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United States Patent (10) Patent No.: US 7,235,237 B2 L0scalz0 Et Al

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United States Patent (10) Patent No.: US 7,235,237 B2 L0scalz0 Et Al USOO7235237B2 (12) United States Patent (10) Patent No.: US 7,235,237 B2 L0ScalZ0 et al. (45) Date of Patent: Jun. 26, 2007 (54) METHODS OF TREATING VASCULAR 5,968,983 A 10/1999 Kaesemeyer DISEASES CHARACTERIZED BY NITRC 5,973,011 A 10/1999 Noack et al. OXIDE INSUFFICIENCY 6,103,769 A 8, 2000 Kelm 6,117,872 A 9, 2000 Maxwell et al. (75) Inventors: Joseph Loscalzo, Dover, MA (US); 6,319,515 B1 1 1/2001 Hidaka et al. Joseph A. Vita, Hingham, MA (US); 6,458,797 B1 10/2002 Adams et al. Michael D. Loberg, Boston, MA (US); 2004, OO63719 A1 4/2004 Adams et al. Manuel Worcel, Boston, MA (US) FOREIGN PATENT DOCUMENTS (73) Assignee: NitroMed, Inc., Lexington, MA (US) EP O327263 A 8, 1989 (*) Notice: Subject to any disclaimer, the term of this EP O 968 713 A1 5, 1998 patent is extended or adjusted under 35 JP O905915.2 3, 1997 U.S.C. 154(b) by 492 days. WO WO95/26725 10, 1995 WO WO 98.21 193 5, 1998 (21) Appl. No.: 10/415,136 WO WO 99.00361 1, 1999 WO WO 99,66921 12/1999 (22) PCT Filed: May 2, 2001 WO WO 99,67231 12/1999 WO WO O1/35961 A 5, 2001 (86). PCT No.: PCT/USO1A14245 OTHER PUBLICATIONS S 371 (c)(1), (2), (4) Date: Apr. 25, 2003 Dupuis, Cardiovascular Drugs and Therapy, 8(3):501-507 (1994). Cohn et al. The New England Journal of Medicine, 325(5):303-310 (87) PCT Pub. No.: WO02/34303 (1991). Cohn et al. The New England Journal of Medicine, 314(24): 1547 PCT Pub. Date: May 2, 2002 1552 (1986). Carson et al. Circulation, Supplement I, 92(8):I31-I32, Abstract No. (65) Prior Publication Data 0145 (1995). Francis et al. Circulation, Supplement VI, 87(6):VI40-VI48 (1993). US 2004/0005306 A1 Jan. 8, 2004 Pierpont et al. Chest, 73(1): 8-13 (1978). Massie et al. The American Journal of Cardiology, 40:794-801 Related U.S. Application Data (1977). (63) Continuation-in-part of application No. 09/697.317, (Continued) filed on Oct. 27, 2000, now Pat. No. 6,635,273, and a continuation-in-part of application No. PCT/US00/ Primary Examiner Jon Weber 29582, filed on Oct. 26, 2000. Assistant Examiner Kailash C. Srivastava (74) Attorney, Agent, or Firm Wilmer Cutler Pickering (60) Provisional application No. 60 179,020, filed on Jan. Hale and Dorr LLP 31, 2000, provisional application No. 60/162,230, filed on Oct. 29, 1999. (57) ABSTRACT (51) Int. Cl. A6 IK 38/43 (2006.01) The present invention provides methods of treating or pre A6 IK 3L/25 (2006.01) venting vascular diseases caused by nitric oxide (NO) insuf AOIN 37/2 (2006.01) ficiency. The methods encompass administering a composi AOIN 33/18 (2006.01) tion comprising an antioxidant, a compound to treat (52) U.S. Cl. ..................... 424/94.1: 514/509: 514/562 cardiovascular diseases, a nitrosated compound, a com s s 51 4676 pound that donates, transfers or relases NO, or is a NO (58) Field of Classification Search 424/94.1 synthase Substrate, or endogenously stimulates NO synthe 424/94.4, 468: 5141s. 248.458 474 509. sis, or stimulates levels of endothelium derived relaxing Is I w \s 514/562.683 factor. In the said composition, a hydralazine compound See application file for complete search history. may be an antioxidant, isosorbide mono-ordinitrate may be the compound to donate, transfer, release, or stimulate 56 References Cited endogenous9. NO SVnthesis.y The isorsorbide mavy also elevate endogenous levels of endotherlium-derived relaxing factor, U.S. PATENT DOCUMENTS or be a NO synthase Substrate and angiotensin enzyme 4.293,565 A 10, 1981 Cordes et al. inhibitor may be nitrosated compound. Disclosed in the 4.584,315 A 4, 1986 Marshall invention is also a method to treat, or prevent Renaud's 4,868,179 A 9, 1989 Cohn syndrome by administering a therapeutically effective 5,627, 191 A 5, 1997 Birch et al. amount of an antioxidant, a NO donor, a nitrosated com 5,645,839 A 7, 1997 Chobanian et al. pound and novel Sustained-release formulations (e.g. a trans 5,760,069 A 6/1998 Lukas-Laskey et al. dermal patch). 