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(12) Patent Application Publication (10) Pub. No.: US 2006/0009513 A1 Garvey (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2006/0009513 A1 Garvey (43) Pub US 2006OOO9513A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0009513 A1 Garvey (43) Pub. Date: Jan. 12, 2006 (54) NEBIVOLOLAND ITS METABOLITES IN (52) U.S. Cl. ............................................ 514/459; 549/330 COMBINATION WITH NITRC OXDE DONORS, COMPOSITIONS AND METHODS OF USE (57) ABSTRACT (75) Inventor: David S. Garvey, Dover, MA (US) Correspondence Address: WILMER CUTLER PICKERING HALE AND The invention describes novel compositions comprising DORR LLP nebivolol and/or at least one metabolite of nebivolol and at THE WILLARD OFFICE BUILDING 1455 PENNSYLVANIAAVE, NW least one nitric oxide donor, and, optionally, at least one WASHINGTON, DC 20004 (US) antioxidant or a pharmaceutically acceptable Salt thereof, and/or at least one compound used to treat cardiovascular (73) Assignee: NitroMed, Inc., Lexington, MA (US) diseases or a pharmaceutically acceptable Salt thereof, and/ (21) Appl. No.: 11/135,418 or at least one nitroSated compound used to treat cardiovas cular diseases. The compounds and compositions of the (22) Filed: Jul. 13, 2005 invention can also be bound to a matrix. The nitric oxide Related U.S. Application Data donor is a compound that donates, transferS or releases nitric oxide, elevates endogenous levels of endothelium-derived (60) Division of application No. 10/695,644, filed on Oct. relaxing factor, Stimulates endogenous Synthesis of nitric 29, 2003, which is a continuation of application No. oxide or is a Substrate for nitric oxide Synthase and may PCT/US02/13667, filed on May 1, 2002. preferably be isosorbide dinitrate and/or isosorbide mono (60) Provisional application No. 60/287,725, filed on May nitrate. The antioxidant may preferably be a hydralazine 2, 2001. compound or a pharmaceutically acceptable Salt thereof. The invention also provides methods for treating and/or Publication Classification preventing vascular diseases characterized by nitric oxide (51) Int. Cl. insufficiency; and for treating and/or preventing Raynaud's C07D 493/00 (2006.01) Syndrome; and for treating and/or preventing cardiovascular A6 IK 31/353 (2006.01) diseases or disorders. Patent Application Publication Jan. 12, 2006 Sheet 1 of 16 US 2006/0009513 A1 Figure 1 0-6-Ge-O-P' -3-(Gr-o-No 0-6-Gr-o-No k . O f Patent Application Publication Jan. 12, 2006 Sheet 2 of 16 US 2006/0009513 A1 Figure 2 OH OH OS-1 N N-O F 9 Re -C-G-S-P k . OF F O Re Patent Application Publication Jan. 12, 2006 Sheet 3 of 16 US 2006/0009513 A1 Figure 3 Patent Application Publication Jan. 12, 2006 Sheet 4 of 16 US 2006/0009513 A1 Figure 4 O Re p3 OH p3 o-C-(C)p-N-R Patent Application Publication Jan. 12, 2006 Sheet 5 of 16 US 2006/0009513 A1 Figure 5 OH O OH F 11 OH R O ONS e c-Ge-O-P F 12 R o-P R O ONSc-(p-o-No e R Patent Application Publication Jan. 12, 2006 Sheet 6 of 16 US 2006/0009513 A1 Figure 6 OH O OH F 11 OH O O.Yö-(c)-s-p O Re F 14 R OH R O O.Y-C-S-H O e F 15 R Patent Application Publication Jan. 12, 2006 Sheet 7 of 16 US 2006/0009513 A1 Figure 7 OH 11 OH O O R. O ---o-o: w k R C Patent Application Publication Jan. 12, 2006 Sheet 8 of 16 US 2006/0009513 A1 Figure 8 OH O OH F 11 OH O Re p3 O O-N C-(q)-N-R F R 16 OH M"-- O N O On 9 Fly So F 3-(cis-N-RR Patent Application Publication Jan. 12, 2006 Sheet 9 of 16 US 2006/0009513 A1 Figure 9 - OH Patent Application Publication Jan. 12, 2006 Sheet 10 of 16 US 2006/0009513 A1 Figure 10 P pH (Gr-o-No R B Patent Application Publication Jan. 12, 2006 Sheet 11 of 16 US 2006/0009513 A1 Figure 11 .. IIIC Patent Application Publication Jan. 12, 2006 Sheet 12 of 16 US 2006/0009513 A1 Figure 12 P1’ o1 O OH F O 20 pi o1 O O (-s-pR. F O R D Patent Application Publication Jan. 12, 2006 Sheet 13 of 16 US 2006/0009513 A1 Figure 13 Patent Application Publication Jan. 12, 2006 Sheet 14 of 16 US 2006/0009513 A1 Figure 14 OH IF Patent Application Publication Jan. 12, 2006 Sheet 15 of 16 US 2006/0009513 A1 Figure 15 -6-(C)p-N-R Patent Application Publication Jan. 12, 2006 Sheet 16 of 16 US 2006/0009513 A1 Figure 16 Pl' O1 O OH F O 20 o1 R. P. O O-N (q)-N-Re F O R 29 US 2006/0009513 A1 Jan. 12, 2006 NEBIVOLOLAND ITS METABOLITES IN 244 per 100,000; the rate for black females was 226 per COMBINATION WITH NITRICOXIDE DONORS, 100,000; while that for white females was 135 per 100,000. COMPOSITIONS AND METHODS OF USE Consonant with this important demographic parameter is the observation that there is a higher prevalence of Several of the RELATED APPLICATIONS important risk factors for cardiovascular disease, e.g., hyper tension, Smoking, diabetes mellitus, obesity, and left ven 0001. This application is a divisional of U.S. application tricular hypertrophy, among blackS compared with whites. Ser. No. 