist, a B-adrenergic agonist, an antimicrobial enterococci, and the like. compound, a B-adrenergic antagonist, a calcium channel 0014) “Sexual dysfunction” refers to and includes male blocker, a carbonic anhydrase inhibitor, a nonsteroidal anti erectile dysfunction and female sexual dysfunction. Sexual inflammatory compound (NSAID), a phosphodiesterase dysfunction includes, but is not limited to, for example, inhibitor, a potassium channel blocker, a prostaglandin, a sexual pain disorders, sexual desire disorders, sexual arousal proton pump inhibitor, a selective cyclooxygenase-2 (COX dysfunction, orgasmic dysfunction, dyspareunia, vaginis 2) inhibitor, a steroid, and a compound used for the treatment mus, and the like. of glaucoma. In another embodiment the ophthalmic disorder 0015. “Therapeutic agent” includes any therapeutic agent is glaucoma, elevated ocular pressure, macular degeneration, that can be used to treat or prevent the diseases described ophthalmic infection, dry eye disorder, ocular hypertension, herein. "Therapeutic agents' include, for example, aldoster and diabetic retinopathy. The nitric oxide enhancing prostag one antagonists, C.-adrenergic receptor agonists, C.-adrener landin compounds, nitric oxide enhancing compounds, and/ gic receptor antagonists, f-adrenergic agonists, anti-allergic or therapeutic agents can be administered separately or as compounds, antidiabetic compounds, antimicrobial com components of the same composition in one or more pharma pounds, anti-hyperlipidemic drugs, antitussive compounds, ceutically acceptable carriers. angiotensin II antagonists, angiotensin-converting enzyme 0009. Another embodiment of the invention provides kits (ACE) inhibitors, antioxidants, antithrombotic and vasodila comprising at least one nitric oxide enhancing prostaglandin tor drugs, (3-adrenergic antagonists, bronchodilators, cal compound, and, optionally, at least one nitric oxide enhanc cium channel blockers, carbonic anhydrase inhibitors, diuret ing compound. The kit can further comprise at least one ics, endothelin antagonists, expectorants, hydralazine therapeutic agent, such as, for example, aldosterone antago compounds, H receptor antagonists, neutral endopeptidase nists, C.-adrenergic receptor agonists, C.-adrenergic receptor inhibitors, nonsteroidal antiinfiammatory compounds antagonists, B-adrenergicagonists, antidiabetic compounds, (NSAIDs), phosphodiesterase inhibitors, potassium channel antimicrobial compounds, anti-hyperlipidemic drugs, angio blockers, platelet reducing agents, prostaglandins, proton tensin II antagonists, angiotensin-converting enzyme (ACE) pump inhibitors, renin inhibitors, selective cyclooxygenase-2 inhibitors, antioxidants, antithrombotic and vasodilator (COX-2) inhibitors, steroids, compounds used for the treat drugs, B-adrenergic antagonists, calcium channel blockers, ment of glaucoma, and the like. Therapeutic agent includes carbonic anhydrase inhibitors, diuretics, endothelin antago the pharmaceutically acceptable salts thereof, pro-drugs, and nists, hydralazine compounds. He receptor antagonists, neu pharmaceutical derivatives thereof including, but not limited tral endopeptidase inhibitors, nonsteroidal antiinflammatory to, the corresponding nitrosated and/or nitrosylated and/or compounds (NSAIDs), phosphodiesterase inhibitors, potas heterocyclic nitric oxide donor derivatives and/or nitroxide sium channel blockers, platelet reducing agents, prostaglan derivatives. Although nitric oxide donors have therapeutic dins, proton pump inhibitors, renin inhibitors, selective activity, the term “therapeutic agent” does not include the cyclooxygenase-2 (COX-2) inhibitors, Steroids, compounds nitric oxide donors described herein, since nitric oxide donors used for the treatment of glaucoma, and combinations of two are separately defined. or more thereof. The nitric oxide enhancing prostaglandin 0016 “Prodrug” refers to a compound that is made more compound, the nitric oxide enhancing compound and/or active in vivo. therapeutic agent, can be separate components in the kit or 0017 “Antioxidant’ refers to and includes any compound can be in the form of a composition in one or more pharma that can react and quench a free radical. ceutically acceptable carriers. 0018 Angiotensin converting enzyme (ACE) inhibitor 0010. These and other aspects of the invention are refers to compounds that inhibit an enzyme which catalyzes described in detail herein. the conversion of angiotensin Ito angiotensin II. ACE inhibi tors include, but are not limited to, amino acids and deriva DETAILED DESCRIPTION OF THE INVENTION tives thereof, peptides, including di- and tri-peptides, and 0011. As used throughout the disclosure, the following antibodies to ACE which intervene in the renin-angiotensin terms, unless otherwise indicated, shall be understood to have system by inhibiting the activity of ACE thereby reducing or the following meanings. eliminating the formation of the pressor Substance angio 0012 “Ophthalmic disorders' include, but are not limited tensin II. to, glaucoma, elevated intraocular pressure, ocular pain (e.g., 0019 Angiotensin. II antagonists’ refers to compounds following corneal Surgery), cataracts, ophthalmic infections, which interfere with the function, synthesis or catabolism of US 2010/024.0622 A1 Sep. 23, 2010

angiotensin II. Angiotensin II antagonists include peptide than about 5uM, in the human whole blood COX-2 assay (as compounds and non-peptide compounds, including, but not described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) limited to, angiotensin II antagonists, angiotensin II receptor and also has a selectivity ratio of cyclooxygenase-2 inhibition antagonists, agents that activate the catabolism of angiotensin over cyclooxygenase-1 inhibition of at least 10, and prefer II, and agents that prevent the synthesis of angiotensin I from ably of at least 40. In another embodiment, the compound has angiotensin II. The renin-angiotensin System is involved in a cyclooxygenase-1 ICs of greater than about 1 uM, and the regulation of hemodynamics and water and electrolyte preferably of greater than 20 LM. The compound can also balance. Factors that lower blood volume, renal perfusion inhibit the enzyme, lipoxygenase. Such selectivity may indi pressure, or the concentration of sodium in plasma tend to cate an ability to reduce the incidence of common NSA/D- activate the system, while factors that increase these param induced side effects. eters tend to Suppress its function. 0029. “Patient” refers to animals, preferably mammals, 0020 Anti-hyperlipidemic compounds’ refers to any most preferably humans, and includes males and females, and compound or agent that has the effect of beneficially modi children and adults. fying serum cholesterol levels such as, for example, lowering 0030. “Transdermal refers to the delivery of a compound serum low density lipoprotein (LDL) cholesterol levels, or by passage through the skin and into the blood stream. inhibiting oxidation of LDL cholesterol, whereas high den 0031 “Transmucosal” refers to delivery of a compound by sity lipoprotein (HDL) serum cholesterol levels may be low passage of the compound through the mucosal tissue and into ered, remain the same, or be increased. Preferably, the anti the blood stream. hyperlipidemic compound brings the serum levels of LDL 0032 “Penetration enhancement” or “permeation cholesterol and HDL cholesterol (and, more preferably, trig enhancement” refers to an increase in the permeability of the lyceride levels) to normal or nearly normal levels. skin or mucosal tissue to a selected pharmacologically active 0021 “Diuretic compound” refers to and includes any compound Such that the rate at which the compound perme compound or agent that increases the amount of urine ates through the skin or mucosal tissue is increased. excreted by a patient. 0033 “Carriers' or “vehicles' refers to carrier materials 0022 “Neutral endopeptidase inhibitors’ refers to and Suitable for compound administration and include any Such includes compounds that are antagonists of the renin angio material known in the art such as, for example, any liquid, gel. tensin aldosterone system including compounds that are dual solvent, liquid diluent, solubilizer, or the like, which is non inhibitors of neutral endopeptidases and angiotensin convert toxic and which does not interact with any components of the ing (ACE) enzymes. composition in a deleterious manner. 0023 “Renin inhibitors’ refers to compounds which inter 0034 “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 0024 “Phosphodiesterase inhibitor” or “PDE inhibitor” the active compound are maintained within a desirable thera refers to any compound that inhibits the enzyme phosphodi peutic range over a period of time. The Sustained release esterase. The term refers to selective or non-selective inhibi formulation can be prepared using any conventional method tors of cyclic guanosine 3',5'-monophosphate phosphodi known to one skilled in the art to obtain the desired release esterases (cGMP-PDE) and cyclic adenosine 3',5'- characteristics. monophosphate phosphodiesterases (cAMP-PDE). 0035 “Nitric oxide enhancing refers to compounds and 0025 “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, fibrinolytic 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 0036 “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 0026 “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 0037. “Nitric oxide adduct' or “NO adduct refers to com inhibiting the H/K-ATPase enzyme system at the secretory pounds and functional groups which, under physiological Surface of the gastric parietal cell. conditions, can donate, release and/or directly or indirectly 0027. “NSAID' refers to a nonsteroidal anti-inflamma transfer any of the three redox forms of nitrogen monoxide tory compound or a nonsteroidal anti-inflammatory drug. (NO", NO, NO.), such that the biological activity of the NSAIDs inhibit cyclooxygenase, the enzyme responsible for nitrogen monoxide species is expressed at the intended site of the biosyntheses of the prostaglandins and certain autocoid action. inhibitors, including inhibitors of the various isozymes of 0038 “Nitric oxide releasing or "nitric oxide donating cyclooxygenase (including but not limited to cyclooxyge refers to methods of donating, releasing and/or directly or nase-1 and -2), and as inhibitors of both cyclooxygenase and indirectly transferring any of the three redox forms of nitro lipoxygenase. gen monoxide (NO", NO, NO.), such that the biological 0028 “Cyclooxygenase-2 (COX-2) selective inhibitor” activity of the nitrogen monoxide species is expressed at the refers to a compound that selectively inhibits the cyclooxy intended site of action. genase-2 enzyme over the cyclooxygenase-1 enzyme. In one 0039 “Nitric oxide donor or “NO donor refers to com embodiment, the compound has a cyclooxygenase-2 ICso of pounds that donate, release and/or directly or indirectly trans less than about 2 LM and a cyclooxygenase-1 ICso of greater fera nitrogen monoxide species, and/or stimulate the endog US 2010/024.0622 A1 Sep. 23, 2010

enous production of nitric oxide or endothelium-derived carbon-carbon triple bonds. Exemplary alkynyl groups relaxing factor (EDRF) in vivo and/or elevate endogenous include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1- levels of nitric oxide or EDRF in vivo and/or are oxidized to yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, produce nitric oxide and/or are substrates for nitric oxide hexyl-3-yl, 3.3-dimethyl-butyn-1-yl, and the like. synthase and/or cytochrome P450. "NO donor also includes 0049) “Bridged cycloalkyl” refers to two or more compounds that are precursors of L-arginine, inhibitors of the cycloalkyl groups, heterocyclic groups, or a combination enzyme arginase and nitric oxide mediators. thereof fused via adjacent or non-adjacent atoms. Bridged 0040 “Heterocyclic nitric oxide donor refers to a trisub cycloalkyl groups can be substituted or Substituted with one, stituted 5-membered ring comprising two or three nitrogen two or three substituents independently selected from alkyl, atoms and at least one oxygen atom. The heterocyclic nitric alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, car oxide donor is capable of donating and/or releasing a nitrogen boxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcar monoxide species upon decomposition of the heterocyclic boxylic ester, carboxamido, alkylcarboxamido, oxo and ring. Exemplary heterocyclic nitric oxide donors include nitro. Exemplary bridged cycloalkyl groups include adaman oXatriazol-5-ones, oXatriazol-5-imines, Sydnonimines, tyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3.3.0) furoxans, and the like. octane, 7-Oxabicyclo(2.2.1)heptyl, 8-azabicyclo(3.2.1)oct-2- 0041 Alkyl refers to a lower alkyl group, a substituted enyl and the like. lower alkyl group, a haloalkyl group, a hydroxyalkyl group, 0050 “Cycloalkyl refers to a saturated or unsaturated an alkenyl group, a Substituted alkenyl group, an alkynyl cyclic hydrocarbon comprising from about 3 to about 10 group, a bridged cycloalkyl group, a cycloalkyl group or a carbon atoms. Cycloalkyl groups can be unsubstituted or heterocyclic ring, as defined herein. An alkyl group may also substituted with one, two or three substituents independently comprise one or more radical species, such as, for example a selected from alkyl, alkoxy, amino, alkylamino, dialky cycloalkylalkyl group or a heterocyclicalkyl group. lamino, arylamino, diarylamino, alkylarylamino, aryl, 0042 “Lower alkyl refers to branched or straight chain amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, acyclic alkyl group comprising one to about ten carbonatoms alkylcarboxylic ester, carboxamido, alkylcarboxamido, OXo, (preferably one to about eight carbon atoms, more preferably alkylsulfinyl, and nitro. Exemplary cycloalkyl groups include one to about six carbonatoms). Exemplary lower alkyl groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex include methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, enyl, cyclohepta-1,3-dienyl, and the like. sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, 0051) “Heterocyclic ring or group' refers to a saturated or and the like. unsaturated cyclic hydrocarbon group having about 2 to about 0043 “Substituted lower alkyl refers to a lower alkyl 10 carbon atoms (preferably about 4 to about 6 carbonatoms) group, as defined 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 R' groups, nitrogen, oxygen and/or Sulfur atoms. Sulfur may be in the wherein each R' is independently a hydroxy, an ester, an thio, sulfinyl 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 oran amino group, Heterocyclic groups can be unsubstituted or substituted with as defined herein. one, two or three substituents independently selected from 0044) “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 defined herein, to carboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic which is appended one or more halogens, as defined herein. acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, aryl Exemplary haloalkyl groups include trifluoromethyl, chlo carbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, romethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the arylcarboxamido, Sulfonic acid, Sulfonic ester, Sulfonamide like. nitrate and nitro. Exemplary heterocyclic groups include pyr 0045 “Alkenyl refers to a branched or straight chain rolyl, furyl, thienyl, 3-pyrrolinyl, 4.5,6-trihydro-2H-pyranyl, C-Cohydrocarbon (preferably a C-C hydrocarbon, more pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl pyrim preferably a C-C 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-1-yl, isobutenyl, penten-1- pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, y1, 2.2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, hepten-1-yl, octen-1-yl, and the like. isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadia 0046 “Lower alkenyl refers to a branched or straight Zolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl. chain C-C hydrocarbon that can comprise one or two car morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, pip bon-carbon double bonds. erazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophe 0047. “Substituted alkenyl refers to a branched or nyl, benzimidazolyl, benzothiazolinyl, quinolinyl. 2,6-diox straight chain C-C hydrocarbon (preferably a C-Cs abicyclo(3.3.0)octane, and the like. hydrocarbon, more preferably a C-C hydrocarbon) which 0.052 “Heterocyclic compounds’ refer to mono- and poly 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 R'groups, wherein each R" is 0053 Aryl refers to a monocyclic, bicyclic, carbocyclic independently a hydroxy, an oxo, a carboxyl, a carboxamido, or heterocyclic ring system comprising one or two aromatic a halo, a cyano or an amino group, as defined herein. rings. Exemplary aryl groups include phenyl, pyridyl, 0048 “Alkynyl refers to an unsaturated acyclic C-Co napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, inde hydrocarbon (preferably a C-C hydrocarbon, more prefer nyl, indoyl, and the like. Aryl groups (including bicyclic aryl ably a C-C hydrocarbon) that can comprise one or more groups) can be unsubstituted or Substituted with one, two or US 2010/024.0622 A1 Sep. 23, 2010 three substituents independently selected from alkyl, alkoxy, as defined herein. Exemplary arylalkoxy groups include ben alkylthio, amino, alkylamino, dialkylamino, arylamino, dia Zyloxy, phenylethoxy, chlorophenylethoxy, and the like. rylamino, alkylarylamino, halo, cyano, allylsulfinyl, 0069 Arylalklythio’ refers to an alkylthio group, as hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, defined herein, to which is appended an aryl group, as defined alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxy herein. Exemplary arylalklythio groups include benzylthio. lic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxa phenylethylthio, chlorophenylethylthio, and the like. mido, alkylcarboxamido, carbomyl, Sulfonic acid, Sulfonic (0070 "Arylalklythioalkyl refers to an arylalkylthio ester, Sulfonamido and nitro. Exemplary Substituted aryl group, as defined herein, to which is appended an alkyl group, groups include tetrafluorophenyl, pentafluorophenyl, Sul as defined herein. Exemplary arylalklythioalkyl groups fonamide, alkylsulfonyl, arylsulfonyl, and the like. include benzylthiomethyl, phenylethylthiomethyl, chlo 0054 “Cycloalkenyl refers to an unsaturated cyclic rophenylethylthioethyl, and the like. C-Cohydrocarbon (preferably a C-Cs hydrocarbon, more 0071 Alkylthioalkyl refers to an alkylthio group, as preferably a C-C hydrocarbon) which can comprise one or defined herein, to which is appended an alkyl group, as more carbon-carbon double bonds. defined herein. Exemplary alkylthioalkyl groups include 0055 Alkylaryl refers to an alkyl group, as defined allylthiomethyl, ethylthiomethyl, trifluoroethylthiomethyl, herein, to which is appended an aryl group, as defined herein. and the like. Exemplary alkylaryl groups include benzyl, phenylethyl, 0072 "Alkoxyalkyl refers to an alkoxy group, as defined hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the herein, appended to an alkyl group, as defined herein. Exem like. plary alkoxyalkyl groups include methoxymethyl, methoxy 0056 "Arylalkyl refers to an aryl radical, as defined ethyl, isopropoxymethyl, and the like. herein, attached to an alkyl radical, as defined herein. Exem 0073 "Alkoxyhaloalkyl refers to an alkoxy group, as plary arylalkyl groups include benzyl, phenylethyl, 4-hy defined herein, appended to a haloalkyl group, as defined droxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and the herein. Exemplary alkoxyhaloalkyl groups include 4-meth like. oxy-2-chlorobutyl and the like. 0057 “Arylalkenyl refers to an aryl radical, as defined 0074 “Cycloalkoxy” refers to RO , wherein Rs is a herein, attached to an alkenyl radical, as defined herein. cycloalkyl group or a bridged cycloalkyl group, as defined Exemplary arylalkenyl groups include styryl, propenylphe herein. Exemplary cycloalkoxy groups include cyclopropy nyl, and the like. loxy, cyclopentyloxy, cyclohexyloxy, and the like. 0058 “Cycloalkylalkyl” refers to a cycloalkyl radical, as 0075 "Cycloalkylthio’ refers to RS , wherein Rs is a defined herein, attached to an alkyl radical, as defined herein. cycloalkyl group or a bridged cycloalkyl group, as defined 0059) “Cycloalkylalkoxy' refers to a cycloalkyl radical, as herein. Exemplary cycloalkylthio groups include cyclopro defined herein, attached to an alkoxy radical, as defined pylthio, cyclopentylthio, cyclohexylthio, and the like. herein. 0076 “Haloalkoxy' refers to an alkoxy group, as defined 0060 “Cycloalkylalkylthio’ refers to a cycloalkyl radical, herein, in which one or more of the hydrogen atoms on the as defined herein, attached to an alkylthio radical, as defined alkoxy group are Substituted with halogens, as defined herein. herein. Exemplary haloalkoxy groups include 1,1,1-trichloroethoxy, 0061 “Heterocyclicalkyl refers to a heterocyclic ring 2-bromobutoxy, and the like. radical, as defined herein, attached to an alkyl radical, as 0.077 “Hydroxy” refers to OH. defined herein. 0078 “Oxy” refers to - O - 0062 “Arylheterocyclic ring refers to a bi- or tricyclic 0079 “Oxo” refers to —O. ring comprised of an aryl ring, as defined herein, appended 0080 “Oxylate” refers to —OR," wherein R, is an via two adjacent carbon atoms of the aryl ring to a heterocy organic or inorganic cation. clic ring, as defined herein. Exemplary arylheterocyclic rings 0081) “Thiol” refers to SH. include dihydroindole, 1.2.3,4-tetrahydroquinoline, and the 0082 “Thio’ refers to - S -. like. I0083 “Oxime” refers to —N OR wherein Rs is a 0063 “Alkylheterocyclic ring refers to a heterocyclic hydrogen, an alkyl group, an aryl group, an alkylsulfonyl ring radical, as defined herein, attached to an alkyl radical, as group, an arylsulfonyl group, a carboxylic ester, an alkylcar defined herein. Exemplary alkylheterocyclic rings include bonyl group, an arylcarbonyl group, a carboxamido group, an 2-pyridylmethyl, 1-methylpiperidin-2-one-3-methyl, and the alkoxyalkyl group or an alkoxyaryl group. like. I0084) “Hydrazone” refers to —N N(Rs)(R's) wherein 0064 Alkoxy' refers to Rs.O—, wherein Rs is an alkyl R's is independently selected from Rs, and Rs is as defined group, as defined herein (preferably a lower alkyl group or a herein. haloalkyl group, as defined herein). Exemplary alkoxy I0085. “Hydrazino” refers to HN N(H)– groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, I0086) “Organic cation” refers to a positively charged trifluoromethoxy, and the like. organic ion. Exemplary organic cations include alkyl Substi 0065 'Aryloxy' refers to Rs.O. , wherein Rss is an aryl tuted ammonium cations, and the like. group, as defined herein. Exemplary arylkoxy groups include I0087. “Inorganic cation” refers to a positively charged napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like. metalion. Exemplary inorganic cations include Group I metal 0066 “Alkylthio’ refers to ROS—, wherein Rs is an cations such as for example, sodium, potassium, magnesium, alkyl group, as defined herein. calcium, and the like. 0067 “Lower alkylthio’ refers to a lower alkyl group, as I0088 “Hydroxyalkyl refers to a hydroxy group, as defined herein, appended to a thio group, as defined herein. defined herein, appended to an alkyl group, as defined herein. 0068 Arylalkoxy' or “alkoxyaryl refers to an alkoxy I0089) “Nitrate” refers to - O NO, i.e. oxidized nitro group, as defined herein, to which is appended an aryl group, gen. US 2010/024.0622 A1 Sep. 23, 2010

