US 2008030O292A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0300292 A1 Letts et al. (43) Pub. Date: Dec. 4, 2008

(54) NITROSATED AND NITROSYLATED Related U.S. Application Data COMPOUNDS, COMPOSITIONS AND METHODS FOR THE TREATMENT OF (60) Provisional application No. 60/625,578, filed on Nov. OPHTHALMC DSORDERS 8, 2004. Publication Classification (75) Inventors: L. Gordon Letts, Dover, MA (US); (51) Int. Cl. David S. Garvey, Dover, MA (US) A63L/4025 (2006.01) A6IP27/12 (2006.01) Correspondence Address: A6IP27/06 (2006.01) WILMERHALEANTROMED (52) U.S. Cl...... 514/422 1875 PENNSYLVANIAAVE, NW (57) ABSTRACT WASHINGTON, DC 20006 (US) The invention describes novel nitrosated and/or nitrosylated compounds or pharmaceutically acceptable salts thereof, and (73) Assignee: NitroMed, Inc, Lexington, MA novel compositions comprising at least one nitrosated and/or (US) nitrosylated compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The inven (21) Appl. No.: 11/667,272 tion also provides novel compositions and kits comprising at least one compound of the invention, that is optionally nitro sated and/or nitrosylated, and, optionally, at least one nitric (22) PCT Filed: Nov. 8, 2005 oxide donor compound and/or at least one therapeutic agent. The invention also provides methods for treating ophthalmic (86). PCT No.: PCT/USOS/40314 disorders. The nitrosated and/or nitrosylated compounds are preferably nitrosated and/or nitrosylated (3-adrenergic S371 (c)(1), antagonists and nitrosated and/or nitrosylated angiotensin (2), (4) Date: Mar. 21, 2008 converting enzyme (ACE) inhibitors. US 2008/030O292 A1 Dec. 4, 2008

NITROSATED AND NITROSYLATED thereof, and substrates of the various isozymes of nitric oxide COMPOUNDS, COMPOSITIONS AND synthase. Thus, another embodiment of the invention pro METHODS FOR THE TREATMENT OF vides compositions comprising at least one compound of the OPHTHALMC DSORDERS invention that is optionally substituted with at least one NO and/or NO group (i.e., nitrosylated and/or nitrosated), and at RELATED APPLICATION least one nitric oxide donor compound. The invention also 0001. This application claims priority under 35 USC S 119 provides for Such compositions in a pharmaceutically accept to U.S. Application No. 60/625,578 filed Nov. 8, 2004, which able carrier. is herein incorporated by reference in its entirety. 0006. The invention provides compositions comprising at least one compound of the invention, that is optionally Sub FIELD OF THE INVENTION stituted with at least one NO and/or NO group (i.e., nitrosy lated and/or nitrosated), and, optionally, at least one nitric 0002. The invention describes novel nitrosated and/or oxide donor compound and/or at least one therapeutic agent, nitrosylated compounds or pharmaceutically acceptable salts including, but not limited to, C.-adrenergic receptor agonists, thereof, and novel compositions comprising at least one nit C.-adrenergic receptor antagonists, angiotensin-converting rosated and/or nitrosylated compound, and, optionally, at enzyme (ACE) inhibitors, antimicrobial compounds, antioxi least one nitric oxide donor and/or at least one therapeutic dants, B-adrenergic antagonists, carbonic anhydrase inhibi agent. The invention also provides novel compositions and tors, hydralazine compounds, nonsteroidal antiinflammatory kits comprising at least one compound of the invention, that is compounds (NSAIDs), prostaglandins, selective cyclooxy optionally nitrosated and/or nitrosylated, and, optionally, at genase-2 (COX-2) inhibitors, steroids, and combinations of least one nitric oxide donor compound and/or at least one two or more thereof. In a preferred embodiment the at least therapeutic agent. The invention also provides methods for one therapeutic agent is selected from the group consisting of treating ophthalmic disorders. The nitrosated and/or nitrosy an C.-adrenergic receptor agonist, an angiotensin-converting lated compounds are preferably nitrosated and/or nitrosylated enzyme (ACE) inhibitor, an antimicrobial compound, a B-adrenergic antagonists and nitrosated and/or nitrosylated B-adrenergic antagonist, a carbonic anhydrase inhibitor, a angiotensin-converting enzyme (ACE) inhibitors. nonsteroidal antiinflammatory compound, a prostaglandin, a selective cyclooxygenase-2 (COX-2) inhibitor and a steroid. BACKGROUND OF THE INVENTION The invention also provides for Such compositions in a phar 0003. Most drugs conventionally used to treat ophthalmic maceutically acceptable carrier. disorders have potentially serious side effects Such as blurring 0007 Another embodiment of the invention provides of vision and other visual side effects which may lead either compositions comprising a therapeutically effective amount to decreased patient compliance or to the termination of of at least one compound of the invention, that is optionally therapy. Occasionally systemically administered drugs can substituted with at least one NO and/or NO group (i.e., also cause serious side effects, such as nausea, dyspepsia, nitrosylated and/or nitrosated), and at least one therapeutic fatigue, and metabolic acidosis, which affect patient compli agent selected from the group consisting of an O-adrenergic ance and/or necessitate the termination of treatment. Addi receptor agonist, an angiotensin-converting enzyme (ACE) tionally, Some B-adrenergic antagonists have increasingly inhibitor, an antimicrobial compound, a B-adrenergic antago become associated with serious pulmonary side effects attrib nist, a carbonic anhydrase inhibitor, a nonsteroidal antiin utable to their effects on B-2 receptors in pulmonary tissue. flammatory compound, a prostaglandin, a selective Hence there is a need in the art for compounds that have cyclooxygenase-2 (COX-2) inhibitor and a steroid. The improved efficacy, lower toxicity and/or fewer side effects invention also provides for Such compositions in a pharma and that can be used at low dosages. The invention is directed ceutically acceptable carrier. to these, as well as other, important ends. 0008. The invention provides methods for treating oph thalmic disorders in a patient in need thereof comprising SUMMARY OF THE INVENTION administering to the patient a therapeutically effective 0004. The invention provides novel compounds that are amount of at least one compound of the invention, that is substituted with at least one NO and/or NO group (i.e., optionally substituted with at least one NO and/or NO group nitrosylated and/or nitrosated), and pharmaceutically accept (i.e., nitrosylated and/or nitrosated), and, optionally, at least able salts thereof. The compounds can be, for example, B-adr one therapeutic agent, such as, for example, C.-adrenergic energic antagonists or ACE inhibitors. The compounds can be receptor agonists, C.-adrenergic receptor antagonists, angio nitrosated and/or nitrosylated through one or more sites Such tensin-converting enzyme (ACE) inhibitors, antimicrobial as oxygen (hydroxyl condensation), Sulfur (sulfhydryl con compounds, antioxidants, B-adrenergic antagonists, carbonic densation) and/or nitrogen. The invention also provides com anhydrase inhibitors, hydralazine compounds, nonsteroidal positions comprising the novel compounds described herein antiinflammatory compounds (NSAIDs), prostaglandins, in a pharmaceutically acceptable carrier. selective cyclooxygenase-2 (COX-2) inhibitors, and combi 0005. The invention is also based on the discovery that nations of two or more thereof. The methods can optionally administering at least one compound of the invention or a further comprise the administration of at least one nitric oxide pharmaceutically acceptable salt thereof, that is optionally donor compound. In this embodiment of the invention, the substituted with at least one NO and/or NO group (i.e., methods can involve (i) administering the nitrosated and/or nitrosylated and/or nitrosated), and, optionally, at least one nitrosylated compounds, (ii) administering the compounds, nitric oxide donor improves the properties of the compound. that are optionally nitrosated and/or nitrosylated, and NO Nitric oxide donors include, for example, S-nitrosothiols, donors, (iii) administering the compounds, that are optionally nitrites, nitrates, N-oxo-N-nitrosamines, furoxans, Sydnon nitrosated and/or nitrosylated, and therapeutic agents, or (iv) imines, SPM 3672, SPM 5185, SPM 5186 and analogues administering the compounds, that are optionally nitrosated US 2008/030O292 A1 Dec. 4, 2008 and/or nitrosylated, NO donors, and therapeutic agents. In a tors, steroids, and the like. Therapeutic agent includes the preferred embodiment the at least one therapeutic agent is pharmaceutically acceptable salts thereof, pro-drugs, and selected from the group consisting of an O-adrenergic recep pharmaceutical derivatives thereof including, but not limited toragonist, an angiotensin-converting enzyme (ACE) inhibi to, the corresponding nitrosated and/or nitrosylated and/or tor, an antimicrobial compound, a B-adrenergic antagonist, a heterocyclic nitric oxide donor derivatives. Although nitric carbonic anhydrase inhibitor, a nonsteroidal antiinflamma oxide donors have therapeutic activity, the term “therapeutic tory compound, a prostaglandin, a selective cyclooxyge agent” does not include the nitric oxide donors described nase-2 (COX-2) inhibitor, and a steroid. The compounds of herein, since nitric oxide donors are separately defined. the invention, nitric oxide donors, and/or therapeutic agents 00.15 “Prodrug” refers to a compound that is made more can be administered separately or as components of the same active in vivo. composition in one or more pharmaceutically acceptable car 0016 “Antioxidant’ refers to and includes any compound riers. that can react and quench a free radical. 0009. Another embodiment of the invention provides kits 0017 “Angiotensin converting enzyme (ACE) inhibitor comprising at least one compound of the invention, that is refers to compounds that inhibit an enzyme which catalyzes optionally nitrosated and/or nitrosylated, and, optionally, at the conversion of angiotensin I to angiotensin II. ACE inhibi least one nitric oxide donor compound. The kit can further tors include, but are not limited to, amino acids and deriva comprise at least one therapeutic agent, Such as, for example, tives thereof, peptides, including di- and tri-peptides, and C.-adrenergic receptor agonists, C.-adrenergic receptor antibodies to ACE which intervene in the renin-angiotensin antagonists, angiotensin-converting enzyme (ACE) inhibi system by inhibiting the activity of ACE thereby reducing or tors, antimicrobial compounds, antioxidants, B-adrenergic antagonists, carbonic anhydrase inhibitors, hydralazine com eliminating the formation of the pressor Substance angio pounds, nonsteroidal antiinflammatory compounds tensin II. (NSAIDs), prostaglandins, selective cyclooxygenase-2 0018 “C.-Adrenergic receptoragonist” refers to any com (COX-2) inhibitors, steroids, and combinations of two or pound that reversibly or irreversibly activates or stimulates more thereof. The compounds of the invention, the nitric any C.-adrenergic receptor. oxide donors and/or therapeutic agents, can be separate com 0019 “NSAID' refers to a nonsteroidal anti-inflamma ponents in the kit or can be in the form of a composition in one tory compound or a nonsteroidal anti-inflammatory drug. or more pharmaceutically acceptable carriers. NSAIDs inhibit cyclooxygenase, the enzyme responsible for 0010. These and other aspects of the invention are the biosyntheses of the prostaglandins and certain autocoid described in detail herein. inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxyge DETAILED DESCRIPTION OF THE INVENTION nase-1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase. 0011. As used throughout the disclosure, the following (0020 “Cyclooxygenase-2 (COX-2) selective inhibitor” terms, unless otherwise indicated, shall be understood to have refers to a compound that selectively inhibits the cyclooxy the following meanings. genase-2 enzyme over the cyclooxygenase-1 enzyme. In one 0012 “Ophthalmic disorders' include, but are not limited embodiment, the compound has a cyclooxygenase-2 ICso of to, ophthalmic infections, cataracts, glaucoma, elevated less than about 2 LM and a cyclooxygenase-1 ICso of greater intraocular pressure, ocular pain (e.g., following corneal Sur than about 5uM, in the human whole blood COX-2 assay (as gery), dry eye disorder, ocular hypertension, ocular bleeding, described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) retinal diseases or disorders, presbyopia, macular degenera and also has a selectivity ratio of cyclooxygenase-2 inhibition tion, choroidal neovascularization (CNV), retinopathies, over cyclooxygenase-1 inhibition of at least 10, and prefer Such as for example, diabetic retinopathy, vitreoretinopathy, ably of at least 40. In another embodiment, the compound has and the like, retinitis, such as for example, cytomegalovirus a cyclooxygenase-1 ICso of greater than about 1 uM, and (CMV) retinitis, uveitis, macular edema, neuropathies and preferably of greater than 20 LM. The compound can also the like. inhibit the enzyme, lipoxygenase. Such selectivity may indi 0013 “Ophthalmic infections' include, but are not limited cate an ability to reduce the incidence of common NSAID to an inflammation of the conjunctiva (conjunctivitis), induced side effects. inflammation of the cornea (keratitis), corneal ulcers, and the like, caused by an organisms such as, for example, Staphylo 0021 “Patient” refers to animals, preferably mammals, cocci, Streptococci, Enterococci, Bacillus, Corynebacte most preferably humans, and includes males and females, and rium, Chlamydia, Neisseria, and the like, including important children and adults. species of these genus Such as, for example, Staphloccus (0022. “Therapeutically effective amount” refers to the aureus, Streptococcus viridans, Staphloccus epidermidis, amount of the compound and/or composition that is effective Streptococcus pneumoniae, staphylococci, Streptococci, to achieve its intended purpose. enterococci, and the like. 0023 “Transdermal refers to the delivery of a compound 0014 “Therapeutic agent” includes any therapeutic agent by passage through the skin and into the blood stream. that can be used to treat or prevent the diseases described 0024 “Transmucosal” refers to delivery of a compound by herein. "Therapeutic agents' include, for example, C.-adren passage of the compound through the mucosal tissue and into ergic receptor agonists, C.-adrenergic receptor antagonists, the blood stream. angiotensin-converting enzyme (ACE) inhibitors, antimicro 0025 “Penetration enhancement” or “permeation bial compounds, antioxidants, B-adrenergic antagonists, car enhancement” refers to an increase in the permeability of the bonic anhydrase inhibitors, hydralazine compounds, nonste skin or mucosal tissue to a selected pharmacologically active roidal antiinflammatory compounds (NSAIDs), compound Such that the rate at which the compound perme prostaglandins, selective cyclooxygenase-2 (COX-2) inhibi ates through the skin or mucosal tissue is increased. US 2008/030O292 A1 Dec. 4, 2008

0026 “Carriers' or “vehicles' refers to carrier materials amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a Suitable for compound administration and include any Such nitrate, a nitrite, a thionitrate, a thionitrite oran amino group, material known in the art such as, for example, any liquid, gel. as defined herein. solvent, liquid diluent, solubilizer, or the like, which is non 0035) “Haloalkyl refers to a lower alkyl group, an alkenyl toxic and which does not interact with any components of the group, an alkynyl group, a bridged cycloalkyl group, a composition in a deleterious manner. cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein. 0027 “Sustained release' refers to the release of a thera Exemplary haloalkyl groups include trifluoromethyl, chlo peutically active compound and/or composition Such that the romethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the blood levels of the therapeutically active compound are main like. tained within a desirable therapeutic range over a period of 0036 “Alkenyl refers to a branched or straight chain time. The Sustained release formulation can be prepared using C-Clo hydrocarbon (preferably a C-Cs hydrocarbon, more any conventional method known to one skilled in the art to preferably a C-C hydrocarbon) that can comprise one or obtain the desired release characteristics. more carbon-carbon double bonds. Exemplary alkenyl 0028 “Nitric oxide adduct' or “NO adduct refers to com groups include propylenyl, buten-1-yl, isobutenyl, penten-1- pounds and functional groups which, under physiological y1, 2.2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, conditions, can donate, release and/or directly or indirectly hepten-1-yl, octen-1-yl, and the like. transfer any of the three redox forms of nitrogen monoxide 0037 “Lower alkenyl refers to a branched or straight (NO", NO, NO.), such that the biological activity of the chain C-C hydrocarbon that can comprise one or two car nitrogen monoxide species is expressed at the intended site of bon-carbon double bonds. action. 0038. “Substituted alkenyl refers to a branched or 0029 “Nitric oxide releasing or "nitric oxide donating straight chain C-Co hydrocarbon (preferably a C-Cs refers to methods of donating, releasing and/or directly or hydrocarbon, more preferably a C-C hydrocarbon) which indirectly transferring any of the three redox forms of nitro can comprise one or more carbon-carbon double bonds, gen monoxide (NO", NO NO.), such that the biological wherein one or more of the hydrogen atoms have been activity of the nitrogen monoxide species is expressed at the replaced with one or more R' groups, wherein each R' is intended site of action. independently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, as defined herein. 0030 “Nitric oxide donor or “NO donor refers to com 0039) “Alkynyl” refers to an unsaturated acyclic C-Co pounds that donate, release and/or directly or indirectly trans hydrocarbon (preferably a C-Cs hydrocarbon, more prefer fera nitrogen monoxide species, and/or stimulate the endog ably a C-C hydrocarbon) that can comprise one or more 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 0040) “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 0031) “Heterocyclic nitric oxide donor refers to a trisub cycloalkyl groups can be unsubstituted or Substituted with stituted 5-membered ring comprising two or three nitrogen one, two or three substituents independently selected from atoms and at least one oxygen atom. The heterocyclic nitric alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, oxide donor is capable of donating and/or releasing a nitrogen halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alky monoxide species upon decomposition of the heterocyclic lcarboxylic 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- 0032 Alkyl refers to a lower alkyl group, a substituted enyl and the like. lower alkyl group, a haloalkyl group, a hydroxyalkyl group, 0041) “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, 0033 “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, 0042 “Heterocyclic ring or group' refers to a saturated or and the like. unsaturated cyclic hydrocarbon group having about 2 to about 0034) “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 maybe in the wherein each R" is independently a hydroxy, an ester, an thio, sulfinyl or sulfonyl oxidation state. The heterocyclic ring US 2008/030O292 A1 Dec. 4, 2008 or group can be fused to an aromatic hydrocarbon group. 0051 “Cycloalkylalkylthio’ refers to a cycloalkyl radical, Heterocyclic groups can be unsubstituted or substituted with as defined herein, attached to an alkylthio radical, as defined one, two or three substituents independently selected from herein. alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, 0.052 “Heterocyclicalkyl refers to a heterocyclic ring hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkyl radical, as defined herein, attached to an alkyl radical, as carboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic defined herein. acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, aryl 0053 “Arylheterocyclic ring refers to a bi- or tricyclic carbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, ring comprised of an aryl ring, as defined herein, appended arylcarboxamido, Sulfonic acid, Sulfonic ester, Sulfonamide via two adjacent carbon atoms of the aryl ring to a heterocy nitrate and nitro. Exemplary heterocyclic groups include pyr clic ring, as defined herein. Exemplary arylheterocyclic rings rolyl, furyl, thienyl, 3-pyrrolinyl, 4.5,6-trihydro-2H-pyranyl, include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl pyrim like. idinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, 0054 Alkylheterocyclic ring refers to a heterocyclic thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, pyrrolinyl, ring radical, as defined herein, attached to an alkyl radical, as pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, defined herein. Exemplary alkylheterocyclic rings include imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, 2-pyridylmethyl, 1-methylpiperidin-2-one-3-methyl, and the isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadia like. Zolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl. 0055 Alkoxy' refers to Rs.O—, wherein Rs is an alkyl morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, pip group, as defined herein (preferably a lower alkyl group or a erazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophe haloalkyl group, as defined herein). Exemplary alkoxy nyl, benzimidazolyl, benzothiazolinyl, quinolinyl. 2,6-diox groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, abicyclo(3.3.0)octane, and the like. trifluoromethoxy, and the like. 0043 “Heterocyclic compounds’ refer to mono- and poly cyclic compounds comprising at least one aryl or heterocyclic 0056 "Aryloxy' refers to RssO—, wherein Rss is an aryl r1ng. group, as defined herein. Exemplary arylkoxy groups include 0044 Aryl refers to a monocyclic, bicyclic, carbocyclic napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like. or heterocyclic ring system comprising one or two aromatic 0057 “Alkylthio’ refers to Rs.S. , wherein Rs is an rings. Exemplary aryl groups include phenyl, pyridyl, alkyl group, as defined herein. napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, inde 0.058 “Lower alkylthio’ refers to a lower alkyl group, as nyl, indoyl, and the like. Aryl groups (including bicyclic aryl defined herein, appended to a thio group, as defined herein. groups) can be unsubstituted or Substituted with one, two or 0059) “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy three substituents independently selected from alkyl, alkoxy, group, as defined herein, to which is appended an aryl group, alkylthio, amino, alkylamino, dialkylamino, arylamino, dia as defined herein. Exemplary arylalkoxy groups include ben rylamino, alkylarylamino, halo, cyano, alkylsulfinyl, Zyloxy, phenylethoxy, chlorophenylethoxy, and the like. hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, 0060 Arylalklythio’ refers to an alkylthio group, as alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxy defined herein, to which is appended an aryl group, as defined lic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxa herein. Exemplary arylalklythio groups include benzylthio. mido, alkylcarboxamido, carbonyl, Sulfonic acid, Sulfonic phenylethylthio, chlorophenylethylthio, and the like. ester, Sulfonamido and nitro. Exemplary Substituted aryl 0061 Arylalklythioalkyl refers to an arylalkylthio groups include tetrafluorophenyl, pentafluorophenyl, Sul group, as defined herein, to which is appended an alkyl group, fonamide, alkylsulfonyl, arylsulfonyl, and the like. as defined herein. Exemplary arylalklythioalkyl groups 0045 “Cycloalkenyl refers to an unsaturated cyclic include benzylthiomethyl, phenylethylthiomethyl, chlo C-Clo hydrocarbon (preferably a C-Cs hydrocarbon, more rophenylethylthioethyl, and the like. preferably a C-C hydrocarbon) which can comprise one or 0062 Alkylthioalkyl refers to an alkylthio group, as more carbon-carbon triple bonds. defined herein, to which is appended an alkyl group, as 0046 “Alkylaryl refers to an alkyl group, as defined defined herein. Exemplary alkylthioalkyl groups include herein, to which is appended an aryl group, as defined herein. allylthiomethyl, ethylthiomethyl, trifluoroethylthiomethyl, Exemplary alkylaryl groups include benzyl, phenylethyl, and the like. hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the 0063 “Alkoxyalkyl refers to an alkoxy group, as defined like. herein, appended to an alkyl group, as defined herein. Exem 0047 'Arylalkyl refers to an aryl radical, as defined plary alkoxyalkyl groups include methoxymethyl, methoxy herein, attached to an alkyl radical, as defined herein. Exem ethyl, isopropoxymethyl, and the like. plary arylalkyl groups include benzyl, phenylethyl, 4-hy 0064 Alkoxyhaloalkyl refers to an alkoxy group, as droxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and the defined herein, appended to a haloalkyl group, as defined like. herein. Exemplary alkoxyhaloalkyl groups include 4-meth 0048 Arylalkenyl refers to an aryl radical, as defined oxy-2-chlorobutyl and the like. herein, attached to an alkenyl radical, as defined herein. 0065 “Cycloalkoxy” refers to RO , wherein Rs is a Exemplary arylalkenyl groups include styryl, propenylphe cycloalkyl group or a bridged cycloalkyl group, as defined nyl, and the like. herein. Exemplary cycloalkoxy groups include cyclopropy 0049. “Cycloalkylalkyl refers to a cycloalkyl radical, as loxy, cyclopentyloxy, cyclohexyloxy, and the like. defined herein, attached to an alkyl radical, as defined herein. 0.066 “Cycloalkylthio’ refers to RS , wherein Rs is a 0050 “Cycloalkylalkoxy' refers to a cycloalkyl radical, as cycloalkyl group or a bridged cycloalkyl group, as defined defined herein, attached to an alkoxy radical, as defined herein. Exemplary cycloalkylthio groups include cyclopro herein. pylthio, cyclopentylthio, cyclohexylthio, and the like. US 2008/030O292 A1 Dec. 4, 2008

