US 2010O240622A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/024.0622 A1 Garvey (43) Pub. Date: Sep. 23, 2010 (54) NITRICOXIDE ENHANCING Publication Classification PROSTAGLANDIN COMPOUNDS, (51) Int. Cl. COMPOSITIONS AND METHODS OF USE A6II 3/56 (2006.01) C07D 271/08 (2006.01) A6II 3/42.45 (2006.01) (75) Inventor: David S. Garvey, Dover, MA (US) A6IP27/02 (2006.01) A6IPI3/08 (2006.01) A6IP 9/00 (2006.01) Correspondence Address: A6IPL/04 (2006.01) WILMERHALEANTROMED A6IP 5/04 (2006.01) 1875 PENNSYLVANIAAVE, NW C07D 413/04 (2006.01) WASHINGTON, DC 20006 (US) A 6LX 3/5.377 (2006.01) A63L/454 (2006.01) C07D 265/06 (2006.01) (73) Assignee: NITROMED, INC., Laxington, A 6LX 3/535 (2006.01) MA (US) A 6LX 3/55.75 (2006.01) CD7C 403/10 (2006.01) (52) U.S. Cl. ......... 514/171; 548/125; 514/364; 54.4/138: (21) Appl. No.: 12/294,642 514/236.2:546/210: 514/326; 544/97: 514/228.8; 514/573; 562/503 (22) PCT Fled: Mar. 19, 2007 (57) ABSTRACT The invention provides compositions and kits comprising at least one nitric oxide enhancing prostaglandin compound ora (86) PCT NO.: PCT/US2007/006749 pharmaceutically acceptable Salt thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one S371 (c)(1), therapeutic agent. The invention also provides methods for (2), (4) Date: Sep. 26, 2008 (a) treating ophthalmic disorders; (b) treating cerebrovascu lar disorders; (c) treating cardiovascular disorders; (d) treat ing benign prostatic hyperplasia (BPH); (e) treating peptic Related U.S. Application Data ulcers; (e) treating sexual dysfunctions and (f) inducing abor tions. The nitric oxide enhancing prostaglandin compounds (60) Provisional application No. 60/786,689, filed on Mar. comprise at least one heterocyclic nitric oxide donor group 29, 2006. and/or at least one nitroxide group. US 2010/024.0622 A1 Sep. 23, 2010 NITRC OXDE ENHANCING example, S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitro PROSTAGLANDIN COMPOUNDS, samines, furoxans, sydnonimines, SPM 3672, SPM 4757, COMPOSITIONS AND METHODS OF USE SPM 5185, SPM 5186 and analogues thereof, substrates of the various isozymes of nitric oxide synthase, and nitroxides. RELATED APPLICATIONS Thus, another embodiment of the invention provides compo 0001. This application claims priority under 35 USC S119 sitions comprising at least one nitric oxide enhancing pros to U.S. Application No. 60/786,689 filed Mar. 29, 2006; the taglandin compound and at least one nitric oxide enhancing disclosure of which is incorporated by reference herein in its compound. The invention also provides for Such composi entirety. tions in a pharmaceutically acceptable carrier. 0006. The invention provides compositions comprising at FIELD OF THE INVENTION least one nitric oxide enhancing prostaglandin compound, and, optionally, at least one nitric oxide enhancing compound 0002 The invention describes compositions and kits com and/or at least one therapeutic agent, including, but not lim prising at least one nitric oxide enhancing prostaglandin com ited to, aldosterone antagonists, C.-adrenergic receptor ago pound or a pharmaceutically acceptable salt thereof, and, nists, C.-adrenergic receptor antagonists, B-adrenergic ago optionally, at least one nitric oxide enhancing compound nists, antidiabetic compounds, antimicrobial compounds, and/or at least one therapeutic agent. The invention also pro antihyperlipidemic drugs, angiotensin II antagonists, angio vides methods for (a) treating ophthalmic disorders; (b) treat tensin-converting enzyme (ACE) inhibitors, antioxidants, ing cerebrovascular disorders; (c) treating cardiovascular dis antithrombotic and vasodilator drugs, B-adrenergic antago orders; (d) treating benign prostatic hyperplasia (BPH); (e) nists, calcium channel blockers, carbonic anhydrase inhibi treating peptic ulcers; (e) treating sexual dysfunctions and (f) tors, diuretics, endothelin antagonists, hydralazine com inducing abortions. The nitric oxide enhancing prostaglandin pounds, H2 receptor antagonists, neutral endopeptidase compounds comprise at least one heterocyclic nitric oxide inhibitors, nonsteroidal antiinflammatory compounds donor group and/or at least one nitroxide group. (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, prostaglandins, proton BACKGROUND OF THE INVENTION pump inhibitors, renin inhibitors, selective cyclooxygenase-2 0003 Most drugs conventionally used to treat ophthalmic (COX-2) inhibitors, steroids, compounds used for the treat disorders have potentially serious side effects Such as blurring ment of glaucoma, and combinations of two or more thereof. of vision and other visual side effects which may lead either The invention also provides for such compositions in a phar to decreased patient compliance or to the