0090 “Nitrite” refers to - O NO i.e. oxidized nitrogen. 0115 Arylsulfonic acid refers to a sulfonic acid group, 0091) “Thionitrate” refers to —S NO. as defined herein, appended to an aryl group, as defined 0092. “Thionitrite” and “nitrosothiol refer to S NO. herein. 0093. “Nitro” refers to the group - NO, and “nitrosated” I0116 “Sulfonic ester” refers to —S(O)ORs, wherein refers to compounds that have been substituted therewith. Rss is an alkyl group, an aryl group, or an aryl heterocyclic 0094) “Nitroso’ refers to the group - NO and “nitrosy ring, as defined herein. lated refers to compounds that have been substituted there 0117 “Sulfonamido” refers to —S(O) N(Rs) (Rs.), with. wherein Rs and Rs, are each independently a hydrogen 0.095 “Nitrile” and “cyano” refer to CN. atom, an alkyl group, an aryl group or an arylheterocyclic 0096). “Halogen” or “halo” refers to iodine (I), bromine ring, as defined herein, or Rs and Rs, when taken together are (Br), chlorine (Cl), and/or fluorine (F). a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl 0097. “Imine” refers to –C(=N-R) wherein R is group, as defined herein. a hydrogen atom, an alkyl group, an aryl group or an arylhet 0118 “Alkylsulfonamido” refers to a sulfonamido group, erocyclic ring, as defined herein as defined herein, appended to an alkyl group, as defined 0098 “Amine” refers to any organic compound that con herein. tains at least one basic nitrogen atom. 0119 'Arylsulfonamido” refers to a sulfonamido group, 0099 “Amino” refers to NH, an alkylamino group, a as defined herein, appended to an aryl group, as defined dialkylamino group, an arylamino group, a diarylamino herein. group, an alkylarylamino group or a heterocyclic ring, as I0120 Alkylthio’ refers to Rs.S. , wherein Rs is an defined herein. alkyl group, as defined herein (preferably a lower alkyl group, as defined herein). 0100 Alkylamino” refers to RsNH , wherein Rs is an I0121 "Arylthio’ refers to RssS , wherein Rss is an aryl alkyl group, as defined herein. Exemplary alkylamino groups group, as defined herein. include methylamino, ethylamino, butylamino, cyclohexy 0.122 "Arylalkylthio’ refers to an aryl group, as defined lamino, and the like. herein, appended to an alkylthio group, as defined herein. 0101) "Arylamino” refers to RNH , wherein Rss is an I0123 “Alkylsulfinyl refers to Rs S(O)—, wherein Rso aryl group, as defined herein. is an alkyl group, as defined herein. 0102 “Dialkylamino” refers to RsRN , wherein Rs. 0.124 Alkylsulfonyl refers to Rs S(O) , wherein and Rs are each independently an alkyl group, as defined Rso is an alkyl group, as defined herein. herein. Exemplary dialkylamino groups include dimethy I0125 “Alkylsulfonyloxy” refers to Rs S(O), O , lamino, diethylamino, methyl propargylamino, and the like. wherein Rso is an alkyl group, as defined herein. 0103) "Diarylamino” refers to RssRN , wherein Rss I0126 "Arylsulfinyl" refers to Rs. S(O)—, wherein Rss and Reo are each independently an aryl group, as defined is an aryl group, as defined herein. herein. I0127. 'Arylsulfonyl refers to Rss S(O)—, wherein 0104 Alkylarylamino” or “arylalkylamino” refers to Rss is an aryl group, as defined herein. RsRN—, wherein Rs is an alkyl group, as defined herein, I012.8 “Arylsulfonyloxy' refers to Rss S(O). O—, and Rss is an aryl group, as defined herein. wherein Rss is an aryl group, as defined herein. 0105. “Alkylarylalkylamino” refers to RsRN , I0129. “Amidyl” refers to RC(O)N(Rs.)— wherein Rs wherein Rs is an alkyl group, as defined herein, and Rio is an and Rs 7 are each independently a hydrogen atom, an alkyl arylalkyl group, as defined herein. group, an aryl group or an arylheterocyclic ring, as defined 0106 “Alkylcycloallcylamino” refers to RRsN , herein. wherein Rs is an alkyl group, as defined herein, and Rso is a 0.130 “Ester refers to RC(O)Rs— wherein Rs is a cycloalkyl group, as defined herein. hydrogen atom, an alkyl group, an aryl group or an arylhet 0107 “Aminoalkyl refers to an amino group, an alky erocyclic ring, as defined herein and Rs is oxygen or Sulfur. lamino group, a dialkylamino group, an arylamino group, a 0131 “Carbamoyl refers to —O C(O)N(R)(Rs), diarylamino group, an alkylarylamino group or a heterocyclic wherein Rs and Rs, are each independently a hydrogen ring, as defined herein, to which is appended an alkyl group, atom, an alkyl group, an aryl group or an arylheterocyclic as defined herein. Exemplary aminoalkyl groups include dim ring, as defined herein, or Rs and Rs, taken together are a ethylaminopropyl, diphenylaminocyclopentyl, methylami heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl nomethyl, and the like. group, as defined herein. 0108 “Aminoaryl' refers to an aryl group to which is 0.132. “Carboxyl refers to —C(O)OR, wherein R, is a appended an alkylamino group, an arylamino group or an hydrogen, an organic cation oran inorganic cation, as defined arylalkylamino group. Exemplary aminoaryl groups include herein. anilino, N-methylanilino, N-benzylanilino, and the like. I0133). “Carbonyl refers to C(O)-. 0109 "Sulfinyl refers to S(O)-. I0134) “Alkylcarbonyl refers to Rs. C(O)—, wherein 0110 “Methanthial” refers to C(S)-. Rs is an alkyl group, as defined herein. 0111. “Thial refers to —S. I0135 “Arylcarbonyl refers to Rss C(O) , wherein 0112 “Sulfonyl refers to S(O). Rss is an aryl group, as defined herein. 0113 "Sulfonic acid refers to —S(O)OR, wherein Rze 0.136 Arylallcylcarbonyl refers to Rss-Rs C(O)—, is a hydrogen, an organic cation or an inorganic cation, as wherein Rss is an aryl group, as defined herein, and Rs is an defined herein. alkyl group, as defined herein. 0114 Alkylsulfonic acid refers to a sulfonic acid group, 0.137 “Alkylarylcarbonyl refers to Rs-Rss C(O)—, as defined herein, appended to an alkyl group, as defined wherein Rss is an aryl group, as defined herein, and Rs is an herein. alkyl group, as defined herein. US 2010/024.0622 A1 Sep. 23, 2010

0138 “Heterocyclicalkylcarbonyl refer to RC(O)— tives of PGE including, for example, 19-OH-PGE2, 18-OH wherein R-7s is a heterocyclicalkyl group, as defined herein. PGE, 20-OH-PGE and the salts and esters thereof as 0.139. “Carboxylic ester” refers to C(O)ORs, wherein disclosed in WO99/02164, the disclosure of which is incor Rss is an alkyl group, an aryl group or an aryl heterocyclic porated by reference herein in its entirety. Other prostaglan ring, as defined herein. din compound for use in the present invention include iso 0140 “Alkylcarboxylic acid” and “alkylcarboxyl refer to prostanes, such as 8-iso-PGE, 8-iso-PGE, iPF.C.-VI, an alkyl group, as defined herein, appended to a carboxyl 12-iso-PGF2, and the like, as described by, for example, group, as defined herein. Rokach et al Prostaglandins, 54: 823-851, (1997) and 0141 'Alkylcarboxylic ester” refers to an alkyl group, as Rokach et al. Prostaglandins, 54: 853-873, (1997), the dis defined herein, appended to a carboxylic ester group, as closure of which is incorporated by reference herein in its defined herein. entirety. In one embodiment the prostaglandin is selected 0142 Alkyl ester refers to an alkyl group, as defined from the group consisting of arbaprostil, alprostadil, bera herein, appended to an ester group, as defined herein. prost, bimatoprost, carboprost, cloprostenol, dimoxaprost, 0143 Arylcarboxylic acid refers to an aryl group, as dinoprost, enprostil, enisoprost, fluprostenol, fenprostalene, defined herein, appended to a carboxyl group, as defined froxiprost, gemeprost, latanoprost, limaprost, meteneprost, herein. mexiprostil, misoprostol, misoprost, misoprostol acid, noclo 0144) “Arylcarboxylic ester” and “arylcarboxyl refer to prost, ONO373, ornoprostil, prostalene, PGE, PGE PGF, an aryl group, as defined herein, appended to a carboxylic PGF rioprostil, rosaprostol, remiprostol, Sulprostone, taf ester group, as defined herein. luprost, trimoprostil, tiprostanide, travoprost and unopros 0145 'Aryl ester” refers to an aryl group, as defined tone. PGE compounds include, but are not limited to, alpros herein, appended to an ester group, as defined herein. tadil, misoprostol and emprostil and their a-cyclodextrin 0146 “Carboxamido” refers to —C(O)N(Rs)(Rs.), complexes. All the prostaglandins described herein can be wherein Rs and Rs 7 are each independently a hydrogen modified to contain at least one nitric oxide enhancing group atom, an alkyl group, an aryl group or an arylheterocyclic following the methods described herein. ring, as defined herein, or Rs and Rs, when taken together are 0155 The contemplated prostaglandin compounds of the a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl invention are described more fully in the literature, such as in group, as defined herein. Goodman and Gilman, The Pharmacological Basis of Thera 0147 “Alkylcarboxamido” refers to an alkyl group, as peutics (9th Edition), McGraw-Hill, (1996); Merck Index on defined herein, appended to a carboxamido group, as defined CD-ROM, 13" Edition; STN Express, file phar and file reg herein. istry, the disclosures of each of which are incorporated by 0148 Arylcarboxamido” refers to an aryl group, as reference herein in their entirety. defined herein, appended to a carboxamido group, as defined 0156. In one embodiment, the invention describes pros herein. taglandins of Formula (I) and pharmaceutically acceptable 0149 “Urea” refers to N(Rs.) C(O)N(Rs)(Rs.) salts thereof: wherein Rs. Rs 7, and Rs are each independently a hydrogen 0157 wherein the compound of Formula (I) is: atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or Rs and Rs, taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl R (I) group, as defined herein. R R2 Rs 9 0150 “Phosphoryl” refers to - P(R)(R)(R), wherein Rio is a lone pair of electrons, thial or oxo, and R, '-- X and R7 are each independently a covalent bond, a hydrogen, R10 Z Rs a lower alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or an aryl, as defined herein. 0151. “Phosphoric acid” refers to -P(O)(ORs)OH R7 Sks. wherein Rs is a hydrogenatom, an alkyl group, an aryl group R3 R4 or an arylheterocyclic ring, as defined herein. 0152 “Phosphinic acid” refers to -P(O)(R)OH wherein w indicates a single or a double bond; wherein Rs is a hydrogenatom, an alkyl group, an aryl group 0158 R is OD, or - Cl; or an arylheterocyclic ring, as defined herein. 0159 R and R are a hydrogen; or R and R taken 0153 “Silyl” refers to Si(R)(R)(Rs), wherein R. together are —CH or —O; R7 and R-7s are each independently a covalent bond, a lower alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein. (0160 R and Ra are each independently a hydrogen, a 0154 Suitable prostaglandins include, but are not limited fluorine. —OD or —CH, or R and R taken together are to, naturally occurring prostaglandins such as, for example, –O; PGE PGE, PGA, PGB, PGF, PGF, PGE, 19-hy 0.161 Rs and R are each independently a hydrogen, droxy-PGA, 19-hydroxy-PGB, PGE PGA, PGB, 19-hy —OD, —CH, OCH or —CH=CH: droxy-pCA 19-hydroxy-PGB, PGE PGF, PGD, PGI, (0162 R, is a hydrogen or —OD; prostacyclins, thromboxanes, leukotrienes, 6-keto-PGE 0163 R is hydrogen or absent when the carbon to which derivatives and carbacyclin derivatives; or semisynthetic or it is attached is the central carbon of an allene functionality; or synthetic derivatives of natural prostaglandins, including, but Rs and Ro taken together with the chain to which they are not limited to, carboprost tromethamine, dinoprost attached form a substituted benzene ring with the proviso that tromethamine, dinoprostone, gemeprost, metenoprost, Sul R is an oxygenatom which is attached to the carbon atom at prostone and triprost. Also included are the hydroxy deriva the position of the benzene ring defined by B; US 2010/024.0622 A1 Sep. 23, 2010

0164 Rio is a hydrogen; or is absent when the carbon to (0177) V, is: which it is attached is

(1) -CE:

0.165 A is —CH=, —CH2—S —O— or

-CE: (2)

0166 B is —CH=, —CH2, —S , or—C(O)—: (0167 X is —CHOR, C(O)OR or –C(O)N(D) R12: 0168 R is D, a lower alkyl group, or ( )-- ( ) (3)

0169 R is a hydrogen, —CHs: —S(O)CH or —C(O) (4) CH: 0170 Z is (a) an ethyl, (b) abutyl, (c) ahexyl, (d) a benzyl,

(e) 's-n (5) (f) *-n

(g) (6) '',kor O (h) '', (7)

0171 R is a hydrogen, CF or —Cl; 0172 D is a hydrogen or K; with the proviso that at least one D, in formula (I) must be a nitric oxide enhancing group: (0173 K is —(W),E,-(C(R)(R)-E-(C(R)(R)), (8) (W), (C(R)(R)) (Ws),-E-(W), (C(R)(R)). Va: 0174 a, b, c, d, g, i and are each independently an integer from 0 to 3: 0175 p. x, y and Zare each independently an integer from O to 10; 0176 V is V. R. —U Vs Or Ve:

US 2010/024.0622 A1 Sep. 23, 2010

0182 T is oxygen, sulfur or NR; 0183 R is a hydrogen, a lower alkyl group, or an aryl -continued group; (3) 0184 V is:

(1) H3C CH3 (4) N-O Zs CH3 HC (2) H3C CH3 (5) N-O Z6

H3C CH3 (3) H3C CH3

(6) N-O or Z5 HC CH (4) H3C CH3 21 N-O; N (0190. T is a S(O) ; a carbonyl or a covalent bond; HC CH 0191 o is an integer from 0 to 2: (01921 R, and R are independently selected from an alkyl group, an aryl group, or R, and R taken together with the 0185 Z is —CH or oxygen; nitrogen atom to which they are attached are a heterocylic 0186 Z is —CH or nitrogen; ring: 0187 W. at each occurrence is independently —C(O) , 0193 T at each occurrence is independently a covalent —C(S)-, -T-, -(C(R)(R)), , – N(R)R, an alkyl bond, a carbonyl, an oxygen, —S(O) - or —N(R)R. group, an aryl group, a heterocyclic ring, an arylheterocyclic 0194 h is an integer form 1 to 10; 0.195 q is an integer from 1 to 5: ring, -(CH2CH2O) — or a heterocyclic nitric oxide donor; (0196) R, and R, are each independently a hydrogen, an 0188 Eat each occurrence is independently-T-, an alkyl alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, group, an aryl group, —(C(R)(R)), , a heterocyclic ring, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an an arylheterocyclic ring, -(CH2CH2O) — orY.: alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, (0189 Y is: a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky (1) 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 (2) nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar boxylic ester, an arylcarboxylic ester, a Sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U, Vs, V, -(C(R)(R))—Us Vs —(C(R) (R)—Us V, -(C(R)(R)—Us V, -(C(R)(R)) US 2010/024.0622 A1 Sep. 23, 2010

—Us C(O) V, or R, and R, taken together with the 0200 k is an integer from 1 to 3: carbons to which they are attached form a carbonyl, a meth 0201 R is a lone pair of electrons, a hydrogen oran alkyl anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, group; an oxime, an imine, a hydraZone, a bridged cycloalkyl group, 0202 R is a hydrogen, an alkyl, an aryl, an alkylcarboxy lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an (1) arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsul phonyloxy, a Sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH2—C—(U Vs) (R) (R), a bond to an adjacent atom creating a double bond to that atom or —(N2O ).M.", wherein M, is an organic or inor (2) ganic cation; and 0203 with the proviso that the prostaglandin compound of Formula (I) must contain at least heterocyclic nitric oxide donor group and/or nitroxide group linked to the prostaglan din compound of Formula (I) through an oxygen atom, a nitrogen atom or a Sulfur atom via a bond or moiety that can be hydrolyzed. HC CH 0204. In cases where multiple designations of variables which reside in sequence are chosen as a “covalent bond' or (0197) R, and R are each independently a hydrogen, an the integer chosen is 0, the intent is to denote a single covalent alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, bond connecting one radical to another. For example, Eo an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an would denote a covalent bond, while E. denotes (E-E) and alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, (C(R)(R)) denotes —C(R)(R)—C(R)(R)—. a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an 0205 The compound of Formula (I) that contains at least alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an one nitric oxide enhancing group linked to the compound of alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky Formula (I) through an oxygen atom, a nitrogen atom or a lamino, an arylamino, a diarylamino, an alkylarylamino, an Sulfur atom via a bond or moiety that can be hydrolyzed are alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul prodrugs of the parent prostaglandin compound and can be fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio. hydrolyzed to give the parent prostaglandin compound and a an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an moiety that contains the nitric oxide enhancing group. arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, 0206. In other embodiments of the invention the com an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an pound of Formula (I) is a nitric oxide enhancing arbaprostil alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo analogue, a nitric oxide enhancing alprostadil analogue, a nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar nitric oxide enhancing bimatoprost analogue, a nitric oxide boxylic ester, an arylcarboxylic ester, a Sulfonamido, an enhancing carboprost analogue, a nitric oxide enhancing clo alkylsulfonamido, an arylsulfonaxnido, an alkylsulfonyl, an prostenol analogue, a nitric oxide enhancing dimoxaprost alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul analogue, a nitric oxide enhancing dinoprost analogue, a fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, nitric oxide enhancing emprostill analogue, a nitric oxide a nitro, -U, Vs, Vs, or R, and R, taken together with the enhancing enisoprost analogue, a nitric oxide enhancing fen carbons to which they are attached form a carbonyl, a meth prostalene analogue, a nitric oxide enhancing froxiprostana anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, logue, a nitric oxide enhancing gemeprost analogue, a nitric an oxime, an imine, a hydraZone a bridged cycloalkyl group, oxide enhancing latanoprost analogue, a nitric oxide enhanc ing meteneprostanalogue, a nitric oxide enhancing mexipros (1) til analogue, a nitric oxide enhancing misoprostol analogue, a H3C CH3 nitric oxide enhancing misoprostil analogue, a nitric oxide enhancing misoprostol acid analogue, a nitric oxide enhanc ing nocloprost analogue, a nitric oxide enhancing ONO 373 NHO or analogue, a nitric oxide enhancing ornoprostill analogue, a Z5 nitric oxide enhancing prostalene analogue, a nitric oxide CH enhancing PGE analogue, a nitric oxide enhancing PGE HC analogue, a nitric oxide enhancing PGF analogue, a nitric (2) oxide enhancing PGF2, analogue, a nitric oxide enhancing H3C CH3 rioprostil analogue, a nitric oxide enhancing rosaprostol ana logue, a nitric oxide enhancing remiprostol analogue, a nitric oxide enhancing Sulprostone analogue, a nitric oxide enhanc ing tafluprost analogue, a nitric oxide enhancing travoprost analogue, a nitric oxide enhancing trimoprostil analogue, a HC CH nitric oxide enhancing tiprostanide analogue, a nitrosated unoprostone analogue, and pharmaceutically acceptable salts thereof. 0198 Us is an oxygen, Sulfur or —N(R)R, 0207. In other embodiments of the invention the com 0199. Vs is NO or —NO (i.e. an oxidized nitrogen); pound of Formula (I) is a nitric oxide enhancing arbaprostil US 2010/024.0622 A1 Sep. 23, 2010 12 analogue of Formula (II), a nitric oxide enhancing alprostadil 0210 wherein the compound of Formula (IV) is: or PGE analogue of Formula (III), a nitric oxide enhancing bimatoprost analogue of Formula (IV), a nitric oxide enhanc ing carboprost analogue of Formula (V), a nitric oxide enhancing cloprostenol analogue of Formula (VI), a nitric (IV) oxide enhancing dimoxaprost analogue of Formula (VII), a Rim-Rn nitric oxide enhancing dinoprost analogue of Formula (VIII), a nitric oxide enhancing enprostill analogue of Formula (IX), a nitric oxide enhancing enisoprost analogue of Formula (X), N-Y-1 M T-Rn a nitric oxide enhancing femprostalene analogue of Formula (XI), a nitric oxide enhancing froxiprost analogue of Formula Ph (XII), a nitric oxide enhancing gemeprost analogue of For mula (XIII), a nitric oxide enhancing latanoprost analogue of Formula (XIV), a nitric oxide enhancing meteneprost ana logue of Formula (XV), a nitric oxide enhancing mexiprostil analogue of Formula (XVI), a nitric oxide enhancing miso prostol analogue of Formula (XVII), a nitric oxide enhancing 0211 wherein the compound of Formula (V) is: misoprostol acid analogue of Formula (XVIII), a nitric oxide enhancing nocloprost analogue of Formula (XIX), a nitric oxide enhancing ONO 373 analogue of Formula (XX), a nitric oxide enhancing ornoprostil analogue of Formula (V) (XXI), a nitric oxide enhancing prostalene analogue of For mula (XXII), a nitric oxide enhancing PGE analogue of Formula (XXIII), a nitric oxide enhancing PGF analogue of Formula (XXIV), a nitric oxide enhancing PGF analogue of Formula (XXV), a nitric oxide enhancing rioprostil ana logue of Formula (XXVI), a nitric oxide enhancing rosapros tol analogue of Formula (XXVII), a nitric oxide enhancing remiprostol analogue of Formula (XXVIII), a nitric oxide enhancing Sulprostone analogue of Formula (XXIX), a nitric oxide enhancing tafluprost analogue of Formula (XXX), a nitric oxide enhancing travoprost analogue of Formula (XXXI), a nitric oxide enhancing trimoprostil analogue of Formula (XXXII), a nitric oxide enhancing tiprostanide ana 0212 wherein the compound of Formula (VI) is: logue of Formula (XXXIII), a nitric oxide enhancing unopro stone analogue of Formula (XXXIV), and pharmaceutically acceptable salts thereof: 0208 wherein the compound of Formula (II) is:

(II) O O

s Y=1o (CH2)3. T-Rn

(CH2)4-CH

CSV HC O-Rim-Rnh-Pm Rim-Rn

0209 wherein the compound of Formula (III) is: 0213 wherein the compound of Formula (VII) is:

(III) US 2010/024.0622 A1 Sep. 23, 2010 13

0214 wherein the compound of Formula (VIII) is: 0218 wherein the compound of Formula (XII) is:

(VIII)

0215 wherein the compound of Formula (IX) is: 0219 wherein the compound of Formula (XIII) is:

(IX) (XIII)

0216 wherein the compound of Formula (X) is: 0220 wherein the compound of Formula (XIV) is:

(X) (XIV) Rim-Rn / O O . w (CH2) s N=1 23 T-Rn

Ph

Rin - Rin - $ O-R-Rn

0217 wherein the compound of Formula (XI) is: 0221 wherein the compound of Formula (XV) is:

(XI) (XV) US 2010/024.0622 A1 Sep. 23, 2010 14

0222 wherein the compound of Formula (XVI) is: 0226 wherein the compound of Formula (XX) is:

(XVI) (XX)

0223 wherein the compound of Formula (XVII) is: 0227 wherein the compound of Formula (XXI) is:

(XXI)

(XVII) O OMe ls

O-R-Rn

0224 wherein the compound of Formula (XVIII) is: 0228 wherein the compound of Formula (XXII) is:

(XVIII) V (CH2)6 T-Rn (XXII)

O-R-Rn

0225 wherein the compound of Formula (XIX) is:

0229 wherein the compound of Formula (XXIII) is:

(XIX)

(XXIII) O O

w Y-"-o T Rn (CH2)4-CH

6-Rm-Rn 6– Rim Rn US 2010/024.0622 A1 Sep. 23, 2010 15

0230 wherein the compound of Formula (XXIV) is: 0235 wherein the compound of Formula (XXIX) is:

(XXIV) Rim-Rn / O O (XXIX) 2. w(CH2) s S 26 T-Rn

(CH2)4-CH

Rim-Rn n Rim-Rn

0231 wherein the compound of Formula (XXV) is: SRn O-R-RnE (XXV) in-R 0236 wherein the compound of Formula (XXX) is: O O - s N=1 (CH2)23 T-Rn (CH2)4-CH (XXX) s : Rim-Rn CS S / V O-Rim-Rn O O Rim-Rn Y-1 (CH2)3 T-Rn 0232 wherein the compound of Formula (XXVI) is: - Ph w O (XXVI) Rn-Rm-O F F O (CH2)7 s YO-Rm-Rn 0237 wherein the compound of Formula (XXXI) is:

O-R-Rn CH

0233 wherein the compound of Formula (XXVII) is: (XXVII) Rim-Rn M O O (CH2)2 --- Rn 0238 wherein the compound of Formula (XXXII) is: (CH2)5-CH

0234 wherein the compound of Formula (XXVIII) is:

(XXXII) (XXVIII)

T-Rn US 2010/024.0622 A1 Sep. 23, 2010

0239 wherein the compound of Formula (XXXIII) is: 0264 R is: 0265 a hydrogen or:

(XXXIII) (1)

N| Ph O ofO C Or (CH2)4-CH (2) S HC O-Rim-Rn

0240 wherein the compound of Formula (XXXIV) is: (3)

(XXXIV)

(4)

0241 wherein (5) 0242 T is oxygen, sulfur or NR; 0243 nBu is the lower alkyl group CH, CH, CH CH2—, 0244 OEt is the alkoxy group —OCH CH: 0245 OPh is the alkoxy group —OCHs: (6) 0246 Ph is a aryl group —CHs; 0247 R is a hydrogen, a lower alkyl group, an aryl group; 0248 wherein 0249 Re-R, taken together are a hydrogen atom; or (0250 R is: (7) (0251 (i) –C (O)–: 0252 (ii) - C -(O) NR; (0253 (iii) –C(O) O : (0254 (iv) –C(O)–S: 0255 (v) - CH-O : 0256 (vi) -CH(CH)-O-, (8) (0257 (vii) a covalent bond; (0258 (viii) —(C (R)(R)) is : (0259 (ix) (C (R)(R)).s-T-: 10260 (x) (C (R)(R)-s-T-C(O) ; or 0261 (xi) - N C(O) S ; 0262 (xii) - N C(O) CH-; 0263 (xiii) - N C(O)-O-, US 2010/024.0622 A1 Sep. 23, 2010 17

-continued -continued (9) (17) O

T -- - O21 i. N N-R-T-Rs (10) (18) X, O N (Nt \ (11) No N-R-T-Rs

(19)

N"-N (12) t Yo O

(20) H3C CH3

(13) N-O Zs CH3 HC

(21) (14) H3C CH3 N-O N Z6 Nt ( \, HC CH N o1 (22) H3C CH3 (15) Rs N-N N - O Zs

H3C CH3 (16) (23) H3C CH3 US 2010/024.0622 A1 Sep. 23, 2010 18

nitric oxide enhancing enisoprost analogue of Formula -continued (XLIII), a nitric oxide enhancing femprostalene analogue of (24) Formula (XLIV), a nitric oxide enhancing froxiprost ana As R24 logue of Formula (XLV), a nitric oxide enhancing gemeprost analogue of Formula (XLVI), a nitric oxide enhancing latano z 'kl "Y-Y, lo prost analogue of Formula (XLVII), a nitric oxide enhancing ()); N O meteneprost analogue of Formula (XLVIII), a nitric oxide O NNo. enhancing mexiprostill analogue of Formula (XLIX), a nitric oxide enhancing misoprostol analogue of Formula (L), a N2 nitric oxide enhancing misoprostol acid analogue of Formula R24 (LI), a nitric oxide enhancing nocloprostanalogue of Formula (N/ (LII), a nitric oxide enhancing ONO373 analogue of Formula O (LIII), a nitric oxide enhancing ornoprostil analogue of For O (25) mula (LIV), a nitric oxide enhancing prostalene analogue of O Formula (LV), a nitric oxide enhancing PGE analogue of Formula (LVI), a nitric oxide enhancing PGF analogue of y Formula (LVII), a nitric oxide enhancing PGF analogue of O R24 Formula (LVIII), a nitric oxide enhancing rioprostil analogue (K). R24 of Formula (LIX), a nitric oxide enhancing rosaprostol ana kiO logue of Formula (LX), a nitric oxide enhancing remiprostol N. analogue of Formula (LXI), a nitric oxide enhancing Sulpro ()); N O stone analogue of Formula (LXII), a nitric oxide enhancing O NNo. tafluprostanalogue of Formula (LXIII), a nitric oxide enhanc ing travoprost analogue of Formula (LXIV), a nitric oxide Na enhancing trimoprostil analogue of Formula (LXV), a nitric R24 oxide enhancing tiprostanide analogue of Formula (LXVI), a (N/ nitric oxide enhancing unoprostone analogue of Formula O (LXVII), and pharmaceutically acceptable salts thereof; (0278 wherein the compound of Formula (XXXV) is: 0266 Z5 is —CH2 or oxygen; 0267 Z is —CH or nitrogen; (XXXV) 0268 R2 is —CHR-7, —CN. —S(O). CHR-7, O O w (CH2)3 —C(O) N(R)(R), NO. —C(O)—ORs or —S(O) w N=1 R45 R2s: 0269 Rs is an aryl group, a lower alkyl group, a haloalkyl (CH2)4-CH group, a hydroxyalkyl group or an arylalkyl group; 0270 R is C(O)—or —S(O) ; 0271 R, is a hydrogen, —CN.—S(O) Rs. —C(O)— R HC O-R N(R)(R), —NO or —C(O)—ORs: R46 0272 T is oxygen, sulfur or NR; 0273 R is a hydrogen, a lower alkyl group, or an aryl (0279 wherein the compound of Formula (XXXVI) is: group; (XXXVI) 0274 k is an integer from 1 to 3: (0275 R, and R are independently selected from an alkyl group, an aryl group, or R, and R, taken together with the nitrogen atom to which they are attached are a heterocylic ring; and 0276 with the proviso that the compounds of Formula (II) to Formula (XXXIV) must contain at least one nitric oxide enhancing group linked to the compounds of Formula (II) to Formula (XXXIV) via a bond or moiety that can be hydro lyzed. (0280 wherein the compound of Formula (XXXVII) is: 0277. In other embodiments of the invention the com R4 (XXXVII) pound of Formula (I) is a nitric oxide enhancing arbaprostil 6 analogue of Formula (XXXV), a nitric oxide enhancing / alprostadil or PGE analogue of Formula (XXXVI), a nitric O O . w (CH2)3. oxide enhancing bimatoprost analogue of Formula (XXX Y N=1 R45 VII), a nitric oxide enhancing carboprost analogue of For mula (XXXVIII), a nitric oxide enhancing cloprostenol ana 21 Ph logue of Formula (XXXIX), a nitric oxide enhancing dimoxaprost analogue of Formula (XL), a nitric oxide R46-O O-R enhancing dinoprost analogue of Formula (XLI), a nitric oxide enhancing emprostil analogue of Formula (XLII), a US 2010/024.0622 A1 Sep. 23, 2010 19

(0281 wherein the compound of Formula (XXXVIII) is: 0286 wherein the compound of Formula (XLIII) is:

(XXXVIII)

, (XLIII) O O , s N=1 (CH2)3. R45

(CH2)4-CH3 R Hyd o-Ri.

0282 wherein the compound of Formula (XXXIX) is:

(XXXIX) 0287 wherein the compound of Formula (XLIV) is:

(XLIV)

0283 wherein the compound of Formula (XL) is:

i R46

0288 wherein the compound of Formula (XLV) is:

(XLV) 0284 wherein the compound of Formula (XLI) is:

R4 (XLI) M 6 O O 2. w (CH2)3. Y N=1 R45 CH R-O 6- R46 0285 wherein the compound of Formula (XIII) is: (0289 wherein the compound of Formula (XLVI) is:

(XLII) (XLVI) US 2010/024.0622 A1 Sep. 23, 2010 20

0290 wherein the compound of Formula (XLVII) is: 0294 wherein the compound of Formula (LI) is:

R4 (XLVII) (LI) / 6 O O . W N=1 (CH2)3. R45

Ph R-O 6- R46

0291 wherein the compound of Formula (XLVIII) is: 0295 wherein the compound of Formula (LII) is:

(XLVIII) (LII)

0292 wherein the compound of Formula (XLIX) is: 0296 wherein the compound of Formula (LIII) is:

(XLIX) R46 (LIII) A O O w w N=1 (CH2)3. R45 (CH2)4-CH R Hyd b-R R46

0297 wherein the compound of Formula (LIV) is: 0293 wherein the compound of Formula (L) is:

(LIV)

(L) US 2010/024.0622 A1 Sep. 23, 2010

0298 wherein the compound of Formula (LV) is: 0302 wherein the compound of Formula (LIX) is:

(LV) (LIX)

0303 wherein the compound of Formula (LX) is:

(L) 0299 wherein the compound of Formula (LVI) is: O O

(LVI) (CH2)5-CH 0304 wherein the compound of Formula (LXI) is:

(LI)

0300 wherein the compound of Formula (LVII) is:

R4 (LVII) M 6 (0305 wherein the compound of Formula (LXIII) is: O O . (CH2)6 NL R45 (LXII) (CH2)4-CH

R46 SR

0301 wherein the compound of Formula (LVIII) is:

(LVIII) 0306 wherein the compound of Formula (LXIII) is: R46 M O O (LXIII) 2. w N=1 (CH2)3. R45 (CH2)4-CH

V O-R US 2010/024.0622 A1 Sep 23, 2010 22

0307 wherein the compound of Formula (LXIV) is: 0314 OPh is the alkoxy group —OCHs: 0315 Ph is an aryl group —CHs: (LXIV) 0316 Rs is:

(1) R4s y O 1-9 ? ( N-No

(2) 0308 wherein the compound of Formula (LXV) is:

(LXV)

(3)

0309 wherein the compound of Formula (LXVI) is: (4)

(LXVI) N R49 - N R65 O O X--- (CH2)6 -I- O O (5) -OH: (CH2)4-CH3 (6) s^X. H3C CH3

0310 wherein the compound of Formula (LXVII) is: --O-H3C CH3

(LXVII) (7) O H3C CH3 O O w (CH2)3 N-1No N=1 NL R45 N-O (CH2)6-CH3 H3C CH3 (8) H3C CH3 O wherein: N-O 0311 nBu is the lower alkyl group CH CH-CH CH-. 0312 OMe is the alkoxy group —O CH: HC CH 0313 OEt is the alkoxy group —OCH CH: US 2010/024.0622 A1 Sep. 23, 2010 23

-continued -continued (9) (4)

O -(N-6ski Z. iO R4s ), \ -O O NN/

Na R4 O M 8 (5)

(10)

(6)

O NN/ (7) N2 (N4 R48 O (8) 0317 Ras is —S(O). CHs: —CN, —C(O) NH or —C(O)CCH, and 0318 Rao is a hydrogen or chlorine; 0319 Rs is a hydrogen or a methyl group: 0320 k is an integer from 1 to 3: (9) 0321 Z is CH or nitrogen; 0322 Rae is:

(1)

(10)

(2)

(11) (3) US 2010/024.0622 A1 Sep. 23, 2010 24

-continued -continued (12) O (19) O

O N-N O R4s (S)- R4s N -ko1 \ R65 O k O (7): N O O -O O NN/ (13) Na (b. 4 R48 O O O N- NtW O (20) x -->f O R66 O R48 (14) (S)- R48 O k O (2): N O -O (15) O NN/ N2 6-4 R48 O (21) R66

(16) O -N-ONZ \ kiO R4s O ()); N -O O NN/

Na (N/ R4s (17) O

0323 wherein: 0324 R is —(CH), O C(O)—CH or —(CH), NH C(O)-CH: 0325 R, is –CN, -C(O) NH or - C(O) OCH: 0326 Rao, Rs. Z and k are as defined herein; and (18) 0327 with the proviso that the compounds of Formula (XXXV) to (LXVII) must contain at least one nitric oxide enhancing group linked to the compounds of Formula (XXXV) to (LXVII) via a bond or moiety that can be hydro lyzed. 0328 Compounds of the invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric race mates. It is to be understood that the invention anticipates and includes within its scope all Such isomers and mixtures thereof. US 2010/024.0622 A1 Sep. 23, 2010

0329. Another embodiment of the invention describes the Forsch. Drug Res., 47 (II): 847-854 (1997); the disclosures of metabolites of the nitric oxide enhancing prostaglandin com each of which are incorporated by reference herein in their pounds and pharmaceutically acceptable salts thereof. These entirety. The methods of linking the nitric oxide enhancing metabolites, include but are not limited to, the non-nitric group to compounds described in these references can be oxide enhancing derivatives, degradation products, hydroly applied by one skilled in the art to produce any of the nitric sis products, and the like, of the nitric oxide enhancing pros oxide enhancing prostaglandin compounds described herein. taglandin compounds and pharmaceutically acceptable salts The prostaglandin compounds of the invention comprising at thereof. least one nitric oxide enhancing group donate or transfer a 0330. Another embodiment of the invention provides pro biologically active form of nitrogen monoxide (i.e., nitric cesses for making the novel compounds of the invention and oxide). to the intermediates useful in Such processes. The reactions 0333 Compounds contemplated for use in the invention, are performed in solvents appropriate to the reagents and e.g., prostaglandin compounds that contain at least one nitric materials used are suitable for the transformations being oxide enhancing group, linked through one or more sites Such effected. It is understood by one skilled in the art of organic as oxygen (hydroxyl condensation), Sulfur (sulfhydryl con synthesis that the functionality present in the molecule must densation) and/or nitrogen, via a bond or moiety that is hydro be consistent with the chemical transformation proposed. lyzed, are, optionally, used in combination with nitric oxide This will, on occasion, necessitate judgment by the routineer enhancing compounds that release nitric oxide, increase as to the order of synthetic steps, protecting groups required, endogeneous levels of nitric oxide or otherwise directly or and deprotection conditions. Substituents on the starting indirectly deliver or transfer a biologically active form of materials may be incompatible with some of the reaction nitrogen monoxide to a site of its intended activity. Such as on conditions required in some of the methods described, but a cell membrane in vivo. alternative methods and substituents compatible with the 0334 Nitrogen monoxide can exist in three forms: NO reaction conditions will be readily apparent to one skilled in (nitroxyl), NO. (nitric oxide) and NO" (nitrosonium). NO. is the art. The use of sulfur and oxygen protecting groups is well a highly reactive short-lived species that is potentially toxic to known for protecting thiol and alcohol groups against unde cells. This is critical because the pharmacological efficacy of sirable reactions during a synthetic procedure and many Such NO depends upon the form in which it is delivered. In contrast protecting groups are known and described by, for example, to the nitric oxide radical (NO.), nitrosonium (NO") does not Greene and Wuts, Protective Groups in Organic Synthesis, react with O. or O - species, and functionalities capable of Third Edition, John Wiley & Sons, New York (1999). transferring and/or releasingNO" and NO are also resistant 0331. The chemical reactions described herein are gener to decomposition in the presence of many redox metals. Con ally disclosed in terms of their broadest application to the sequently, administration of charged NO equivalents (posi preparation of the compounds of this invention. Occasionally, tive and/or negative) does not result in the generation of toxic the reactions may not be applicable as described to each by-products or the elimination of the active NO group. compound included within the disclosed scope. The com 0335 The term "nitric oxide encompasses uncharged pounds for which this occurs will be readily recognized by nitric oxide (NO—) and charged nitrogen monoxide species, one skilled in the art. In all such cases, either the reactions can preferably charged nitrogen monoxide species. Such as be successfully performed by conventional modifications nitrosonium ion (NO") and nitroxyl ion (NO). The reactive known to one skilled in the art, e.g., by appropriate protection form of nitric oxide can be provided by gaseous nitric oxide. of interfering groups, by changing to alternative conventional The nitrogen monoxide releasing, delivering or transferring reagents, by routine modification of reaction conditions, and compounds have the structure F NO, wherein F is a nitrogen the like, or other reactions disclosed herein or otherwise con monoxide releasing, delivering or transferring group, and ventional, will be applicable to the preparation of the corre include any and all Such compounds which provide nitrogen sponding compounds of this invention. In all preparative monoxide to its intended site of action in a form active for its methods, all starting materials are known or readily prepared intended purpose. from known starting materials. 0336. The term “NO adducts’ encompasses any nitrogen 0332 The compounds of Formulas (I) to (LVII) can be monoxide releasing, delivering or transferring compounds, synthesized by one skilled in the art using conventional meth including, for example, S-nitrosothiols, nitrites, nitrates, ods. Some of the parent prostaglandin compounds (i.e. pros S-nitrothiols, Sydnonimines, 2-hydroxy-2-nitrosohydra taglandin compounds that do not contain a nitric oxide zines, (NONOates), (E)-alkyl-2-((E)-hydroxyimino)-5-ni enhancing group) are commercially available or their synthe tro-3-hexeneamide (FK-409), (E)-alkyl-24(E)-hydroxy sis has been reported in the Scientific literature. The prostag imino)-5-nitro-3-hexeneamines, N-((2Z.3E)-4-ethyl-2- landin compounds that are Substituted to contain a nitric (hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3- oxide enhancing group linked to the prostaglandin compound pyridinecarboxamide (FR 146801), N-nitrosoamines, through one or more sites such as oxygen, Sulfur and/or N-hydroxyl nitrosamines, nitrosimines, diazetine dioxides, nitrogen via a bond or moiety that can be hydrolyzed, can be oXatriazole 5-imines, OXimes, hydroxylamines, N-hydrox synthesized using conventional methods known to one skilled yguanidines, hydroxyureas, benzofuroxanes, furoxans as in the art. Known methods for linking the nitric oxide enhanc well as Substrates for the endogenous enzymes which synthe ing groups to compounds are described in WO99/64417, WO size nitric oxide. 94/O1422; EP 0574726A1. EPO 683 159 A1; and in J. Med. 0337 Suitable NONOates include, but are not limited to, Chem., 47:2688-2693 (2004); J. Med Chem., 47: 1840-1846 (Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino)) (2004); J. Med. Chem., 46:3762-3765 (2003); J. Med. Chem., diazen-1-ium-1,2-diolate (“MAHMA/NO”), (Z)-1-(N-(3- 46: 747-754 (2003); Chem. Rev., 102: 1091-1134 (2002); J. ammoniopropyl)-N-(n-propyl)amino)diaZen-1-ium-1,2-di Med. Chem., 42: 1941-1950 (1999); J. Med. Chem., 41:5393 olate (“PAPA/NO”), (Z)-1-(N-(3-aminopropyl)-N-(4-(3- 5401 (1998); J. Med. Chem., 38: 4944-4949 (1995): Arzneim. aminopropylammonio)butyl)-amino) diazen-1-ium-1,2- US 2010/024.0622 A1 Sep. 23, 2010 26 diolate (spermine NONOate or “SPER/NO”) and sodium(Z)- (0347 (iii) HN CH(COH)–(CH), C(O)NH-CH 1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamine (CHSNO) C(O)NH CH, COH: NONOate or “DEA/NO”) and derivatives thereof. NON 0348 wherein m is an integer from 2 to 20; Oates are also described in U.S. Pat. Nos. 6,232,336, 5,910, 316 and 5,650,447, the disclosures of which are incorporated (0349 R and R, are each independently a hydrogen, an herein by reference in their entirety. The “NO adducts’ can be alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/ an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an or poly-nitrosated at a variety of naturally susceptible or alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, artificially provided binding sites for biologically active a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an forms of nitrogen monoxide. alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an 0338 Suitable furoxanes include, but are not limited to, alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky CAS 1609, C93-4759, C92-4678, S35b, CHF 2206, CHF lamino, an arylamino, a diarylamino, an alkylarylamino, an 2363, and the like. alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul 0339 Suitable sydnonimines include, but are not limited fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio. to, molsidomine (N-ethoxycarbonyl-3-morpholinosydnon an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an imine), SIN-1 (3-morpholinosydnonimine) CAS 936 (3-(cis arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, 2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnon an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an imine, pirsidomine), C87-3754 (3-(cis-2,6- alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo dimethylpiperidino)sydnonimine, linsidomine, C4144 (3-(3. nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar 3-dimethyl-1,4-thiazane-4-yl)sydnonimine hydrochloride), boxylic ester, an arylcarboxylic ester, a Sulfonamido, an C89-4095 (3-(3.3-dimethyl-1,1-dioxo-1,4-thiazane-4-yl) alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an sydnonimine hydrochloride, and the like. alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul 0340 Suitable oximes include, but are not limited to, fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, NOR-1, NOR-3, NOR-4, and the like. a nitro, -U, Vs, V, -(C(R)(R)—Us Vs., -(C(R) 0341 One group of NO adducts is the S-nitrosothiols, (R), U, V, -(C(R)(R)). Us C(O) V, or R. which are compounds that include at least one —S NO and R, taken together with the carbons to which they are group. These compounds include S-nitroso-polypeptides (the attached form a carbonyl, a methanthial, a heterocyclic ring, term “polypeptide' includes proteins and polyamino acids a cycloalkyl group, an aryl group, an oxime, a hydraZone, a that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including bridged cycloalkyl group, natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated Sugars; S-nitrosylated, modified and unmodified, oligonucle (1) otides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, Substituted or unsubstituted S-nitrosy lated hydrocarbons; and S-nitroso heterocyclic compounds. S-nitrosothiols and methods for preparing them are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al. Org. Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures of each of which are incor (2) porated by reference herein in their entirety. 0342 Another embodiment of the invention is S-nitroso amino acids where the nitroso group is linked to a Sulfur group of a Sulfur-containing amino acid or derivative thereof. Such compounds include, for example, S-nitroso-N-acetyl cysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicil lamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-ni HC CH troso-glutathione, S-nitroso-cysteinyl-glycine, and the like. 0343 Suitable S-nitrosylated proteins include thiol-con 10350 R and R are each independently a hydrogen, an taining proteins (where the NO group is attached to one or alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, more Sulfur groups on an amino acid oramino acid derivative an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an thereof) from various functional classes including enzymes, alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, Such as tissue-type plasminogen activator (TPA) and cathep a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an sin B; transport proteins, such as lipoproteins; heme proteins, alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an Such as hemoglobin and serum albumin; and biologically alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky protective proteins, such as immunoglobulins, antibodies and lamino, an arylamino, a diarylamino, an alkylarylamino, an cytokines. Such nitrosylated proteins are described in WO alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul 93/09806, the disclosure of which is incorporated by refer fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio. ence herein in its entirety. Examples include polynitrosylated an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an albumin where one or more thiol or other nucleophilic centers arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, in the protein are modified. an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an 0344) Other examples of suitable S-nitrosothiols include: alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo (0345 (i) HS(C(R)(R)), SNO; nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar (0346) (ii) ONS(C(R)(R)), R.; or boxylic ester, an arylcarboxylic ester, a Sulfonamido, an US 2010/024.0622 A1 Sep. 23, 2010 27 alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an natural and synthetic amino acids and their stereoisomers and alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul racemic mixtures); ON O - or ON N-sugars; ON O— fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, or —ON N— modified or unmodified oligonucleotides a nitro, -U, Vs, V, or R, and R taken together with the (comprising at least 5 nucleotides, preferably 5-200 nucle carbons to which they are attached form a carbonyl, a meth otides); ON O— or ON N straight or branched, satu anthial, a heterocyclic ring, a cycloalkyl group, an aryl group, rated or unsaturated, aliphatic or aromatic, Substituted or an oxime, an imine, a hydraZone, a bridged cycloalkyl group, unsubstituted hydrocarbons; and ON O—, ON N— or ON C-heterocyclic compounds. Examples of compounds comprising at least one ON O— or ON N-group include (1) butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, H3C CH3 isoamyl nitrite, N-nitrosamines, N-nitrosamides, N-ni trosourea, N-nitrosoguanidines, N-nitrosocarbamates, N-acyl-N-nitroso compounds (such as, N-methyl-N-ni N-O or trosourea); N-hydroxy-N-nitrosamines, cupferron, Zs alanosine, dopastin, 1.3-disubstituted nitrosiminobenzimida CH3 Zoles, 1,3,4-thiadiazole-2-nitrositnines, benzothiazole-2 HC (3H)-nitrosimines, thiazole-2-nitrosimines, oligonitroso Syd (2) nonimines, 3-alkyl-N-nitroso-Sydnonimines, 2H-1,3,4- H3C CH3 thiadiazine nitrosimines. 0359 Another group of NO adducts for use in the inven tion include nitrates that donate, transfer or release nitric N-O; oxide, such as compounds comprising at least one ON O—, ON.—N— or ON S-group. Among these com H3C CH3 pounds are ON O—, ON N or ON. S. polypep tides (the term “polypeptide' includes proteins and also polyamino acids that do not possess an ascertained biological 0351 k is an integer form 1 to 3: function, and derivatives thereof); ON O—, ON N— or 0352 U is an oxygen, sulfur- or N(R)R.; ON-S-amino acids (including natural and synthetic 0353 Vs is NO or - NO (i.e. an oxidized nitrogen); amino acids and their stereoisomers and racemic mixtures); 0354 R is a lone pair of electrons, a hydrogen or an alkyl ON O ON N— or ON S sugars; ON O , group; ON N or ON S modified and unmodified oligo 0355 R, is a hydrogen, an alkyl, an aryl, an alkylcarboxy nucleotides (comprising at least 5 nucleotides, preferably lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an 5-200 nucleotides); ON-O-, ON N- or ON-S arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa straight or branched, Saturated or unsaturated, aliphatic or mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an aromatic, Substituted or unsubstituted hydrocarbons; and alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulpho ON O ON N— or ON. S. heterocyclic com nyloxy, a Sulfonamido, a carboxamido, a carboxylic ester, an pounds. Examples of compounds comprising at least one aminoalkyl, an aminoaryl, -CH, C(U, Vs)(R)(R), a ON O ON N or ON S group include isosor bond to an adjacent atom creating a double bond to that atom bide dinitrate, isosorbide mononitrate, clonitrate, erythrityl or —(N.O. ).M.", wherein M is an organic or inorganic tetranitrate, mannitol hexanitrate, nitroglycerin, pentaeryth cation. ritoltetranitrate, pentrinitrol, propatylnitrate and organic 0356. In cases where R and Rare independently a het nitrates with a sulfhydryl-containing amino acid such as, for erocyclic ring or taken together R, and Rare a heterocyclic example SPM 3672, SPM 4757, SPM 5185, SPM 5186 and ring, then R, can be a substituent on any disubstituted nitrogen those disclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661, contained within the radical wherein R, is as defined herein. 129, 5,807,847 and 5,883,122 and in WO 97/46521, WO 0357 Nitrosothiols can be prepared by various methods of 00/54756 and in WO 03/013432, the disclosures of each of synthesis. In general, the thiol precursor is prepared first, then which are incorporated by reference herein in their entirety. converted to the S-nitrosothiol derivative by nitrosation of the 0360 Another group of NO adducts are N-oxo-N-ni thiol group with NaNO under acidic conditions (pH is about troSoamines that donate, transfer or release nitric oxide and 2.5) which yields the S-nitroso derivative. Acids which can be are represented by the formula: R'"R"N N(O-M'))-NO, used for this purpose include aqueous Sulfuric, acetic and where R'" and Rare each independently a polypeptide, an hydrochloric acids. The thiol precursor can also be nitrosy amino acid, a Sugar, a modified or unmodified oligonucle lated by reaction with an organic nitrite Such as tert-butyl otide, a straight or branched, saturated or unsaturated, ali nitrite, or a nitrosonium salt Such as nitrosonium tetrafluo phatic or aromatic, Substituted or unsubstituted hydrocarbon, roborate in an inert solvent. or a heterocyclic group, and where M is an organic or 0358 Another group of NO adducts for use in the inven inorganic cation, such, as for example, an alkyl Substituted tion, where the NO adduct is a compound that donates, trans ammonium cation or a Group I metal cation. fers or releases nitric oxide, include compounds comprising 0361. The invention is also directed to compounds that at least one ON O— or ON N— group. The compounds stimulate endogenous NO or elevate levels of endogenous that include at least one ON O— or ON N-group are endothelium-derived relaxing factor (EDRF) in vivo or are preferably ON O— or ON N-polypeptides (the term oxidized to produce nitric oxide and/or are substrates for "polypeptide' includes proteins and polyamino acids that do nitric oxide synthase and/or cytochrome P450. Such com not possess an ascertained biological function, and deriva pounds include, for example, L-arginine, L-homoarginine, tives thereof); ON O - or ON N-amino acids (including and N-hydroxy-L-arginine, N-hydroxy-L-homoarginine, US 2010/024.0622 A1 Sep. 23, 2010 28