0067 "Haloalkoxy' refers to an alkoxy group, as defined (0094) “Alkylarylalkylamino” refers to R.R.N , herein, in which one or more of the hydrogen atoms on the wherein Rs is an alkyl group, as defined herein, and Rio is an alkoxy group are Substituted with halogens, as defined herein. arylalkyl group, as defined herein. Exemplary haloalkoxy groups include 1,1,1-trichloroethoxy, I0095 “Alkylcycloalkylamino” refers to RRsN , 2-bromobutoxy, and the like. wherein Rs is an alkyl group, as defined herein, and Rso is a 0068 “Hydroxy” refers to OH. cycloalkyl group, as defined herein. 0069 “Oxy” refers to - O - 0096 “Aminoalkyl refers to an amino group, an alky 0070 “Oxo” refers to —O. lamino group, a dialkylamino group, an arylamino group, a (0071 "Oxylate” refers to —OR," wherein R, is an diarylamino group, an alkylarylamino group or a heterocyclic organic or inorganic cation. ring, as defined herein, to which is appended an alkyl group, 0072 “Thiol” refers to SH. as defined herein. Exemplary aminoalkyl groups include dim 0073. “Thio” refers to - S - ethylaminopropyl, diphenylaminocyclopentyl, methylami 0074 “Oxime” refers to —N ORs, wherein Rs is a nomethyl, and the like. hydrogen, an alkyl group, an aryl group, an alkylsulfonyl 0097 Aminoaryl refers to an aryl group to which is group, an arylsulfonyl group, a carboxylic ester, an alkylcar appended an alkylamino group, a arylamino group or an bonyl group, an arylcarbonyl group, a carboxamido group, an arylalkylamino group. Exemplary aminoaryl groups include alkoxyalkyl group or an alkoxyaryl group. anilino, N-methylanilino, N-benzylanilino, and the like. 0075) “Hydrazone refers to —N N(Rs)(R's) wherein (0098 “Sulfinyl refers to S(O)-. R", is independently selected from Rs1, and Rs is as defined (0099 “Methanthial” refers to C(S)-. herein. 0100 “Thial” refers to -S. 0076 “Hydrazino” refers to HN N(H)– 0101. “Sulfonyl refers to S(O), . 0077. “Organic cation” refers to a positively charged I0102 "Sulfonic acid” refers to S(O),OR, wherein R organic ion. Exemplary organic cations include alkyl Substi is a hydrogen, an organic cation or an inorganic cation, as tuted ammonium cations, and the like. defined herein. 0078. “Inorganic cation” refers to a positively charged 0103 “Alkylsulfonic acid refers to a sulfonic acid group, metalion. Exemplary inorganic cations include Group I metal as defined herein, appended to an alkyl group, as defined cations such as for example, sodium, potassium, magnesium, herein. calcium, and the like. 0104 "Arylsulfonic acid refers to a sulfonic acid group, 0079) “Hydroxyalkyl” refers to a hydroxy group, as as defined herein, appended to an aryl group, as defined herein defined herein, appended to an alkyl group, as defined herein. 0105. “Sulfonic ester” refers to S(O)ORs, wherein 0080 “Nitrate” refers to - O NO, i.e. oxidized nitro R is an alkyl group, an aryl group, or an aryl heterocyclic gen. ring, as defined herein. I0081. “Nitrite” refers to - O NO i.e. oxidized nitrogen. 0106 “Sulfonamido” refers to —S(O) N(Rs) (Rs.), I0082 “Thionitrate” refers to —S NO. wherein Rs and Rs, are each independently a hydrogen 0083. “Thionitrite” and “nitrosothiol refer to S NO. atom, an alkyl group, an aryl group or an arylheterocyclic I0084) “Nitro” refers to the group - NO, and “nitrosated” ring, as defined herein, or Rs and Rs, when taken together are refers to compounds that have been substituted therewith. a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl I0085 “Nitroso’ refers to the group - NO and “nitrosy group, as defined herein. lated refers to compounds that have been substituted there 0107 “Alkylsulfonamido” refers to a sulfonamido group, with. as defined herein, appended to an alkyl group, as defined I0086 “Nitrile” and “cyano” refer to CN. herein. I0087. “Halogen” or “halo” refers to iodine (I), bromine 0.108 “Arylsulfonamido” refers to a sulfonamido group, (Br), chlorine (Cl), and/or fluorine (F). as defined herein, appended to an aryl group, as defined 0088 Amino” refers to —NH, an alkylamino group, a herein. dialkylamino group, an arylamino group, a diarylamino 0109 "Alkylthio’ refers to Rs.S. , wherein Rs is an group, an alkylarylamino group or a heterocyclic ring, as alkyl group, as defined herein (preferably a lower alkyl group, defined herein. as defined herein). I0089. “Alkylamino” refers to RNH , wherein Rs is an 0110 "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 0111 Arylalkylthio’ refers to an aryl group, as defined lamino, and the like. herein, appended to an alkylthio group, as defined herein. 0090 Arylamino” refers to RsNH , wherein Rss is an 0112 Alkylsulfinyl refers to Rs S(O)—, wherein Rso aryl group, as defined herein. is an alkyl group, as defined herein. 0091 “Dialkylamino” refers to RsRN , wherein Rs. 0113 Alkylsulfonyl refers to Rs S(O) , wherein and Rs are each independently an alkyl group, as defined R is an alkyl group, as defined herein. herein. Exemplary dialkylamino groups include dimethy I0114 "Alkylsulfonyloxy” refers to Rs S(O), O , lamino, diethylamino, methyl propargylamino, and the like. wherein Rso is an alkyl group, as defined herein. 0092 “Diarylamino” refers to RssRN , wherein Rss 0115 Arylsulfinyl refers to Rss S(O)—, wherein Rss and Reo are each independently an aryl group, as defined is an aryl group, as defined herein. herein. 0116 'Arylsulfonyl refers to Rss S(O)—, wherein 0093 “Alkylarylamino or arylalkylamino” refers to R is an aryl group, as defined herein. RRSN , wherein Rs is an alkyl group, as defined herein, 0117 '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. US 2008/030O292 A1 Dec. 4, 2008

0118 “Amidyl refers to RC(O)N(Rs.)— wherein Rs ring, as defined herein, or Rs and Rs, taken together are a and Rs, are each independently a hydrogen atom, an alkyl heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, an aryl group or an arylheterocyclic ring, as defined group, as defined herein. herein. 0.139. “Phosphoryl” refers to P(R)(R)(R), 0119) “Ester refers to RC(O)R, wherein Rs is a wherein Rio is a lone pair of electrons, thial or oxo, and R7 hydrogen atom, an alkyl group, an aryl group or an arylhet and R7 are each independently a covalent bond, a hydrogen, erocyclic ring, as defined herein and Rze is oxygen or Sulfur. a lower alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or 0120 “Carbamoyl refers to - O C(O)N(Rs)(Rs), an aryl, as defined herein. wherein Rs and Rs, are each independently a hydrogen I0140 “Silyl” refers to Si(R)(R)(Rs), wherein R. atom, an alkyl group, an aryl group or an arylheterocyclic Ra and R-7s are each independently a covalent bond, a lower ring, as defined herein, or Rs and Rs, taken together are a alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein. heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl 0.141. “Organic acid refers to compound having at least group, as defined herein. one carbon atom and one or more functional groups capable I0121 "Carboxyl” refers to —C(O)CR, wherein R is a of releasing a proton to a basic group. The organic acid hydrogen, an organic cation oran inorganic cation, as defined preferably contains a carboxyl, a Sulfonic acid or a phospho herein. ric acid moeity. Exemplary organic acids include acetic acid, 0122 “Carbonyl refers to C(O)-. benzoic acid, citric acid, camphorsulfonic acid, methane 0123 “Alkylcarbonyl refers to Rs C(O)—, wherein Sulfonic acid, taurocholic acid, chlordronic acid, glyphos R is an alkyl group, as defined herein. phate, medronic acid, and the like. 0.124 'Arylcarbonyl refers to Rss C(O)—, wherein 0.142 “Inorganic acid refers to a compound that does not R is an aryl group, as defined herein. contain at least one carbonatom and is capable of releasing a I0125 "Alylalkylcarbonyl” refers to Rss Rs. C(O) , proton to a basic group. Exemplary inorganic acids include wherein Rss is an aryl group, as defined herein, and Rs is an hydrochloric acid, Sulfuric acid, nitric acid, phosphoric acid, alkyl group, as defined herein. and the like. 0126 “Alkylarylcarbonyl refers to Rs. Rss C(O)—, 0.143 “Organic base' refers to a carbon containing com wherein Rss is an aryl group, as defined herein, and Rs is an pound having one or more functional groups capable of alkyl group, as defined herein. accepting a proton from an acid group. The organic base 0127. “Heterocyclicalkylcarbonyl refer to RC(O)— preferably contains anamine group. Exemplary organic bases wherein Rs is a heterocyclicalkyl group, as defined herein. include triethylamine, benzyldiethylamine, dimethylethyl 0128 “Carboxylic ester” refers to C(O)CRs, wherein amine, imidazole, pyridine, pipyridine, and the like. R is an alkyl group, an aryl group oran arylheterocyclic ring, 0144. The compounds used in the compounds and com as defined herein. positions of the invention are preferably B-adrenergic antago 0129. “Alkylcarboxylic acid” and “alkylcarboxyl refer to nists and ACE inhibitors. an alkyl group, as defined herein, appended to a carboxyl 0145 Suitable f3-adrenergic antagonists include, but are group, as defined herein. not limited to, acebutolol, alprenolol, amoSulalol, arotinolol. 0130 Alkylcarboxylic ester” refers to an alkyl group, as atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopin defined herein, appended to a carboxylic ester group, as dolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, defined herein. bupranolol, butofilolol, carazolol, capsinolol, carteolol. carvedilol (COREGR), celiprolol, cetamolol, cindolol, clo 0131 “Alkyl ester refers to an alkyl group, as defined ranolol, dilevalol, diprafenone, epanolol, ersentilide, herein, appended to an ester group, as defined herein. esmolol, esprolol, hydroxalol, indenolol, labetalol, landiolol, 0132 Arylcarboxylic acid refers to an aryl group, as laniolol, levobunolol, mepindolol, methylpranol, metindol, defined herein, appended to a carboxyl group, as defined metipranolol, metrizoranolol, metoprolol, moprolol, nadolol. herein. nadoxolol, nebivolol, nifenalol, nipradillol, oXprenolol, pen 0.133 "Arylcarboxylic ester” and “arylcarboxyl refer to butolol, pindolol, practolol, pronethalol, propranolol, Sotalol, an aryl group, as defined herein, appended to a carboxylic Sotalolnadolol, sulfinalol, taliprolol, talinolol, tertatolol, til ester group, as defined herein. isolol, timolol, toliprolol, tomalolol, trimepranol, Xamoterol, 0134 "Aryl ester” refers to an aryl group, as defined xibenolol, 2-(3-(1,1-dimethylethyl)-amino-2-hydroxypro herein, appended to an ester group, as defined herein. poxy)-3-pyridenecarbonitrilHCl, 1-butylamino-3-(2,5- 0135 “Carboxamido” refers to C(O)N(R)(Rs), dichlorophenoxy)-2-propanol. 1-isopropylamino-3-(4-(2- wherein Rs and Rs 7 are each independently a hydrogen cyclopropylmethoxyethyl) phenoxy)-2-propanol, atom, an alkyl group, an aryl group or an arylheterocyclic 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, ring, as defined herein, or Rs and Rs, when taken together are 2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl 2-thienyl)thiazol, 7-(2-hydroxy-3-t-butylaminpropoxy)ph group, as defined herein. thalide, Acc 9369, AMO-140, BIB-16S, CP-331684, 0.136 “Alkylcarboxamido” refers to an alkyl group, as Fr-172516, ISV-208, L-653328, LM-2616, SB-226552, defined herein, appended to a carboxamido group, as defined SR-58894A, SR-59230A, TZC-5665, UK-1745, YM-430, herein. and the like. Suitable f3-adrenergic antagonists are described 0.137 'Arylcarboxamido” refers to an aryl group, as more fully in the literature, such as in Goodman and Gilman, defined herein, appended to a carboxamido group, as defined The Pharmacological Basis of Therapeutics (9th Edition), herein. McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13th 0138 “Urea” refers to N(Rs.) C(O)N(Rs)(Rs.) Edition; and on STN Express, file phar and file registry. wherein Rs. Rs 7, and Rs are each independently a hydrogen 0146 Suitable angiotensin-converting enzyme inhibitors atom, an alkyl group, an aryl group or an arylheterocyclic (ACE inhibitors) include, but are not limited to, alacepril, US 2008/030O292 A1 Dec. 4, 2008

benazepril (LOTENSINR), CIBACENR), benazeprilat, cap O153 Y is —C(O)—CHs or D; topril, ceranapril, cilaZapril, delapril, duinapril, enalapril, 0154) Z is: enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, glycopril, idrapril, imidapril, lisinopril, moexipril, movel tipril, naphthopidil, omapatrilat, pentopril, perindopril, per (1) indoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rent ipril, Saralasin acetate, spirapril, temocapril, trandolapril, trandolaprilat, urapidil, Zofenopril, acylmercapto and mer captoalkanoyl pralines, carboxyalkyl dipeptides, carboxy alkyl dipeptide, phosphinylalkanoyl prolines, registry no. 79.6406, AVE 7688, BP1.137, CHF 1514, E 4030, ER 3295, FPL-66564, MDL 100240, RL 6134, RL 6207, RL 6893, SA (2) 760, S-5590, Z 13752A, and the like. 0147 The contemplated compounds of the invention are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, (1996); Merck Index on CD-ROM, 13 Edition; STN Express, file phar and file registry, the dis closures of each of which are incorporated by reference herein in their entirety. (3) 0148. In one embodiment the compounds of the invention are B-adrenergic antagonists and ACE inhibitors, which must contain one or more of the following functionalities: a car boxylic acid group (-COOH), a hydroxyl group (-OH), a thiol group (-SH) and/or a primary or secondary amine group (-NH). The compounds of the invention are nitrosated and/or nitrosylated through one or more of these functional ities such as oxygen (hydroxyl condensation), sulfur (sulfhy dryl condensation) and/or nitrogen. O155 Ro is: 0149. In another embodiment, the invention provides nit 0156 (1) —C(O)—(CH) CH: rosated and/or nitrosylated B-adrenergic antagonists of For O157 (2) - O CH-CH=CH: mula (I) and pharmaceutically acceptable salts thereof: 0158 (3) a hydrogen; 0159) (4) methyl: (I) (0160 (5) methoxy; (0161 (6) cyclopentyl: (0162 (7) halo: (0163 (8) - O CH, C(O) ND-CH: (0164 (9) cyano; wherein: 01.65 (10) —CH-CH=CH; or 0150 X is: 0151 (1)-CH(CH): (11) 0152 (2) - C(CH): o-c-k)O (3)

(CH2) R15; or (0166 R is a hydrogen, methyl or a halo; or (0167 Ro and R taken together are W. U Va; (0168 wherein W. U V is (4) (0169 (1) —CH=C(R) ND-: 0170 (2)-CH=CH-CH : 0171 (3) - CH-CH=CH-; 0172 (4) -CH=CH-CH=CH ; 0173 (5) - O CH-CH(ONO-)-CH ; 0174 (6) - O C(O) CH=CH-; 0175 (7) —(CH), C(O) ND-; (0176) (8) —(CH2), C(O)—; 0.177 (9) - CH-CH(ODI)-CH(ODI)-CH : 0178 (10) —S-(CH2) ; US 2008/030O292 A1 Dec. 4, 2008