10/695,644, filed Oct. 29, 2003, which is a S371 of In addition, outcomes of cardiovascular events are worse for PCT/US02/13667, filed May 1, 2002, which claims priority blacks than whites. Following myocardial infarction, blackS under 35 USC S 119 to U.S. Provisional Application No. have a 50% higher annual mortality rate than whites, and 60/287,725 filed May 2, 2001. their five-year Survival is only 70%. Thus, the many advances in cardiovascular medicine that account for the FIELD OF THE INVENTION overall improvement in cardiovascular health in the general 0002 The invention describes novel nitrosated and/or population has failed to translate into comparable racial nitrosylated nebivolol, novel nitrosated and/or nitroSylated benefits. metabolites of nebivolol and novel compositions comprising 0005 There is a need in the art for new and more at least one nitrosated and/or nitrosylated nebivolol and/or at effective compositions and methods for treating vascular least one nitrosated and/or nitrosylated metabolite of nebiv diseases. The invention is directed to these, as well as other, olol, and, optionally, at least one nitric oxide donor and/or at important ends. least one antioxidant or a pharmaceutically acceptable Salt thereof, and/or at least one compound used to treat cardio SUMMARY OF THE INVENTION vascular diseases or a pharmaceutically acceptable Salt thereof, and/or at least one nitrosated compound used to treat 0006 The invention describes novel nitrosated and/or cardiovascular diseases. The invention also provides novel nitrosylated nebivolol, novel nitroSated and/or nitrosylated compositions comprising nebivolol and/or at least one metabolites of nebivolol and methods of treating and/or metabolite of nebivolol and at least one nitric oxide donor, preventing vascular diseases characterized by nitric oxide and, optionally, at least one antioxidant or a pharmaceuti insufficiency, and Raynaud's Syndrome by administering at cally acceptable Salt thereof, and/or at least one compound least one nitrosated and/or nitrosylated nebivolol and/or at used to treat cardiovascular diseases or a pharmaceutically least one nitrosated and/or nitrosylated metabolite of nebiv acceptable Salt thereof, and/or at least one nitrosated com olol that is capable of releasing a therapeutically effective pound used to treat cardiovascular diseases. The compounds amount of nitric oxide to a targeted Site effected by the and compositions of the invention can also be bound to a vascular disease. matrix. The nitric oxide donor is a compound that donates, 0007 One embodiment of the invention provides novel transferS or releases nitric oxide, elevates endogenous levels nitrosated and/or nitrosylated nebivolol and/or novel nitro of endothelium-derived relaxing factor, Stimulates endog sated and/or nitrosylated metabolites of nebivolol. The enous Synthesis of nitric oxide or is a Substrate for nitric nebivolol and/or its metabolites can be nitrosated and/or oxide Synthase and may preferably be isosorbide dinitrate nitrosylated through one or more Sites Such as oxygen and/or isosorbide mononitrate. The antioxidant may prefer (hydroxyl condensation), Sulfur (Sulfhydryl condensation) ably be a hydralazine compound or a pharmaceutically and/or nitrogen. The invention also provides compositions acceptable Salt thereof. The invention also provides methods comprising a therapeutically effective amount of Such com for treating and/or preventing vascular diseases character pounds in a pharmaceutically acceptable carrier. ized by nitric oxide insufficiency; and for treating and/or preventing Raynaud's Syndrome, and for treating and/or 0008 Another embodiment of the invention provides preventing cardiovascular diseases or disorders. compositions comprising a therapeutically effective amount of nebivolol that is optionally substituted with at least one BACKGROUND OF THE INVENTION NO and/or NO group (i.e., nitrosylated and/or nitrosated), and/or at least one metabolite of nebivolol, that is optionally 0003. The decline in cardiovascular morbidity and mor substituted with at least one NO and/or NO group (i.e., tality in the United States over the past three decades has nitrosylated and/or nitrosated), and at least one compound been the result of Significant advances in research on car that donates, transferS or releases nitrogen monoxide as a diovascular disease mechanisms and therapeutic Strategies. charged species, i.e., nitrosonium (NO") or nitroxyl (NO-), The incidence and prevalence of myocardial infarction and or as the neutral species, nitric oxide (NO), and/or stimu death from myocardial infarction, as well as that from lates endogenous production of nitric oxide or EDRF in vivo cerebrovascular accident, have decreased significantly over and/or is a SubStrate for nitric oxide Synthase.
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