N-hydroxydebrisoquine, N-hydroxypentamidine including 0363 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, nitrosylated 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, C.-adrenergic pounds, amidoxime, ketoximes, aldoxime compounds, that receptor agonists, C.-adrenergic receptor antagonists, B-adr can be oxidized in vivo to produce nitric oxide. Compounds energic agonists, antidiabetic compounds, antimicrobial that may be substrates for a cytochrome P450, include, for compounds, anti-hyperlipidemic drugs, angiotensin II example, imino(benzylamino)methylhydroxylamine, imino antagonists, angiotensin-converting enzyme (ACE) inhibi (((4-methylphenyl)methyl)amino)methylhydroxylamine, tors, antioxidants, antithrombotic and vasodilator drugs, imino(((4-methoxyphenyl)methyl)amino) methylhydroxy B-adrenergic antagonists, calcium channel blockers, carbonic lamine, imino(((4-(trifluoromethypphenyl)methyl)amino) anhydrase inhibitors, diuretics, endothelin antagonists, methylhydroxylamine, imino(((4-nitrophenyl)methyl) hydralazine compounds, H receptor antagonists, neutral amino)methylhydroxylamine, (butylamino) iminornethythy endopeptidase inhibitors, nonsteroidal antiinflammatory droxylamine, imino (propylamino) methylhydroxylamine, compounds (NSAIDs), phosphodiesterase inhibitors, potas imino(pentylamino)methylhydroxylamine, imino (propy sium channel blockers, platelet reducing agents, prostaglan lamino)methylhydroxylamine, imino (methylethyl)amino) dins, proton pump inhibitors, renin inhibitors, selective methylhydroxylamine, (cyclopropylamino) iminomethylhy cyclooxygenase-2 (COX-2) inhibitors, Steroids, compounds droxylamine, imino-2-1,2,3,4-tetrahydroisoquinolyl used for the treatment of glaucoma, and combinations of two methylhydroxylamine, imino(1-methyl(2-1.2.3,4-tetrahy or more thereof. droisoquinolyl))methylhydroxylamine, (1,3-dimethyl(2-1.2. 0364 Suitable aldosterone antagonists include, but are not 3,4-tetrahydroisoquinolyl)) iminomethylhydroxylamine, limited to, canrenone, potassium canrenoate, drospirenone, (((4-chlorophenyl)methyl)amino)iminomethylhydroxy spironolactone, eplerenone (INSPRAR), epoxymexrenone, lamine, ((4-chlorophenyl)amino) iminomethylhydroxy fadrozole, pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy lamine, (4-chlorophenyl)(hydroxyimino) methylamine, and 17-hydroxy-3-oxo, Y-lactone, methyl ester, (7C.11C. 17 B.)-; 1-(4-chlorophenyl)-1-(hydroxyimino) ethane, and the like, pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hy precursors of L-arginine and/or physiologically acceptable droxy-3-oxo-dimethyl ester, (7C.11C. 17 B.)-; 3'H-cyclopropa salts thereof, including, for example, citruline, ornithine, (6.7)pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7- glutamine, lysine, polypeptides comprising at least one of dihydro-17-hydroxy-3-oxo-, y-lactone, (6,3,7B...11C.17(3)-; these amino acids, inhibitors of the enzyme arginase (e.g., pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hy N-hydroxy-L-arginine and 2CS)-amino-6-boronohexanoic droxy-3-oxo-, 7-(1-methylethyl) ester, monopotassium salt, acid), nitric oxide mediators and/or physiologically accept (7C.11C. 17 B.)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11 able salts thereof, including, for example, pyruvate, pyruvate epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium precursors, a-keto acids having four or more carbon atoms, salt, (7C,11C. 17 B.)-; 3'H-cyclopropa(6.7) pregna-1,4,6- precursors of a-keto acids having four or more carbon atoms triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hy (as disclosed in WO 03/017996, the disclosure of which is droxy-3-oxo-, y-lactone, (6?.7(3,11C)-; 3'H-cyclopropa(6.7) incorporated herein in its entirety), and the substrates for pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7- nitric oxide synthase, cytokines, adenosin, bradykinin, cal dihydro-17-hydroxy-3-oxo-, methyl ester, (6?.7f8,11C. 17(3)-; reticulin, bisacodyl, and phenolphthalein. EDRF is a vascular 3'H-cyclopropa (6.7)pregna-4,6-diene-21-carboxylic acid, relaxing factor Secreted by the endothelium, and has been 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotas identified as nitric oxide (NO) or a closely related derivative sium salt, (6?.7f8,11C, 17(3)-; 3'H-cyclopropa(6.7)pregna-1,4, thereof (Palmeretal, Nature, 327:524-526 (1987); Ignarro et 6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hy al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)). droxy-3-oxo-, y-lactone, (63.7B...11C.17B)-; pregn-4-ene-7, 0362. The invention is also directed to nitric oxide enhanc 21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-. ing compounds that can increase endogenous nitric oxide. y-lactone, ethyl ester, (7C.11C,17B)-; pregn-4-ene-7,21-di Such compounds, include for example, nitroxide containing carboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, y-lactone, compounds, include, but are not limited to, Substituted 2.2.6. 1-methylethyl ester, (7C.11C., 17 B)-; RU-28318, and the like. 6-tetramethyl-1-piperidinyloxy compounds, Substituted 2.2, Suitable aldosterone antagonists are described more fully in 5.5-tetramethyl-3-pyrroline-1-oxyl compounds, substituted the literature, such as in Goodman and Gilman, The Pharma 2.2.5.5-tetramethyl-1-pyrrolidinyloxyl compounds, Substi cological Basis of Therapeutics (9th Edition), McGraw-Hill, tuted 1,1,3,3-tetramethylisoindolin-2-yloxyl compounds, 1995; and the Merck Index on CD-ROM, 13" Edition; and on substituted 2,2,4,4-tetramethyl-1-oxazolidinyl-3-oxyl com STN Express, file phar and file registry. pounds, Substituted 3-imidazolin-1-yloxy, 2.2.5.5-tetram 0365. In some embodiments the aldosterone antagonists is ethyl-3-imidazolin-1-yloxyl compounds, OT-551, 4-hy eplerenone or spironolactone (a potassium sparing diuretic droxy-2.2.6.6-tetramethyl-1-piperidinyloxy (tempol), and that acts like an aldosterone antagonist). In more particular the like. Suitable substituents, include, but are not limited to, embodiments eplerenone is administered in an amount of aminomethyl, benzoyl 2-bromoacetamido. 2-(2-(2-bro about 25 milligrams to about 300 milligrams as a single dose moacetamido)ethoxy)ethylcarbamoyl, carbamoyl, carboxy, or as multiple doses per day; the spironolactone is adminis cyano, 5-(dimethylamino)-1-naphthalenesulfonamido, tered in an amount of about 25 milligrams to about 150 ethoxyfluorophosphinyloxy, ethyl, 5-fluoro-2,4-dinitroa milligrams as a single dose or as multiple doses per day. nilino, hydroxy, 2-iodoacetamido, isothiocyanato, isothiocy 0366 Suitable O.-adrenergic receptoragonists include, but anatomethyl, methyl, maleimido, maleimidoethyl 2-(2-ma are not limited to, agnatine, p-aminoclonidine, apraclonidine leimidoethoxy)ethylcarbamoyl, maleimidomethyl, (IOPIDINER), 2-(arylamino) imidazolidine derivatives, maleimido, oxo, phosphonooxy, and the like. aZepexole, azepin derivatives, such as for example, 2-amino US 2010/024.0622 A1 Sep. 23, 2010 29