(0204) R, and R are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, (11) O an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an O alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an / CH3; or alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky lamino, an arylamino, a diarylamino, an alkylarylamino, an (12) alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul ND 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, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar 0179 R is: boxylic ester, an arylcarboxylic ester, a Sulfonamido, an 0180 (1) - ND-C(O)–(CH), CH: alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an 0181 (2)-(CH), C(O) OD; alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul 0182 (3) - C(O) (CH), CH: fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, 0183 (4) halo: a nitro, K or R, and R, taken together with the carbons to (0.184 (5) – ND-C(O) N(CHs): which they are attached form a carbonyl, a methanthial, a 0185 (6) - CH, C(O) N(H)D; heterocyclic ring, a cycloalkyl group, an aryl group, an 0186 (7) - O C(O) CH: Oxime, a hydraZone or a bridged cycloalkyl group; 0205 U at each occurrence is independently an oxygen, (8) —S(O) or N(R)R, 0206 o is an integer from 0 to 2: co-o-c-A 0207 R is a lone pair of electrons, a hydrogen oran alkyl group; (9) 0208 R, is a hydrogen, an alkyl, an aryl, an alkylcarboxy lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulpho nyloxy, a Sulfonamido, a carboxamido, a carboxylic ester, an 0187. (10) —CH2—O (CH), O CH(CH): aminoalkyl, an aminoaryl, -CH C(Us V)(R)(R), a 0188 (11) methyl; or bond to an adjacent atom creating a double bond to that atom, (0189 (12) —(CH), O—CH: —(N.O. ).M.", wherein M is an organic or inorganic 0190. R is a hydrogen, methyl or halo; cation; and 0191 R is a hydrogen or a lower alkyl: 0209 with the proviso that the compounds of Formula (I) (0192 R at each occurrence is independently selected must contain at least one NO group, and/or at least one NO from —OCH —OD, NO, methyl or ND-S(O). CH: group; wherein the at least one NO group and/or the at least 0193 k is an integer from 0 to 4: one NO. group is linked to the B-adrenergic antagonist 0194 D is a hydrogen, V or K: through an oxygen atom, a nitrogen atom or a Sulfur atom. (0195 K is —(W)-E,-(C(R)(R)).-E.-(C(R)(R)), 0210. In cases where multiple designations of variables which reside in sequence are chosen as a “covalent bond' or wCR (R), (W.E.W. ) (C(R)(R)) — the integer chosen is 0, the intent is to denote a single covalent (0196) V, is NO or - NO; bond connecting one radical to another. For example, Eo 0197) a, b, c, d, g, i and are each independently an integer would denote a covalent bond, while E. denotes (E-E) and from 0 to 3: (C(R)(R)), denotes—C(R)(R)-C(R)(R)-. (0198 p. x,y and Zare eachindependently an integer from 0211. In another embodiment, the invention described nit O to 10; rosated and/or nitrosylated B-adrenergic antagonist of For 0199 W at each occurrence is independently —C(O)—, mula (II) and pharmaceutically acceptable salts thereof: —C(S)-, -T-, -(C(R)(R)), , an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, or -(CH2CH2O)— (II) 0200 E at each occurrence is independently -T-, an alkyl OD1 D1 group, an aryl group, —(C(R)(R)), , a heterocyclic ring, an arylheterocyclic ring, or -(CH2CH2O)-; --- X4 0201 T at each occurrence is independently a covalent Y. Sk Z4' bond, a carbonyl, an oxygen. —S(O) - or —N(R)R. 0202 h is an integer form 1 to 10; 0203 q is an integer from 1 to 5: US 2008/030O292 A1 Dec. 4, 2008

wherein: 0212 Y is: -continued (3)

CH-O ; or (1)

R15: H3CO O (4) R / \ I6 -ND-C-N O; (2) --- \ / CH-O 0215 Z and Zare independently selected from a methyl or a hydrogen; 0216 R is: CH3: 0217 (1) hydrogen; 0218 (2) - C(O) N(D)H: (3) 0219 (3) - S(O)-CH; or 0220 (4) - S(O), N(D)H: 0221 R, is a hydrogen, —OCH or —NO; 0222 or is an integer from 0 to 2: 0223 U. Rs and D are as defined herein; and ND; 0224 with the proviso that the compounds of Formula (II) must contain at least one NO group, and/or at least one NO group; wherein the at least one NO group and/or the at least one NO. group is linked to the f-adrenergic antagonist through an oxygen atom, a nitrogen atom or a Sulfur atom. (4) 0225. In another embodiment of the invention, the nitro sated B-adrenergic antagonist compounds of Formula (I) and (II) do not include compounds in which a —ONO and/or - CH, ONO. group are directly attached to the B-adrener gic antagonist core structure (i.e. nitrosation of—OH and/or —CH2—OH group respectively) and any of the following (5) compounds of ACS registry number 586348-49-4, 596348 -CH3: 48-3, 326850-94-6, 302543-93-7, 301669-72-7, 207987-09 CH 5, 207987-07-3, 170995-51-4, 170995-50-3, 170995-23-0, 170995-20-7, 164340-36-7, 164340-33-4, 152670-58-1, O 118642-96-9, 118642-95-8, 106158-05-8, 102564-91-0, 81845-15-0, 81801-83-4, 81801-82-3, 81786-18-7, 81786 N 01-8, 81785-32-2, 71761-90-5, 71761-78-9, 71761-77-8, 71760-21-9 and the compounds disclosed in U.S. Pat. No. (6) 4,288,452, U.S. Pat. No. 4,363,805, U.S. Pat. No. 4,727,085, U.S. Pat. No. 4,863,949, U.S. Pat. No. 5,502,237, U.S. Pat. No. 6,242,432, U.S. Pat. No. 6,645,965, and in WO95/19952, WO 98/21193, WO 99/67231, WO 00/61537, WO 00/61549, CH-O Cy U3D; or WO 00/61541, WO 01/12584, WO 02/11707, WO02/ 053185, WO 02/053188, WO 2004/047837, WO 2004/ 050639 and in EP 280951, EP 1336602 and in JP 05247015: (7) O the disclosures of each of which are incorporated herein in their entirety. S S 0226. In another embodiment, the invention described nit CH-S \ f NHD rosated and/or nitrosylated angiotensin-converting enzyme (ACE) inhibitors of Formula (III) and pharmaceutically -s-k\ | acceptable salts thereof:

0213 X is: X (III) 0214) (1) methyl: / 6

Z6 w V6 (2) N/

(CH2) R17: Y. O X R19 R20 US 2008/030O292 A1 Dec. 4, 2008 10 wherein: 0227 X is: -continued 0228 (1) - UD; (4) 0229 (2) - O CH-CH; or y CH (3) %. NH 0233. V is a hydrogen: O UD 0234 Z is: 0235 (1) hydrogen: 0236 (2) methyl; or 0230 Y is: 0237 (3)-(CH), N(H)D; 0231 (1) —CH2—S R: 0238 Rio and Ro are a hydrogen; or 0239 Ro and Ro taken together are an oxo; or (2) 0240 Ro and W taken together are: O o- (1) OD1 s (3)

(4) -O- (2) O (5)

NH CH3: 0241 R is: 0242 (1) = C(O) CH-CH: 0243 (2) hydrogen; 0244 (3) K; or 0232 W, is:

(4) O 2. (1) 10245. R. is U.D, or OCH, CH, 0246 D. U and K are as defined herein; and X with the proviso that the compounds of Formula (III) must N-CH contain at least one NO group, and/or at least one NO. group; wherein the at least one NO group and/or the at least one NO. group is linked to the angiotensin-converting enzyme (ACE) (3) inhibitor through an oxygenatom, a nitrogenatom or a Sulfur S atOm. } Or 0247. In another embodiment, the invention described nit rosated and/or nitrosylated angiotensin-converting enzyme S (ACE) inhibitors of Formula (IV) and pharmaceutically acceptable salts thereof: US 2008/030O292 A1 Dec. 4, 2008

least one NO. group is linked to the angiotensin-converting enzyme (ACE) inhibitor through an oxygenatom, a nitrogen (IV) atom or a Sulfur atom. O O U3D O 0256 In another embodiment, the invention described nit rosated and/or nitrosylated angiotensin-converting enzyme UD N 31 (ACE) inhibitors of Formula (V) and pharmaceutically NH V acceptable salts thereof: B. Q6 / Go-D (V) O wherein: X7 0248 B is: R22 O DU3 (1) HC N Ye NH Ny. CH2 O

O 0249 (2) a nitrogen; wherein: 0250 G is: 0257 X, is a hydrogen; (1) 0258 Y, is

(2) --CO A 0259 or X, and Y, taken together are:

0251 D is: R23 (1) R23;

(2) 0260 R is a hydrogen or —OCH: 0261 R U and D are as defined herein; and k W \, 0262 with the proviso that the compounds of Formula (V) S must contain at least one NO group, and/or at least one NO group; wherein the at least one NO group and/or the at least 4. one NO. group is linked to the angiotensin-converting enzyme (ACE) inhibitor through an oxygenatom, a nitrogen or B and De taken together form a phenyl ring; atom or a Sulfur atom. 0252 Q is a hydrogen; or 0263. In another embodiment of the invention, the nitro 0253) B is a nitrogen and Q is CH and taken together sated angiotensin-converting enzyme (ACE) inhibitor com form the ring: pounds of Formula (III), (IV) and (V) do not include com pounds in which a —ONO and/or —CH2—ONO group are directly attached to the angiotensin-converting enzyme N (ACE) inhibitor core structure (i.e. nitrosation of —OH and/ or —CH2—OH group respectively) and any of the following N compounds of ACS registry number 690655-42-6, 690655 41-5, 326850-44-6, 302543-85-7, 301669-71-6, 207987-25 5, 207987-21-1, 207987-13-1, 207987-11-9, and the com 0254 U and D are as defined herein; and pounds disclosed in U.S. Pat. No. 6,645,965, U.S. Pat. No. 0255 with the proviso that the compounds of Formula 6,242,432, and in WO 98/21193, WO 99/00361, WO (IV) must contain at least one NO group, and/or at least one 99/67231, WO 00/61537, WO 00/61549, WO 00/61541, WO NO, group; wherein the at least one NO group and/or the at 01/12584, WO 02/11707, WO02/053185, WO 02/053188, US 2008/030O292 A1 Dec. 4, 2008

and in EP 1 336 602; the disclosures of each of which are tertatolol, a nitrosated and nitrosylated tertatolol, a nitrosated incorporated herein in their entirety. tilisolol, a nitrosylated tilisolol, a nitrosated and nitrosylated tilisolol, a nitrosated timolol, a nitrosylated timolol, a nitro 0264. In another embodiment of the invention, the nitrosy sated and nitrosylated timolol, a nitrosated toliprolol, a lated angiotensin-converting enzyme (ACE) inhibitor com nitrosylated toliprolol, a nitrosated and nitrosylated tolip pounds of Formula (III), (IV) and (V) do not include any of rolol, a nitrosated xibenolol, a nitrosylated Xibenolol, a nit the following compounds of ACS registry number 122 130 rosated and nitrosylated xibenolol; the compound of Formula 63-6, and the compounds disclosed in U.S. Pat. No. 4,900, (II) is a nitrosated amoSulalol, a nitrosylated amoSulalol, a 719, U.S. Pat. No. 5,002,964, U.S. Pat. No. 5,025,001, U.S. nitrosated and nitrosylated amoSulalol, a nitrosated aroti Pat. No. 5,187,183, U.S. Pat. No. 5,356,890, U.S. Pat. No. nolol, a nitrosylated arotinolol, a nitrosated and nitrosylated 5,536,723, and in WO 89/12627; the disclosures of each of arotinolol, a nitrosated bufuralol, a nitrosylated bufuralol, a which are incorporated herein in their entirety. nitrosated and nitrosylated bufuralol, a nitrosated carvedilol, 0265. In other embodiments of the invention the com a nitrosylated carvedilol, a nitrosated and nitrosylated pound of Formula (I) is a nitrosated acebutolol, a nitrosylated carvedilol, a nitrosated dilevalol, a nitrosylated dilevalol, a acebutolol, a nitrosated and nitrosylated acebutolol, a nitro nitrosated and nitrosylated dilevalol, a nitrosated labetalol, a sated alprenolol, a nitrosylated alprenolol, a nitrosated and nitrosylated labetalol, a nitrosated and nitrosylated labetalol, a nitrosated landiolol, a nitrosylated landiolol, a nitrosated nitrosylated alprenolol, a nitrosated atenolol, a nitrosylated and nitrosylated landiolol, a nitrosated nifemalol, a nitrosy atenolol, a nitrosated and nitrosylated atenolol, a nitrosated lated nifemalol, a nitrosated and nitrosylated nifemalol, a nit befunolol, a nitrosylated befunolol, a nitrosated and nitrosy rosated pronethalol, a nitrosylated pronethalol, a nitrosated lated befunolol, a nitrosated betaxolol, a nitrosylated betax and nitrosylated pronethalol, a nitrosated Sotalol, a nitrosy olol, a nitrosated and nitrosylated betaxolol, a nitrosated lated Sotalol, a nitrosated and nitrosylated Sotalol, a nitrosated bevantolol, a nitrosylated bevantolol, a nitrosated and nitrosy Sulfinalol, a nitrosylated Sulfinalol, a nitrosated and nitrosy lated bevantolol, a nitrosated bisoprolol, a nitrosylated biso lated sulfinalol; the compound of Formula (III) is a nitrosated prolol, a nitrosated and nitrosylated bisoprolol, a nitrosated alacepril, a nitrosylated alacepril, a nitrosated and nitrosy bopindolol, a nitrosylated bopindolol, a nitrosated and lated alacepril, a nitrosated captopril, a nitrosylated captopril, nitrosylated bopindolol, a nitrosated bucindolol, a nitrosy a nitrosated and nitrosylated captopril, a nitrosated cero lated bucindolol, a nitrosated and nitrosylated bucindolol, a napril, a nitrosylated ceronapril, a nitrosated and nitrosylated nitrosated bucumolol, a nitrosylated bucumolol, a nitrosated ceronapril, a nitrosated enalapril, a nitrosylated enalapril, a and nitrosylated bucumolol, a nitrosated bufetolol, a nitrosy nitrosated and nitrosylated enalapril, a nitrosated enalaprilat, lated bufetolol, a nitrosated and nitrosylated bufetolol, a nit a nitrosylated enalaprilat, a nitrosated and nitrosylated enala rosated bunitrolol, a nitrosylated bunitrolol, a nitrosated and prilat, a nitrosated fosinopril, a nitrosylated fosinopril, a nit nitrosylated bunitrolol, a nitrosated bupranolol, a nitrosylated rosated and nitrosylated fosinopril, a nitrosated imidapril, a bupranolol, a nitrosated and nitrosylated bupranolol, a nitro nitrosylated imidapril, a nitrosated and nitrosylated imi sated butofilolol, a nitrosylated butofilolol, a nitrosated and dapril, a nitrosated lisinopril, a nitrosylated lisinopril, a nit nitrosylated butofilolol, a nitrosated carazolol, a nitrosylated rosated and nitrosylatedlisinopril, a nitrosated moveltipril, a carazolol, a nitrosated and nitrosylated carazolol, a nitrosated nitrosylated moveltipril, a nitrosated and nitrosylated movel carteolol, a nitrosylated carteolol, a nitrosated and nitrosy tipril, a nitrosated perindopril, a nitrosylated perindopril, a lated carteolol, a nitrosated celiprolol, a nitrosylated celip nitrosated and nitrosylated perindopril, a nitrosated ramipril, rolol, a nitrosated and nitrosylated celiprolol, a nitrosated a nitrosylated ramipril, a nitrosated and nitrosylated ramipril, cetamolol, a nitrosylated cetamolol, a nitrosated and nitrosy a nitrosated spirapril, a nitrosylated spirapril, a nitrosated and lated cetamolol, a nitrosated cloranolol, a nitrosylated clo nitrosylated spirapril, a nitrosated trandolapril, a nitrosylated ranolol, a nitrosated and nitrosylated cloranolol, a nitrosated trandolapril, a nitrosated and nitrosylated trandolapril; the esmolol, a nitrosylated esmolol, a nitrosated and nitrosylated compound of Formula (IV) is a nitrosated benazepril, a esmolol, a nitrosated indenolol, a nitrosylated indenolol, a nitrosylated benazepril, a nitrosated and nitrosylated nitrosated and nitrosylated indenolol, a nitrosated benazepril, a nitrosated cilaZapril, a nitrosylated cilaZapril, a levobunolol, a nitrosylated levobunolol, a nitrosated and nitrosated and nitrosylated cilaZapril, a nitrosated temocapril, nitrosylated levobunolol, a nitrosated mepindolol, a nitrosy a nitrosylated temocapril, a nitrosated and nitrosylated lated mepindolol, a nitrosated and nitrosylated mepindolol, a temocapril; the compound of Formula (V) is a nitrosated nitrosated metipranolol, a nitrosylated metipranolol, a nitro delapril, a nitrosylated delapril, a nitrosated and nitrosylated sated and nitrosylated metipranolol, a nitrosated metoprolol. delapril, a nitrosated moexipril, a nitrosylated moexipril, a a nitrosylated metoprolol, a nitrosated and nitrosylated meto nitrosated and nitrosylated moexipril, a nitrosated quinapril, a prolol, a nitrosated moprolol, a nitrosylated moprolol, a nit nitrosylated quinapril, a nitrosated and nitrosylated quinapril, rosated and nitrosylated moprolol, a nitrosated nadolol, a and pharmaceutically acceptable salts thereof. nitrosylated nadolol, a nitrosated and nitrosylated nadolol, a 0266. In one embodiment of the invention for the nitro nitrosated nipradillol, a nitrosylated nipradillol, a nitrosated sated compounds of Formula (I), (II), (III), (IV) or (V) and and nitrosylated nipradillol, a nitrosated oXprenolol, a nitrosy pharmaceutically acceptable salts thereof, K is: lated oXprenolol, a nitrosated and nitrosylated oXprenolol, a nitrosated penbutolol, a nitrosylated penbutolol, a nitrosated 10267 (1) - Y (CRR)-T-(CRR"). ONO; and nitrosylated penbutolol, a nitrosated pindolol, a nitrosy lated pindolol, a nitrosated and nitrosylated pindolol, a nitro (2) sated practolol, a nitrosylated practolol, a nitrosated and y-T-CR,R)-ONO. nitrosylated practolol, a nitrosated propranolol, a nitrosylated propranolol, a nitrosated and nitrosylated propranolol, a nit -y-crea-( ) rosated talinolol, a nitrosylated talinolol, a nitrosated and nitrosylated talinolol, a nitrosated tertatolol, a nitrosylated

US 2008/030O292 A1 Dec. 4, 2008 14

-continued

(1) (10) O ckY N-1)- --~n SNO,

(11) >s-rr- 'No, (2) SO

(12) ONO

ONO Y N O

Y (3) ". N1)-x. Y x-rr O N- son - y-T-CH-ONo. (13) O Yi N / (4) (14)

>s-r ~ Y O ONO N- N n-1SoNo. ". N-1 n N --- 2 (5) R6

vas-s ONO 0324 wherein T maybe ortho, meta or para )n' (6) (15)

(7) i O >s-s-s-s (16) vrc N n-Ns, (17) O (8) N-1N l 1n 1a ckY N-1\x1y-21'No, O w NR6 NR6 ONO. (18) (9)

N--O On Y.uCl lsO ck r- NO NR6 NR6 1N1 Sono, US 2008/030O292 A1 Dec. 4, 2008

-continued -continued (28) R6 * - N S-asso,O O R6 (29) ckY N No 1YNo,O O (30) YSr- O YNO, R6 (31) R6 A 8. N No1 N1, O No, O (32) O X, n ^- O SNO, O R6 (33)

O N NO > O 2 O (34) 1No >, Y n O YNO, (35) ONO

(26) (36)

(37) (27) >s-Y S Ns 1YO NO, US 2008/030O292 A1 Dec. 4, 2008 16

-continued -continued (38) (48) O Y O Y H >s-N-y >, S-S. O S So-S- NO (49) O H. ONO, Y T O (39) >, N-1 SS,-- YNO, O T O (50) X, n YNO, R6 O O N O (40) >, ---1YNo, / v NO N No1 R6 (51) Yi n ONO O Y O (41) O > - YNO, i T NO OH (52) * 8. m -N- 2 O O (42) Ys 11 ye so, O i T Xs O S. ^ - Y-1, N1, No, (53) O (43) R6

n T O >, O v 1YNo, (54) O (44) O (55) NO o1 2

(45) O Y (56) >, 4)l -N- NO2 N (46) R6 O O n wherein: cxs --- JN-4'No, 0325 Y'a covalent bond, a carbonyl, an oxygen, S(O) O - or —NR; (47) 0326 T is oxygen, sulfur or NR; N O 0327 X is oxygen, (S(O)), or NR; r YNO, 0328 R is a hydrogen, a lower alkyl group, an aryl group: N Yi n 0329 R, is a lower alkyl group or an aryl group: 0330 Rs at each occurrence is independently is a hydro O gen, a hydroxyl group, a lower alkyl group, an aryl group, —NO. —CH2—ONO or —CH2—OH: US 2008/030O292 A1 Dec. 4, 2008 17

0331 n' and m'are each independently an integer from 0 to 0337 and the compound of Formula (IX) is: 10; and 0332 o is an integer from 0 to 2. 0333. In other embodiments of the invention, the B-adren (IX) ergic antagonists of Formula (I) is a nitrosated atenolol of CH Formula (VI), a nitrosated bisoprolol of Formula (VII), a 1. nitrosated metoprolol of Formula (VIII), a nitrosated propra- O N CH nolol of Formula (IX), a nitrosated timolol of Formula (X), a nitrosated betaxolol of Formula (XI); the B-adrenergic 'N"n antagonist of Formula (II) is a nitrosated carvedilol of For mula (XII), and the nitrosated angiotensin-converting O enzyme (ACE) inhibitor of Formula (III) is a nitrosated cap topril of Formula (XIII), a nitrosated enalapril of Formula (XIV), a nitrosated fosinopril of Formula (XV), a nitrosated 0338 and the compound of Formula (X) is: lisinopril of Formula (XVI), a nitrosated ramipril of Formula (XVII) or Formula (XVIII), a nitrosated trandolaprilat of Formula (XIX): a nitrosated trandolapril of Formula (XIX) or Formula (XX), the nitrosated angiotensin-converting enzyme S (X) inhibitor of Formula (IV) is a nitrosated benazepril of For- N N mula (XXI) or Formula (XXII); the nitrosated angiotensin- ) k k" converting enzyme inhibitor of Formula (V) is a nitrosated 3 moexipril of Formula (XXIII) or Formula (XXIV), a nitro- r irr CH sated quinapril of Formula (XXV) or Formula (XXVI), or a pharmaceutically acceptable salt thereof, 0334 wherein the compound of Formula (VI) is: 0339 and the compound of Formula (XI) is: (VI)

HC O HC os-4 Rim-Rn O-Rin -N HC ^^.