termination of maceutically acceptable carrier. therapy. Occasionally systemically administered drugs can 0007 Another embodiment of the invention provides also cause serious side effects, such as nausea, dyspepsia, compositions comprising at least one nitric oxide enhancing fatigue, and metabolic acidosis, which affect patient compli prostaglandin compound, and at least one therapeutic agent ance and/or necessitate the termination of treatment. Addi selected from the group consisting of an O-adrenergic recep tionally, Some B-adrenergic antagonists have increasingly tor antagonist, a B-adrenergic agonist, an antimicrobial com become associated with serious pulmonary side effects attrib pound, a B-adrenergic antagonist, a calcium channel blocker, utable to their effects on B-2 receptors in pulmonary tissue. a carbonic anhydrase inhibitor, a nonsteroidal antiinflamma Hence there is a need in the art for compounds that have tory compound (NSAID), a phosphodiesterase inhibitor, a improved efficacy, lower toxicity and/or fewer side effects potassium channel blocker, a prostaglandin, a proton pump and that can be used at low dosages. The invention is directed inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitor, a to these, as well as other, important ends. steroid, a compound used for the treatment of glaucoma, and combinations of two or more thereof. The invention also SUMMARY OF THE INVENTION provides for Such compositions in a pharmaceutically accept 0004. The invention provides novel nitric oxide enhancing able carrier. prostaglandin compounds that are Substituted with at least 0008. The invention provides methods for(a)treating oph one heterocyclic nitric oxide donor group and/or at least one thalmic disorders; (b) treating cerebrovascular disorders; (c) nitroxide group and pharmaceutically acceptable salts treating cardiovascular disorders; (d) treating benign pros thereof. The prostaglandin compound can be substituted with tatic hyperplasia (BPH); (e) treating peptic ulcers; (e) treating the heterocyclic nitric oxide donor group and/or the nitroxide sexual dysfunctions and (f) inducing abortions in a patient in group through one or more sites Such as oxygen (hydroxyl need thereof comprising administering to the patient an effec condensation), Sulfur (sulfhydryl condensation) and/or nitro tive amount of at least one nitric oxide enhancing prostaglan gen via a bond or moiety that can be hydrolyzed. The hetero din compound, and, optionally, at least one therapeutic agent, cyclic nitric oxide donors are furoxans, Sydnonimines, Such as, for example, aldosterone antagonists, B-adrenergic oXatriazole-5-ones and/or oxatriazole-5-imines. The inven receptor agonists, C.-adrenergic receptor antagonists, B-adr tion also provides compositions comprising the novel com energic agonists, antidiabetic compounds, antimicrobial pounds described herein in a pharmaceutically acceptable compounds, anti-hyperlipidemic drugs, angiotensin II carrier. antagonists, angiotensin-converting enzyme (ACE) inhibi 0005. The invention is also based on the discovery that tors, antioxidants, antithrombotic and vasodilator drugs, administering at least one nitric oxide enhancing prostaglan B-adrenergic antagonists, calcium channel blockers, carbonic din compound (i.e. heterocyclic nitric oxide donor group anhydrase inhibitors, diuretics, endothelin antagonists, and/or nitroxide group), or a pharmaceutically acceptable salt hydralazine compounds. He receptor antagonists, neutral thereof, and, optionally, at least one nitric oxide enhancing endopeptidase inhibitors, nonsteroidal antiinflammatory compound improves the properties of the prostaglandin com compounds (NSAIDs), phosphodiesterase inhibitors, potas pound. Nitric oxide enhancing compounds include, for sium channel blockers, platelet reducing agents, prostaglan US 2010/024.0622 A1 Sep. 23, 2010 dins, proton pump inhibitors, renin inhibitors, selective dry eye disorder, ocular hypertension, ocular bleeding, retinal cyclooxygenase-2 (COX-2) inhibitors, Steroids, compounds diseases or disorders, presbyopia, macular degeneration, cho used for the treatment of glaucoma, and combinations of two roidal neovascularization (CNV), retinopathies, such as for or more thereof. The methods can optionally further com example, diabetic retinopathy, vitreoretinopathy, and the like, prises the administration of at least one nitric oxide enhancing retinitis, such as for example, cytomegalovirus (CMV) retini compound. In this embodiment of the invention, the methods tis, uveitis, macular edema, neuropathies and the like. can involve (i) administering the nitric oxide enhancing pros 0013 “Ophthalmic infections' include, but are not limited taglandin compounds, (ii)