6-alkyl-4,5,7,8-tetrahydro-6H-thiazolo-(5.4.d) aZepine, pioglitaZone, repaglinide, rosiglitaZone, tolaZamide, tolbuta 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-thiazolo-(5.4.d) mide, tolcyclamide, troglitaZone, Voglibose, and the like. azepine, 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-(5. Suitable antidiabetic compounds are described more fully in 4.d) azepine, and the like; brimonidine, clonidine, clonidine the literature, such as in Goodman and Gilman, The Pharma derivatives, detomidine, dexmedetomidine, diplivefrin, cological Basis of Therapeutics (9th Edition), McGraw-Hill, dipivalylepinephrine, epinephrine, guanabenz, guanfacine, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; imidazolidine derivatives, such as, for example, 5-bromo-6- and on STN Express, file phar and file registry. (2-imidazolidine-2-ylamino)cquinoxaline, and the like; p-io doclonidine, medetomidine, methoxamine (VASOXYL(R), 0371 Suitable antimicrobial compounds include, but are mephentermine, metaraminol (ARAMINE(R), methyldopa, not limited to, acediasulfone, aceturate, acetyl Sulfameto mitodrine, naphazoline (PRIVINE(R), NAPHCONR), norepi ssipirazine, acetyl Sulfamethoxypyrazine, acranil, albenda nephrine, oxymetazoline (AFRINR, OCUCLEAR(R), phe Zole, alexidine, amatadine, ambazone, amdinocillin, amika nylepinephrine (NEOSYNEPHRINE(R), rilmenidine, tet cin, p-aminosalicylic acid, p-aminosalicylic acid hydrazine, rahydrozoline (TYZINE(R), VISINE(R), tramazoline, amoxicillin, amplicillin, anisomycin, apalcillin, apicyclin, xylazine, xylometazoline (OTRIVINR), B-HT 920 (6-allyl apramycin, arbekacin, argininsa, aspoxicillin, azidamfenicol, 2-amino-5,6,7,8-tetrahydro-4H-thiazolo(4.5-d)-azepine, azidocillin, azithromycin, azlocillin, aztreonam, bacampicil B-HT933 and UK 14.304, and the like. Suitable C.-adrenergic lin, bacitracin, benzoylpas, benzylpenicillin acid, benzyl Sul receptor agonists are described more fully in the literature, famide, bicoZamycin, bipenam, brodimoprim, capreomycin, Such as in Goodman and Gilman, The Pharmacological Basis carbenicillin, carbomycin, cafaZedone, carindacillin, caru of Therapeutics (9th Edition), McGraw-Hill, (1996); Merck monam, cefcapene pivoxil, cefaclor, cefadroxil, cefafroxil, Index on CD-ROM, 13" Edition; STN Express, file phar and cefamandole, cefatamet, cefatrizine, cefazedone, cefazolin, file registry, the disclosures of each of which are incorporated cefbuperaZone, cefclidin, cefdinir, cefditoren, cefixime, cefinenoXime, cefinetazole, cefrninox, cefodizime, by reference herein in their entirety. cefonicid, cefoperaZone, ceforanide, cefotaxime, cefotetan, 0367. In some embodiments the O.-adrenergic receptor cefotiam, cefoxitin, cefoZopran, cefpimizole, cefpiramide, agonists are aminoclonidine, apraclonidine (IOPIDINE(R), cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cef brimonidine, clonidine and clonidine derivatives. Sulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftio 0368 Suitable C.-adrenergic receptor antagonists receptor fur, ceftizoxime, ceftriaxone, cefuroxime, cefuZonam, ceph antagonists include, but are not limited to, phentolamine, acetrile sodium, cephadrine, cephalexin, cephaloglycin, tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408, cephaloridine, cephalosporin C, cephalothin, cephapirin BRL 44409, BAM 1303, labetelol, ifenprodil, rauwolscine, Sodium, cephradine, chibrorifamycin, chloramphenicol, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, chlorotetracycline, cinoxacin, ciprofloxacin, claritromycin, akuammigine, B-yohimbine, yohimbol, yohimbine, clavulanic acid, clinafloxacin, clindamycin, clofazimine, clo pseudoyohimbine, epi-3C.-yohimbine, 10-hydroxy-yohim foctal, clometocillin, clomocycline, cloxacillin, cloxyquin, bine, 11-hydroxy-yohimbine, tamsulosin, benoxathian, ati colistin, cyclacilline, cycloserine, danoflaxcin, dapsone, parnezole, BE 2254, WB 4101, HU-723, tedisamil, mir deoxycycline, deoxydihydrostreptomycin, dibekacin, taZipine, Setiptiline, reboxitine, deleguamine, naftopil, dicloxacillin, difloxacin, dihydrostreptomycin, dimetrida saterinone, SL 89.0591, ARC 239, urapidil, 5-methylurapi Zole, diminaZene, dirirtomycin, duramycin, eflornithine, dil, monatepi, haloperidol, indoramin, SB 216469, moxisy enrofloxacin, enviomycin, epicillin, erythromycin, etacillin, lyte, trazodone, dapiprozole, efaroxan, Recordati 15/2739, ethambutol, ethionamide, famcyclovir, fenbecillin, fleroxa SNAP 1069, SNAP 5089, SNAP 5272, RS 17053, SL cin, flomoxef floxacillin, flumequine, n-formamidoylthiena 89.0591, KMD 3213, spiperone, AH 11110A, chloroethyl mycin, furonazide, fortimycin, furazolium chloride, genta clonidine, BMY 7378, niguldipine, and the like. Suitable mycin, glyconiazide, gramicidin, grepafloxacin, alpha-adrenergic receptor antagonists are described more guamecycline, halofuginone, hetacillin, homidium, fully in the literature, such as in Goodman and Gilman, The hydroxyl-Stilbamidine, ibostamycin, imidocarb, imipenam, Pharmacological Basis of Therapeutics (9th Edition), ipronidazole, isoniazide.josamycin, inosine, kanamycin, lau McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir roguadine, lenampicillin, lincomycin, lomefloxacin, loracar teenth Edition; and on STN Express, file phar and file registry. bef, lymecyclin, mafenide, mebendazole, meclocyclin, mero 0369 Suitable B-adrenergic agonists include, but are not penem, metampicillin, metacicline, methacycline, limited to, albuterol, bambuterol, bitolterol, carbuterol, clen methicillin sodium, metronidazole, 4'-(methylsulfamoyl) buterol, dobutamine, fenoterol, formoterol, hexoprenaline, Sulfanilanilide, mezlocillin, meZiocillin, micronomycin, isoprotenerol, mabuterol, metaproterenol, pirbuterol, prenal midecamycin A, minocycline, miocamycin, miokamycin, terol, procaterol, protokylol, ritodrine, rimiterol, reproterol, morfaZinamide, moxalactam, mupirocin, myxin, nadifloxa salmeterol, Soterenol, terbutaline, tretoquinol, tulobuterol, cin, nalidixic acid, negamycin, neomycin, netlimycin, nifur and the like. Suitable 3-adrenergic agonists are described foline, nifurpirinol, nifurprazine, nimorazole, nitroxoline, more fully in the literature. Such as in Goodman and Gilman, norfloxacin, novobiocin, ofloxacin, oleandomycin, opiniaz The Pharmacological Basis of Therapeutics (9th Edition), ide, oxacillin, oxophenarsine, oxolinic acid, Oxytetracycline, McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' panipenam, paromycin, paZufloxacin, pefloxacin, penicillin Edition; and on STN Express, file phar and file registry. G potassium salt, penicillin N, penicillin O, penicillin V. 0370 Suitable antidiabetic compounds include, but are penethamate hydroiodide, pentamidine, phenamidine, not limited to, acarbose, acetohexamide, buformin, carbuta phenethicillin potassium salt, phenyl aminosalicyclate, pipa mide, chlorpropamide, glibornuride, gliclazide, glimepiride, cycline, pipemidic acid, piperacillin, pirlimycin, piromidic glipizide, gliquidone, glisoxepid, glyburide, glybuthiazol(e), acid, pivampicillin, pivoefalexin, polymyxin B, profiromy glybuzole, glyhexamide, glymidine, glypinamide, insulin, cin, propamidine, propicillin, protionamide, pluraltadone, metformin, miglitol, nateglinide, phenbutamide, phenformin, puromycin, pyrazinamide, pyrimethamine, quinacillin, US 2010/024.0622 A1 Sep. 23, 2010 30 quinacrine, quinapyramine, quintine, ribostamycin, rifabu cholystyramine, colestipol, niacin, nicotinic acid, bile acid tine, rifamide, rifampin, rifamycin, rifanpin, rifapentine, rif sequestrants, such as, for example, cholestyramine, coleseve axyrnine, ritipenem, rokitamycin, rollitetracycline, rosamy lam, colestipol, poly(methyl-(3-trimethylaminopropyl) cin, rufloxacin, Salazosulfadimidine, Salinazid, Sancycline, imino-trimethylene dihalide) and the like; probucol; fibric Sarafloxacin, Sedacamycin, secnidazole, Sisomycin, spar acid agents or fibrates, such as, for example, beZafibrate floxacin, spectinomycin, spiramycin, spiramycin I, spiramy (BezalipTM), beclobrate, binifibrate, ciprofibrate, clinofibrate, cin II, spiramycin III, stilbamidine, streptomycin, streptoni clofibrate, etofibrate, fenofibrate (LipidilTM, Lipidil cizid, Sulbactam, Sulbenicillin, Succisulfone, Sulfanilamide, MicroTM), gemfibrozil (LopidTM), nicofibrate, pirifibrate, Sulfabenzamide, Sulfacetamide, Sulfachloropyridazine, Sul ronifibrate, simfibrate, theofibrate and the like; cholesterol fachrysoidine, Sulfacytine, Sulfadiazine, Sulfadicramide, Sul ester transfer protein (CETP) inhibitors, such as for example, fadimethoxine, Sulfadoxine, Sulfadrazine, Sulfaetidol, Sul CGS 25159, CP-529414 (torcetrapid), JTT-705, substituted fafenaZol, Sulfaguanidine, Sulfaguanole, Sulfalene, N-3-(1,1,2,2-tetrafluoroethoxy)benzyl-N-(3-phenoxyphe Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, nyl)-trifluoro-3-amino-2-propanols, N,N-disubstituted trif Sulfaxnethomidine, Sulfamethoxazole, Sulfamethoxypy luoro-3-amino-2-propanols, PD 140195 (4-phenyl-5-tride ridazine, sulfamethylthiazol, sulfamethylthiazole, sulfame cyl-4H-1,2,4-triazole-3-thiol), SC-794, SC-795, SCH58149, trole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide, and the like. 4-sulfanilamido Salicylic acid, 4-4'-sulfanilylbenzylamine, 0375. In some embodiments the anti-hyperlipidemic com p-sulfanilylbenzylamine, 2-p-sulfinylanilinoethanol, Sulfa pounds are atorvastatin, fluvastatin, lovastatin, pravastatin, nillylurea, Sulfoniazide, Sulfaperine, Sulfaphenazole, Sul rosuvastatin or simvastatin. In more particular embodiments faproxyline, Sulfapyrazine, Sulfapyridine, Sulfathiazole, Sul the atorvastatin is administered in an amount of about 10 faethidole, Sulfathiourea, Sulfisomidine, Sulfasomizole, milligrams to about 80 milligrams as a single dose or as sulfasymazine, sulfisoxazole, 4,4'-sulfinyldianiline, N-sul multiple doses per day; the fluvastatin is administered in an fanilylsulfanilamide, N-sulfanilyl-3,4-xylamide, Sultamicil amount of about 20 milligrams to about 80 milligrams as a lin, talampicillin, tambutol, taurolidine, teiclplanin, temocil single dose or as multiple doses per day; the lovastatin is lin, tetracycline, tetroXoprim, thiabendazole, thiazolsulfone, administered in an amount of about 10 milligrams to about 80 tibeZonium iodide, ticarcillin, tigemonam, tinidazole, tobra milligrams as a single dose or as multiple doses per day; the mycin, to Sufloxacin, trimethoprim, troleandromycin, tros pravastatin is administered in an amount of about 10 milli pectomycin, trovafloxacin, tubercidine, miokamycin, olean grams to about 80 milligrams as a single dose or as multiple domycin, troleandromycin, Vancomycin, Verazide, Viomycin, doses per day; the rosuvastatin is administered in an amount virginiamycin, Zalcitabine, PA-1806 and PA-2794, and the of about 5 milligrams to about 40 milligrams as a single dose like. Suitable antimicrobial compounds are described more or as multiple doses per day; the simvastatin is administered fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), in an amount of about 5 milligrams to about 80 milligrams as McGraw-Hill, (1996); Merck Index on CD-ROM, 13" Edi a single dose or as multiple doses per day. tion; STN Express, file phar and file registry, the disclosures 0376 Suitable angiotensin II antagonists include, but are of each of which are incorporated by reference herein in their not limited to, angiotensin, abitesartan, candesartan, cande entirety. Sartan cilexetil, elisartan, embusartan, enoltaSosartan, epro Sartan, fonsartan, forasartan, glycylosartan, irbesartan, losa 0372. In some embodiments the antimicrobial compounds rtan, olmesartan, milfasartan, medoxomil, ripisartan, include, but are not limited to, amikacin, azithromycin, aze pomisartan, pratosartan, Saprisartan, Saralasin, Sarmesin, treonam, bacitracin, carbenicillin, cefazolin, cefoxitin, tasosartan, telmisartan, Valsartan, Zolasartan, 3-(2'(tetrazole cephaloridine, chibrorifamycin, chloramphenicol, colistin, 5-yl)-1,1'-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imi duramycin, n-formamidoylthienamycin, gentamycin, grami dazo[4,5-b]pyridine, antibodies to angiotensin II, A-81282, cidin, kanamycin, neomycin, penicillin G, polymyxin B, A-81988, BAY 106734, BIBR-363, BIBS-39, BIBS-222, Sisomicin, tetracyclines, tigecycline, tobramycin, Vancomy BMS-180560, BMS-184698, BMS-346567, CGP-38560A, cin, PA-1806 and PA-2794. CGP-42112A, CGP-48369, CGP-49870, CGP-63170, 0373) In other embodiments the antimicrobial compound CI-996, CP-148130, CL-329167, CV-11194, CV-11974, is an antiviral compound, including but not limited to, acy DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, DuP clovir, amatadine, cidofovir, cytarabine, didanosine, 753, E-1477, E-4177, E-4188, EMD-66397, EMD-666R4, dideoxyadenosine, edoxudine, famciclovir, floXuridine, gan EMD-73495, EMD-66684, EXP-063, EXP-929, EXP-3134, cyclovir, idoxuridine, indanavir, kethoxal, lamivudine, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, MADU, penciclovir, podophyllotoxin, ribavirine, rimanta EXP-9954, FK-739, FR11:53332, GA-0050, GA-0056, dine, saquinavir, Sorivudine, stavudine, trifluridine, Valacy HN-65021, HOE-720, HR-720, IC-D6888, IC-D7155, IC clovir, Vidarabine, Xenazoic acid, Zalcitabine, Zidovudine, D8731, KR1-1177, KT3-671, KT-3579, KW-3433, and the like. L-158809, L-158978, L-159282 (MK-996), L-159689, 0374 Suitable anti-hyperlipidemic compounds include, L-159874, L-161177, L-162154, L-162234, L-162441, but are not limited to, statins or HMG-CoA reductase inhibi L-163007, L-163017, LF-70156, LRB-057, LRB-081, LRB tors, such as, for example, atorvastatin (LIPITORR), bervas 087, LY-235656, LY-266099, LY-285.434, LY-301875, tatin, cerivastatin (BAYCOLR), dalvastatin, fluindostatin LY-302289, LY-315995, ME-3221, MK-954, PD-123177, (Sandoz XU-62-320), fluvastatin, glenvastatin, lovastatin PD-1233.19, PD-126055, PD-150304, RG-13647, RWJ (MEVACORR), mevastatin, pravastatin (PRAVACHOL(R), 38970, RWJ-46458, S-8307, S-8308, SC-51757, SC-54629, rosuvastatin (CRESTROR), simvastatin (ZOCORR), SC-52458, SC-52459, SK 1080, SL-910102, SR-47436, velostatin (also known as synvinolin), VYTORINTM TAK-536, UP-2696, U-96849, U-97018, UK-77778, (ezetimibe/simvastatin), GR-95.030, SQ 33,600, BMY UP-275-22, WAY-126227, WK-1260, WK-1360, WK-1492, 22089, BMY 22,566, CI-980, and the like: gemfibrozil, WY 126227, YH-1498, YM-358, YM-31472, X-6803, US 2010/024.0622 A1 Sep. 23, 2010

XH-148, XR-510, ZD-6888, ZD-7155, ZD-8731, ZD 8.131, doses per day; the Valsartan is administered in an amount of the compounds of ACS registry numbers 133240-46-7, about 80 milligrams to about 320 milligrams as a single dose 135070-05-2, 139958-16-0, 145160-84-5, 147403-03-0, or as multiple doses per day. 153806-29-2, 439904-54-8P 439904-55-9P, 439904-56-OP, 0378 Suitable angiotensin-converting enzyme inhibitors 439904-57-1P,439904-58-2P 155918-60-8P, 155918-61-9P, (ACE inhibitors) include, but are not limited to, alacepril, 272438-16-1P, 272446-75-0P, 223926-77-OP. 169281-89-4, benazepril (LOTENSINR), CIBACENR), benazeprilat, cap 165113-17-7P, 165113-18-8P, 165113-19-9P, 165113-20-2P topril, ceronapril, cilaZapril, delapril, duinapril, enalapril, 165113-13-3P, 165113-14-4P 165113-15-5P, 165113-16-6P. enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, glycopril, idrapril, imidapril, lisinopril, moexipril, movel 165113-21-3P, 165113-22-4P 165113-23-5P, 165113-24-6P. tipril, naphthopidil, omapatrilat, pentopril, perindopril, per 165113-25-7P, 165113-26-8P 165113-27-9P, 165113-28 indoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rent OP. 165113-29-1P, 165113-30-4P, 165113-31-5P, 165113 ipril, Saralasin acetate, spirapril, temocapril, trandolapril, 32-6P, 165113-33-7P 165113-34-8P, 165113-35-9P, trandolaprilat, urapidil, Zofenopril, acylmercapto and mer 165113-36-OP. 165113-37-1P, 165113-38-2P 165113-39 captoalkanoyl pralines, carboxyalkyl dipeptides, carboxy 3P, 165113-40-6P, 165113-41-7P 165113-42-8P 165113 alkyl dipeptide, phosphinylalkanoyl pralines, registry no. 43-9P, 165113-44-OP. 165113-45-1P, 165113-46-2P 796406, AVE 7688, BP1.137, CHF 1514, E 4030, ER 3295, 165113-47-3P, 165113-48-4P 165113-49-5P, 165113-50-8P. FPL-66564, MDL 100240, RL 6134, RL 6207, RL 6893, SA 165113-51-9P, 165113-52-0P, 165113-53-1P, 165113-54-2P 760, S-5590, Z 13752A, and the like. Suitable angiotensin 165113-55-3P, 165113-56-4P 165113-57-5P, 165113-58-6P. converting enzyme inhibitors are described more fully in the 165113-59-7P, 165113-60-OP. 165113-6.1-1P 165113-62 literature. Such as in Goodman and Gilman, The Pharmaco 2P, 165113-63-3P, 165113-64-4P 165113-65-5P, 165113 logical Basis of Therapeutics (9th Edition), McGraw-Hill, 66-6P, 165113-67-7P 165113-68-8P, 165113-69-9P, 1995; and the Merck Index on CD-ROM, Twelfth Edition, 165113-70-2P, 165113-71-3P, 165113-72-4P, 165113-73-5P, Version 12:1, 1996; and on STN Express, file phar and file 165113-74-6P, 114798-27-5, 114798-28-6, 114798-29-7, registry. 124749-82-2, 114798-28-6, 124749-84-4, 124750-88-5, 0379. In some embodiments the angiotensin-converting 124750-91-0, 124750-93-2, 161946-65-2P 161947-47-3P, enzyme inhibitors are benazepril, captopril, enalapril, fosino 161947-48-4P 161947-51-9P, 161947-52-OP 161947-55 pril, lisinopril, moexipril, quinapril, ramipril, trandolapril or 3P 161947-56-4P 161947-60-OP. 161947-61-1P 161947 trandolaprilat. In more particular embodiments the 68-8P 161947-69-9P 161947-70-2P 161947-71-3P, benazepril is administered as benazepril hydrochloride in an 161947-72-4P 161947-74-6P 161947-75-7P 161947-81-5P, amount of about 5 milligrams to about 80 milligrams as a 161947-82-6P 161947-83-7P 161947-84-8P, 161947-85-9P, single dose or as multiple doses per day; the captopril is 161947-86-OP. 161947-87-1P 161947-88-2P 161947-89 administered in an amount of about 12.5 milligrams to about 3P 161947-90-6P 161947-91-7P 161947-92-8P 161947 450 milligrams as a single dose or as multiple doses per day; 93-9P 161947-94-OP 161947-95-1P 161947-96-2P the enalapril is administered as enalapril maleate in an 161947-97-3P, 161947-98-4P 161947-99-5P, 161948-00-1P amount of about 2.5 milligrams to about 40 milligrams as a 161948-01-2P 161948-O-3P, 168686-32-6P, 167301-42 single dose or as multiple doses per day; the fosinopril is OP. 166813-82-7P 166961-56-4P 166961-58-6P, 158872 administered as fosinopril sodium in an amount of about 5 96-9P, 158872-97-0P, 158807-14-8P, 158807-15-9P, milligrams to about 60 milligrams as a single dose or as 158807-16-0P, 158807-17-1P, 158807-18-2P, 158807-19-3P, multiple doses per day; the lisinopril is administered in an 158807-20-6P, 155884-08-5P, 154749-99-2, 167371-59-7P. amount of about 2.5 milligrams to about 75 milligrams as a 244126-99-6P, 177848-35-OP 141309-82-2P, and the like. single dose or as multiple doses per day; the moexipril is Suitable angiotensin II antagonists are described more fully administered as moexipril hydrochloride in an amount of in the literature, such as in Goodman and Gilman, The Phar about 7.5 milligrams to about 45 milligrams as a single dose macological Basis of Therapeutics (9th Edition), McGraw or as multiple doses per day; the quinapril is administered as Hill, 1995; and the Merck Index on CD-ROM, 13" Edition; quinapril hydrochloride in an amount of about 5 milligrams to and on STN Express, file phar and file registry. about 40 milligrams as single or multiple doses per day; the 0377. In some embodiments the angiotensin II antagonists ramipril hydrochloride in an amount of about 1.25 milligrams are candesartan, eprosartan, irbesartan, losartan, omlesartan, to about 40 milligrams as single or multiple doses per day; the telmisartan or Valsartan. In more particular embodiments the trandolapril is administered as in an amount of about 0.5 candesartan is administered as candesartan cilexetil in an milligrams to about 4 milligrams as single or multiple doses amount of about 15 milligrams to about 100 milligrams as a per day; the trandolaprilat is administered as in an amount of single dose or as multiple doses per day; the eprosartan, is about 0.5 milligrams to about 4 milligrams as single or mul administered as eprosartan mesylate in an amount of about tiple doses per day. 400 milligrams to about 1600 milligrams as a single dose or as 0380 Suitable antioxidants include, but are not limited to, multiple doses per day; the irbesartan is administered in an Small-molecule antioxidants and antioxidant enzymes. Suit amount of about 75 milligrams to about 1200 milligrams as a able small-molecule antioxidants include, but are not limited single dose or as multiple doses per day; the losartan is admin to, hydralazine compounds, glutathione, Vitamin C, vitamin istered as losartan potassium in an amount of about 25 milli E. cysteine, N-acetyl-cysteine, B-carotene, ubiquinone, grams to about 100 milligrams as a single dose or as multiple ubiquinol-10, tocopherols, coenzyme Q, Superoxide dismu doses per day; the omlesartan is administered as omlesartan tase mimetics, such as, for example, 2.2.6.6-tetramethyl-1- medoxomil in an amount of about 5 milligrams to about 40 piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide milligrams as a single dose or as multiple doses per day; the compounds; 4-hydroxy-2.2.6.6-tetramethyl-1-piperidiny telmisartan is administered in an amount of about 20 milli loxy (Tempol), M-40401, M-40403, M-40407, M-40419, grams to about 80 milligrams as a single dose or as multiple M-40484, M-40587, M-40588, and the like. Suitable antioxi US 2010/024.0622 A1 Sep. 23, 2010 32 dant enzymes include, but are not limited to, Superoxide SR-59230A, TZC-5665, UK-1745, YM-430, and the like. dismutase, catalase, glutathione peroxidase, NADPH oxidase Suitable f-adrenergic antagonists are described more fully in inhibitors, such as, for example, apocynin, aminoguanidine, the literature, such as in Goodman and Gilman, The Pharma ONO 1714, S17834 (benzo(b)pyran-4-one derivative), and cological Basis of Therapeutics (9th Edition), McGraw-Hill, the like; Xanthine oxidase inhibitors, such as, for example, 1995; and the Merck Index on CD-ROM, 13 Edition; and on allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, STN Express, file phar and file registry. 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, myricetin, isorhamnetin, benzophenones such as 2.2',4,4'- 0384. In some embodiments the B-adrenergic antagonists tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxyben are atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, Zophenone and 4,4'-dihydroxybenzophenone; benzothiazi propranolol or timolol. In more particular embodiments the none analogues such as 2-amino-4H-1,3-benzothiazine-4- atenolol is administered in an amount of about 50 milligrams one, 2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine; to about 200 milligrams as a single dose or as multiple doses N-hydroxyguanidine derivative such as, PR5 (1-(3,4- per day; the bisoprolol is administered as bisoprolol fumarate dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguani in an amount of about 2.5 milligrams to about 30 milligrams dine); 6-formylpterin, and the like. The antioxidant enzymes as a single dose or as multiple doses per day; the carvedilol is can be delivered by gene therapy as a viral vector and/or a administered in an amount of about 3.125 milligrams to about non-viral vector. Suitable antioxidants are described more 200 milligrams as a single dose or as multiple doses per day; fully in the literature, such as in Goodman and Gilman, The the metoprolol is administered as metoprolol tartarate or Pharmacological Basis of Therapeutics (9th Edition), metoprolol Succinate in an amount of about 25 milligrams to McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir about 300 milligrams as a single dose or as multiple doses per teenth Edition; and on STN Express, file phar and file registry. day; the nebivolol is administered as nebivolol hydrochloride 0381. In some embodiments the antioxidants are apocy in an amount of about 2.5 milligrams to about 20 milligrams nin, hydralazine compounds and Superoxide dimutase as a single dose or as multiple doses per day; the propranolol mimetics. is administered as propranolol hydrochloride in an amount of 0382 Suitable antithrombotic and vasodilator compounds about 40 milligrams to about 240 milligrams as a single dose include, but are not limited to, abciximab, acetorphan, ace or as multiple doses per day; the timolol is administered as tylsalicylic acid, argatroban, bamethan, benfurodil, benzio timolol maleate in an amount of about 10 milligrams to about darone, betahistine, bisaramil, brovincamine, bufeniode, citi 30 milligrams as a single dose or as multiple doses per day. coline, clobenfurol, clopidogrel, cyclandelate, dalteparin, 0385 Suitable calcium channel blockers include, but are dipyridamol, droprenilamine, enoxaparin, fendiline, ifen not limited to, amlodipine (NORVASCR), anipamil, aranid prodil, iloprost, indobufen, isobogrel, isoxSuprine, heparin, ipine, aminone, azelnidipine, barnidipine, bencyclane, beni lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylid dipine, bepridil, cilnidipine, cinnarizine, clentiazem, dilt rin, OZagrel, perhexyline, phenylpropanolamine, preny iazem, dotarizine, efonidipine. elgodipine, fantofarone, lamine, papaveroline, reviparin Sodium salt, ridogrel, Suloc felodipine, fendiline, flunarizine, fluspirilene, furnidipine, tidil, tinofedrine, tinzaparin, trifusal, Vintoperol, Xanthinal gallopamil, ipenoxazone, isradipine, lacidipine, lemildipine, niacinate, and the like. Suitable antithrombotic and vasodila lercanidipine, lomerizine, manidipine, mibefradil, tor compounds are described more fully in the literature, such monatepil, nicardipine, nifedipine, niguldipine, niludipine, as in Goodman and Gilman, The Pharmacological Basis of nilvadipine, nimodipine, nisoldipine, nitrendipine, nival Therapeutics (9th Edition), McGraw-Hill, 1995; and the dipine, Oxodipine, perhexylene, phenyloin, phenylpreny Merck Index on CD-ROM, Thirteenth Edition; and on STN lamine, pranidipine, ranolazine, ryosidine, semotiadil, tamo Express, file phar and file registry. larizine, temiverine hydrochloride, terodiline, tiapamil, 0383 Suitable f3-adrenergic antagonists include, but are Vatanidipine hydrochloride, Verapamil, Ziconotide, AE-0047. not limited to, acebutolol, alprenolol, amoSulalol, arotinolol. CAI, JTV-519, CHF-1521, L-651582, NS-7, NW-1015, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopin RO-2933, SB-237376, SL-34.0829-08, S-312d, SD-3212, dolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, TA-993, YM-430, and the like. Suitable calcium channel bupranolol, butofilolol, carazolol, capsinolol, carteolol. blockers are described more fully in the literature, such as in carvedilol (COREGR), celiprolol, cetamolol, cindolol, clo Goodman and Gilman, The Pharmacological Basis of Thera ranolol, dilevalol, diprafenone, epanolol, ersentilide, peutics (9th Edition), McGraw-Hill, 1995; and the Merck esmolol, esprolol, hydroxalol, indenolol, labetalol, landiolol, Index on CD-ROM. Thirteenth Edition; and on STN Express, laniolol, levobunolol, mepindolol, methylpranol, metindol, file phar and file registry. metipranolol, metrizoranolol, metoprolol, moprolol, nadolol. 0386. In some embodiments the calcium channel blockers nadoxolol, nebivolol, nifenalol, nipradillol, oXprenolol, pen are amlodipine, diltiazem, isradipine, nicardipine, nifedipine, butolol, pindolol, practolol, pronethalol, propranolol, Sotalol, nimodipine, nisoldipine, nitrendipine, Verapamil. Sotalohiadolol, sulfinalol, taliprolol, talinolol, tertatolol, til 0387 Suitable carbonic anhydrase inhibitors include, but isolol, timolol, toliprolol, tomalolol, trimepranol, Xamoterol, are not limited to, acetazolamide, brinzolamide, dorzolamide, xibenolol, 2-(3-(1,1-dimethylethyp-amino-2-hydroxypro ethoXZolamide, 6-hydroxy-2-benzothiazolesulfonamide, poxy)-3-pyridenecarbonitrilHCl, 1-butylamino-3-(2,5- methazolamide, thiophene Sulfonamide, an aromatic Sulfona dichlorophenoxy)-2-propanol. 1-isopropylamino-3-(4-(2- mide, an ester of 6-hydroxy-2-benzothiazolesulfonamide, an cyclopropylmethoxyethyl)phenoxy)-2-propanol, ester of 5-hydroxy-2-benzothiazolesulfonamide, and the like. 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, Suitable carbonic anhydrase inhibitors are described more 2-(3-t-butylamino-2-hydroxypropylthio)-4-(5-carbamoyl-2- fully in the literature, such as in Goodman and Gilman, The thienyl)thiazol, 7-(2-hydroxy-3-t-butylaminpropoxy)phtha Pharmacological Basis of Therapeutics (9th Edition), lide, Acc 9369, AMO-140, BIB-16S, CP-331684, Fr-172516, McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' ISV-208, L-653328, LM-2616, SB-226552, SR-58894A, Edition; and on STN Express, file phar and file registry. US 2010/024.0622 A1 Sep. 23, 2010