0335) and the compound of Formula (VII) is: and the compound of Formula (XII) is:

(VII) O (XII) HC-- or-in-HC Rm- Rn o 1N1 O H3C ^^o N O O SRn Rm YRn H,C-O

0336 and the compound of Formula (VIII) is: 0340 and the compound of Formula (XIII) is: (VIII) (XIII) - "-" O T-Rn N-N- St. O

Hics, HC -x.HC H US 2008/030O292 A1 Dec. 4, 2008 18

0341 anddth the compoundd of FFormula la (XIV) 1Si (0345 andd theth compoundd of FFormula la (XVII) 1Si

(XIV) T-Rn O HC O O HC3 O O 3 N1 CH N1 H3C

N N N Rm O H R"> O YRn

0342 and the compound of Formula (XV) is: 0346 and the compound of Formula (XIX) is:

(XV) (XIX)

R1 T

H3C

CH3 0347 and the compound of Formula (XX) is: 0343 and the compound of Formula (XVI) is:

(XX) (XVI)

NH-R-R O T-Rin

N N R"> O O T-Rn 0348 and the compound of Formula (XXI) is:

0344 and the compound of Formula (XVI) is: (XXI) O T-Rn

(XVII) 1. is a 1 TRn Rn O N 1. O \ Rn HC N H N Rm N YRn H Rm O YRn US 2008/030O292 A1 Dec. 4, 2008 19

0349 and the compound of Formula (XXII) is: 0353 and the compound of Formula (XXVI) is:

i (XXII) (XXVI) s -R T-Rn HC O O H3C-N-O , N in 1 CH3

CO RmN N. O Rm Rn YRn

0350 and the compound of Formula (XXM) is: wherein 0354 T is oxygen, sulfur or NR; (XXIII) 0355 R is a hydrogen, a lower alkyl group, an aryl group; i 0356 Re-R, taken together can be a hydrogen atom; or TRn 0357 R is: Rn 1N-29 CH3 On CH3 0358 (i) –C (O)–:s 0359 (ii) - C (O) NR; N N o1 CH3 0360 (iii)- - - - C(O) O-; Rm N O 0361 (iv) - C(O) S; Rn 0362 (v) —CH-O-; or 0363 (vi) -CH(CH) O-; 0364 R is: 0365 a hydrogen or 0351) and the compound of Formula (XXIV) is: (1) * -- NO2 (XXIV) (2) T-Rin O On H3C-N-O O On NO CH CH (3) N 1 CH 3 N 1. O * -->- NOIn 2 R"> O (4) 1\-1 O SNO, (5) 0352 and the compound of Formula (XXV) is: N NO o1 2 (XXV) (6) O T-Rn T O 1. R1 CH 2 O N N (7) Rm N. O N NO Rn - V2 US 2008/030O292 A1 Dec. 4, 2008 20

-continued -continued N (8) (19) n s O-NO2 - NO2 2 O "No N (9) 2 s O O (20)

tri-n- SNO, ls NO --- 2 (10) On T N NO o1 NO (21)

O 2 (11) >n-n-r- T NO O

(12)

(13) (23)

(24) (14)

(15) (25)

(16)

(26)

(17)

(27)

(18)

US 2008/030O292 A1 Dec. 4, 2008 22

0374. In another embodiment, the invention describes nit nitrogen using conventional methods known to one skilled in rosated compounds of the invention and pharmaceutically the art. Known methods for nitrosating and/or nitrosylating acceptable salts thereof. In one embodiment, the pharmaceu compounds are described in U.S. Pat. Nos. 5,380,758, 5,859, tically acceptable salts do not include the nitrate salt. 053, 5,703,073 and 6,297,260; and in WO 94/03421, WO 0375 Compounds of the invention that have one or more 94/04484, WO 94/12463, WO95/09831, WO95/19952, WO asymmetric carbon atoms may exist as the optically pure 95/30641, WO 97/27749, WO 98/09948, WO 98/19672, WO enantiomers, pure diastereomers, mixtures of enantiomers, 98/21193, WO 00/51988, WO 00/61604, WO 00/72838, WO mixtures of diastereomers, racemic mixtures of enantiomers, 01/00563, WO 01/04082, WO 01/10814, WO 01/12584, WO diastereomeric racemates or mixtures of diastereomeric race 01/45703, WO 00/61541, WO 00/61537, WO 02/11707, WO mates. It is to be understood that the invention anticipates and 02/30866 and in Oae et al. Org. Prep. Proc. Int., 15(3):165 includes within its scope all such isomers and mixtures 198 (1983), the disclosures of each of which are incorporated thereof. by reference herein in their entirety. The methods of nitrosat 0376 Another embodiment of the invention describes the ing and/or nitrosylating the compounds described in these metabolites of the nitrosated and/or nitrosylated compounds references can be applied by one skilled in the art to produce and pharmaceutically acceptable salts thereof. These metabo any of the nitrosated and/or nitrosylated compounds lites, include but are not limited to, the non-nitrosated and/or described herein. The nitrosated and/or nitrosylated com nitrosylated derivatives, degradation products, hydrolysis pounds of the invention donate, transfer or release a biologi products, and the like, of the nitrosated and/or nitrosylated cally active form of nitrogen monoxide (i.e., nitric oxide). compounds and pharmaceutically acceptable salts thereof. 0380 Compounds contemplated for use in the invention, 0377 Another embodiment of the invention provides pro e.g., compounds that are nitrosated and/or nitrosylated, cesses for making the novel compounds of the invention and through one or more sites Such as oxygen (hydroxyl conden to the intermediates useful in Such processes. The reactions sation), Sulfur (Sulfhydryl condensation) and/or nitrogen, are, are performed in solvents appropriate to the reagents and optionally, used in combination with nitric oxide and com materials used are suitable for the transformations being pounds that release nitric oxide or otherwise directly or indi effected. It is understood by one skilled in the art of organic rectly deliver or transfer a biologically active form of nitrogen synthesis that the functionality present in the molecule must monoxide to a site of its intended activity, such as on a cell be consistent with the chemical transformation proposed. membrane in vivo. Nitrogen monoxide can exist in three This will, on occasion, necessitate judgment by the routineer forms: NO (nitroxyl), NO. (nitric oxide) and NO" (nitroso as to the order of synthetic steps, protecting groups required, nium). NO. is a highly reactive short-lived species that is and deprotection conditions. Substituents on the starting potentially toxic to cells. This is critical because the pharma materials may be incompatible with some of the reaction cological efficacy of NO depends upon the form in which it is conditions required in some of the methods described, but delivered. In contrast to the nitric oxide radical (NO.), alternative methods and substituents compatible with the nitrosonium (NO") does not react with O. or O-species, and reaction conditions will be readily apparent to one skilled in functionalities capable of transferring and/or releasing NO" the art. The use of sulfur and oxygen protecting groups is well and NO—are also resistant to decomposition in the presence known for protecting thiol and alcohol groups against unde of many redox metals. Consequently, administration of sirable reactions during a synthetic procedure and many Such charged NO equivalents (positive and/or negative) does not protecting groups are known and described by, for example, result in the generation of toxic by-products or the elimina Greene and Wuts, Protective Groups in Organic Synthesis, tion of the active NO moiety. Third Edition, John Wiley & Sons, New York (1999). 0381. The term "nitric oxide encompasses uncharged 0378. The chemical reactions described herein are gener nitric oxide (NO.) and charged nitrogen monoxide species, ally disclosed in terms of their broadest application to the preferably charged nitrogen monoxide species. Such as preparation of the compounds of this invention. Occasionally, nitrosonium ion (NO") and nitroxyl ion (NO ). The reactive the reactions may not be applicable as described to each form of nitric oxide can be provided by gaseous nitric oxide. compound included within the disclosed scope. The com The nitrogen monoxide releasing, delivering or transferring pounds for which this occurs will be readily recognized by compounds have the structure F NO, wherein F is a nitrogen one skilled in the art. In all such cases, either the reactions can monoxide releasing, delivering or transferring group, and be successfully performed by conventional modifications include any and all Such compounds which provide nitrogen known to one skilled in the art, e.g., by appropriate protection monoxide to its intended site of action in a form active for its of interfering groups, by changing to alternative conventional intended purpose. reagents, by routine modification of reaction conditions, and 0382. The term “NO adducts’ encompasses any nitrogen the like, or other reactions disclosed herein or otherwise con monoxide releasing, delivering or transferring compounds, ventional, will be applicable to the preparation of the corre including, for example, S-nitrosothiols, nitrites, nitrates, sponding compounds of this invention. In all preparative S-nitrothiols, Sydnonimines, 2-hydroxy-2-nitrosohydra methods, all starting materials are known or readily prepared zines, (NONOates), (E)-alkyl-2-((E)-hydroxyimino)-5-ni from known starting materials. tro-3-hexeneamide (FK-409), (E)-alkyl-2-(E)-hydroxy 0379 The compounds of Formulas (I) to (XXX) can be imino)-5-nitro-3-hexeneamines, N-((2Z.3E)-4-ethyl-2- synthesized by one skilled in the art using conventional meth (hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3- ods. Some of the parent compounds (i.e. non-nitrosated and/ pyridinecarboxamide (FR 146801), N-nitrosoamines, or non-nitrosylated angiotensin-converting enzyme (ACE) N-hydroxyl nitrosamines, nitrosimines, diazetine dioxides, inhibitors and B-adrenergic antagonists) are commercially oXatriazole 5-imines, OXimes, hydroxylamines, N-hydrox available or their synthesis has been reported in the scientific yguanidines, hydroxyureas, benzofuroxanes, furoxans as literature. The compounds are nitrosated and/or nitrosylated well as Substrates for the endogenous enzymes which synthe through one or more sites such as oxygen, Sulfur and/or size nitric oxide. US 2008/030O292 A1 Dec. 4, 2008

0383 Suitable NONOates include, but are not limited to, in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; (Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino)) WO 98/19672; and Oae et al. Org. Prep. Proc. Int., 15(3): diazen-1-ium-1,2-diolate (“MAHMA/NO”), (Z)-1-(N-(3- 165-198 (1983), the disclosures of each of which are incor ammoniopropyl)-N-(n-propyl)amino)diaZen-1-ium-1,2-di porated by reference herein in their entirety. olate (“PAPA/NO”), (Z)-1-(N-(3-aminopropyl)-N-(4-(3- 0389. Another embodiment of the invention is S-nitroso aminopropylammonio)butyl)-amino)diazen-1-ium-1,2- amino acids where the nitroso group is linked to a Sulfur diolate (spermine NONOate or “SPER/NO”) and sodium(Z)- group of a Sulfur-containing amino acid orderivative thereof. 1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamine Such compounds include, for example, S-nitroso-N-acetyl NONOate or “DEA/NO”) and derivatives thereof. NON cysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicil Oates are also described in U.S. Pat. Nos. 6,232,336, 5,910, lamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-ni 316 and 5,650,447, the disclosures of which are incorporated troso-glutathione, S-nitroso-cysteinyl-glycine, and the like. herein by reference in their entirety. The “NO adducts’ can be 0390 Suitable S-nitrosylated proteins include thiol-con mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/ taining proteins (where the NO group is attached to one or or poly-nitrosated at a variety of naturally susceptible or more Sulfur groups on an amino acid oramino acid derivative artificially provided binding sites for biologically active thereof) from various functional classes including enzymes, forms of nitrogen monoxide. Such as tissue-type plasminogen activator (TPA) and cathep 0384 Suitable furoxanes include, but are not limited to, sin B; transport proteins, such as lipoproteins; heme proteins, CAS 1609, C93-4759, C92-4678, S35b, CHF 2206, CHF Such as hemoglobin and serum albumin; and biologically 2363, R-substituted phenylfuroxans, di-R-substituted phenyl protective proteins, such as immunoglobulins, antibodies and furoxans, and the like. cytokines. Such nitrosylated proteins are described in WO 0385 Suitable sydnonimines include, but are not limited 93/09806, the disclosure of which is incorporated by refer to, molsidomine (N-ethoxycarbonyl-3-morpholinosydnon ence herein in its entirety. Examples include polynitrosylated imine), SIN-1 (3-morpholinosydnonimine) CAS 936 (3-(cis albumin where one or more thiol or other nucleophilic centers 2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnon in the protein are modified. imine, pirsidomine), C87-3754 (3-(cis-2,6- 0391. Other examples of suitable S-nitrosothiols include: dimethylpiperidino)sydnonimine, linsidomine, C4144 (3-(3. 10392 (i) HS(C(R)(R)), SNO; 3-dimethyl-1,4-thiazane-4-yl)sydnonimine hydrochloride), (0393 (ii) ONS(C(R)(R)), R.; or C89-4095 (3-(3.3-dimethyl-1,1-dioxo-1,4-thiazane-4-yl) 0394 (iii) HN CH(COH)–(CH), C(O)NH-CH Sydnonimine hydrochloride, and the like. (CHSNO) C(O)NH-CH-COH: 0386 Suitable oximes, include, but are not limited to, 0395 wherein m is an integer from 2 to 20; NOR-1, NOR-3, NOR-4, and the like. (0396) R, and R, are each independently a hydrogen, an 0387 Suitable nitroxide containing compounds, include, alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, but are not limited to, substituted 2.2.6,6-tetramethyl-1-pip an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an eridinyloxy compounds, substituted 2.2.5.5-tetramethyl-3- alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, pyrroline-1-oxyl compounds, Substituted 2.2.5.5-tetram a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an ethyl-1-pyrrolidinyloxyl compounds, substituted 1,1,3,3- alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an tetramethylisoindolin-2-yloxyl compounds, Substituted 2.2, alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky 4,4-tetramethyl-1-oxazolidinyl-3-oxyl compounds, lamino, an arylamino, a diarylamino, an alkylarylamino, an substituted 3-imidazolin-1-yloxy, 2.2.5.5-tetramethyl-3-imi alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul dazolin-1-yloxyl compounds, OT-551, 4-hydroxy-2.2.6,6- fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio. tetramethyl-1-piperidinyloxy (tempol), and the like. Suitable an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an Substituents, include, but are not limited to, aminomethyl, arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, benzoyl, 2-bromoacetamido. 2-(2-(2-bromoacetamido) an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an ethoxy)ethylcarbamoyl, carbamoyl, carboxy, cyano, 5-(dim alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo ethylamino)-1-naphthalenesulfonamido, ethoxyfluorophos nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar phinyloxy, ethyl, 5-fluoro-2,4-dinitroanilino, hydroxy, boxylic ester, an arylcarboxylic ester, a Sulfonamido, an 2-iodoacetamido, isothiocyanato, isothiocyanatomethyl, alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an methyl, maleimido, maleimidoethyl, 2-(2-maleimidoethoxy) alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul ethylcarbamoyl, maleimidomethyl, maleimido, OXo, fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, phosphonooxy, and the like. a nitro, -U, Vs, V, -C(R)(R), Us Vs, or R and 0388 One group of NO adducts is the S-nitrosothiols, R taken together with the carbons to which they are attached which are compounds that include at least one —S NO form a carbonyl, a methanthial, a heterocyclic ring, a group. These compounds include S-nitroso-polypeptides (the cycloalkyl group, an aryl group, an oxime, a hydrazone, a term “polypeptide' includes proteins and polyamino acids bridged cycloalkyl group, that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and (1) racemic mixtures and derivatives thereof); S-nitrosylated Sugars; S-nitrosylated, modified and unmodified, oligonucle 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 US 2008/030O292 A1 Dec. 4, 2008 24

