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(12) Patent Application Publication (10) Pub. No.: US 2008/0300292 A1 Letts Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0300292 A1 Letts Et Al 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,
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