0388. In some embodiments the carbonic anhydrase 1995; and the Merck Index on CD-ROM, Thirteenth Edition; inhibitors are brinzolamide and dorzolamide. and on STN Express, file phar and file registry. 0389 Suitable diuretics include, but are not limited to, 0393 Suitable hydralazine compounds include, but are thiazides (such as, for example, althiazide, bendroflumethi not limited to, compounds having the formula: azide, benzclortriazide, benzhydrochlorothiazide, benzthiaz ide, buthiazide, chlorothiazide, cyclopenethiazide, cyclothiazide, epithiazide, ethiazide, hydrobenzthiazide, R4 R3 hydrochlorothiazide, hydroflumethiazide, methylclothiaz RFN FN FR2 ide, methylcyclothiazide, penflutazide, polythiazide, teclothiazide, trichlormethiazide, triflumethazide, and the 0394 wherein a, b and c are independently a single or like); allilusem, ambuside, amiloride, aminometradine, double bond; R and R2 are each independently a hydrogen, aZosemide, bemetizide, bumetanide, butazolamide, butizide, an alkyl, an ester or a heterocyclic ring, wherein alkyl, ester canrenone, carperitide, chloraminophenamide, chlorazanil, and heterocyclic rind areas defined herein; R and Rare each chlormerodrin, chlorthalidone, cicletanide, clofenamide, clo independently alone pair of electrons or a hydrogen, with the pamide, clorexolone, conivaptan, daglutril, dichlorophena proviso that at least one of R. R. RandR is not a hydrogen. mide, disulfamide, ethacrynic acid, ethoXZolamide, etoZolon, Exemplary hydralazine compounds include budralazine, fenoldopam, fenguizone, furosemide, indapamide, mebutiz cadralazine, dihydralazine, endralazine, hydralazine, ide, mefruside, meralluride, mercaptomerin Sodium, mercu pildralazine, todralazine, and the like. Suitable hydralazine mallylic acid, mersalyl, methazolamide, meticane, metola compounds are described more fully in the literature, Such as Zone, moZavaptan, muZolimine, N-(5-1,3,4-thiadiazol-2-yl) in Goodman and Gilman, The Pharmacological Basis of acetamide, nesiritide, pamabrom, paraflutizide, piretanide, Therapeutics (9th Edition), McGraw-Hill, 1995; and the protheobromine, quinethaZone, scoparius, Spironolactone, Merck Index on CD-ROM, Thirteenth Edition; and on STN theobromine, ticrynafen, torsemide, torvaptan, triamterene, Express, file phar and file registry. tripamide, ularitide, Xipamide or potassium, AT 189000, AY 0395. In some embodiments the hydralazine compound is 31906, BG 9928, BG 9791, C2921, DTI 0017, JDL961, KW hydralazine or a pharmaceutically acceptable salt thereof 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP Such as hydralazine hydrochloride. In more particular 120, and the like. Suitable diuretics are described more fully embodiments the hydralazine is administered as hydralazine in the literature, such as in Goodman and Gilman. The Phar hydrochloride in an amount of about 10 milligrams to about macological Basis of Therapeutics (9th Edition), McGraw 300 milligrams as a single dose or as multiple doses per day. Hill, 1995; and the Merck Index on CD-ROM, 13" Edition; 0396 Suitable H receptor antagonists include, but are not and on STN Express, file phar and file registry. limited to, burimamide, cimetidine, ebrotidin, famotidine, 0390 Depending on the diuretic employed, potassium nizatidine, roXatidine, rantidine, tiotidine, and the like. Suit may also be administered to the patient in order to optimize able H receptor antagonists are described more fully in the the fluid balance while avoiding hypokalemic alkalosis. The literature. Such as in Goodman and Gilman, The Pharmaco 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, 13' 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 U.S. Pat. No. 4,868,179, the their entirety. disclosure of which is incorporated by reference herein in its 0397 Suitable neutral endopeptidase inhibitors include, entirety. but are not limited to, atrial natriuretic peptides, diazapins, 0391. In some embodiments the diuretics are amiloride, azepinones, ecadotril, fasidotril, fasidotrilat, omapatrilat, furosemide, chlorthalidone, hydrochlorothiazide or triam sampatrilat, BMS 189,921, Z 13752A, 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, file phar and file registry. a single dose or as multiple doses per day; the chlorthalidone 0398 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, carprofen, cinmetacin, clopirac, diclofenac, etod about 12.5 milligrams to about 300 milligrams as a single olac, felbinac, fenclozic acid, fenbufen, fenoprofen, fen dose or as multiple doses per day; the triamterene is admin tiazac, flunoxaprofen, flurbiprofen, 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 0392 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 28.608, and the like. fen, Zomepirac, aspirin, acemetcin, bumadizon, carprofenac, Suitable endothelin antagonists are described more fully in clidanac, diflunisal, enfenamic acid, fendosal, flufenamic the literature, such as in Goodman and Gilman, The Pharma acid, flunixin, gentisic acid, ketorolac, meclofenamic acid, cological Basis of Therapeutics (9th Edition), McGraw-Hill, mefenamic acid, mesalamine, prodrugs thereof, and the like. US 2010/024.0622 A1 Sep. 23, 2010 34

Suitable NSAIDs are described more fully in the literature, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, Such as in Goodman and Gilman, The Pharmacological Basis SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 44994, artilide fumarate, lorazepam, temazepam, ril 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. maZafone, nimetazepam, midazolam, lormetazepam, lopra Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed. Zolam, ibutilide fumarate, haloxazolam, flunitrazepam, esta Inc., the disclosures of which are incorporated herein by Zolam, doxefazepam, clonazepam, cinolazepam, brotizolam, reference in their entirety. and the like. Suitable potassium channel blockers are 0399. In some embodiments the NSAIDs are acetami described more fully in the literature, such as in Goodman and nophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, Gilman, The Pharmacological Basis of Therapeutics (9th ketoprofen, naproxen or aspirin. In more particular embodi Edition), McGraw-Hill, 1995; and the Merck Index on CD ments the acetaminophen is administered in an amount of ROM. Thirteenth Edition; and on STN Express, file phar and about 325 milligrams to about 4 grams as a single dose or as file registry. multiple doses per day; the diclofenac is administered in an 0402 Suitable platelet reducing agents include, but are not amount of about 50 milligrams to about 250 milligrams as a limited to, fibrinolytic agents such as for example, ancrod, single dose or as multiple doses per day; the flurbiprofen is anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e. administered in an amount of about 100 milligrams to about factor XII) fragments, plasminogen activators such as, for 300 milligrams as a single dose or as multiple doses per day; example, Streptokinase, tissue plasminogen activators (TPA), the ibuprofen is administered in an amount of about 400 urokinase, pro-Urokinase, recombinant TPA, plasmin, plas milligrams to about 3.2 grams as a single dose or as multiple minogen, and the like; anti-coagulantagents including but are doses per day; the indomethacin is administered in an amount not limited to, inhibitors of factor Xa, factor TFPI, factor Vila, of about 25 milligrams to about 200 milligrams as a single factor IXc, factor Va, factor VIIIa, inhibitors of other coagul dose or as multiple doses per day; the ketoprofen is adminis lation factors, and the like; Vitamin Kantagonists, such as, for tered in an amount of about 50 milligrams to about 300 example, coumarin, coumarin derivatives (e.g., warfarin milligrams as a single dose or as multiple doses per day; the Sodium); glycosoaminoglycans such as, for example, hep naproxen is administered in an amount of about 250 milli arins both in unfractionated form and in low molecular weight grams to about 1.5 grams as a single dose or as multiple doses form; ardeparin Sodium, bivalirudin, bromindione, coumarin, per day; the aspirin is administered in an amount of about 10 dalteparin Sodium, danaparoid sodium; daZOXiben hydro milligrams to about 2 grams as a single dose or as multiple chloride, desirudin, dicumarol, efegatran Sulfate, enoxaparin doses per day. sodium, ifetroban, ifetroban sodium, lyapolate sodium, nafa 0400 Suitable phosphodiesterase inhibitors include, but mostat mesylate, phenprocoumon, Sulfatide, tinzaparin are not limited to, filaminast, piclaimilast, rolipram, Org Sodium, retaplase; trifenagrel, warfarin, dextrans and the like; 20241, MCI-154, roflumilast, toborinone, posicar, lixazi abciximab, acadesine, anipamil, argatroban, aspirin, clopi none, Zaprinast, sildenafil, pyrazolopyrimidinones, motapi dogrel, diadenosine 5'5"-P1-P4-tetraphosphate (Ap4A) ana Zone, pimobendan, Zardaverine, siguaZodan, CI-930, EMD logs, difibrotide, dilazep dihydrochloride, dipyridamole, 53998, imazodan, saterinone, loprinone hydrochloride, 3-py dopamine, 3-methoxytyramine, glucagon, glycoprotein IIb/ ridinecarbonitrile derivatives, acefylline, albifylline, bami IIIa antagonists, such as, for example, Ro-43-8857, L-700, fylline, denbufyllene, diphylline, doxofylline, etofylline, tor 462, iloprost, isocarbacyclin methyl ester; itaZigrel, ket bafylline, theophylline, nanterinone, pentoxofylline, anserin, BM-13.177, lamifiban, lifarizine, molsidomine, proxyphylline, cilostazol, cilostamide, MS 857, piroximone, nifedipine, oxagrelate, prostaglandins, platelet activating fac milrinone, aminone, tolafentrine, dipyridamole, papavero tor antagonists such as, for example, lexipafant, prostacy line, E4021, thienopyrimidine derivatives, triflusal, ICOS clins, pyrazines, pyridinol carbamate, ReoPro (i.e., abcix 351, tetrahydropiperazino(1.2-b)beta-carboline-1,4-dione imab), sulfinpyrazone, synthetic compounds BN-50727, derivatives, carboline derivatives, 2-pyrazolin-5-one deriva BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, tives, fused pyridazine derivatives, quinazoline derivatives, KBT-3022, KC-404, KF-4939, OP-41483, TRK-100, anthranilic acid derivatives, imidazoquinazoline derivatives, TA-3090, TFC-612, ZK-36374, 2,4,5,7-tetrathiaoctane, 2,4, tadalafil. Vardenafil, and in Goodman and Gilman, The Phar 5,7-tetrathiaoctane 2,2-dioxide, 2,4,5-trithiahexane, theo macological Basis of Therapeutics (9th Ed.), McGraw-Hill, phyllin pentoxifyllin, thromboxane and thromboxane Syn Inc. (1995), The Physician's Desk Reference (49th Ed.), thetase inhibitors such as, for example, picotamide, Medical Economics (1995), Drug Facts and Comparisons Sulotroban, ticlopidine, tirofiban, trapidil, ticlopidine, (1993 Ed), Facts and Comparisons (1993), and the Merck trifenagrel, trilinolein, 3-substituted 5,6-bis(4-methoxyphe Index on CD-ROM, 13" Edition; and the like. Phosphodi nyl)-1,2,4-triazines; antibodies to glycoprotein IIb/IIIa, anti esterase inhibitors and their nitrosated and/or nitrosylated serotonin drugs, such as, for example, clopridogrel; Sulfin derivatives are also disclosed in U.S. Pat. Nos. 5,932,538, pyrazone and the like; aspirin; dipyridamole; clofibrate; 5,994,294, 5,874,437, 5,958,926 reissued as U.S. Pat. Nos. pyridinol carbamate; glucagon, caffeine; theophyllin pen RE 03772346, 172,060, 6,197,778, 6,177,428, 6,172,068, toxifyllin: ticlopidine, and the like. 6,221,881, 6,232,321, 6,197,782, 6,133,272, 6,211,179, 0403 Suitable prostaglandins include, but are not limited 6,316,457 and 6,331,542, the disclosures of each of which are to, naturally occurring prostaglandins such as, for example, incorporated herein by reference in their entirety. arbaprostil, alprostadil, beraprost, bimatoprost, carboprost, 0401 Suitable potassium channel blockers include, but cloprostenol, dimoxaprost, dinoprost, enprostil, enisoprost, are not limited to, nicorandil, pinacidil, cromakalim (BRL fluprostenol, fenprostalene, froxiprost, gemeprost, latano 34915), aprikalim, bimakalim, emakalim, lemakalim, prost, limaprost, meteneprost, mexiprostil, misoprostol, minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-py misoprost, misoprostol acid, nocloprost, ONO 373, orno rimido(5,4-d)(2)-benzazepine, Ribi, CPG-1 1952, CGS prostil, prostalene, PGE, PGE PGF, PGF rioprostil, 9896, ZD6169, diazixide, Bay X 9227, P1075, Bay X 9228, rosaprostol, remiprostol, Sulprostone, tafluprost, trimopros US 2010/024.0622 A1 Sep. 23, 2010

til, tiprostanide, travoprost, unoprostone, Viprostol and 189), parecoxib (DYNSTATR), rofecoxib (VIOXX(R), tira viprostol. Suitable prostaglandins are described more fully in coxib (JTE-522), valdecoxib (BEXTRAR), ABT 963, BMS the literature, such as in Goodman and Gilman, The Pharma 347070, CS502, DuP 697, GW-406381, NS-386, SC-57666, cological Basis of Therapeutics (9th Edition), McGraw-Hill, SC-58125, SC-58635, and the like, and mixtures of two or 1995; and the Merck Index on CD-ROM, 13" Edition; and on more thereof. Suitable COX-2 inhibitors are in U.S. Pat. Nos. STN Express, file phar and file registry. 5,344.991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, 04.04. In some embodiments the prostaglandins are PGE1, 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, cloprostenol, fluprostenol, latanoprost and travoprost. 5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 04.05 Suitable proton pump inhibitors include, but are not 5,932,598 and 6,633,272, and in WO 94/03387, WO limited to, disulprazole, esomeprazole, lanSoprazole, lemino 94/15723, WO 94/20480, WO 94/26731, WO 94/27980, WO prazole, omeprazole, pantoprazole, rabeprazole, timopra 95/00501, WO95/15316, WO 96/03387, WO 96/03388, WO Zole, tenatoprazole, 2-(2-benzimidazolyl)-pyridine, tricyclic 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO imidazole, thienopydidine benzimidazole, fluoroalkoxy sub 97/14691, WO 97/16435, WO 01/45703 and WO 01/87343, stituted benzimidazole, dialkoxy benzimidazole, N-substi tuted 2-(pyridylalkenesulfinyl)benzimidazole, cyclohep the disclosures of each of which are incorporated herein by tenepyridine, 5-pyrrolyl-2-pyridylmethylsulfinyl reference in their entirety; and in the literature, such as in benzimidazole, alkylsulfinyl benzimidazole, fluoropyridyl Goodman and Gilman, The Pharmacological Basis of Thera methylsulfinyl benzimidazole, imidazo[4,5-b]pydridine, RO peutics (9th Edition), McGraw-Hill, 1995; and the Merck 18-5362, IY 81149, 4-amino-3-carbonyl quinoline, 4-amino Index on CD-ROM. Thirteenth Edition; and on STN Express, 3-acylnaphthyride, 4-aminoquinoline, 4-amino-3-acylquino file phar and file registry. line, 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy 0408. In some embodiments the COX-2 inhibitors are ethoxy)guinoline, quinazoline, tetrahydroisoquinolin-2-yl celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or pyrimidine, YH 1885, 3-substituted 1,2,4-thiadiazolo(4.5-a) Valdecoxib. In more particular embodiments the celecoxib is benzimidazole, 3-substituted imidazo(1,2-d)-thiadiazole, administered in an amount of about 100 milligrams to about 2-sulfinylnicotinamide, pyridylsulfinylbenz, imidazole, 800 milligrams as a single dose or as multiple doses per day; pyridylsulfinyl thieno imidazole, theinoimidazole-toluidine, the etoricoxib is administered in an amount of about 50 mil 4,5-dihydrooxazole, thienoimidazole-toluidine, Hoe-731, ligrams to about 200 milligrams as a single dose or as multiple imidazol-2-alpyridine, pyrrolo2,3-bipyridine, and the like. doses per day; the lumiracoxib is administered in an amount Suitable proton pump inhibitors are described more fully in of about 40 milligrams to about 1200 milligrams as a single the literature, such as in Goodman and Gilman, The Pharma dose or as multiple doses per day; the paracoxib is adminis cological Basis of Therapeutics (9th Edition), McGraw-Hill, tered in an amount of about 20 milligrams to about 100 1995; the Merck Index 13' Edition; and in WO 00/50037 milligrams as a single dose or as multiple doses per day; the assigned to NitroMed. Inc., the disclosures of which are rofecoxib is administered in an amount of about 12.5 milli incorporated herein by reference in their entirety. grams to about 50 milligrams as a single dose or as multiple 0406 Suitable renin inhibitors include, but are not limited doses per day; the Valdecoxib is administered in an amount of to, aldosterone, aliskiren (SPP-100), ditekiren, enalkrein about 10 milligrams to about 40 milligrams as a single dose or (A-64662), medullipin, terlkiren, tonin, Zankiren, RO as multiple doses per day. 42-5892 (remikiren), A 62198. A 64662, A 65317. A 69729, 04.09 Suitable steroids include, but are not limited to, A 72517 (Zankiren), A 74273, CP80794, CGP 29287, CGP 21-acetoxypregnenolone, alcolometaSone, algestone, amci 38560A, EMD 47942, ES305, ES1005, ES8891, FK906, FK nonide, beclomethasone, betamethasone, budesonide, chlor 744, H 113, H-142, KR11314, pepstatin A, RO 44-9375 prednisone, clobetasol, clobentaSone, clocortolone, clopred (ciprokiren), RO 42-5892, RO 66-1132, RO 66-1168, SP500, nol, corticosterone, cortisine, corticaZol (cortivatol), SP 800, SR-43845, SQ 34017, U 71038, YM-21095, deflazacort, desonide, desoximetaSone, dexamethasone, YM-26365, urea derivatives of peptides, amino acids con diflorasone, diflucortolone, difluprednate, enoxolone, fluza nected by nonpeptide bonds, di- and tri-peptide derivatives cort, flucloronide, flumethasone, flunisolide, flucinolone (e.g., Act-A, Act-B, Act-C, ACT-D, and the like), amino acids acetonide, fluocininide, fluocortin butyl, fluocortolone, fluo and derivatives thereof, diol sulfonamides and sulfinyls, rometholone, fluperolone acetate, fluprednidene acetate, flu modified peptides, peptidyl beta-aminoacyl aminodiol car prednisolone, flurandrenolide, fluticasone propionate, fluti bamates, monoclonal antibodies to renin. Suitable renin casone propionate, formocortal, halcinonide, halobetasol inhibitors are described more fully in U.S. Pat. Nos. 5,116, propionate, halometasone, haloprednone acetate, hydrocor 835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, tamate, hydrocortisone and its derivatives (such as phosphate, 5,098,924), 5,095,006, 5,089,471, 5,075451, 5,066,643, 21-sodium Succinate and the like), hydrocortisone terbutate, 5,063,208, 4,845,079, 5,055,466, 4,980,283, 4,885.292), isoflupredone, loteprednol etabonate, maZipredone, 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, medrysone, meprednisone, methylprednisolone, mometa 5,036,053, 5,034,512, and 4,894,437, the disclosures of each Sone furoate, paremethasone, prednicarbate, prednisolone of which are incorporated herein by reference in their and its derivatives (such as 21-stearoylglycolate, sodium entirety; and in the literature. Such as in Goodman and Gil phosphate and the like), prednisone, prednival, prednylidene man, The Pharmacological Basis of Therapeutics (9th Edi and its derivatives (such as 21-diethylaminoactetate and the tion), McGraw-Hill, 1995; and the Merck Index on like), rimexolone, tiXocortol, trimcinolone and its derivatives CD-ROM. Thirteenth Edition; and on STN Express, file phar (such as acetonide, benetonide and the like), and the like. and file registry. Suitable NSAIDs are described more fully in the literature, 0407 Suitable COX-2 inhibitors include, but are not lim Such as in Goodman and Gilman, The Pharmacological Basis ited to, nimesulide, celecoxib (CELEBREXR), etoricoxib of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 (ARCOXIAR), flosulide, lumiracoxib (PREXIG(R, COX 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. US 2010/024.0622 A1 Sep. 23, 2010 36

Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed. times throughout the day; or as a Sustained-release oral for Inc., the disclosures of which are incorporated herein by mulation, or as an injectable formulation. reference in their entirety. 0413. The invention provides methods for treating oph 0410. In some embodiments the steroids are dexametha thalmic disorders by administering to the patient in need Sone, fluorometholone, hydrocortisone, and prednisolone. thereof an effective amount of the compounds and/or compo 0411 Suitable compounds used for the treatment of glau sitions described herein. For example, the patient can be coma include, but are not limited to, acetylcholinesterase administered an effective amount of at least one nitric oxide inhibitors (such as, for example, citicoline, donepezil, hep enhancing prostaglandin compound. In another embodiment, tatigmine, galantamine, metafonate, physostignine, rivastig the patient can be administered an effective amount of at least nine, tarcine, Velnacrine, and the like) carbachol, pilocarpine one nitric oxide enhancing prostaglandin compound, and at and the like. Suitable compounds used for the treatment of least one nitric oxide enhancing compound. In yet another glaucoma are described more fully in the literature. Such as in embodiment, the patient can be administered an effective Goodman and Gilman, The Pharmacological Basis of Thera amount of at least one nitric oxide enhancing prostaglandin peutics (9th Edition), McGraw-Hill, 1995; and the Merck compound, and, at least one therapeutic agent, including but Index on CD-ROM, 13' Edition; and on STN Express, file not limited to. Such as, for example, aldosterone antagonists, phar and file registry. C.-adrenergic receptor agonists, C.-adrenergic receptor 0412. The invention provides compositions comprising (i) antagonists, B-adrenergic agonists, antidiabetic compounds, a nitric oxide enhancing prostaglandin compound or a phar antimicrobial compounds, anti-hyperlipidemic drugs, angio maceutically acceptable salt thereof, (ii) a nitric oxide tensin Hantagonists, angiotensin-converting enzyme (ACE) enhancing compound, such as, isosorbide dinitrate and/or inhibitors, antioxidants, antithrombotic and vasodilator isosorbide mononitrate (preferably isosorbide dinitrate), and drugs, B-adrenergic antagonists, calcium channel blockers, (i) a hydralazine compound (such as hydralazine hydrochlo carbonic anhydrase inhibitors, diuretics, endothelin antago ride). In one embodiment, the hydralazine hydrochloride can nists, hydralazine compounds, H receptor antagonists, neu be administered in an amount of about 30 milligrams per day tral endopeptidase inhibitors, nonsteroidal antiinflammatory to about 400 milligrams per day; the isosorbide dinitrate can compounds (NSAIDs), phosphodiesterase inhibitors, potas be administered in an amount of about 10 milligrams per day sium channel blockers, platelet reducing agents, prostaglan to about 200 milligrams per day; or the isosorbide mononi dins, proton pump inhibitors, renin inhibitors, selective trate can be administered in an amount of about 5 milligrams cyclooxygenase-2 (COX-2) inhibitors, Steroids, compounds per day to about 120 milligrams per day. In another embodi used for the treatment of glaucoma, and combinations of two ment, the hydralazine hydrochloride can be administered in or more thereof. In another embodiment, the patient can be an amount of about 50 milligrams per day to about 300 administered an effective amount of at least one nitric oxide milligrams per day; the isosorbide dinitrate can be adminis enhancing prostaglandin compound, and, at least one thera tered in an amount of about 20 milligrams per day to about peutic agent, and, at least one nitric oxide enhancing com 160 milligrams per day; or the isosorbide mononitrate can be pound. In one embodiment the ophthalmic disorder is glau administered in an amount of about 15 milligrams per day to coma, elevated ocular pressure, macular degeneration, about 100 milligrams per day. In yet another embodiment, the ophthalmic infection, dry eye disorder, ocular hypertension, hydralazine hydrochloride can be administered in an amount and diabetic retinopathy. The nitric oxide enhancing prostag of about 37.5 milligrams to about 75 milligrams one to four landin compounds, nitric oxide enhancing compounds, and/ times per day; the isosorbide dinitrate can be administered in or therapeutic agents can be administered separately or as an amount of about 20 milligrams to about 40 milligrams one components of the same composition in one or more pharma to four times per day; or the isosorbide mononitrate can be ceutically acceptable carriers. administered in an amount of about 10 milligrams to about 20 0414. The invention provides methods for treating cere milligrams one to four times per day. In another embodiment brovascular disorders; treating cardiovascular disorders; of the methods of the invention, the patient can be adminis treating benign prostatic hyperplasia (BPH); treating peptic tered a composition comprising about 225 mg hydralazine ulcers; treating sexual dysfunctions and inducing abortions hydrochloride and about 120 mg isosorbide dinitrate once per by administering to the patient in need thereof an effective day (i.e., q.d.). In another embodiment of the methods of the amount of the compounds and/or compositions described invention, the patient can be administered a composition herein. For example, the patient can be administered an effec comprising about 112.5 mg hydralazine hydrochloride and tive amount of at least one nitric oxide enhancing prostaglan about 60 mg isosorbide dinitrate twice per day (i.e., b.i.d.). In din compound. In another embodiment, the patient can be another embodiment of the methods of the invention, the administered an effective amount of at least one nitric oxide patient can be administered a composition comprising about enhancing prostaglandin compound, and at least one nitric 56.25 mg hydralazine hydrochloride and about 30 mg isos oxide enhancing compound. In yet another embodiment, the orbide dinitrate twice per day (i.e., b.i.d.). In another embodi patient can be administered an effective amount of at least one ment of the methods of the invention, the patient can be nitric oxide enhancing prostaglandin compound, and, at least administered a composition comprising about 75 mg hydrala one therapeutic agent including, but not limited to, such as, zine hydrochloride and about 40 mg isosorbide dinitrate three for example, aldosterone antagonists, C.-adrenergic receptor times per day (i.e., t.i.d.). In another embodiment of the agonists, C.-adrenergic receptor antagonists, B-adrenergic methods of the invention, the patient can be administered a agonists, antidiabetic compounds, antimicrobial compounds, composition comprising about 37.5 mg hydralazine hydro anti-hyperlipidemic drugs, angiotensin II antagonists, angio chloride and about 20 mg isosorbide dinitrate three times per tensin-converting enzyme (ACE) inhibitors, antioxidants, day (i.e., t.i.d.). The particular amounts of hydralazine and antithrombotic and vasodilator drugs, B-adrenergic antago isosorbide dinitrate or isosorbide mononitrate can be admin nists, calcium channel blockers, carbonic anhydrase inhibi istered as a single dose once a day; or in multiple doses several tors, diuretics, endothelin antagonists, hydralazine com US 2010/024.0622 A1 Sep. 23, 2010 37 pounds, H2 receptor antagonists, neutral endopeptidase desirable to increase ocular absorption of the active com inhibitors, nonsteroidal antiinflammatory compounds pound, to decrease variability in dispensing the formulations, (NSAIDs), phosphodiesterase inhibitors, potassium channel to decrease physical separation of components of a Suspen blockers, platelet reducing agents, prostaglandins, proton sion or emulsion of formulation and/or otherwise to improve pump inhibitors, renin inhibitors, selective cyclooxygenase-2 the ophthalmic formulation. Suitable viscosity enhancers, (COX-2) inhibitors, steroids, compounds used for the treat include, but are not limited to, polyvinyl alcohol, methyl ment of glaucoma, and combinations of two or more thereof. cellulose, hydroxy propyl carboxymethyl cellulose, In another embodiment, the patient can be administered an hydroxymethylcellulose, hydroxyethylcellulose, hydrox effective amount of at least one nitric oxide enhancing pros ypropylmethylcellulose, methylcellulose, polyvinylpyrroli taglandin compound, and, at least one therapeutic agent, and, done, and the like. Gelling agents can also be used, including, at least one nitric oxide enhancing compound. The nitric but not limited to, gellan and Xanthan gum, and the like. oxide enhancing prostaglandin compounds, nitric oxide Viscosity enhancers are typically employed at a concentra enhancing compounds, and/or therapeutic agents can be tion between about 0.01% and about 2% by weight. administered separately or as components of the same com 0419 Ophthalmic solution formulations may be prepared position in one or more pharmaceutically acceptable carriers. by dissolving a compound in a physiologically acceptable 0415. When administered separately, the nitric oxide isotonic aqueous buffer. Alternatively, the ophthalmic solu enhancing prostaglandin compound, nitric oxide enhancing tion may include an opthalmologically acceptable surfactant compound and/or therapeutic agent can be administered to assist in dissolving the compound. Additionally for sterile about the same time as part of the overall treatment regimen, ophthalmic ointment formulations, the compounds of the i.e., as a combination therapy. About the same time' includes invention may be combined with a preservative in an appro administering the nitric oxide enhancing prostaglandin com priate vehicle, such as, mineral oil, liquid lanolin, or white pound, simultaneously, sequentially, at the same time, at dif petrolatum. Sterile ophthalmic gel formulations may be pre ferent times on the same day, or on different days, as long as pared by Suspending the active ingredient in a hydrophilic they are administered as part of an overall treatment regimen, base prepared from the combination of for example, car i.e., combination therapy or a therapeutic cocktail. bopol-974, and the like. 0416. When administered in vivo, the compounds and 0420 Various delivery systems are known and can be used compositions of the invention can be administered in combi to administer the compounds or compositions of the inven nation with pharmaceutically acceptable carriers and in dos tion, including, for example, encapsulation in liposomes, ages described herein. When the compounds and composi microbubbles, emulsions, microparticles, microcapsules and tions of the invention are administered as a combination of at the like. The required dosage can be administered as a single least one nitric oxide enhancing prostaglandin compound unit or in a Sustained release form. and/or at least one nitric oxide enhancing compound and/or 0421. The bioavailability of the compositions can be therapeutic agent, they can also be used in combination with enhanced by micronization of the formulations using conven one or more additional compounds which are known to be tional techniques such as grinding, milling, spray drying and effective against the specific disease state targeted for treat the like in the presence of suitable excipients or agents such as ment. The nitric oxide enhancing compounds, therapeutic phospholipids or Surfactants. agents and/or other additional compounds can be adminis 0422 Sustained release dosage forms of the invention may tered simultaneously with, Subsequently to, or prior to admin comprise microparticles and/or nanoparticles having a thera istration of the nitric oxide enhancing prostaglandin com peutic agent dispersed therein or may comprise the therapeu pound. tic agent in pure, preferably crystalline, Solid form. For Sus 0417. The compounds of the invention can be incorpo tained release administration, micro particle dosage forms rated into various types of pharmaceutical compositions, such comprising pure, crystalline, therapeutic agents. The thera as, for example, ophthalmic formulations for delivery to the peutic dosage forms of this aspect of the invention may be of eye (e.g., topically, intracamerally, or via an implant). The any configuration Suitable for Sustained release. compounds are preferably incorporated into topical oph 0423 Nanoparticle sustained release therapeutic dosage thalmic formulations, such as for example, Solutions, Suspen forms are preferably biodegradable and, optionally, bind to sions, gels, ointments, implants, and the like. The compounds the vascular Smooth muscle cells and enter those cells, pri of the invention may be combined with opthalmologically marily by endocytosis. The biodegradation of the nanopar acceptable preservatives, viscosity enhancers, penetration ticles occurs over time (e.g., 30 to 120 days; or 10 to 21 days) enhancers, buffers, Sodium chloride, water to form an aque in prelysosomic vesicles and lysosomes. Larger microparticle ous, sterile ophthalmic Suspensions or solutions, and the like. therapeutic dosage forms of the invention release the thera 0418 Suitable preservatives include, but are not limited peutic agents for Subsequent target cell uptake with only a few to, benzalkonium chloride, thimerosal, chlorobutanol, methyl of the Smaller microparticles entering the cell by phagocyto paraben, propyl paraben, phenylethyl alcohol, edetate diso sis. A practitioner in the art will appreciate that the precise dium, sorbic acid, ONAMER(R), and the like. The preserva mechanism by which a target cell assimilates and metabolizes tives are typically employed at a concentration between about a dosage form of the invention depends on the morphology, 0.001% and about 1.0% by weight. Appropriate co-solvents physiology and metabolic processes of those cells. The size of include, but are not limited to, Polysorbate 20, 60 and 80; the particle Sustained release therapeutic dosage forms is also Pluronic F-68, F-84 and P-103; TyloxapolR); Cremophor(R) important with respect to the mode of cellular assimilation. EL: sodium dodecyl sulfate; glycerol; PEG 400; propylene For example, the smaller nanoparticles can flow with the glycol, cyclodextrins, and the like. The co-solvents are typi interstitial fluid between cells and penetrate the infused tis cally employed at a concentration between about 0.01% and Sue. The larger microparticles tend to be more easily trapped about 2% by weight. Viscosity enhancers are required as a interstitially in the infused primary tissue, and thus are useful Viscosity greater than that of simple aqueous Solutions may be to deliver anti-proliferative therapeutic agents. US 2010/024.0622 A1 Sep. 23, 2010 38

0424 Particular sustained release dosage forms of the dose to be used in the formulation will also depend on the invention comprise biodegradable microparticles or nanopar route of administration, and the seriousness of the disease or ticles. More particularly, biodegradable microparticles or disorder, and should be decided by the physician and the nanoparticles are formed of a polymer containing matrix that patient's circumstances. biodegrades by random, nonenzymatic, hydrolytic Scission 0428 The invention also provides pharmaceutical kits ing to release therapeutic agent, thereby forming pores within comprising one or more containers filled with one or more of the particulate structure. the ingredients of the pharmaceutical compounds and/or 0425 The compounds and compositions of the invention compositions of the invention, including, at least, one or more can be formulated as pharmaceutically acceptable salt forms. of the novel nitric oxide enhancing prostaglandin compound, Pharmaceutically acceptable salts include, for example, and one or more of the nitric oxide enhancing compounds alkali metal salts and addition salts of free acids or free bases. described herein. Associated with such kits can be additional The nature of the salt is not critical, provided that it is phar therapeutic agents or compositions (e.g., aldosterone antago maceutically-acceptable. Suitable pharmaceutically-accept nists, C.-adrenergic receptor agonists, C.-adrenergic receptor able acid addition salts may be prepared from an inorganic antagonists, B-adrenergic agonists, antidiabetic compounds, acid or from an organic acid. Examples of Such inorganic antimicrobial compounds, anti-hyperlipidemic drugs, angio acids include, but are not limited to, hydrochloric, hydrobro tensin II antagonists, angiotensin-converting enzyme (ACE) mic, hydroiodic, nitric, carbonic, Sulfuric and phosphoric inhibitors, antioxidants, antithrombotic and vasodilator acid and the like. Appropriate organic acids include, but are drugs, B-adrenergic antagonists, calcium channel blockers, not limited to, aliphatic, cycloaliphatic, aromatic, heterocy carbonic anhydrase inhibitors, diuretics, endothelin antago clic, carboxylic and Sulfonic classes of organic acids, such as, nists, hydralazine compounds, H receptor antagonists, neu for example, formic, acetic, propionic, succinic, glycolic, tral endopeptidase inhibitors, nonsteroidal antiinflammatory gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, compounds (NSAIDs), phosphodiesterase inhibitors, potas maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthra sium channel blockers, platelet reducing agents, prostaglan nilic, mesylic, Salicylic, p-hydroxybenzoic, phenylacetic, dins, proton pump inhibitors, renin inhibitors, selective mandelic, embonic (pamoic), methanesulfonic, ethane cyclooxygenase-2 (COX-2) inhibitors, Steroids, compounds Sulfonic, benzenesulfonic, pantothenic, toluenesulfonic, used for the treatment of glaucoma, and combinations of two 2-hydroxyethanesulfonic, Sulfanilic, Stearic, algenic, B-hy or more thereof), devices for administering the compositions, droxybutyric, cyclohexylaminosulfonic, galactaric and and notices in the form prescribed by a governmental agency galacturonic acid and the like. Suitable pharmaceutically regulating the manufacture, use or sale of pharmaceuticals or acceptable base addition salts include, but are not limited to, biological products which reflects approval by the agency of metallic salts made from aluminum, calcium, lithium, mag manufacture, use or sale for humans. nesium, potassium, Sodium and Zinc or organic salts made 0429. The disclosure of each patent, patent application from primary, secondary and tertiary amines, cyclic amines, and publication cited or described in the present specification N,N'-dibenzylethylenediamine, chloroprocaine, choline, is hereby incorporated by reference herein in its entirety. diethanolamine, ethylenediamine, meglumine (N-methylglu 0430 Although the invention has been set forth in detail, camine) and procaine and the like. All of these salts may be one skilled in the art will appreciate that numerous changes prepared by conventional means from the corresponding and modifications can be made to the invention, and that such compound by reacting, for example, the appropriate acid or changes and modifications can be made without departing base with the compound. In one embodiment, the pharma from the spirit and scope of the invention. ceutically acceptable salts of the compounds of the invention What is claimed is: do not include the nitrate salt. 1. A compound of Formula (I), or a pharmaceutically 0426. While individual needs may vary, determination of acceptable salt thereof: optimal ranges for effective amounts of the compounds and/ wherein the compound of Formula (I) is: or compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the com pounds and compositions, which can be adjusted by one of (I) ordinary skill in the art, will vary depending on the age, Rs Ro health, physical condition, sex, diet, weight, extent of the R. R. ... X dysfunction of the recipient, frequency of treatment and the B 11-1 R10 Z1 nature and scope of the dysfunction or disease, medical con Rs dition of the patient, the route of administration, pharmaco logical considerations such as the activity, efficacy, pharma A. R6 cokinetic and toxicology profiles of the particular compound R R3 R4 used, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination. 0427. The amount of a given prostaglandin compound of wherein the invention compound comprising at least one nitric oxide w indicates a single or a double bond; enhancing group that will be effective in the treatment of a R is —OD or —Cl; particular disorder or condition will depend on the nature of R and Rs are a hydrogen; or R and R taken together are the disorder or condition, and can be determined by standard =CH, or =O; clinical techniques, including reference to Goodman and Gil R and R are each independently a hydrogen, a fluorine, man, supra: The Physician's Desk Reference, Medical Eco —OD or —CH, or R and R taken together are =O; nomics Company, Inc., Oradell, N.J., 1995; and Drug Facts Rs and R are each independently a hydrogen, —OD, and Comparisons, Inc., St. Louis, Mo., 1993. The precise —CH —OCH or —CH=CH: US 2010/024.0622 A1 Sep. 23, 2010 39

R is a hydrogen or —OD; V is: R is hydrogen or absent when the carbon to which it is attached is the central carbon of an allene functionality; or Rs and R taken together with the chain to which they are attached form a substituted benzene ring with the (1) proviso that R is an oxygen atom which is attached to the carbon atom at the position of the benzene ring defined by B: N N Ro is a hydrogen; or is absent when the carbon to which it N / n is attached is O O

-CE;o (2)

N 1 / O N O -CE;

(3) B is —CH=, —CH, -S , or —C(O)—: X is —CHOR, —C(O)OR or —C(O)N(D.)R; Me R is D, a lower alkyl group, or W \ N N N / n O O O K)--N K) (4) Me R is a hydrogen, —CHs: —S(O)CH or —C(O)CH: Z is (a) an ethyl, (b) a butyl, (c) a hexyl, (d) a benzyl, f \

(e) (5) 's-n CN (f) P.N N N / n O O S. (6)

(g) CN * R13 O o -O1P. NNo1 N (h) (7)

R is a hydrogen, CF or —Cl; D is a hydrogen or K; with the proviso that at least one D, (8) in formula (I) must be a nitric oxide enhancing group; K is —(Ws),-E,-(C(R)(M-E-(C(R)(R)).-(W), (C (R)(R)) (W),E,-(W), (C(R)(R)). Va: a, b, c, d, g, i and are each independently an integer from W \ O to 3: N N p. x,y and Zare each independently an integer from 0 to 10; o1 No1 V is V. R. —U Vs or Ve:

US 2010/024.0622 A1 Sep. 23, 2010

R is a hydrogen, a lower alkyl group, or an aryl group; V is: -continued (3)

(1) H3C CH3

N - O Zs (4) CH3 H3C (2) H3C CH3 N-O (5)

H3C*A CH3 (3) R-N Re H3C CH3 Y. ( \ - -T O -O or Z5 No N1 (6) HC CH (4) r; 4. Re N-R A ( Nt\, NN o1