bond to an adjacent atom creating a double bond to that atom -continued or —(N2O ).M.", wherein M is an organic or inorganic (2) cation. H3C CH3 (0403. In cases where R and Rare independently a het erocyclic ring or taken together R, and Rare a heterocyclic N-O; ring, then R, can be a Substituent on any disubstituted nitrogen Z5 contained within the radical wherein R, is as defined herein. 0404 Nitrosothiols can be prepared by various methods of HC CH synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the 10397 R and R are each independently a hydrogen, an thiol group with NaNO under acidic conditions (pH is about alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, 2.5) which yields the S-nitroso derivative. Acids which can be analkoxyalkyl, analylheterocyclic ring, an alkylaryl, an alky used for this purpose include aqueous Sulfuric, acetic and lcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a hydrochloric acids. The thiol precursor can also be nitrosy cycloalkylthio, an arylalklythio, an alylalklythioalkyl, an lated by reaction with an organic nitrite Such as tert-butyl alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an nitrite, or a nitrosonium salt Such as nitrosonium tetrafluo alkoxy, a haloalkoxy, an amino, an alkylamino, a dialky roborate in an inert solvent. lamino, an arylamino, a diarylamino, an alkylarylamino, an 04.05 Another group of NO adducts for use in the inven alkoxyhaloalkyl, a Sulfonic acid, a Sulfonic ester, an alkylsul tion, where the NO adduct is a compound that donates, trans fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio. fers or releases nitric oxide, include compounds comprising an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an at least one ON O— or ON N— group. The compounds arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, that include at least one ON O— or ON N— group are an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an preferably ON O— or ON N-polypeptides (the term alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbo "polypeptide' includes proteins and polyamino acids that do nyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcar not possess an ascertained biological function, and deriva boxylic ester, an arylcarboxylic ester, a Sulfonamido, an tives thereof); ON O - or ON N-amino acids (including alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an natural and synthetic amino acids and their stereoisomers and alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a Sul racemic mixtures); ON O - or ON N-sugars; ON O— fonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, or —ON N— modified or unmodified oligonucleotides a nitro, -U, Vs, Vs, 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. Preferred examples of compounds comprising at least one ON O - or ON N— (1) group include butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite, N-nitrosauines, N-nitrosamides, N-nitrosourea, N-nitrosoguanidines, N-nitrosocarbamates, N-acyl-N-nitroso compounds (such as, N-methyl-N-ni trosourea); N-hydroxy-N-nitrosamines, cupferron, alanosine, dopastin, 1.3-disubstitued nitrosiminobenzimida Zoles, 1,3,4-thiadiazole-2-nitrosimines, benzothiazole-2 (3H)-nitrosimines, thiazole-2-nitrosimines, oligonitroso Syd (2) nonimines, 3-alkyl-N-nitroso-Sydnonimines and 2H-1,3,4- thiadiazine nitrosimines. 0406 Another group of NO adducts for use in the inven tion include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one ON O—, ON N— or ON S group. Preferred among these compounds are ON O—, ON N.— or ON S polypeptides (the term “polypeptide' includes proteins and 0398 k is an integer form 1 to 3: also polyamino acids that do not possess an ascertained bio logical function, and derivatives thereof); ON O , 0399 U is an oxygen, sulfur- or N(R)R.; ON-N- or ON-S-amino acids (including natural and 0400 Vs is —NO or - NO (i.e. an oxidized nitrogen); synthetic amino acids and their Stereoisomers and racemic 04.01 R is a lone pair of electrons, a hydrogen or an alkyl mixtures); ON O—, ON N— or ON S Sugars; group; ON O ON N— or ON S modified and unmodi 0402 R is a hydrogen, an alkyl, an aryl, an alkylcarboxy fied oligonucleotides (comprising at least 5 nucleotides, pref lic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an erably 5-200 nucleotides); ON O ON N or ON.— arylcarboxylic ester, an alkylcarboxamido, an arylcarboxa S— straight or branched, Saturated or unsaturated, aliphatic mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an or 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. Preferred examples of compounds comprising at aminoalkyl, an aminoaryl, —CH2—C(Us Vs)(R)(R), a least one ON O—, ON N— or ON.—S group US 2008/030O292 A1 Dec. 4, 2008

include isosorbide dinitrate, isosorbide mononitrate, cloni nitric oxide synthase, cytokines, adenosin, bradykinin, cal trate, erythrityl tetranitrate, mannitol hexanitrate, nitroglyc reticulin, bisacodyl, and phenolphthalein. EDRF is a vascular erin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate relaxing factor secreted by the endothelium, and has been and organic nitrates with a sulfhydryl-containing amino acid identified as nitric oxide (NO) or a closely related derivative such as, for example SPM3672, SPM 4757, SPM 5185, SPM thereof (Palmeretal, Nature, 327:524-526 (1987); Ignarro et 51.86 and those disclosed in U.S. Pat. Nos. 5,284,872, 5,428, al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)). 061, 5,661,129, 5,807,847 and 5,883,122 and in WO 04.09. In another embodiment of the invention the combi 97/.46521, WO 00/54756 and in WO 03/013432, the disclo nation of the B-adrenergic antagonists or ACE inhibitors of sures of each of which are incorporated by reference herein in the invention (i.e. non-nitrosated and/or non-nitrosylated their entirety. B-adrenergic antagonists and/or ACE inhibitors) with nitric 0407 Another group of NO adducts are N-oxo-N-ni oxide donor compounds do not include the combinations troSoamines that donate, transfer or release nitric oxide and disclosed in US 2003/0216384, the disclosure of which is are represented by the formula: R'"R"N N(O-M'.) NO, incorporated herein in its entirety. where R'" and Rare each independently a polypeptide, an 0410 The invention is also based on the discovery that amino acid, a Sugar, a modified or unmodified oligonucle compounds and compositions of the invention may be used in otide, a straight or branched, saturated or unsaturated, ali conjunction with other therapeutic agents for co-therapies, phatic or aromatic, Substituted or unsubstituted hydrocarbon, partially or completely, in place of other therapeutic agents, or a heterocyclic group, and where M is an organic or Such as, for example, C.-adrenergic receptor agonists, C.-adr inorganic cation, such, as for example, an alkyl Substituted energic receptor antagonists, angiotensin-converting enzyme ammonium cation or a Group I metal cation. (ACE) inhibitors, antimicrobial compounds, antioxidants, 0408. The invention is also directed to compounds that B-adrenergic antagonists, carbonic anhydrase inhibitors, stimulate endogenous NO or elevate levels of endogenous hydralazine compounds, nonsteroidal antiinflammatory endothelium-derived relaxing factor (EDRF) in vivo or are compounds (NSAIDs), prostaglandins, selective cyclooxy oxidized to produce nitric oxide and/or are substrates for genase-2 (COX-2) inhibitors, steroids, and combinations of nitric oxide synthase and/or cytochrome P450. Such com two or more thereof. The therapeutic agent may optionally be pounds include, for example, L-arginine, L-homoarginine, nitrosated and/or nitrosylated. and N-hydroxy-L-arginine, N-hydroxy-L-homoarginine, 0411 Suitable C-adrenergic receptor agonists, including, N-hydroxydebrisoquine, N-hydroxypentamidine including but are not limited to, agnatine, p-aminoclonidine, apracloni their nitrosated and/or nitrosylated analogs (e.g., nitrosated dine (IOPIDINER), 2-(arylamino)imidazolidine derivatives, L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L- aZepexole, azepin derivatives, such as for example, 2-amino arginine, nitrosylated N-hydroxy-L-arginine, nitrosated and 6-alkyl-4,5,7,8-tetrahydro-6H-thiazolo-(5.4.d) aZepine, nitrosylated L-homoarginine), N-hydroxyguanidine com 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-thiazolo-(5.4.d) pounds, amidoxime, ketoximes, aldoxime compounds, that azepine, 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-(5. can be oxidized in vivo to produce nitric oxide. Compounds 4.d) azepine, and the like; brimonidine, clonidine, clonidine that may be substrates for a cytochrome P450, include, for derivatives, detomidine, dexmedetomidine, diplivefrin, example, imino(benzylamino)methylhydroxylamine, imino dipivalylepinephrine, epinephrine, guanabenz, guanfacine, (((4-methylphenyl)methyl)amino)methylhydroxylamine, imidazolidine derivatives, such as, for example, 5-bromo-6- imino(((4-methoxyphenyl)methyl)amino) methylhydroxy (2-imidazolidine-2-ylamino)cquinoxaline, and the like; p-io lamine, imino(((4-(trifluoromethyl)phenyl)methyl)amino) doclonidine, medetomidine, methoxamine (VASOXYL(R), methylhydroxylamine, imino(((4-nitrophenyl)methyl) mephentermine, metaraminol (ARAMINE(R), methyldopa, amino)methylhydroxylamine, (butylamino) iminomethylhy mitodrine, naphazoline (PRIVINE(R), NAPHCONR), norepi droxylamine, imino (propylamino)methylhydroxylamine, nephrine, oxymetazoline (AFRINR, OCUCLEAR(R), phe imino(pentylamino)methylhydroxylamine, imino (propy nylepinephrine (NEOSYNEPHRINE(R), rilmenidine, tet lamino)methylhydroxylamine, imino (methylethyl)amino) rahydrozoline (TYZINE(R), VISINE(R), tramazoline, methylhydroxylamine, (cyclopropylamino) iminomethylhy xylazine, xylometazoline (OTRIVINR), B-HT 920 (6-allyl droxylamine, imino-2-1,2,3,4-tetrahydroisoquinolyl 2-amino-5,6,7,8-tetrahydro-4H-thiazolo(4,5-d)-azepine, methylhydroxylamine, imino(1-methyl(2-1.2.3,4-tetrahy B-HT933 and UK 14.304, and the like. Suitable C.-adrenergic droisoquinolyl))methylhydroxylamine, (1,3-dimethyl(2-1.2. receptor agonists are described more fully in the literature, 3,4-tetrahydroisoquinolyl)) iminomethylhydroxylamine, Such as in Goodman and Gilman, The Pharmacological Basis (((4-chlorophenyl)methyl)amino)iminomethylhydroxy of Therapeutics (9th Edition), McGraw-Hill, (1996); Merck lamine, ((4-chlorophenyl)amino)iminomethylhydroxy Index on CD-ROM, 13" Edition; STN Express, file phar and lamine, (4-chlorophenyl)(hydroxyimino)methylamine, and file registry, the disclosures of each of which are incorporated 1-(4-chlorophenyl)-1-(hydroxyimino) ethane, and the like, by reference herein in their entirety. precursors of L-arginine and/or physiologically acceptable 0412. In some embodiment the C-adrenergic receptorago salts thereof, including, for example, citruline, ornithine, nist are aminoclonidine, apraclonidine (IOPIDINE(R), bri glutamine, lysine, polypeptides comprising at least one of monidine, clonidine and clonidine derivatives. these amino acids, inhibitors of the enzyme arginase (e.g., 0413 Suitable alpha-adrenergic receptor antagonists N-hydroxy-L-arginine and 2CS)-amino-6-boronohexanoic include but are not limited to, phentolamine, tolaZoline, ida acid), nitric oxide mediators and/or physiologically accept Zoxan, deriglidole, RX 821002, BRL 44408, BRL 44409, able salts thereof, including, for example, pyruvate, pyruvate BAM 1303, labetelol, ifenprodil, rauwolscine, corynathine, precursors, C.-keto acids having four or more carbon atoms, raubascine, tetrahydroalstonine, apoyohimbine, akuam precursors of C.-keto acids having four or more carbon atoms migine, B-yohimbine, yohimbol, yohimbine, pseudoyohim (as disclosed in WO 03/017996, the disclosure of which is bine, epi-3C.-yohimbine, 10-hydroxy-yohimbine, 11-hy incorporated herein in its entirety), and the substrates for droxy-yohimbine, tamsulosin, benoxathian, atipamezole, BE US 2008/030O292 A1 Dec. 4, 2008 26

2254, WB 4101, HU-723, tedisamil, mirtazipine, setiptiline, 0416) Suitable antimicrobial compounds, include, but are reboxitine, delequamine, naftopil, saterinone, SL 89.0591, not limited to, acediasulfone, aceturate, acetyl Sulfameto ARC 239, urapidil, 5-methylurapidil, monatepi, haloperidol, ssipirazine, acetyl Sulfamethoxypyrazine, acranil, albenda indoramin, SB 216469, moxisylyte, trazodone, dapiprozole, Zole, alexidine, amatadine, ambazone, amdinocillin, amika efaroxan, Recordati 15/2739, SNAP 1069, SNAP 5089, cin, p-aminosalicylic acid, p-aminosalicylic acid hydrazine, SNAP 5272, RS 17053, SL 89.0591, KMD 3213, spiperone, amoxicillin, amplicillin, anisomycin, apalcillin, apicyclin, AH 11110A, chloroethylclonidine, BMY 7378, niguldipine, apramycin, arbekacin, argininsa, aspoxicillin, azidamfenicol, and the like. Suitable alpha-adrenergic receptor antagonists azidocillin, azithromycin, azlocillin, aztreonam, bacampicil are described more fully in the literature, such as in Goodman lin, bacitracin, benzoylpas, benzylpenicillin acid, benzyl Sul and Gilman, The Pharmacological Basis of Therapeutics (9th famide, bicoZamycin, bipenam, brodimoprim, capreomycin, Edition), McGraw-Hill, 1995; and the Merck Index on CD carbenicillin, carbomycin, cafaZedone, carindacillin, caru ROM. Thirteenth Edition; and on STN Express, file phar and monam, cefcapene pivoxil, cefaclor, cefadroxil, cefafroxil, file registry. cefamandole, cefatamet, cefatrizine, cefazedone, cefazolin, 0414 Suitable angiotensin-converting enzyme inhibitors cefbuperaZone, cefclidin, cefdinir, cefditoren, cefixime, (ACE inhibitors) include, but are not limited to, alacepril, cefinenoXime, cefimetazole, cefiminox, cefodizime, benazepril (LOTENSINR), CIBACENR), benazeprilat, cap cefonicid, cefoperaZone, ceforanide, cefotaxime, cefotetan, topril, ceronapril, cilaZapril, delapril, duinapril, enalapril, cefotiam, cefoxitin, cefoZopran, cefpimizole, cefpiramide, enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cef glycopril, idrapril, imidapril, lisinopril, moexipril, movel Sulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftio fur, ceftizoxime, ceftriaxone, cefuroxime, cefuZonam, ceph tipril, naphthopidil, omapatrilat, pentopril, perindopril, per acetrile sodium, cephadrine, cephalexin, cephaloglycin, indoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rent cephaloridine, cephalosporin C, cephalothin, cephapirin ipril, Saralasin acetate, spirapril, temocapril, trandolapril, Sodium, cephradine, chibrorifamycin, chloramphenicol, trandolaprilat, urapidil, Zofenopril, acylmercapto and mer chlorotetracycline, cinoxacin, ciprofloxacin, claritromycin, captoalkanoyl pralines, carboxyalkyl dipeptides, carboxy clavulanic acid, clinafloxacin, clindamycin, clofazimine, clo alkyl dipeptide, phosphinylalkanoyl pralines, registry no. foctal, clometocillin, clomocycline, cloxacillin, cloxyquin, 79.6406, AVE 7688, BP1.137, CHF 1514, E 4030, ER 3295, colistin, cyclacilline, cycloserine, danoflaxcin, dapsone, FPL-66564, MDL 100240, RL 6134, RL 6207, RL 6893, SA deoxycycline, deoxydihydrostreptomycin, dibekacin, 760, S-5590, Z 13752A, and the like. Suitable angiotensin dicloxacillin, difloxacin, dihydrostreptomycin, dimetrida converting enzyme inhibitors are described more fully in the Zole, diminaZene, dirirtomycin, duramycin, eflornithine, literature. Such as in Goodman and Gilman, The Pharmaco enrofloxacin, enviomycin, epicillin, erythromycin, etacillin, logical Basis of Therapeutics (9th Edition), McGraw-Hill, ethambutol, ethionamide, famcyclovir, fenbecillin, fleroxa 1995; and the Merck Index on CD-ROM, Twelfth Edition, cin, flomoxef floxacillin, flumequine, n-formamidoylthiena Version 12:1, 1996; and on STN Express, file phar and file mycin, furonazide, fortimycin, furazolium chloride, genta registry. mycin, glyconiazide, gramicidin, grepafloxacin, 0415. In some embodiments the angiotensin-converting guamecycline, halofuginone, hetacillin, homidium, enzyme inhibitors are benazepril, captopril, enalapril, fosino hydroxyl-Stilbamidine, ibostamycin, imidocarb, imipenam, pril, lisinopril, moexipril, quinapril, ramipril, trandolapril or ipronidazole, isoniazide.josamycin, inosine, kanamycin, lau trandolaprilat. In more particular embodiments the roguadine, lenampicillin, lincomycin, lomefloxacin, loracar benazepril is administered as benazepril hydrochloride in an bef, lymecyclin, mafenide, mebendazole, meclocyclin, mero amount of about 5 milligrams to about 80 milligrams as a penem, metampicillin, metacicline, methacycline, single dose or as multiple doses per day; the captopril is methicillin sodium, metronidazole, 4'-(methylsulfamoyl) administered in an amount of about 12.5 milligrams to about Sulfanilanilide, mezlocillin, meZiocillin, micronomycin, 450 milligrams as a single dose or as multiple doses per day; midecamycin A, minocycline, miocamycin, miokamycin, the enalapril is administered as enalapril maleate in an morfaZinamide, moxalactam, mupirocin, myxin, nadifloxa amount of about 2.5 milligrams to about 40 milligrams as a cin, nalidixic acid, negamycin, neomycin, netlimycin, nifur single dose or as multiple doses per day; the fosinopril is foline, nifurpirinol, nifurprazine, nimorazole, nitroxoline, administered as fosinopril sodium in an amount of about 5 norfloxacin, novobiocin, ofloxacin, oleandomycin, opiniaz milligrams to about 60 milligrams as a single dose or as ide, oxacillin, oxophenarsine, oxolinic acid, Oxytetracycline, multiple doses per day; the lisinopril is administered in an panipenam, paromycin, paZufloxacin, pefloxacin, penicillin amount of about 2.5 milligrams to about 75 milligrams as a G potassium salt, penicillin N, penicillin O, penicillin V. single dose or as multiple doses per day; the moexipril is penethamate hydroiodide, pentamidine, phenamidine, administered as moexipril hydrochloride in an amount of phenethicillin potassium salt, phenyl aminosalicyclate, pipa about 7.5 milligrams to about 45 milligrams as a single dose cycline, pipemidic acid, piperacillin, pirlimycin, piromidic or as multiple doses per day; the quinapril is administered as acid, pivampicillin, pivoefalexin, polymyxin B, profiromy quinapril hydrochloride in an amount of about 5 milligrams to cin, propamidine, propicillin, protionamide, pluraltadone, about 40 milligrams as single or multiple doses per day; the puromycin, pyrazinamide, pyrimethamine, quinacillin, ramapril hydrochloride in an amount of about 1.25 milli quinacrine, quinapyramine, quintine, ribostamycin, rifabu grams to about 40 milligrams as single or multiple doses per tine, rifamide, rifampin, rifamycin, rifanpin, rifapentine, rif day; the trandolapril is administered as in an amount of about axymine, ritipenem, rokitamycin, rollitetracycline, rosamy 0.5 milligrams to about 4 milligrams as single or multiple cin, rufloxacin, Salazosulfadimidine, Salinazid, sancycline, doses per day; the trandolaprilat is administered as in an Sarafloxacin, Sedacamycin, secnidazole, Sisomycin, spar amount of about 0.5 milligrams to about 4 milligrams as floxacin, spectinomycin, spiramycin, spiramycin I, spiramy single or multiple doses per day. cin II, spiramycin III, stilbamidine, streptomycin, streptoni US 2008/030O292 A1 Dec. 4, 2008 27 cizid, Sulbactam, Sulbenicillin, Succisulfone, Sulfanilamide, myricetin, isorhamnetin, benzophenones such as 2.2',4,4'- Sulfabenzamide, Sulfacetamide, Sulfachloropyridazine, Sul tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxyben fachrysoidine, Sulfacytine, Sulfadiazine, Sulfadicramide, Sul Zophenone and 4,4'-dihydroxybenzophenone; benzothiazi fadimethoxine, Sulfadoxine, Sulfadrazine, Sulfaetidol, Sul none analogues such as 2-amino-4H-1,3-benzothiazine-4- fafenaZol, Sulfaguanidine, Sulfaguanole, Sulfalene, one, 2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine; Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, N-hydroxyguanidine derivative such as, PR5 (1-(3,4- Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypy dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguani ridazine, sulfamethylthiazol, sulfamethylthiazole, sulfame dine); 6-formylpterin, and the like. The antioxidant enzymes trole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide, 4-sulfanilamido Salicylic acid, 4-4'-sulfanilylbenzylamine, can be delivered by gene therapy as a viral vertor and/or a p-sulfanilylbenzylamine, 2-p-sulfinylanilinoethanol, Sulfa non-viral vector. Suitable antioxidants are described more nillylurea, Sulfoniazide, Sulfaperine, Sulfaphenazole, Sul fully in the literature, such as in Goodman and Gilman, The faproxyline, Sulfapyrazine, Sulfapyridine, Sulfathiazole, Sul Pharmacological Basis of Therapeutics (9th Edition), faethidole, Sulfathiourea, Sulfisomidine, Sulfasomizole, McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir sulfasymazine, sulfisoxazole, 4,4'-sulfinyldianiline, N-sul teenth Edition; and on STN Express, file phar and file registry. fanilylsulfanilamide, N-sulfanilyl-3,4-xylamide, Sultamicil 0420. In some embodiments the antioxidants are apocy lin, talampicillin, tambutol, taurolidine, teiclplanin, temocil nin, hydralazine compounds and Superoxide dimutase lin, tetracycline, tetroXoprim, thiabendazole, thiazolsulfone, mimetics. tibeZonium iodide, ticarcillin, tigemonam, timidazole, tobra 0421 Suitable antioxidants include, but are not limited to, mycin, to Sufloxacin, trimethoprim, troleandromycin, tros Small-molecule antioxidants and antioxidant enzymes. Suit pectomycin, trovafloxacin, tubercidine, miokamycin, olean able small-molecule antioxidants include, but are not limited domycin, troleandromycin, Vancomycin, Verazide, Viomycin, to, hydralazine compounds, glutathione, Vitamin C, vitamin virginiamycin, Zalcitabine, PA-1806 and PA-2794, and the E. cysteine, N-acetyl-cysteine, B-carotene, ubiquinone, like. Suitable antimicrobial compounds are described more ubiquinol-10, tocopherols, coenzyme Q, Superoxide dismu fully in the literature, such as in Goodman and Gilman, The tase mimetics, such as, for example, 2.2.6.6-tetramethyl-1- Pharmacological Basis of Therapeutics (9th Edition), piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide McGraw-Hill, (1996); Merck Index on CD-ROM, 13" Edi compounds; 4-hydroxy-2.2.6.6-tetramethyl-1-piperidiny tion; STN Express, file phar and file registry, the disclosures loxy (Tempol), M-40401, M-40403, M-40407, M-40419, of each of which are incorporated by reference herein in their M-40484, M-40587, M-40588, and the like. Suitable antioxi entirety. dant enzymes include, but are not limited to, Superoxide 0417. In some embodiments the antimicrobial compound dismutase, catalase, glutathione peroxidase, NADPH oxidase amikacin, azithromycin, azetreonam, bacitracin, carbenicil inhibitors, such as, for example, apocynin, aminoguanidine, lin, cefazolin, cefoxitin, cephaloridine, chibrorifamycin, ONO 1714, S17834 (benzo(b)pyran-4-one derivative), and chloramphenicol, colistin, duramycin, n-formamidoylthiena the like; Xanthine oxidase inhibitors, such as, for example, mycin, gentamycin, gramicidin, kanamycin, neomycin, peni allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, cillin G, polymyxin B, Sisomicin, tetracyclines, tigecycline, 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, tobramycin, Vancomycin, PA-1806 and PA-2794. myricetin, isorhamnetin, benzophenones such as 2.2',4,4'- 0418. In other embodiments the antimicrobial compound tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxyben is an antiviral compound, including but not limited to, acy Zophenone and 4,4'-dihydroxybenzophenone; benzothiazi clovir, amatadine, cidofovir, cytarabine, didanosine, none analogues such as 2-amino-4H-1,3-benzothiazine-4- dideoxyadenosine, edoxudine, famciclovir, floXuridine, gan one, 2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine; cyclovir, idoxuridine, indanavir, kethoxal, lamivudine, N-hydroxyguanidine derivative such as, PR5 (1-(3,4- MADU, penciclovir, podophyllotoxin, ribavirine, rimanta dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguani dine, saquinavir, Sorivudine, stavudine, trifluridine, Valacy dine); 6-formylpterin, and the like. The antioxidant enzymes clovir, Vidarabine, Xenazoic acid, Zalcitabine, Zidovudine, can be delivered by gene therapy as a viral vertor and/or a and the like. non-viral vector. Suitable antioxidants are described more 0419 Suitable antioxidants include, but are not limited to, fully in the literature, such as in Goodman and Gilman, The Small-molecule antioxidants and antioxidant enzymes. Suit Pharmacological Basis of Therapeutics (9th Edition), able small-molecule antioxidants include, but are not limited McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir to, hydralazine compounds, glutathione, Vitamin C, Vitamin teenth Edition; and on STN Express, file phar and file registry. E. cysteine, N-acetyl-cysteine, B-carotene, ubiquinone, 0422. In some embodiments the antioxidants are apocy ubiquinol-10, tocopherols, coenzyme Q, Superoxide dismu nin, hydralazine compounds and Superoxide dimutase tase mimetics, such as, for example, 2.2.6.6-tetramethyl-1- mimetics. piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide 0423 Suitable carbonic anhydrase inhibitors, include, but compounds; 4-hydroxy-2.2.6,6-tetramethyl-1-piperidiny are not limited to, acetazolamide, brinzolamide, dorzolamide, loxy (Tempol), M-40401, M-40403, M-40407, M-40419, ethoXZolamide, 6-hydroxy-2-benzothiazolesulfonamide, M-40484, M-40587, M-40588, and the like. Suitable antioxi methazolamide, thiophene Sulfonamide, an aromatic Sulfona dant enzymes include, but are not limited to, Superoxide mide, an ester of 6-hydroxy-2-benzothiazolesulfonamide, an dismutase, catalase, glutathione peroxidase, NADPH oxidase ester of 5-hydroxy-2-benzothiazolesulfonamide, and the like. inhibitors, such as, for example, apocynin, aminoguanidine, Suitable carbonic anhydrase inhibitors are described more ONO 1714, S17834 (benzo(b)pyran-4-one derivative), and fully in the literature, such as in Goodman and Gilman, The the like; Xanthine oxidase inhibitors, such as, for example, Pharmacological Basis of Therapeutics (9th Edition), allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, Edition; and on STN Express, file phar and file registry. US 2008/030O292 A1 Dec. 4, 2008 28

