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(12) United States Patent (10) Patent No.: US 6,635,273 B1 Loscalz0 Et Al

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(12) United States Patent (10) Patent No.: US 6,635,273 B1 Loscalz0 Et Al USOO6635273B1 (12) United States Patent (10) Patent No.: US 6,635,273 B1 LOScalZ0 et al. (45) Date of Patent: Oct. 21, 2003 (54) METHODS OF TREATING VASCULAR Dries et al, The New England Journal of Medicine, DISEASES CHARACTERIZED BY NITRIC 340(8):609-616 (Feb. 25, 1999). OXDE INSUFFICIENCY Freedman et al, Drugs, 54(Supp. 3):41-50 (1997). Sherman et al., Cardiologia, 42(2):177-187 (1997). (75) Inventors: Joseph Loscalzo, Dover, MA (US); Biegelson et al., Coronary Artery Disease, 10:241-256 Joseph A. Vita, Hingham, MA (US); (1999). Michael D. Loberg, Boston, MA (US); Rudd et al, Am. J. Physiol., 277(46):H732–H739 (1999). Manuel Worcel, Boston, MA (US) Hammerman et al, Am. J. Physiol., 277(46):H1579-H1592 (1999). (73) Assignees: Trustees of Boston University, Boston, LoScalzo et al., Transactions of the American and Climato MA (US); NitroMed, Inc., Bedford, logical ASS., 111:158-163 (2000). MA (US) Cohn et al, The New England Journal of Medicine, 325(5):303-310 (1991). (*) Notice: Subject to any disclaimer, the term of this Cohn et al, The New England Journal of Medicine , patent is extended or adjusted under 35 314(24): 1547–1552 (1986). U.S.C. 154(b) by 0 days. Carson et al., Circulation, Supplement I, 92(8):I31-I32, Abstract No. 0145 (1995). (21) Appl. No.: 09/697,317 (List continued on next page.) (22) Filed: Oct. 27, 2000 Primary Examiner-Jon P. Weber Related U.S. Application Data ASSistant Examiner-Kalash C. Srivastava (60) Provisional application No. 60/179,020, filed on Jan. 31, (74) Attorney, Agent, or Firm-Hale and Dorr LLP 2000, and provisional application No. 60/162,230, filed on Oct. 29, 1999. (57) ABSTRACT The present invention provides methods of treating vascular (51) Int. Cl." ......................... A61L 15/16; A61K 47/00; diseases where nitric oxide insufficiency is a contributing A61 K9/20: A61 K31/00; CO7D 515/02 factor by administering a therapeutically effective amount of (52) U.S. Cl. ....................... 424/444; 424/400; 424/439; at least one antioxidant, or a pharmaceutically acceptable 424/440, 424/443; 424/451; 424/464; 424/474; Salt thereof, and at least one of isosorbide dinitrate and 424/489; 424/944; 514/218; 514/248; 514/303; isosorbide mononitrate, and, optionally, at least one nitro 514/310; 514/364; 514/470; 54.6/118 Sated angiotensin-converting enzyme inhibitor, nitrosated (58) Field of Search ................................. 424/400, 439, beta-adrenergic blocker, nitroSated calcium channel blocker, 424/444, 944, 440, 443, 451, 464, 474, nitrosated endothelin antagonist, nitrosated angiotensin II 489; 514/303,564, 218, 248, 364, 310, receptor antagonist, nitroSated renin inhibitor, and/or at least 470; 54.6/118 one compound used to treat cardiovascular diseases. The antioxidant is preferably a hydralazine compound or a (56) References Cited pharmaceutically acceptable Salt thereof. The present inven U.S. PATENT DOCUMENTS tion also provides methods of treating vascular diseases where nitric oxide insufficiency is a contributing factor by 4,868,179 A 9/1989 Cohn administering a therapeutically effective amount of at least 5,627,191. A 5/1997 Birch et al. one nitrosated angiotensin-converting enzyme inhibitor, nit 5,645,839 A 7/1997 Chobanian et al. rosated beta-adrenergic blocker, nitrosated calcium channel 5,891.459 A 4/1999 Cooke et al. 5,968.983 A 10/1999 Kaesemeyer blocker, nitrosated endothelin antagonist, nitrosated angio 5,973,011 A 10/1999 Noack et al. tensin II receptor antagonist, nitrosated renin inhibitor, and, 6,103,769 A 8/2000 Kelm optionally, at least one antioxidant and/or at least one 6,117.872 A 9/2000 Maxwell et al. compound used to treat cardiovascular diseases. The present 6,319,515 B1 11/2001 Hidaka et al. invention also provides methods of treating Raynaud's Syn drome by administering a therapeutically effective amount FOREIGN PATENT DOCUMENTS of at least one antioxidant and at least one of isosorbide WO WO95/26725 10/1995 dinitrate and isosorbide mononitrate and/or at least one WO WO 98/21193 5/1998 nitrosated angiotensin-converting enzyme inhibitor, nitro WO WO 99/00361 1/1999 Sated calcium channel blocker, nitrosated endothelin WO WO 99/66921 12/1999 antagonist, nitrosated angiotensin II receptor antagonist, WO WO 99/67231 12/1999 nitrosated renin inhibitor. The present invention also pro OTHER PUBLICATIONS vides novel transdermal patches comprising at least one antioxidant and at least one of isosorbide dinitrate and von Lutterotti et al, American Journal of Hypertension, 4 (4 isosorbide mononitrate and/or at least one nitrosated Part 2):346S-349S (1991). angiotensin-converting enzyme inhibitor, nitrosated beta Burneir et al., Hypertension, 22(3):339–347 (Sep. 1993). adrenergic blocker, nitrosated calcium channel blocker, nit Dupuis, Cardiovascular Drugs and Therapy, 8(3):501-507 rosated endothelin antagonist, nitroSated angiotensin II (1994). receptor antagonist, nitrosated renin inhibitor. Carson et al., Journal of Cardiac Failure, 5(3):178-187 (Sep. 10, 1999). 