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(12) Patent Application Publication (10) Pub. No.: US 2007/023874.0 A1 Garvey Et Al US 20070238740A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/023874.0 A1 Garvey et al. (43) Pub. Date: Oct. 11, 2007 (54) NITROSATED AND NITROSYLATED Publication Classification CARDIOVASCULAR COMPOUNDS, COMPOSITIONS AND METHODS OF USE (51) Int. Cl. A6II 3/4I (2006.01) A61K 31/4164 (2006.01) A61K 31/4184 (2006.01) A61K 31/4439 (2006.01) (75) Inventors: David S. Garvey, Dover, MA (US); L. A61K 3/444 (2006.01) Gordon Letts, Dover, MA (US); A6II 3 L/506 (2006.01) Manuel Worcel, Boston, MA (US) A 6LX 3/59 (2006.01) C07D 233/42 (2006.01) C07D 233/54 (2006.01) C07D 239/22 (2006.01) C07D 257/04 (2006.01) Correspondence Address: C07D 40/10 (2006.01) WILMERHALEANTROMED C07D 403/0 (2006.01) 1875 PENNSYLVANIAAVE, NW C07D 47L/04 (2006.01) WASHINGTON, DC 20006 (US) C07D 487/04 (2006.01) (52) U.S. Cl. ................ 514/259.31; 514/264.1: 514/269; 514/300: 514/340; 514/381: 514/385; 514/394: 514/397; 544/263; 544/279; 54.4/319; (73) Assignee: NitroMed, Inc., Lexington, MA (US) 54.6/123: 546/268.4: 548/250; 548/253: 548/3114: 548/315.1; 548/322.5 (21) Appl. No.: 10/568,819 (57) ABSTRACT The invention describes novel nitrosated and/or nitrosylated cardiovascular compounds or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and/or nitrosylated cardiovascular compound, (22) PCT Filed: Aug. 20, 2004 and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides novel compositions and kits comprising at least one cardiovascular compound of the invention, that is optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide (86). PCT No.: PCT/USO4/26910 donor compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating cardiovas cular diseases; (b) treating renovascular diseases; (c) treating diabetes; (d) treating diseases resulting from oxidative S 371(c)(1), stress; (e) treating endothelial dysfunctions, (f) treating (2), (4) Date: Nov. 3, 2006 diseases caused by endothelial dysfunctions; (g) treating cirrhosis: (h) treating pre-eclampsia; () treating osteoporo sis; and (k) treating nephropathy. The nitrosated and/or nitrosylated cardiovascular compounds are preferably nitro Related U.S. Application Data sated and/or nitrosylated aldosterone antagonists, nitrosated and/or nitrosylated angiotensin II antagonists, nitrosated and/or nitrosylated calcium channel blockers, nitrosated and/or nitrosylated endothelin antagonists, nitrosated and/or (60) Provisional application No. 60/498.309, filed on Aug. nitrosylated hydralazine compounds, nitrosated and/or 28, 2003. Provisional application No. 60/535,542, nitrosylated neutral endopeptidase inhibitors and nitrosated filed on Jan. 12, 2004. and/or nitrosylated renin inhibitors. US 2007/023874.0 A1 Oct. 11, 2007 NITROSATED AND NITROSYLATED group (i.e., nitrosylated and/or nitrosated), and pharmaceu CARDIOVASCULAR COMPOUNDS, tically acceptable salts thereof. The cardiovascular com COMPOSITIONS AND METHODS OF USE pounds can be, for example, aldosterone antagonists, angio tensin II antagonists, calcium channel blockers, diuretics, RELATED APPLICATIONS endothelin antagonists, hydralazine compounds, neutral 0001. This application claims priority under 35 USC S endopeptidase inhibitors and renin inhibitors. The cardio 119 to U.S. Application No. 60/498.309 filed Aug. 28, 2003, vascular compounds can be nitrosated and/or nitrosylated and to U.S. Application No. 60/535,542 filed Jan. 12, 2004. through one or more sites Such as oxygen (hydroxyl con densation), Sulfur (sulfhydryl condensation) and/or nitrogen. FIELD OF THE INVENTION The invention also provides compositions comprising the 0002 The invention describes novel nitrosated and/or novel compounds described herein in a pharmaceutically nitrosylated cardiovascular compounds or pharmaceutically acceptable carrier. acceptable salts thereof, and novel compositions comprising 0006 The invention is also based on the discovery that at least one nitrosated and/or nitrosylated cardiovascular administering at least one cardiovascular compound or a compound, and, optionally, at least one nitric oxide donor pharmaceutically acceptable salt thereof, that is optionally and/or at least one therapeutic agent. The invention also provides novel compositions and kits comprising at least one substituted with at least one NO and/or NO. group (i.e., cardiovascular compound of the invention, that is optionally nitrosylated and/or nitrosated), and, optionally, at least one nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor improves the properties of the cardiovas nitric oxide donor compound and/or at least one therapeutic cular compound. Nitric oxide donors include, for example, agent. The invention