0424. In some embodiments the carbonic anhydrase Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed. inhibitors are brinzolamide and dorzolamide. Inc., the disclosures of which are incorporated herein by 0425 Suitable hydralazine compounds include, but are reference in their entirety. not limited to, compounds having the formula: 0431. In some embodiments the NSAIDs are acetami nophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin. In more particular embodi R4 R3 ments the acetaminophen is administered in an amount of a b c about 325 milligrams to about 4 grams as a single dose or as RIN - N - R2 multiple doses per day; the diclofenac is administered in an amount of about 50 milligrams to about 250 milligrams as a single dose or as multiple doses per day; the flurbiprofen is 0426 wherein a, b and c are independently a single or administered in an amount of about 100 milligrams to about double bond; R and R are each independently a hydrogen, 300 milligrams as a single dose or as multiple doses per day; an alkyl, an ester or a heterocyclic ring, wherein alkyl, ester the ibuprofen is administered in an amount of about 400 and heterocyclic rind areas defined herein; R and Rare each milligrams to about 3.2 grams as a single dose or as multiple independently alone pair of electrons or a hydrogen, with the doses per day; the indomethacin is administered in an amount proviso that at least one of R. R. R. and R is not a hydrogen. of about 25 milligrams to about 200 milligrams as a single Exemplary hydralazine compounds include budralazine, dose or as multiple doses per day; the ketoprofen is adminis cadralazine, dihydralazine, endralazine, hydralazine, tered in an amount of about 50 milligrams to about 300 pildralazine, todralazine, and the like. Suitable hydralazine milligrams as a single dose or as multiple doses per day; the compounds are described more fully in the literature, Such as naproxen is administered in an amount of about 250 milli in Goodman and Gilman, The Pharmacological Basis of grams to about 1.5 grams as a single dose or as multiple doses Therapeutics (9th Edition), McGraw-Hill, 1995; and the per day; the aspirin is administered in an amount of about 10 Merck Index on CD-ROM, Thirteenth Edition; and on STN milligrams to about 2 grams as a single dose or as multiple Express, file phar and file registry. doses per day. 0427. In some embodiments the hydralazine compound is 0432 Suitable steroids include, but are not limited to, hydralazine or a pharmaceutically acceptable salt thereof 21-acetoxypregnenolone, alcolometaSone, algestone, amci Such as hydralazine hydrochloride. In more particular nonide, beclomethasone, betamethasone, budesonide, chlor embodiments the hydralazine is administered as hydralazine prednisone, clobetasol, clobentaSone, clocortolone, clopred nol, corticosterone, cortisine, corticaZol (cortivatol), hydrochloride in an amount of about 10 milligrams to about deflazacort, desonide, desoximetaSone, dexamethasone, 300 milligrams as a single dose or as multiple doses per day. diflorasone, diflucortolone, difluprednate, enoxolone, fluza 0428 Suitable prostaglandins, include but are not limited cort, flucloronide, flumethasone, flunisolide, flucinolone to, naturally occurring prostaglandins such as, for example, acetonide, fluocininide, fluocortin butyl, fluocortolone, fluo arbaprostil, alprostadil, beraprost, carboprost, cloprostenol, rometholone, fluperolone acetate, fluprednidene acetate, flu dimoxaprost, emprostil, enisoprost, fluprostenol, fenprostal prednisolone, flurandrenolide, fluticasone propionate, fluti ene, gemeprost, latanaprost, limaprost, meteneprost, mex casone propionate, formocortal, halcinonide, halobetasol iprostil, misoprostol, misoprost, misoprostol acid, noclo propionate, halometasone, haloprednone acetate, hydrocor prost, ornoprostil, prostalene, PGE, PGE PGF, PGF tamate, hydrocortisone and its derivatives (such as phosphate, rioprostil, rosaprostol, remiprostol, Sulprostone, trimoprostil, 21-sodium Succinate and the like), hydrocortisone terbutate, tiprostanide, travoprost, unoprostone, Viprostol, Viprostol. isoflupredone, loteprednol etabonate, maZipredone, Suitable prostaglandins are described more fully in the litera medrysone, meprednisone, methylprednisolone, mometa ture, such as in Goodman and Gilman, The Pharmacological Sone furoate, paremethasone, prednicarbate, prednisolone Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and and its derivatives (such as 21-stearoylglycolate, sodium the Merck Index on CD-ROM, 13' Edition; and on STN phosphate and the like), prednisone, prednival, prednylidene Express, file phar and file registry. and its derivatives (such as 21-diethylaminoactetate and the 0429. In some embodiments the prostaglandins are clo like), rimexolone, tiXocortol, trimcinolone and its derivatives prostenol, fluprostenol and travoprost. (such as acetonide, benetonide and the like), and the like. 0430 Suitable NSAIDs include, but are not limited to, Suitable NSAIDs are described more fully in the literature, acetaminophen, acemetacin, aceclofenac, alminoprofen, Such as in Goodman and Gilman, The Pharmacological Basis amfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 butibufen, carprofen, cinmetacin, clopirac, diclofenac, etod 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. olac, felbinac, fenclozic acid, fenbufen, fenoprofen, fen Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed. tiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, Inc., the disclosures of which are incorporated herein by indomethacin, isofeZolac, isoxepac, indoprofen, ketoprofen, reference in their entirety. lonazolac, loxoprofen, metiazinic acid, mofeZolac, miropro 0433. In some embodiments the steroids are dexametha fen, naproxen, oxaprozin, piroZolac, pirprofen, pranoprofen, Sone, fluorometholone, hydrocortisone, and prednisolone. protizinic acid, Salicylamide, Sulindac, Suprofen, SuXibuZone, 0434 Suitable COX-2 inhibitors include, but are not lim tiaprofenic acid, tolmetin, Xenbucin, Ximoprofen, Zaltopro ited to, nimeSulide, celecoxib (CELEBREXR), etoricoxib fen, Zomepirac, aspirin, acemetcin, bumadizon, carprofenac, (ARCOXIAR), flosulide, lumiracoxib (PREXIG(R), COX clidanac, diflunisal, enfenamic acid, fendosal, flufenamic 189), parecoxib (DYNSTATR), rofecoxib (VIOXX(R), tira acid, fluniXin, gentisic acid, ketorolac, meclofenamic acid, coxib (JTE-522), valdecoxib (BEXTRAR), ABT 963, BMS mefenamic acid, mesalamine, prodrugs thereof, and the like. 347070, CS502, DuP 697, GW-406381, NS-386, SC-57666, Suitable NSAIDs are described more fully in the literature, SC-58125, SC-58635, and the like, and mixtures of two or Such as in Goodman and Gilman, The Pharmacological Basis more thereof. Suitable COX-2 inhibitors are in U.S. Pat. Nos. of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 5,344.991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, US 2008/030O292 A1 Dec. 4, 2008 29

5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, be administered a therapeutically effective amount of at least 5,932,598 and 6,633,272, and in WO 94/03387, WO one nitrosated and/or nitrosylated compound of the invention. 94/15723, WO 94/20480, WO 94/26731, WO 94/27980, WO In another embodiment, the patient can be administered a 95/00501, WO95/15316, WO 96/03387, WO 96/03388, WO therapeutically effective amount of at least compound of the 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO invention, that is optionally nitrosated and/or nitrosylated, 97/14691, WO 97/16435, WO 01/45703 and WO 01/87343, and at least one nitric oxide donor compound. In yet another the disclosures of each of which are incorporated herein by embodiment, the patient can be administered a therapeuti reference in their entirety; and in the literature, such as in cally effective amount of at least one compound of the inven Goodman and Gilman, The Pharmacological Basis of Thera tion, that is optionally nitrosated and/or nitrosylated, and, at peutics (9th Edition), McGraw-Hill, 1995; and the Merck least one therapeutic agent, including but not limited to. Such Index on CD-ROM. Thirteenth Edition; and on STN Express, as, for example, C.-adrenergic receptoragonists, C.-adrenergic file phar and file registry. receptor antagonists, angiotensin-converting enzyme (ACE) 0435. In some embodiments the COX-2 inhibitors are inhibitors, antimicrobial compounds, antioxidants, B-adren celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or ergic antagonists, carbonic anhydrase inhibitors, hydralazine Valdecoxib. In more particular embodiments the celecoxib is compounds, nonsteroidal antiinflammatory compounds administered in an amount of about 100 milligrams to about (NSAIDs), prostaglandins, selective cyclooxygenase-2 800 milligrams as a single dose or as multiple doses per day; (COX-2) inhibitors, steroids, and combinations of two or the etoricoxib is administered in an amount of about 50 mil more thereof. In another embodiment, the patient can be ligrams to about 200 milligrams as a single dose or as multiple administered a therapeutically effective amount of at least doses per day; the lumiracoxib is administered in an amount one compound of the invention, that is optionally nitrosated of about 40 milligrams to about 1200 milligrams as a single and/or nitrosylated, and, at least one therapeutic agent, and, at dose or as multiple doses per day; the paracoxib is adminis least one nitric oxide donor compound. In one embodiment tered in an amount of about 20 milligrams to about 100 the opthalmic disorder is ophthalmic infection, glaucoma, milligrams as a single dose or as multiple doses per day; the elevated intraocular pressure, ocular pain following corneal rofecoxib is administered in an amount of about 12.5 milli Surgery, dry eye disorder, ocular hypertension, ocular bleed grams to about 50 milligrams as a single dose or as multiple ing, retinal diseases or disorders. The compounds that are doses per day; the Valdecoxib is administered in an amount of optionally nitrosated and/or nitrosylated, nitric oxide donors, about 10 milligrams to about 40 milligrams as a single dose or and/ortherapeutic agents can be administered separately or as as multiple doses per day. components of the same composition in one or more pharma 0436 The invention provides methods for treating oph ceutically acceptable carriers. thalmic disorders by administering to the patient in need 0438. When administered separately, the compound of the thereof a therapeutically effective amount of the compounds invention, that is optionally nitrosated and/or nitrosylated, and/or compositions described herein. For example, the nitric oxide donor and/or therapeutic agent can be adminis patient can be administered a therapeutically effective tered about the same time as part of the overall treatment amount of at least one nitrosated and/or nitrosylated com regimen, i.e., as a combination therapy. About the same pound of the invention. In another embodiment, the patient time includes administering the compound of the invention, can be administered a therapeutically effective amount of at which is optionally nitrosated and/or nitrosylated, simulta least compound of the invention, that is optionally nitrosated neously, sequentially, at the same time, at different times on and/or nitrosylated, and at least one nitric oxide donor com the same day, or on different days, as long as they are admin pound. In yet another embodiment, the patient can be admin istered as part of an overall treatment regimen, i.e., combina istered atherapeutically effective amount of at least one com tion therapy or a therapeutic cocktail. pound of the invention, that is optionally nitrosated and/or 0439 When administered in vivo, the compounds and nitrosylated, and, at least one therapeutic agent, including but compositions of the invention can be administered in combi not limited to. Such as, for example, C.-adrenergic receptor nation with pharmaceutically acceptable carriers and in dos agonists, C.-adrenergic receptor antagonists, angiotensin ages described herein. When the compounds and composi converting enzyme (ACE) inhibitors, antimicrobial com tions of the invention are administered as a combination of at pounds, antioxidants, B-adrenergic antagonists, carbonic least one compound of the invention and/or at least one nit anhydrase inhibitors, hydralazine compounds, nonsteroidal rosated and/or nitrosylated compound of the invention and/or antiinflammatory compounds (NSAIDs), prostaglandins, at least one nitric oxide donor and/or therapeutic agent, they selective cyclooxygenase-2 (COX-2) inhibitors, steroids, and can also be used in combination with one or more additional combinations of two or more thereof. In another embodiment, compounds which are known to be effective against the spe the patient can be administered a therapeutically effective cific disease state targeted for treatment. The nitric oxide amount of at least one compound of the invention, that is donors, therapeutic agents and/or other additional com optionally nitrosated and/or nitrosylated, and, at least one pounds can be administered simultaneously with, Subse therapeutic agent, and, at least one nitric oxide donor com quently to, or prior to administration of the nitrosated and/or pound. The compounds, which are optionally nitrosated and/ nitrosylated compound of the invention. or nitrosylated, nitric oxide donors, and/or therapeutic agents 0440 The compounds of the invention, can be incorpo can be administered separately or as components of the same rated into various types of pharmaceutical compositions, such composition in one or more pharmaceutically acceptable car as, for example, ophthalmic formulations for delivery to the 1S. eye (e.g., topically, intracamerally, or via an implant). The 0437. The invention provides methods for treating oph compounds are preferably incorporated into topical oph thalmic infection, glaucoma, ocular pain following corneal thalmic formulations, such as for example, Solutions, Suspen Surgery, dry eye disorder, ocular hypertension, ocular bleed sions, gels, ointments, implants, and the like. The compounds ing, retinal diseases or disorders and lowering of intraocular of the invention may be combined with opthalmologically pressure by administering to the patient in need thereof a acceptable preservatives, viscosity enhancers, penetration therapeutically effective amount of the compounds and/or enhancers, buffers, Sodium chloride, water to form an aque compositions described herein. For example, the patient can ous, sterile ophthalmic Suspensions or solutions, and the like. US 2008/030O292 A1 Dec. 4, 2008 30