33 Claims, 3 Drawing Sheets US 6,635,273 B1 Page 2 OTHER PUBLICATIONS Carson et al., Journal of Cardiac Failure, 5(3):178-187 (Sep. Francis et al, Circulation, Supplement VI, 87(6):VI40-VI48 10, 1999). (1993). Dries et al, The New England Journal of Medicine, Pierpont et al, Chest, 73(1):8–13 (1978). 34(8):609-616 (Feb. 25, 1999). Massie et al., The American Journal of Cardiology, Freedman et al, Drugs, 54(Supp. 3):41-50 (1997). 40:794-801 (1977). Sherman et al., Cardiologia, 42(2):177-187 (1997). Kaplan et al., Annals of Internal Medicine, 84:639-645 Biegelson et al., Coronary Artery Disease, 10:241-256 (1976). (1999). Bauer et al., Circulation, 84(1):35-39 (1991). Rudd et al, Am. J. Physiol., 277(46):H732–H739 (1999). The SOLVD Investigators, The New England Journal of Hammerman et al, Am. J. Physiol., 277(46):H1579-H1592 Medicine, 327(10):685–691 (1992). (1999). Ziesche et al., Circulation, 87(6):VI56-VI64 (1993). LoScalzo et al., Transactions of the American and Climato Rector et al., Circulation, 87(6):VI71-VI77 (1993). logical ASS., 111:158-163 (2000). U.S. Patent Oct. 21, 2003 Sheet 1 of 3 US 6,635,273 B1 Fig. 1 Decreased Renin Release NO Insufficiency Salt/Water Retention Increased Intracellular Increased Sensitivity to Sodium & Calcium a techolamines and Angiotensin II LVH Decreased Capillary Density Increased Vascular Tone Myocardial Fibrosis Hypertension Microvascular Increased LV Mass Cardiac Ischemia Diastolic Dysfunction FIG. 2 -O-White Hypertensives -o- Black Hypertensives a 15 9 9. S 10 CS O E o-1 -1 PCOOO1 Baseline O.3 1.O 3.0 10 Methacholine Dose (g/min) U.S. Patent Oct. 21, 2003 Sheet 2 of 3 US 6,635,273 B1 FIG. 3A -o-White normotensives -o- Black nomotensives a 9.Q 15 / 9. S 10 8 N-1 5 l - O Baseline 0.3 10 3.0 1O Nitropiusside Dose (g/min) FIG. 3B -O-White normotensives -O-Black nomotensives Baseline O.3 1.O 3.O 1O Methacholine Dose (g/min) U.S. Patent Oct. 21, 2003 Sheet 3 of 3 US 6,635,273 B1 FIG. 4A -o- Salt Resistant (n=25) -e - Satt Sensitive (n-6) 15 C Baseline 0.3 1.0 3.0 10. Methachotine Dose (g/min) FIG. 4B -O-Salt Resistant (n=25) -O - Satt Sensitive (n=6) g 15 9. E 10 N- 5 21 - G2-2 I- O PEO.16 Baseline O.3 1.O 3.0 10 Nitroprussiae Dose (g/min) US 6,635,273 B1 1 2 METHODS OF TREATING WASCULAR than among white Americans. In this decade, the death rate DISEASES CHARACTERIZED BY NITRIC from cardiovascular disease for black males was 353 per OXDE INSUFFICIENCY 100,000 population, while that for white males was 244 per 100,000; the rate for black females was 226 per 100,000; RELATED APPLICATIONS while that for white females was 135 per 100,000. Conso This application claims priority to U.S. Provisional Appli nant with this important demographic parameter is the cation No. 60/162,230 filed Oct. 29, 1999 and U.S. Provi observation that there is a higher prevalence of Several of the important risk factors for cardiovascular disease, e.g., sional Application No. 60/179,020 filed Jan. 31, 2000. hypertension, Smoking, diabetes mellitus, obesity, and left FIELD OF THE INVENTION Ventricular hypertrophy, among blacks compared with whites. In addition, outcomes of cardiovascular events are The present invention provides methods of treating and/or worse for blacks than whites. Following myocardial preventing vascular diseases characterized by nitric oxide infarction, blacks have a 50% higher annual mortality rate insufficiency by administering a therapeutically effective than whites, and their five year Survival is only 70%. Thus, amount of at least one antioxidant or a pharmaceutically 15 the many advances in cardiovascular medicine that account acceptable Salt thereof, and at least one of isosorbide dini for the overall improvement in cardiovascular health in the trate and isosorbide mononitrate, and, optionally, at least one general population have failed to translate into comparable nitrosated angiotensin-converting enzyme inhibitor, nitro racial benefits. Sated beta-adrenergic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angio There is a need in the art for new and more effective tensin II receptor antagonist, nitroSated renin inhibitor, and/ compositions and methods for treating vascular diseases. or at least one compound used to treat cardiovascular The present invention is directed to these, as well as other, diseases. The antioxidant is preferably a hydralazine com important ends. pound or a pharmaceutically acceptable Salt thereof. The SUMMARY OF THE INVENTION present invention also provides methods of treating and/or 25
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