also provides methods for (a) treating S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, cardiovascular diseases; (b) treating renovascular diseases; furoxans, sydnonimines, SPM 3672, SPM 5185, SPM 5186 (c) treating diabetes; (d) treating diseases resulting from and analogues thereof, and Substrates of the various oxidative stress; (e) treating endothelial dysfunctions; (f) isozymes of nitric oxide synthase. Thus, another embodi treating diseases caused by endothelial dysfunctions; (g) ment of the invention provides compositions comprising at treating cirrhosis: (h) treating pre-eclampsia; () treating least one cardiovascular compound that is optionally Sub osteoporosis; and (k) treating nephropathy. The nitrosated stituted with at least one NO and/or NO group (i.e., nitrosy and/or nitrosylated cardiovascular compounds are prefer lated and/or nitrosated), and at least one nitric oxide donor ably nitrosated and/or nitrosylated aldosterone antagonists, compound. The invention also provides for Such composi nitrosated and/or nitrosylated angiotensin II antagonists, tions in a pharmaceutically acceptable carrier. nitrosated and/or nitrosylated calcium channel blockers, nitrosated and/or nitrosylated endothelin antagonists, nitro 0007. The invention provides compositions comprising at sated and/or nitrosylated hydralazine compounds, nitrosated least one cardiovascular compound, that is optionally Sub and/or nitrosylated neutral endopeptidase inhibitors and stituted with at least one NO and/or NO group (i.e., nitrosy nitrosated and/or nitrosylated renin inhibitors. lated and/or nitrosated), and, optionally, at least one nitric oxide donor compound and/or at least one therapeutic agent, BACKGROUND OF THE INVENTION including, but not limited to, aldosterone antagonists, alpha adrenergic receptor antagonists, angiotensin II antagonists, 0003. The decline in cardiovascular morbidity and mor angiotensin-converting enzyme (ACE) inhibitors, antidia tality in the United States over the past three decades has betic compounds, anti-hyperlipidemic compounds, antioxi been the result of significant advances in research on car dants, antithrombotic and vasodilator compounds, B-adren diovascular disease mechanisms and therapeutic strategies. ergic antagonists, calcium channel blockers, digitalis, The incidence and prevalence of myocardial infarction and diuretics, endothelin antagonists, hydralazine compounds, death from myocardial infarction, as well as that from H, receptor antagonists, neutral endopeptidase inhibitors, cerebrovascular accident, have decreased significantly over nonsteroidal antiinflammatory compounds (NSAIDs), phos this period largely owing to advances in prevention, early phodiesterase inhibitors, potassium channel blockers, plate diagnosis, and treatment of these very common diseases. let reducing agents, proton pump inhibitors, renin inhibitors, 0004 The compounds administered for the treatment of selective cyclooxygenase-2 (COX-2) inhibitors, and combi diuresis, cardiovascular diseases, and diseases resulting nations of two or more thereof. In a preferred embodiment from oxidative and/or endothelial dysfunctions often result the at least one therapeutic agent is selected from the group in toxic, chronic and/or debilitating side effects. Cardiovas consisting of an aldosterone antagonist, an angiotensin II cular compounds such as ACE inhibitors, beta-adrenergic antagonist, an angiotensin-converting enzyme (ACE) inhibi blockers, antithrombotic and vasodilator compounds or anti tors, a B-adrenergic antagonist, a digitalis, a diuretic, and a hyperlipidemic compounds, show, for example, respiratory hydralazine compound. The invention also provides for Such toxicity resulting in asthma and/or bronchitis. Hence there is compositions in a pharmaceutically acceptable carrier. a need in the art for compounds that have improved efficacy, lower toxicity and that can be used at low dosages. The 0008 Another embodiment of the invention provides invention is directed to these, as well as other, important compositions comprising a therapeutically effective amount ends. of at least one cardiovascular compound of the invention, that is optionally substituted with at least one NO and/or NO, group (i.e., nitrosylated and/or nitrosated), and at least SUMMARY OF THE INVENTION one therapeutic agent selected from the group consisting of 0005 The invention provides novel cardiovascular com an aldosterone antagonist, an angiotensin II antagonist, an pounds that are substituted with at least one NO and/or NO angiotensin-converting enzyme (ACE) inhibitor, a B-adren US 2007/023874.0 A1 Oct. 11, 2007 ergic antagonist, a diuretic and a hydralazine compound. The two
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