0441 Suitable preservatives include, but are not limited the cell by phagocytosis. A practitioner in the art will appre to, benzalkonium chloride, thimerosal, chlorobutanol, methyl ciate that the precise mechanism by which a target cell assimi paraben, propyl paraben, phenylethyl alcohol, edetate diso lates and metabolizes a dosage form of the invention depends dium, sorbic acid, ONAMER(R), and the like. The preserva on the morphology, physiology and metabolic processes of tives are typically employed at a concentration between about those cells. The size of the particle sustained release thera 0.001% and about 1.0% by weight. Appropriate co-solvents peutic dosage forms is also important with respect to the include, but are not limited to, Polysorbate 20, 60 and 80; mode of cellular assimilation. For example, the Smaller nano Pluronic F-68, F-84 and P-103; TyloxapolR); Cremophor(R) particles can flow with the interstitial fluid between cells and EL: sodium dodecyl sulfate; glycerol; PEG 400; propylene penetrate the infused tissue. The larger microparticles tend to glycol, cyclodextrins, and the like. The co-solvents are typi be more easily trapped interstitially in the infused primary cally employed at a concentration between about 0.01% and tissue, and thus are useful to deliver anti-proliferative thera about 2% by weight. Viscosity enhancers are required as a peutic agents. Viscosity greater than that of simple aqueous Solutions may be desirable to increase ocular absorption of the active com 0447 Particular sustained release dosage forms of the pound, to decrease variability in dispensing the formulations, invention comprise biodegradable microparticles or nanopar to decrease physical separation of components of a suspen ticles. More particularly, biodegradable microparticles or sion or emulsion of formulation and/or otherwise to improve nanoparticles are formed of a polymer containing matrix that the ophthalmic formulation. Suitable viscosity enhancers, biodegrades by random, nonenzymatic, hydrolytic Scission include, but are not limited to, polyvinyl alcohol, methyl ing to release therapeutic agent, thereby forming pores within cellulose, hydroxy propyl carboxymethyl cellulose, the particulate structure. hydroxymethylcellulose, hydroxyethylcellulose, hydrox 0448. The compounds and compositions of the invention ypropylmethylcellulose, methylcellulose, polyvinylpyrroli can be formulated as pharmaceutically acceptable salt forms. done, and the like. Gelling agents can also be used, including, Pharmaceutically acceptable salts include, for example, but not limited to, gellan and Xanthan gum, and the like. alkali metal salts and addition salts of free acids or free bases. Viscosity enhancers are typically employed at a concentra The nature of the salt is not critical, provided that it is phar tion between about 0.01% and about 2% by weight. maceutically-acceptable. Suitable pharmaceutically-accept 0442 Ophthalmic solution formulations may be prepared able acid addition salts may be prepared from an inorganic by dissolving a compound in a physiologically acceptable acid or from an organic acid. Examples of Such inorganic acids include, but are not limited to, hydrochloric, hydrobro isotonic aqueous buffer. Alternatively, the ophthalmic solu mic, hydroiodic, nitric, carbonic, Sulfuric and phosphoric tion may include an opthalmologically acceptable surfactant acid and the like. Appropriate organic acids include, but are to assist in dissolving the compound. Additionally for sterile not limited to, aliphatic, cycloaliphatic, aromatic, heterocy ophthalmic ointment formulations, the compounds of the clic, carboxylic and Sulfonic classes of organic acids, such as, invention may be combined with a preservative in an appro for example, formic, acetic, propionic, Succinic, glycolic, priate vehicle, such as, mineral oil, liquid lanolin, or white gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, petrolatum. Sterile ophthalmic gel formulations may be pre maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthra pared by Suspending the active ingredient in a hydrophilic nilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, base prepared from the combination of for example, car mandelic, embonic (pamoic), methanesulfonic, ethane bopol-974, and the like. Sulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 0443) Various delivery systems are known and can be used 2-hydroxyethanesulfonic, Sulfanilic, Stearic, algenic, B-hy to administer the compounds or compositions of the inven droxybutyric, cyclohexylaminosulfonic, galactaric and tion, including, for example, encapsulation in liposomes, galacturonic acid and the like. Suitable pharmaceutically microbubbles, emulsions, microparticles, microcapsules and acceptable base addition salts include, but are not limited to, the like. The required dosage can be administered as a single metallic salts made from aluminum, calcium, lithium, mag unit or in a Sustained release form. nesium, potassium, Sodium and Zinc or organic salts made 0444 The bioavailability of the compositions can be from primary, secondary and tertiary amines, cyclic amines, enhanced by micronization of the formulations using conven N,N'-dibenzylethylenediamine, chloroprocaine, choline, tional techniques such as grinding, milling, spray drying and diethanolamine, ethylenediamine, meglumine (N-methylglu the like in the presence of suitable excipients or agents such as camine) and procaine and the like. All of these salts may be phospholipids or Surfactants. prepared by conventional means from the corresponding 0445 Sustained release dosage forms of the invention may compound by reacting, for example, the appropriate acid or comprise microparticles and/or nanoparticles having a thera base with the compound. In one embodiment, the pharma peutic agent dispersed therein or may comprise the therapeu ceutically acceptable salts of the compounds of the invention tic agent in pure, preferably crystalline, Solid form. For Sus do not include the nitrate salt. tained release administration, microparticle dosage forms 0449 While individual needs may vary, determination of comprising pure, preferably crystalline, therapeutic agents optimal ranges for effective amounts of the compounds and/ are preferred. The therapeutic dosage forms of this aspect of or compositions is within the skill of the art. Generally, the the invention may be of any configuration Suitable for Sus dosage required to provide an effective amount of the com tained release. pounds and compositions, which can be adjusted by one of 0446 Nanoparticle sustained release therapeutic dosage ordinary skill in the art, will vary depending on the age, forms are preferably biodegradable and, optionally, bind to health, physical condition, sex, diet, weight, extent of the the vascular Smooth muscle cells and enter those cells, pri dysfunction of the recipient, frequency of treatment and the marily by endocytosis. The biodegradation of the nanopar nature and scope of the dysfunction or disease, medical con ticles occurs over time (e.g., 30 to 120 days; or 10 to 21 days) dition of the patient, the route of administration, pharmaco in prelysosomic vesicles and lysosomes. Preferred larger logical considerations such as the activity, efficacy, pharma microparticle therapeutic dosage forms of the invention cokinetic and toxicology profiles of the particular compound release the therapeutic agents for Subsequent target cell used, whether a drug delivery system is used, and whether the uptake with only a few of the Smaller microparticles entering compound is administered as part of a drug combination. US 2008/030O292 A1 Dec. 4, 2008

0450. The amount of a given nitrosated and/or nitrosylated 5-mononitrate (prepared as described in U.S. Pat. No. 4,431, compound of the invention of the invention that will be effec 830, 2.10 g, 10.99 mmole) and a catalytic amount of DMAP tive in the treatment of a particular disorder or condition will were added. After 2 hours, TLC (1:1 ethyl acetate/hexanes) depend on the nature of the disorder or condition, and can be indicated that the reaction was complete. The reaction mix determined by standard clinical techniques, including refer ture was filtered through a short pad of Celite and the clear ence to Goodman and Gilman, supra: The Physician's Desk filtrate was concentrated in vacuo to give a solid residue. The Reference, Medical Economics Company, Inc., Oradell, N.J., residue was triturated with a minimal amount of diethyl ether 1995; and Drug Facts and Comparisons, Inc., St. Louis, Mo., and then filtered. The crystals were washed with a minimal 1993. The precise dose to be used in the formulation will also amount of cold diethyl ether to give the title compound (1.45 depend on the route of administration, and the seriousness of g, 37.4% yield) as a white solid. The filtrate was concentrated the disease or disorder, and should be decided by the physi and triturated as described above, to give an additional 1.05g cian and the patient's circumstances. (27.1%) of the title compound. Mp 109-111° C. "H NMR 0451. The invention also provides pharmaceutical kits (300 MHz, CDC1) & 5.33 (m, 1H), 5.26 (dd, J=14.5, 2.3 Hz, comprising one or more containers filled with one or more of 1H), 4.96 (dt, J–12.9, 5.3 Hz, 1H), 4.47 (d. J=4.9 HZ, 1H), the ingredients of the pharmaceutical compounds and/or 4.26 (m. 1H), 4.04 (m, 3H), 3.90 (m, 2H), 2.24 (m. 1H), 1.91 compositions of the invention, including, at least, one or more (m, 3H), 1.46 (s, 4.5H), 1.42 (s, 4.5H). Mass spectrum (API of the novel compound of the invention, that is optionally TIS) m/z 406 (MNH), 389 (MH"). nitrosated and/or nitrosylated, and one or more of the NO donors described herein. Associated with such kits can be 1b. (1S,2S,5S,6R)-6-(Nitrooxy)-4,8-dioxabicyclo(3. additional therapeutic agents or compositions (e.g., C.-adren 3.0)oct-2-yl (2S)pyrrolidine-2-carboxylate ergic receptor agonists, C.-adrenergic receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, antimicro 0455 bial compounds, antioxidants, B-adrenergic antagonists, car bonic anhydrase inhibitors, hydralazine compounds, nonste roidal antiinflammatory compounds (NSAIDs), prostaglandins, selective cyclooxygenase-2 (COX-2) inhibi tors, Steroids, and the like, and combinations of two or more N thereof), devices for administering the compositions, and H notices in the form prescribed by a governmental agency O regulating the manufacture, use or sale of pharmaceuticals or biological products which reflects approval by the agency of manufacture, use or sale for humans. H-Cl EXAMPLES 0456. The product of Example la (1.00 g, 2.96 mmole) 0452. The following non-limiting examples further was added in one portion to hydrochloric acid in ethyl acetate (30 mL of a 14% w/w solution) cooled to 0° C. All of the describe and enable one of ordinary skill in the art to make and solids went into solution after ca. 5 minutes. The reaction use the present invention. In each of the examples, flash mixture was stirred at 0°C. for 30 minutes at which time TLC chromatography was performed on 40 micron silica gel (1:1 ethyl acetate/hexanes) indicated that the reaction was (Baker). complete. The solvent was removed in vacuo to give a clear Example 1 oil. Trituration with methylene chloride and filtration of the solids gave the title compound (808 mg, 96.7% yield) as a Ethyl (2S)-2-(((1S)-2-((2S)-2-(((1S,2S,5S,6R)-6- white powdery solid. Mp 160° C. (dec). H NMR (300 MHz, (nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycar CDC1) & 10.09 (bs, 1H), 9.07 (bs, 1H), 5.54 (td, J=5.4, 2.3 bonyl)pyrrolidinyl)-1-methyl-2-oxoethyl)amino)-4- HZ, 1H), 5.23 (d. J=3.1 Hz, 1H), 5.01 (t, J=5.3 Hz, 1H), 4.51 phenylbutanoate (d. J=5.0 Hz, 1H), 4.39 (bt, J–7.7 Hz, 1H), 4.03 (m, 2H), 3.87 (m. 2H), 3.21 (m. 2H), 2.24 (m. 1H), 2.04 (m. 1H), 1.91 (m, 0453 2H). Mass spectrum (API-TIS) m/z 289 (MH"). 1c. Ethyl (2S)-2-(((1S)-2-((2S)-2-(((1S,2S,5S,6R)-6- (nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycar bonyl)pyrrolidinyl)-1-methyl-2-oxoethyl)amino)-4- phenylbutanoate 0457

n1 CH3 N % - O 1a. (1S,2S,5S,6R)-6-(Nitrooxy)-4,8-dioxabicyclo(3. N 3.0)oct-2-yl (2S)-1-((tert-butyl)oxycarbonyl)pyrroli O O e dine-2-carboxylate O 1 0454 N BOC-L-Proline (Aldrich, 2.15g, 9.99 mmole) NO was dissolved in dry methylene chloride (20 mL). Dicyclo hexylcarbodiimide (DCC, 10.99 mmole, 1.1 eq) in methylene 0458. To the product of Example 1b (448 mg, 1.47 mmole) chloride was added at ambient temperature. Isosorbide were added water (6 mL) and acetone (6 mL) were added and US 2008/030O292 A1 Dec. 4, 2008 32 the solution was cooled to 0°C. under Argon. Solid sodium carbonate (233 mg, 2.20 mmole) was added followed by the -continued addition of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-ala (4) nine-N-carboxyanhydride (Lancaster Synthesis, 500 mg. D 1.54 mmole) dissolved in 6mL of acetone at 0°C. The reac N tion mixture was stirred at 0°C. for 1 hour at which point TLC (1:1 ethyl acetate/hexanes) showed that the reaction was com CH3 plete. The pH was adjusted to pH 5 using 5M HCl and the Solvent was removed in vacuo to give a solid residue. The residue was dissolved in ethyl acetate and dried over sodium sulfate. The product was filtered, 1 g silica gel added and the SC solvent removed in vacuo. The product was subjected to flash Y is —C(O)—CHs or D; chromatography eluting with 200 mL 1:1 ethyl acetate/hex Zs is: anes and then 250 mL ethyl acetate. Concentration of the desired fractions gave the title compound (490 mg, 61.0% yield) as a colorless oil. "H NMR (300 MHz, CDC1) & 7.27 (1) (m. 2H), 7.18 (m, 3H), 5.33 (td, J=5.5, 2.7 Hz, 1H), 5.24 (d. H R13 J=2.7 Hz, 1H), 4.92 (t, J=5.3 Hz, 1H), 4.47 (m, 2H), 4.17 (qd, J=7.1.1.2 Hz, 2H), 4.00 (m,3H), 3.87(m, 1H), 3.57 (bt, J=6.3 Hz, 2H), 3.52 (q, J=6.8 Hz, 1H), 3.22 (t, J=6.6 Hz, 1H), 2.67 (m. 2H), 2.21 (m, 2H), 1.98 (m, 5H), 1.28 (t, J=7.1 Hz, 3H), 1.26 (d. J=6.8 Hz, 3H). Mass spectrum (API-TIS) m/z 550 ---.R10 R11 (MH). (2) 0459. The disclosure of each patent, patent application and publication cited or described in the present specification is hereby incorporated by reference herein in its entirety. 0460 Although the invention has been set forth in detail, N one skilled in the art will appreciate that numerous changes N and modifications can be made to the invention, and that Such YCH, O changes and modifications can be made without departing O from the spirit and scope of the invention. (3) / SS What is claimed is: \ f 1. A method for treating an ophthalmic disorder in a patient in need thereof comprising administering to the patient a composition comprising a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, Ro is: wherein the compound of Formula (I) is: (1) —C(O)—(CH) CH: (2) - O CH-CH=CH: (3) a hydrogen; (I) (4) methyl: (5) methoxy: (6) cyclopentyl: (7) halo: (8) - O CH C(O) ND-CH: (9) cyano; wherein: (10) - CH-CH=CH; or X is: (1) —CH(CH): (11) (2) —C(CH), o-cit ()O (3) R is a hydrogen, methyl or a halo; or Ro and R taken together are W. U V. wherein W. U V is R15 (1) —CH=C(R) ND-; (2)-CH=CH-CH : US 2008/030O292 A1 Dec. 4, 2008 33

(3) - CH-CH=CH-; E at each occurrence is independently -T-, an alkyl group, (4) -CH=CH-CH=CH-; an aryl group, —(C(R)(R)), , a heterocyclic ring, an (5) - O CH-CH(ONO-)-CH ; arylheterocyclic ring, or -(CH2CH2O)—; (6) - O C(O)-CH=CH-; Ts at each occurrence is independently a covalent bond, a (7) —(CH), C(O)—ND-: carbonyl, an oxygen, —S(O) - or —N(R)R, (8) —(CH) C(O)—: (9) - CH-CH(ODI)-CH(ODI)-CH ; his an integer form 1 to 10; (10) —S-(CH2) ; q is an integer from 1 to 5: R, and Rare each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an (11) alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalky lalkyl, a cycloalkylthio, an arylalklythio, an arylalk CH3; or lythioalkyl, an alkylthioalkyl a cycloalkenyl, an hetero >, 2 cyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diary lamino, an alkylarylamino, an alkoxyhaloalkyl, a Sul (12) 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, c. 1 an arylalkyl, an alkylaryl, a carboxamido, a alkylcar boxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a car R2 is: boxylic ester, an alkylcarboxylic ester, an arylcarboxylic (1) —ND-C(O) (CH), CH: ester, a Sulfonamido, an alkylsulfonamido, an arylsul (2) —(CH), C(O)—OD; fonamido, an alkylsulfonyl, an alkylsulfonyloxy, an (3) —C(O)—(CH), CH: arylsulfonyl, arylsulphonyloxy, a Sulfonic ester, an alkyl (4) halo; ester, an aryl ester, aurea, a phosphoryl, a nitro, Kor R. (5) - ND-C(O) N(CH3); and R, taken together with the carbons to which they are (6) - CH C(O) N(H)D; attached form a carbonyl, a methanthial, a heterocyclic (7) - O C(O) CH: ring, a cycloalkyl group, an aryl group, an oxime, a hydrazone or a bridged cycloalkyl group; (8) Us at each occurrence is independently an oxygen, —S(O) - or —N(R)R,; co-o-c-A o is an integer from 0 to 2: R is alone pair of electrons, a hydrogen oran alkyl group; (9) R, is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an aryl carboxylic ester, an alkylcarboxamido, an arylcarboxa mido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, aryl Sulphonyloxy, a Sulfonamido, a carboxamido, a car (10) —CH2—O (CH), O CH(CH), boxylic ester, an aminoalkyl, an aminoaryl, —CH2—C (11) methyl; or (Us Vs)(R)(R), a bond to an adjacent atom creating a (12) —(CH), O—CH: double bond to that atom, —(N.O. ).M.", wherein R is a hydrogen, methyl or halo: M" is an organic or inorganic cation; and Ra is a hydrogen or a lower alkyl: with the proviso that the compounds of Formula (I) must Rs at each occurrence is independently selected from contain at least one NO group, and/or at least one NO —OCH, —OD, NO, methyl or ND-S(O). CH: group; wherein the at least one NO group and/or the at k is an integer from 0 to 4: least one NO. group is linked to the compound through D is a hydrogen, V or K, an oxygen atom, a nitrogen atom or a Sulfur atom; and Kis —(W)-E,-(C(R)(R)).-E.-(C(R)(R)-(Ws), the compound of Formula (II) is: (C(W)(R)) (W), E-(W). (C(R)(R)). U, Vs: V is - NO or - NO; a, b, c, d, g, i and are each independently an integer from (II) O to 3: OD1 D1 p. x, y and Z are each independently an integer from 0 to 10: --- N X4 W at each occurrence is independently —C(O)—, Y. Sk Z4' —C(S)-, -T-, -(C(R)(R)), , an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, or -(CH2CH2O) —; US 2008/030O292 A1 Dec. 4, 2008 34

wherein: -continued (3)

CH-O ; or (1)

(4) O CH-ND-C-N O; (2)

Z and Z are independently selected from a methyl or a hydrogen; R is: (3) (1) hydrogen; (2) - C(O) N(D)H: (3) —S(O)—CH; or (4) —S(O), N(D)H; R, is a hydrogen, —OCH or —NO; ND; o is an integer from 0 to 2; Rs and D are as defined herein; and with the proviso that the compounds of Formula (II) must contain at least one NO group, and/or at least one NO group; wherein the at least one NO group and/or the at (4) least one NO. group is linked to the compound through an oxygen atom, a nitrogen atom or a Sulfur atom; and the compound of Formula (III) is:

(5) (III)

(6)

wherein: X is: (1) —UD; (2) —O—CH2—CH; or (7)

trC)O UD X is: (1) methyl: Y is: (1) —CH2—S—R;

(2) --in-( )– R17: --- (2) US 2008/030O292 A1 Dec. 4, 2008 35

Ro and We taken together are: -continued (3) O | (1) P ODI (4) ; or

NH ; or (2)

O R22 s (5) -- CH: R2 is: (1) —C(O)—CH, CH: O R22 (2) hydrogen; (3) K; or W is:

O (4) Xin (1) R is —UD or —OCH CH: (2) D. U and Kareas defined herein; and with the proviso that the compounds of Formula (III) must contain at least one NO group, and/or at least one NO. group; N-CH wherein the at least one NO group and/or the at least one NO. group is linked to the compound through an oxygen atom, a nitrogen atom or a Sulfur atom; and (3) the compound of Formula (IV) is:

S ) ; or (IV) S O O U3D O

UD N 31 NH (4) B6 Q6 Go-D

wherein: 4. B is:

V is a hydrogen; (1) Zo (1)is: hydrogen; X (2) methyl; or CH (3) —(CH), N(H)D; Ro and Rao are a hydrogen; or Ro and Ro taken together are an oxo; or US 2008/030O292 A1 Dec. 4, 2008 36

O wherein: (2) a nitrogen; X, is a hydrogen; G is: Y, is

(1)

or X, and Y, taken together are: y (2) u% S

D is:

(1) R is a hydrogen or —OCH: R U and D are as defined herein; and with the proviso that the compounds of Formula (V) must contain at least one NO group, and/or at least one NO (2) group; wherein the at least one NO group and/or the at least one NO. group is linked to the compound through y -(y. an oxygen atom, a nitrogen atom or a Sulfur atom. S 2. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier. 3. The method of claim 1, wherein the compound of For mula (I) is a nitrosated acebutolol, a nitrosylated acebutolol. a nitrosated and nitrosylated acebutolol, a nitrosated alpre or B and De taken together form a phenyl ring; nolol, a nitrosylated alprenolol, a nitrosated and nitrosylated Q is a hydrogen; or alprenolol, a nitrosated atenolol, a nitrosylated atenolol, a nitrosated and nitrosylated atenolol, a nitrosated befunolol, a B is a nitrogen and Q is CH and taken together form the nitrosylated befunolol, a nitrosated and nitrosylated ring: befunolol, a nitrosated betaxolol, a nitrosylated betaxolol, a nitrosated and nitrosylated betaxolol, a nitrosated bevantolol, a nitrosylated bevantolol, a nitrosated and nitrosylated bevan N tolol, a nitrosated bisoprolol, a nitrosylated bisoprolol, a nit rosated and nitrosylated bisoprolol, a nitrosated bopindolol, a N nitrosylated bopindolol, a nitrosated and nitrosylated bopin dolol, a nitrosated bucindolol, a nitrosylated bucindolol, a nitrosated and nitrosylated bucindolol, a nitrosated bucu U and D are as defined herein; and molol, a nitrosylated bucumolol, a nitrosated and nitrosylated with the proviso that the compounds of Formula (IV) must bucumolol, a nitrosated bufetolol, a nitrosylated bufetolol, a nitrosated and nitrosylated bufetolol, a nitrosated bunitrolol, contain at least one NO group, and/or at least one NO a nitrosylated bunitrolol, a nitrosated and nitrosylated buni group; wherein the at least one NO group and/or the at trolol, a nitrosated bupranolol, a nitrosylated bupranolol, a least one NO. group is linked to the compound through nitrosated and nitrosylated bupranolol, a nitrosated buto an oxygen atom, a nitrogen atom or a Sulfur atom; and filolol, a nitrosylated butofilolol, a nitrosated and nitrosylated the compound of Formula (V) is: butofilolol, a nitrosated carazolol, a nitrosylated carazolol, a nitrosated and nitrosylated carazolol, a nitrosated carteolol, a nitrosylated carteolol, a nitrosated and nitrosylated carteolol. (V) a nitrosated celiprolol, a nitrosylated celiprolol, a nitrosated and nitrosylated celiprolol, a nitrosated cetamolol, a nitrosy lated cetamolol, a nitrosated and nitrosylated cetamolol, a R22 nitrosated cloranolol, a nitrosylated cloranolol, a nitrosated and nitrosylated cloranolol, a nitrosated esmolol, a nitrosy lated esmolol, a nitrosated and nitrosylated esmolol, a nitro sated indenolol, a nitrosylated indenolol, a nitrosated and nitrosylated indenolol, a nitrosated levobunolol, a nitrosy lated levobunolol, a nitrosated and nitrosylated levobunolol, a nitrosated mepindolol, a nitrosylated mepindolol, a nitro sated and nitrosylated mepindolol, a nitrosated metipranolol. a nitrosylated metipranolol, a nitrosated and nitrosylated US 2008/030O292 A1 Dec. 4, 2008 37 metipranolol, a nitrosated metoprolol, a nitrosylated meto temocapril; the compound of Formula (V) is a nitrosated prolol, a nitrosated and nitrosylated metoprolol, a nitrosated delapril, a nitrosylated delapril, a nitrosated and nitrosylated moprolol, a nitrosylated moprolol, a nitrosated and nitrosy delapril, a nitrosated moexipril, a nitrosylated moexipril, a lated moprolol, a nitrosated nadolol, a nitrosylated nadolol, a nitrosated and nitrosylated moexipril, a nitrosated quinapril, a nitrosated and nitrosylated nadolol, a nitrosated nipradillol, a nitrosylated quinapril, a nitrosated and nitrosylated quinapril, nitrosylated nipradillol, a nitrosated and nitrosylated or a pharmaceutically acceptable salt thereof. nipradillol, a nitrosated oXprenolol, a nitrosylated oXprenolol. 4. The method of claim 1, wherein K is: a nitrosated and nitrosylated oXprenolol, a nitrosated penb (1) - Y (CR.R.')-T-(CRR). ONO; utolol, a nitrosylated penbutolol, a nitrosated and nitrosylated penbutolol, a nitrosated pindolol, a nitrosylated pindolol, a nitrosated and nitrosylated pindolol, a nitrosated practolol, a y-T-(CR,R)-ONO. (2) nitrosylated practolol, a nitrosated and nitrosylated practolol. a nitrosated propranolol, a nitrosylated propranolol, a nitro -Y-(CRR), -( ) sated and nitrosylated propranolol, a nitrosated talinolol, a nitrosylated talinolol, a nitrosated and nitrosylated talinolol, a nitrosated tertatolol, a nitrosylated tertatolol, a nitrosated and wherein T is ortho, meta or para; nitrosylated tertatolol, a nitrosated tilisolol, a nitrosylated tilisolol, a nitrosated and nitrosylated tilisolol, a nitrosated timolol, a nitrosylated timolol, a nitrosated and nitrosylated (3) timolol, a nitrosated toliprolol, a nitrosylated toliprolol, a nitrosated and nitrosylated toliprolol, a nitrosated Xibenolol, a -Y-B-N N-W-(CRR)-ONO, nitrosylated Xibenolol, a nitrosated and nitrosylated xibenolol; the compound of Formula (II) is a nitrosated amo Sulalol, a nitrosylated amoSulalol, a nitrosated and nitrosy (4) - Y (CR.R.), V B-T-(CRR"). ONO; lated amoSulalol, a nitrosated arotinolol, a nitrosylated aroti (5) - Y (CRR)-T-C(O) (CRR), (CH,)— nolol, a nitrosated and nitrosylated arotinolol, a nitrosated ONO; bufuralol, a nitrosylated bufuralol, a nitrosated and nitrosy (6) - Y—(CR.R.'), C(Z)-(CH2)-T-(CRR") - lated bufuralol, a nitrosated carvedilol, a nitrosylated (CH)–ONO; carvedilol, a nitrosated and nitrosylated carvedilol, a nitro (7) —Y—(CRR")-T-(CH2). V-(CRR)- sated dilevalol, a nitrosylated dilevalol, a nitrosated and (CH)–ONO; nitrosylated dilevalol, a nitrosated labetalol, a nitrosylated (8) —Y—(CRR"). V-(CH2). V-(CRR") - labetalol, a nitrosated and nitrosylated labetalol, a nitrosated (CH)–ONO; landiolol, a nitrosylated landiolol, a nitrosated and nitrosy (9) —Y—(CRR), (W), (CRR) -(CH2)— lated landiolol, a nitrosated nifenalol, a nitrosylated nifenalol, ONO; a nitrosated and nitrosylated nifenalol, a nitrosated proneth (10) —NR, O-(CH2). V-(CR.R.')-(CH2)— alol, a nitrosylated pronethalol, a nitrosated and nitrosylated ONO; pronethalol, a nitrosated Sotalol, a nitrosylated Sotalol, a nit rosated and nitrosylated Sotalol, a nitrosated Sulfinalol, a (11) - NR-O-(CH2), (W), (CRR)-(CH2)— nitrosylated Sulfinalol, a nitrosated and nitrosylated Sulfi ONO; malol; the compound of Formula (III) is a nitrosated alacepril, (12) —O NR-(CH2), (W), (CRR)-(CH2)— a nitrosylated alacepril, a nitrosated and nitrosylated alace ONO; pril, a nitrosated captopril, a nitrosylated captopril, a nitro (13) - Y -(CH2) (W), (CH), sated and nitrosylated captopril, a nitrosated ceronapril, a (CRR), (CH)—ONO; nitrosylated ceronapril, a nitrosated and nitrosylated cero (14) - Y -(CRR). V-(CH2), (W), (CR.R.') napril, a nitrosated enalapril, a nitrosylated enalapril, a nitro (CH2). ONO; sated and nitrosylated enalapril, a nitrosated enalaprilat, a (15) —O NR-(CH2). V-(CRR") -(CH2)— nitrosylated enalaprilat, a nitrosated and nitrosylated enalap ONO; rilat, a nitrosated fosinopril, a nitrosylated fosinopril, a nitro (16) —Y—(CRR)-Q'-(CR') V—(CRR) - sated and nitrosylated fosinopril, a nitrosated imidapril, a (CH)–ONO; nitrosylated imidapril, a nitrosated and nitrosylated imi (17) - Y (CRR)-Q'-(CRR), (W), (CR.R.') dapril, a nitrosated lisinopril, a nitrosylated lisinopril, a nit —(CH)—ONO; rosated and nitrosylatedlisinopril, a nitrosated moveltipril, a nitrosylated moveltipril, a nitrosated and nitrosylated movel tipril, a nitrosated perindopril, a nitrosylated perindopril, a (19) - Y—(CRR), C(Z)-(CRR)-(CH2)— nitrosated and nitrosylated perindopril, a nitrosated ramipril, ONO; a nitrosylated ramipril, a nitrosated and nitrosylated ramipril, (20) - Y -(CRR)-Q'-(CRR), (CH2). ONO; a nitrosated spirapril, a nitrosylated spirapril, a nitrosated and (21) - Y -(CRR) P(O)MM'; nitrosylated spirapril, a nitrosated trandolapril, a nitrosylated trandolapril, a nitrosated and nitrosylated trandolapril; the compound of Formula (IV) is a nitrosated benazepril, a nitrosylated benazepril, a nitrosated and nitrosylated (24) - Y -(CRR), (W), (CRR)-Q'-(CR.R.') benazepril, a nitrosated cilaZapril, a nitrosylated cilaZapril, a —(CH)—ONO; nitrosated and nitrosylated cilaZapril, a nitrosated temocapril, (25) - Y -(CRR). V-(CRR)-Q'-(CR.R.'). - a nitrosylated temocapril, a nitrosated and nitrosylated (CH)–ONO;

US 2008/030O292 A1 Dec. 4, 2008 39

-continued -continued (8) (18) >, YN-1\x1-1'No, O O O v-O- 61.1oo, x ----'s (19) x --~'sO O (10) ck R6--- (11) XS-r 1N-"No, NullsO R7 (12) (21) ONO )n N1,N-6 O SNO,

". YN-1\x. N YO (22) O (13) O – Yi \ / - >, YN-1\x1y Nr - m YNO, (14) O

wherein T maybe oitho meta or para

(15) Y --- >, r N so XY N-1\x.--O m 1Y NO, O (16) (25) Y NO

* r N N1,NoNo. ( Omc/ (17) O x --~ X-rY N O US 2008/030O292 A1 Dec. 4, 2008 40

-continued -continued (26) O (37) Y X T O Y NO X N1 N1, NNo. >s-s-s- O O (38) (27) O Y S O ck N-Ns 1. YNo, n Y. O (28) Xs- H R6 O ONO, Yir n' YNO, (39) O R6 (29)

Y N O ck No 1 YNo, (40) O (30) >, YSr- O YNO, R6 (41) (31) R6 O Yi n' No SNO, O O (42) (32) O X, T Ya, Xs anO O x, n Y NO, O (43) O R6 Rs (33) T O O N >, no1 1 YNo. O Y O 2 n (44)

O O (34) Y T 1No n 11-NO2

Y O n >, n m NO2 (45) (35) ONO

Y O n X n m NO2 (46) (36) (Rs)2 US 2008/030O292 A1 Dec. 4, 2008 41

R is a hydrogen, a lower alkyl group, an aryl group; -continued R, is a lower alkyl group or an aryl group; (47) Rs at each occurrence is independently is a hydrogen, a hydroxyl group, a lower alkyl group, an aryl group, NO, CH, ONO or -CH-OH: y 1N-N NO n' and m' are each independently an integer from 0 to 10; Yi and 1st o is an integer from 0 to 2. (48) 6. The method of claim 1, wherein the compound of For mula (I) is a compound of Formula (VI), (VI), (VIII), (IX), (X) or (XI); the compound of Formula (II) is a compound of Formula (XII); the compound of Formula (III) is a compound of Formula (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (49) (XIX) or (XX); the compound of Formula (IV) is a compound of Formula (XXI) or (XXI); and the compound of Formula (V) is a compound of Formula (XXIII), (XXIV), (XXV) or (XXVI); or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (VI) is: (50) (VI) NH-Rm-Rn

(51)

Rim-Rn O-Rin

and the compound of Formula (VII) is:

(52) (VII) HC 1N1O N CH 3 § -s, 21 -NO2 -N HC HC rtr^. O-Rin (53) NO and the compound of Formula (VIII) is:

(54) (VIII) o1 Rin r Rn (55) N---

and the compound of Formula (IX) is: (56) (IX) CH3

O O Rm s wherein: Y RNR Y'a covalent bond, a carbonyl, an oxygen, —S(O) - or T is oxygen, sulfur or NR; Xs is oxygen, (S(O)), or NR; US 2008/030O292 A1 Dec. 4, 2008 42

and the compound of Formula (X) is: and the compound of Formula (XV) is:

S (X) (XV) /n N) {N CH3k" r irr CH3 su O NRNRRm HC and the compound of Formula (XI) is: CH

(XI) and the compound of Formula (XVI) is: H3C Or ou-4 (XVI) NH-Rim-Rn --~~Rim-Rn O-Rin O T-Rin

and the compound of Formula (XII) is: c N

Rm O (XII) YRn i 1" r^^- O O and the compound of Formula (XVII) is: N YRn HC-O Rm

(XVII) T-Rn and the compound of Formula (XIII) is: O T O R1 HC H (XIII) N O T-Rn N O H Rm O -x's YRn HC H

and the compound of Formula (XIV) is: and the compound of Formula (XVIII) is:

(XIV) O T-Rin

HC O O N1 CH3

N N Rm SRn O US 2008/030O292 A1 Dec. 4, 2008 43

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

(XIX) (XXIII) O O T-Rn i T O O R1T O H3C R1 CH3 YCH,

N N 1. CH3 O

H Rm O "N, O YRn and the compound of Formula (XXIV) is and the compound of Formula (XX) is: (XXIV) XX '- (XX) TRn HC O O O H3CN-O O CH 'Nch, 3 N1 HC 3 N -- CH"3 N N "n O Rm 8 H YRn and the compound of Formula (XXV) is: and the compound of Formula (XXI) is: (XXV) O T-Rn T O R1 CH3

(XXI) N O T-Rn 1.T O N- Rm O Rn O N YRn

N and the compoundp of Formula (XXVI) is: Rm YRn (XXVI) O T-Rn HCin 1 O O CH and the compound of Formula (XXII) is: N

Rm O XXII N O T-Rn (XXII) Rn H3CN-O O N O N wherein \ T is oxygen, sulfur or NR; N R is a hydrogen, a lower alkyl group, an aryl group; R-R, taken together can be a hydrogen atom; or Rm Ris: YRn (i) —C-(O)—; (ii) - C -(O) NR; (iii) —C(O)—O—: (iv) —C(O)—S: US 2008/030O292 A1 Dec. 4, 2008 44

(v) —CH2—O—, or (vi) —CH(CH)—O—: -continued R is: (13) a hydrogen or O

(1) >n-T 1-1'N, O o1 NO (14) (2) >n- T C. -NO2 1.

(3) (15)

(4) O 1)N-1 O YNO, (16) (5) o1 NO N O - NO2 IS-N- YNO 21 2

(6) O (17) N NO 21 - ? >n-r- NO2

(7) "No2 N (18) NO NO 2 O 1. >~~~~ 2 On N (8) NO (19) s -NO2 O NO 21 o1 2

O (9) SNO, N O s (20) 1)N-1'No, O 2 ls -NO2 (10) ~~ n T NO N 2 X-r O1 NO (21) O 2 T -NO: (11) T NO O (22) (12) US 2008/030O292 A1 Dec. 4, 2008 45

-continued -continued (32)

(23) H O

(24) O H O-NO

wherein: Ro is a lower alkyl group; T is oxygen, sulfur or NR; (25) R is a hydrogen, a lower alkyl group, an aryl group; and with the proviso that the compounds of Formula (IV) to Formula (XXVI) must contain at least one —NO group. 7. The method of calim 1 wherein the compound of For mula (III) is ethyl (2S)-2-(((1S)-2-((2S)-2-(((2S,6R)-6-(ni trooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycarbonyl)pyrro (26) lidinyl)-1-methyl-2-oxoethyl)amino)-4-phenylbutanoate: (2S)-1-((2S)-2-(((1S)-1-(((2S,6R)-6-(nitrooxy)-4,8-dioxabi cyclo(3.3.0)oct-2-yl)oxycarbonyl)-3-phenylpropyl)amino) propanoyl)pyrrolidine-2-carboxylic acid; (2S,6R)-6-(ni trooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl (2S)-2-(((1S)-2- ((2S)-2-(((2S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)Oct 2-yl)oxycarbonyl)pyrrolidinyl)-1-methyl-2-oxoethyl) (27) amino)-4-phenylbutanoate or a pharmaceutically acceptable salt thereof: 8. The method of claim 1, wherein the ophthalmic disorder is an ophthalmic infection, a cataract, glaucoma, elevated intraocular pressure, ocular pain a dry eye disorder, ocular hypertension, ocular bleeding, a retinal disease, presbyopia, (28) macular degeneration, choroidal neovascularization, a retin opathy or a retinitis. 9. The method of claim 8, wherein the ophthalmic disorder is an ophthalmic infection, glaucoma, ocular pain following corneal Surgery, dry eye disorder, ocular hypertension, ocular bleeding, retinal diseases or disorders, or elevated intraocular pressure. 10. The method of claim 8, wherein the ophthalmic infec tion is an inflammation of the conjunctiva, an inflammation of (29) the cornea or a corneal ulcer. O O SNO, 11. The method of claim 2, further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide donor compound; or (iii) at least one therapeutic agent and at least Xu, one nitric oxide donor compound. (30) 12. The method of claim 11, wherein the therapeutic agent O Ro is an O-adrenergic receptoragonist, an O-adrenergic receptor antagonist, an angiotensin-converting enzyme (ACE) inhibi O tor, an antimicrobial compound, an antioxidant, a 3-adrener Xu, n gic antagonist, a carbonic anhydrase inhibitor, a hydralazine (31) compound, a nonsteroidal antiinflammatory compound, a O prostaglandin, a selective cyclooxygenase-2 inhibitor or a R9 combination of two or more thereof. 13. The method of claim 12, wherein the therapeutic agent -> is at least one compound selected from the group consisting of O YNO, an C.-adrenergic receptor agonist, an angiotensin-converting enzyme (ACE) inhibitor, an antimicrobial compound, a B-adrenergic antagonist, a carbonic anhydrase inhibitor, a US 2008/030O292 A1 Dec. 4, 2008 46 nonsteroidal antiinflammatory compound, a prostaglandin, a 15. The method of claim 11, wherein the nitric oxide donor selective cyclooxygenase-2 (COX-2) inhibitor and a steroid. compound is a compound that stimulates the endogenous 14. The method of claim 11, wherein the nitric oxide donor production of nitric oxide or endothelium-derived relaxing compound is selected from the group consisting of a S-nitro factor in vivo, a compound that elevates endogenous levels of Sothiol, a nitrite, a nitrate, a S-nitrothiol, a Sydnonimine, a nitric oxide, a compound that is oxidized to produce nitric NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a oxide, a compound that is a Substrate for nitric oxide synthase nitrosimine, a diazetine dioxide, an oXatriazole 5-imine, an or a compound that is a substrate for cytochrome P450. oXime, a hydroxylamine, a N-hydroxyguanidine, a hydrox yurea and a furoxan. c c c c c