T is a —S(O) ; a carbonyl or a covalent bond; Zs is —CH or oxygen; o is an integer from 0 to 2: Z is —CH or nitrogen; R, and R are independently selected from an alkyl group, an aryl group, or R, and R taken together with the W at each occurrence is independently —C(O)—, nitrogen atom to which they are attached are a hetero —C(S)-, -T-, -(C(R)(R)), , – N(R)R, an alkyl cylic ring: group, an aryl group, a heterocyclic ring, an arylhetero T at each occurrence is independently a covalent bond, a cyclic ring, -(CH2CH2O) — or a heterocyclic nitric carbonyl, an oxygen, —S(O) - or —N(R)R, oxide donor; his an integer form 1 to 10; Eat each occurrence is independently-T-, an alkyl group, q is an integer from 1 to 5: R, and Rare each independently a hydrogen, an alkyl, a an aryl group, —(C(R)(R)), , a heterocyclic ring, an cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an arylheterocyclic ring, -(CH2CH2O)— or Ya: alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an Y is: alkylcycloalkyl, an alkylheterocyclic ring, a cycloalky lalkyl, a cycloalkylthio, an arylalklythio, an arylalk lythioalkyl, an alkylthioalkyl, a cycloalkenyl, an hetero (1) cyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diary lamino, an alkylarylamino, an alkoxyhaloalkyl, a Sul fonic acid, a Sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcar (2) boxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a car boxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a Sulfonamido, an alkylsulfonamido, an arylsur fonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sulfonic ester, an alkyl US 2010/024.0622 A1 Sep. 23, 2010 42

ester, an aryl ester, a urea, a phosphoryl, a nitro. —U - Vs, V, -(C(R)(R)). U Vs. -C(R)(R)- -continued U. V. —(C(R)(R)) —Us Vs. —C(R)(R) — (2) Us C(O) V, or R, and R, taken together with the H3C CH3 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 N-O; cycloalkyl group, Zs H3C CH3 (1) Us is an oxygen, Sulfur or —N(R)R, Vs is NO or - NO, (i.e. an oxidized nitrogen); k is an integer from 1 to 3: R is alone pair of electrons, a hydrogen oran alkyl group; R, is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an aryl (2) carboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a Sulfonamido, a carboxamido, a car boxylic ester, an aminoalkyl, an aminoaryl, —CH2— C—(Us Vs)(R)(R), a bond to an adjacent atom cre ating a double bond to that atom or —(NO-)-M". wherein M is an organic or inorganic cation; and with the proviso that the prostaglandin compound of For R, and R are each independently a hydrogen, an alkyl, a mula (I) must contain at least heterocyclic nitric oxide cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an donor group and/or nitroxide group linked to the pros alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an taglandin compound of Formula (I) through an oxygen alkylcycloalkyl, an alkylheterocyclic ring, a cycloalky atom, a nitrogen atom or a Sulfur atom via a bond or lalkyl, a cycloalkylthio, an arylalklythio, an arylalk moiety that can be hydrolyzed. lythioalkyl, an alkylthioalkyl a cycloalkenyl, an hetero 2. A composition comprising the compound of claim 1 and cyclicalkyl, an alkoxy, a haloalkoxy, an amino, an a pharmaceutically acceptable carrier. alkylamino, a dialkylamino, an arylamino, a diary 3. The compound of claim 1, wherein the compound of lamino, an alkylarylamino, an alkoxyhaloalkyl, a Sul Formula (I) is a nitric oxide enhancing arbaprostill analogue, fonic acid, a Sulfonic ester, an alkylsulfonic acid, an a nitric oxide enhancing alprostadil analogue, a nitric oxide arylsulfonic acid, an arylalkoxy, an alkylthio, an enhancing bimatoprost analogue, a nitric oxide enhancing arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, carboprost analogue, a nitric oxide enhancing cloprostenol analogue, a nitric oxide enhancing dimoxaprost analogue, a an arylalkyl, an alkylaryl, a carboxamido, an alkylcar nitric oxide enhancing dinoprost analogue, a nitric oxide boxamido, an arylcarboxamido, an amidyl, a carboxyl, a enhancing emprostil analogue, a nitric oxide enhancingeniso carbamoyl, an alkylcarboxylic acid, an arylcarboxylic prost analogue, a nitric oxide enhancing fenprostalene ana acid, an alkylcarbonyl, an arylcarbonyl, an ester, a car logue, a nitric oxide enhancing froxiprost analogue, a nitric boxylic ester, an alkylcarboxylic ester, an arylcarboxylic oxide enhancing gemeprost analogue, a nitric oxide enhanc ester, a Sulfonamido, an alkylsulfonamido, an arylsul ing latanoprost analogue, a nitric oxide enhancing fonamido, an alkylsulfonyl, an alkylsulfonyloxy, an meteneprost analogue, a nitric oxide enhancing mexiprostil arylsulfonyl, arylsulphonyloxy, a Sulfonic ester, an alkyl analogue, a nitric oxide enhancing misoprostol analogue, a ester, an aryl ester, a urea, a phosphoryl, a nitro. —U— nitric oxide enhancing misoprostil analogue, a nitric oxide Vs, Vs, or R, and R, taken together with the carbons to enhancing misoprostol acid analogue, a nitric oxide enhanc which they are attached form a carbonyl, a methanthial, ing nocloprost analogue, a nitric oxide enhancing ONO 373 a heterocyclic ring, a cycloalkyl group, an aryl group, an analogue, a nitric oxide enhancing ornoprostill analogue, a Oxime, an imine, a hydrazone a bridged cycloalkyl nitric oxide enhancing prostalene analogue, a nitric oxide grOup, enhancing PGE analogue, a nitric oxide enhancing PGE analogue, a nitric oxide enhancing PGF analogue, a nitric oxide enhancing PGF2, analogue, a nitric oxide enhancing (1) rioprostil analogue, a nitric oxide enhancing rosaprostol ana logue, a nitric oxide enhancing remiprostol analogue, a nitric oxide enhancing Sulprostone analogue, a nitric oxide enhanc ing tafluprost analogue, a nitric oxide enhancing travoprost analogue, a nitric oxide enhancing trimoprostil analogue, a nitric oxide enhancing tiprostanide analogue, a nitrosated unoprostone analogue, and pharmaceutically acceptable salts thereof. US 2010/024.0622 A1 Sep. 23, 2010 43

4. The compound of claim 1, wherein the compound of wherein the compound of Formula (IV) is: Formula (I) is a nitric oxide enhancing arbaprostil analogue of Formula (II), a nitric oxide enhancing alprostadil or PGE analogue of Formula (III), a nitric oxide enhancing bimato prost analogue of Formula (IV), a nitric oxide enhancing (IV) carboprost analogue of Formula (V), a nitric oxide enhancing Rim-Rn cloprostenol analogue of Formula (VI), a nitric oxide enhanc ing dimoxaprost analogue of Formula (VII), a nitric oxide enhancing dinoprost analogue of Formula (VIII), a nitric ..Y.W 1'''CH a T-Rn oxide enhancing emprostil analogue of Formula (IX), a nitric oxide enhancing enisoprost analogue of Formula (X), a nitric Ph oxide enhancing fenprostalene analogue of Formula (XI), a nitric oxide enhancing froxiprost analogue of Formula (XII), a nitric oxide enhancing gemeprost analogue of Formula (XIII), a nitric oxide enhancing latanoprost analogue of For mula (XIV), a nitric oxide enhancing meteneprost analogue of Formula (XV), a nitric oxide enhancing mexiprostil ana- wherein the compound of Formula (V) is: logue of Formula (XVI), a nitric oxide enhancing misoprostol analogue of Formula (XVII), a nitric oxide enhancing miso prostol acid analogue of Formula (XVIII), a nitric oxide enhancing nocloprost analogue of Formula (XIX), a nitric (V) oxide enhancing ONO 373 analogue of Formula (XX), a nitric oxide enhancing ornoprostil analogue of Formula (XXI), a nitric oxide enhancing prostalene analogue of For mula (XXII), a nitric oxide enhancing PGE analogue of Formula (XXIII), a nitric oxide enhancing PGF analogue of Formula (XXIV), a nitric oxide enhancing PGF2, analogue of Formula (XXV), a nitric oxide enhancing rioprostil ana logue of Formula (XXVI), a nitric oxide enhancing rosapros tol analogue of Formula (XXVII), a nitric oxide enhancing remiprostol analogue of Formula (XXVIII), a nitric oxide enhancing Sulprostone analogue of Formula (XXIX), a nitric oxide enhancing tafluprost analogue of Formula (XXX), a wherein the compound of Formula (VI) is: nitric oxide enhancing travoprost analogue of Formula (XXXI), a nitric oxide enhancing trimoprostil analogue of Formula (XXXII), a nitric oxide enhancing tiprostanide ana logue of Formula (XXVIII), a nitric oxide enhancing unopro stone analogue of Formula (XXXIV), and pharmaceutically acceptable salts thereof: wherein the compound of Formula (II) is:

(II)

(III) US 2010/024.0622 A1 Sep. 23, 2010 44

wherein the compound of Formula (VIII) is: wherein the compound of Formula (XII) is:

(VIII) (XII)

T-Rn

(IX) (XIII)

wherein the compound of Formula (XIV) is:

(X) (XIV) Rim-Rn M O O -Ya-1 (CH2)3. T-Rn

Ph

O-R-Rn

wherein the compound of Formula (XV) is:

(XI) (XV)

6 US 2010/024.0622 A1 Sep. 23, 2010 45

wherein the compound of Formula (XVI) is: wherein the compound of Formula (XX) is:

(XVI) (XX)

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

(XVII) (XXI) O OMe O re T-Rn

O-R-Rn

wherein the compound of Formula (XVIII) is: wherein the compound of Formula (XXII) is

(XVIII)

T-Rn (XXII)

O-R-Rn

wherein the compound of Formula (XIX) is:

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

(XXIII)

O O

s Ya–1o (CH2)3. T-Rn

(CH2)4-CH US 2010/024.0622 A1 Sep. 23, 2010 46

wherein the compound of Formula (XXIV) is: wherein the compound of Formula (XXIX) is:

Rim-Rn (XXIV) (XXIX) M 2. O . w(CH2)6. T-Rn (CH2)4-CH

Rim-Rn n Rim-Rn n Rn E O-Rim-Rn

(XXV) Rim-Rn / wherein the compound of Formula (XXX) is: 2 O 2-N.Y-1'''s o T-Rn (XXX)

(CH2)4-CH CS E V O-R-R Rim-Rn wherein the compound of Formula (XXVI) is:

(XXVI)

O-R-R

O-R-Rn

wherein the compound of Formula (XXVII) is:

(XXVII) Rim-Rn M O O (CH2)6 N-1-

(CH2)5-CH wherein the compound of Formula (XXXII) is: wherein the compound of Formula (XXVIII) is:

(XXXII)

(XXVIII)

T-Rn

T-Rn

-R-Rn

US 2010/024.0622 A1 Sep. 23, 2010 49

prostalene analogue of Formula (LV), a nitric oxide enhanc -continued ing PGE analogue of Formula (LVI), a nitric oxide enhanc (25) ing PGF analogue of Formula (LVII), a nitric oxide enhanc O O N /N Y ing PGF analogue of Formula (LVIII), a nitric oxide enhancing rioprostill analogue of Formula (LIX), a nitric oxide enhancing rosaprostol analogue of Formula (LX), a nitric oxide enhancing remiprostol analogue of Formula (LXI), a nitric oxide enhancing Sulprostone analogue of For mula (LXII), a nitric oxide enhancing tafluprost analogue of Formula (LXIII), a nitric oxide enhancing travoprost ana logue of Formula (LXIV), a nitric oxide enhancing trimo prostill analogue of Formula (LXV), a nitric oxide enhancing tiprostanide analogue of Formula (LXVI), a nitric oxide enhancing unoprostone analogue of Formula (LXVII), and pharmaceutically acceptable salts thereof; wherein the compound of Formula (XXXV) is: (XXXV) O O Zs is —CH or oxygen; w N=1 (CH2)3. R45 Z is —CH or nitrogen;

Rais—CHR-7, —CN. —S(O), —CHR-7, -C(O)— (CH2)4-CH3 N(R)(R), —NO. —C(O)—ORs or —S(O) Rs: Rs is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group; Reis —C(O)— or —S(O) ; Rs7 is a hydrogen, —CN. —S(O) Rs. —C(O)—N(R) (R), NO, or —C(O)—ORs: T is oxygen, Sulfur or NR; R is a hydrogen, a lower alkyl group, or an aryl group; (XXXVI) k is an integer from 1 to 3: R, and R are independently selected from an alkyl group, an aryl group, or R, and R taken together with the nitro gen atom to which they are attached are a heterocylic ring; and with the proviso that the compounds of Formula (II) to 5 Formula (XXXIV) must contain at least one nitric oxide R46 R46 enhancing group linked to the compounds of Formula (II) to Formula (XXXIV) via a bond or moiety that can wherein the compound of Formula (XXXVII) is: be hydrolyzed. 5. The compound of claim 1, wherein the Formula (I) is a (XXXVII) nitric oxide enhancing arbaprostil analogue of Formula (XXXV), a nitric oxide enhancing alprostadil or PGE ana logue of Formula (XXXVI), a nitric oxide enhancing bimato prost analogue of Formula (XXXVII), a nitric oxide enhanc ing carboprost analogue of Formula (XXXVIII), a nitric oxide enhancing cloprostenol analogue of Formula (XXXIX), a nitric oxide enhancing dimoxaprost analogue of Formula (XL), a nitric oxide enhancing dinoprost analogue of Formula (XLI), a nitric oxide enhancing enprostil analogue of Formula (XLII), a nitric oxide enhancingenisoprostanalogue of Formula (XLIII), a nitric oxide enhancing fenprostalene wherein the compound of Formula (XXXVIII) is: analogue of Formula (XLIV), a nitric oxide enhancing froX (XXXVIII) iprost analogue of Formula (XLV), a nitric oxide enhancing R46 W gemeprost analogue of Formula (XLVI), a nitric oxide 2 O enhancing latanoprost analogue of Formula (XLVII), a nitric w (CH2)3. oxide enhancing meteneprost analogue of Formula (XLVIII), w N=1 R45 a nitric oxide enhancing mexiprostill analogue of Formula (XLIX), a nitric oxide enhancing misoprostol analogue of (CH2)4-CH Formula (L), a nitric oxide enhancing misoprostol acid ana logue of Formula (LI), a nitric oxide enhancing nocloprost R HC O-R analogue of Formula (LII), a nitric oxide enhancing ONO373 R46 analogue of Formula (LIII), a nitric oxide enhancing orno prostill analogue of Formula (LIV), a nitric oxide enhancing US 2010/024.0622 A1 Sep. 23, 2010 50

wherein the compound of Formula (XXXIX) is: wherein the compound of Formula (XLIV) is: (XXXIX)

(XLIV)

R46 OPh (XL) O R46

wherein the compound of Formula (XLV) is:

(XLV)

wherein the compound of Formula (XLI) is: R4 (XLI) / 6 O O . w (CH2)3. s N=1 R45

CH3 R-6 i R4 wherein the compound of Formula (XLVI) is: - K46

wherein the compound of Formula (XLII) is:

(XLVI)

(XLII)

(XLIII) (XLVII) R46 M O O w w N=1 (CH2)3. R45

Ph US 2010/024.0622 A1 Sep. 23, 2010 51

wherein the compound of Formula (XLVIII) is: wherein the compound of Formula (LII) is:

(XLVIII) (LII)

wherein the compound of Formula (XLIX) is:

(LIII) (XLIX)

wherein the compound of Formula (LIV) is: wherein the compound of Formula (L) is:

(LIV)

(L)

wherein the compound of Formula (LI) is: (LV) (LI) US 2010/024.0622 A1 Sep. 23, 2010 52

wherein the compound of Formula (LVI) is: wherein the compound of Formula (LXI) is:

(LVI) O O (LI) w N=1 (CH2)3. R45 (CH2)4-CH

O

wherein the compound of Formula (LVII) is: -- )

(LVII) R46 O

(LXII) (CH2)4-CH

wherein the compound of Formula (LVIII) is:

(LVIII) M 6 O O 2. w (CH2)3. s N=1 R45 wherein the compound of Formula (LXIII) is: (CH2)4-CH

V O-R (LXIII) R46

(LIX)

(LXIV)

(L)

O O CF

(CH2)5-CH US 2010/024.0622 A1 Sep. 23, 2010 53

wherein the compound of Formula (LXV) is: -continued (2) l (LXV) O re. R45 CH3 (3) s nBu H.C. O-R

wherein the compound of Formula (LXVI) is:

(4) (LXVI)

N Ph O O (CH2)6 -I- O O

S (CH2)4-CH (5) R-O -OH: H3C O-R (6) H3C CH3 wherein the compound of Formula (LXVI) is:

(LXVII) --O-H3C CH3 (7) O O w (CH2)3 H3C CH3 N=1 NL R45 O N-1 no (CH2)6-CH N-O

HC CH R46 (8) H3C CH3 wherein: O nBu is the lower alkyl group CH-CH CH-CH -: N - O OMe is the alkoxy group —O CH: OEt is the alkoxy group —OCH CH: H3C CH3 OPh is the alkoxy group —OCHs: (9) Ph is an aryl group —CHs; R48 R4s is: --- )its YN-o. O NN o? (1) Na R48 O-N M

O US 2010/024.0622 A1 Sep. 23, 2010 54

-continued -continued O (10) (6) O O

y / \ O R4s N N (K). R48 O1 No1 O k O (7) ): YN-o: O O NN/ R67 N2 R4s | \ (5-4 NNo1 NNo O (8) Ras is S(O). CHs: —CN, —C(O) NH, or —C(O) O OCH and R67 Rao is a hydrogen or chlorine; | \ Res is a hydrogen or a methyl group; O1 NNo1 N k is an integer from 1 to 3: Z is CH or nitrogen; (9) Rao is: r O Nt -- (1) ( \, N o1

(10) (2) O ( \,-- N o1 (3) O (11)

O N-N (4) N ( o1\ . 65

(12)

(5) O N- \

N - o1 O US 2010/024.0622 A1 Sep. 23, 2010 55

-continued -continued (13) O (20) y O O O N-N R49 R66 O R48 (R): R48 N 4 O/ 65 O k O O () \ -O (14) H; O NN/ (15) N2 O H3C CH3 (b. 4 R4s O N-O O (21) R66 HC CH (16) O 1N-ONiZ6 O R48 O H3C CH3 O ()); N -O O NN/ N-O N2 R4s HC CH (N, (17) O O H3C CH3 wherein: N-O Reis —(CH), O—C(O)—CH or —(CH). NH-C (O)—CH: R, is —CN, —C(O) NH or —C(O)—OCH: H3C CH3 Rao, Rs. Z and k are as defined herein; and (18) with the proviso that the compounds of Formula (XXXV) to (LXVII) must contain at least one nitric oxide enhanc O1N, iZ6 1N O R48 ing group linked to the compounds of Formula (XXXV) to (LXVII) via a bond or moiety that can be hydrolyzed. O ()) \ -O 6. A method for treating an ophthalmic disorder in a patient O NN/ in need thereof comprising administering to the patient an effective amount of the composition of claim 2. Na 7. The method of claim 6, wherein the ophthalmic disorder R48 is an inflammation of the conjunctiva, inflammation of the (5-4 cornea or a corneal ulcer. 8. A method for treating a cerebrovascular disorder; treat O ing a cardiovascular disorder, treating a benign prostatic (19) hyperplasia; treating a peptic ulcer, treating a sexual dysfunc O O tion or inducing an abortion in a patient in need thereof comprising administering to the patient an effective amount y of the composition of claim 2. O R48 9. The composition of claim 2, further comprising (i) at (S)- R48 least one therapeutic agent; (ii) at least one nitric oxide O k O enhancing compound; or (iii) at least one therapeutic agent (7): N and at least one nitric oxide enhancing compound. O O M -O 10. The composition of claim 9, wherein the therapeutic NNo. agent is an aldosterone antagonist, an O-adrenergic receptor agonist, an O-adrenergic receptor antagonist, a f-adrenergic N2 agonist, an antidiabetic compound, an antimicrobial com R48 pound, an anti-hyperlipidemic drug, an angiotensin II antago (N/ nist, an angiotensin-converting enzyme inhibitor, an antioxi O dant, an antithrombotic and vasodilator drug, a B-adrenergic antagonist, a calcium channel blocker, a carbonic anhydrase US 2010/024.0622 A1 Sep. 23, 2010 56 inhibitor, a diuretic, an endothelin antagonist, a hydralazine crobial compound, an anti-hyperlipidemic drug, an angio compound, a H2 receptor antagonist, a neutral endopeptidase tensin II antagonist, an angiotensin-converting enzyme inhibitor, a nonsteroidal antiinflammatory compound, a phos inhibitor, an antioxidant, an antithrombotic and vasodilator phodiesterase inhibitor, a potassium channel blocker, a plate drug, a B-adrenergic antagonist, a calcium channel blocker, a let reducing agent, a prostaglandin, a proton pump inhibitor, carbonic anhydrase inhibitor, a diuretic, an endothelin a renin inhibitor, a selective cyclooxygenase-2 inhibitor, a antagonist, a hydralazine compound, a H receptor antago steroid, a compound used for the treatment of glaucoma or a nist, a neutral endopeptidase inhibitor, a nonsteroidal antiin combination of two or more thereof. flammatory compound, a phosphodiesterase inhibitor, a 11. The composition of claim 10, wherein the therapeutic potassium channel blocker, a platelet reducing agent, a pros agent is at least one compound selected from the group con taglandin, a proton pump inhibitor, a renin inhibitor, a selec sisting of an O-adrenergic receptor antagonist, a B-adrenergic tive cyclooxygenase-2 inhibitor, a steroid, a compound used agonist, an antimicrobial compound, a B-adrenergic antago for the treatment of glaucoma or a combinations of two or nist, a calcium channel blocker, a carbonic anhydrase inhibi more thereof. tor, a nonsteroidal antiinflammatory compound (NSAID), a 15. The method of claim 13, wherein the nitric oxide phosphodiesterase inhibitor, a potassium channel blocker, a enhancing compound is selected from the group consisting of prostaglandin, a proton pump inhibitor, a selective cyclooxy a S-nitrosothiol, a nitrite, a nitrate, a S-nitrothiol, a Sydnon genase-2 (COX-2) inhibitor and a steroid. imine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitro 12. The composition of claim 9, wherein the nitric oxide samine, a nitrosimine, a diazetine dioxide, an oXatriazole enhancing compound is selected from the group consisting of 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a S-nitrosothiol, a nitrite, a nitrate, a S-nitrothiol, a Sydnon a hydroxyurea, a furoxan or a nitroxide. imine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitro 16. A kit comprising at least one compound of claim 1. samine, a nitrosimine, a diazetine dioxide, an oXatriazole 17. The kit of claim 16, further comprising further com 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, prising (i) at least one therapeutic agent; (ii) at least one nitric a hydroxyurea, a furoxan or a nitroxide. oxide enhancing compound; or (iii) at least one therapeutic 13. The method of claims 6 or 8, further comprising admin agent and at least one nitric oxide enhancing compound. istering (i) at least one therapeutic agent; (ii) at least one nitric 18. The kit of claim 17, wherein the (i) at least one thera oxide enhancing compound (iii) at least one therapeutic agent peutic agent; (ii) at least one nitric oxide enhancing com and at least one nitric oxide enhancing compound. pound; or (iii) at least one therapeutic agent and at least one 14. The method of claim 13, wherein the therapeutic agent nitric oxide enhancing compound are in the form of separate is the therapeutic agent is an aldosterone antagonist, an O-adr components in the kit. energic receptoragonist, an O-adrenergic receptor antagonist, a B-adrenergic agonist, an antidiabetic compound, an antimi c c c c c