5,891.459 A 4/1999 Cooke et al. 5,902,821 A 5/1999 Lukas-Laskey et al. 17 Claims, 3 Drawing Sheets US 7,235,237 B2 Page 2 OTHER PUBLICATIONS Exner, Derek V., et al., “Lesser Response to Angiotensin-Convert ing-Enzyme Inhibitor Therapy in Black as Compared with White Kaplan et al. 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Med., vol. 344, No. 22, May 31, 2001, Sherman et al. Cardiologia, 42(2): 177-187 (1997). pp. 1711-1712. Biegelson et al. Coronary Artery Disease, 10-241-256 (1999). Schwartz, Robert S., “Racial Profiling in Medical Research.” N. Rudd et al. Am. J. Physiol., 277(46):H723-H739 (1999). Engl. J. Med., vol. 344, No. 18, May 3, 2001, pp. 1392-1393. Hammerman et al. Am. J. Physiol., 277(46):H1579-H1592 (1999). Levine, T. Barry, “Paradoxical Hypertension after Reversal of Heart Loscalzo et al. Transactions of the American and Climatological Failure in Patients Treated with Intensive Vasodilator Therapy.” Ass., 111:158-163 (2000). American Journal of Hypertension, Ltd., 1998; 11:1041-1047. Johnson, Clinical Pharmacy, vol. 5, pp. 536 and 541 (1986). ABSTRACTS Heart Failure 179A, JACC, Feb. 1999. Turner et al. The American Journal of Cardiology, 47:910-916 Kahn, Jonathan, “How a Drug Becomes “Ethnic'. Law, Commerce, (1981). and the Production of Racial Categories in Medicine.” Yale Journal Massie et al. Circulation, 63(3):658-664 (1981). of Heath Policy, Law, and Ethics IV: 1 (2004), pp. 1-46. Nelson etal, Journal of Cardiovascular Pharmacology, 5(4):574-579 Parker, John D., et al., “The Effect of Hydralazine on the Devel (1983). opment of Tolerance to Continuous Nitroglycerin.” The Journal of Leier et al. Circulation, 63(1): 102-109 (1981). Pharmacology and Experimental Therapeutics, vol. 280, No. 2, pp. Wilson et al. The American Journal of Medicine, 71:627-633 866-875. (1981). Kalinowski, Leszek, et al., “Race-Specific Differences in Biddle et al., J. Clin. Pharmacol., 21:343-350 (1981). Endothelial Function—Predisposition of African Americans to Vas Margorien et al. Clinical Research, 27(4): A617 (1979), incomplete. cular Diseases.” Circulation, Jun. 1, 2004, pp. 25.11-2517. Turner et al. Clinical Research, 29(2):246A (1981), abstract only. Tucker, A.T. et al. Nov. 13, 1999, “Effect of nitric-oxide-generating Hibiya et al. Japanese Circulation Journal, 45:966 (Abstract No. system on microcirculatory blood flow in skin of patients with 338) (1981), abstract only. severe Raynaud's syndrome: a randomised trial', lancet vol. 354. Franciosa et al., Circulation, 59(6):1085-1091 (1979). #13, pp. 1670-1675. Lanas et al. Rev. Med. Chile, 107:926-930 (1979), abstract only. Apr. 05, 2005. Supplementary European Search Report from Euro Usdin et al. Coeur, 10(1): 119-128 (1979), article in french only pean Patent Application No. 01932915.0. abstract considered. Jun. 21, 2004. Supplementary Partial European Search Report for Burnier et al. Hypertension, 22(3):339-347 (Sep. 1993), recieved EP OO 97 6651O. May 30, 2006. Franciosa, Joseph A., “African-American Heart Failure Trial von Lutterotti et al. American Journal of Hypertension, 4(4 Part (A-HeFT): Rationale, Design, and Methodology,” Journal of Car 2):346S-349S (1991), recd May 30, 2006. diac Failure, vol. 8, No. 3, 2002, pp. 128-135. Massie et al. Br. Heart J., 45:37.6-384 (1981), recd. May 30, 2006. Yancy, Clyde W., et al., “Race and the Response to Adrenergic Lanas et al. Rev. Med. Chile, 107:926-930 (1979). Blockage with Carvedilol in Patients with Chronic Heart Failure.” Usdin et al. Coeur, 10(1): 119-128 (1979). N. Engl. J. Med., vol. 344, No. 18, May 3, 2001, pp. 1358-1365. Parker, John D., et al., “The Effect of Hydralazine on the Devel Yancy, Clyde W. “Heart Failure in African Americans: A Cardio opment of Tolerance to Continuous Nitroglycerin.” The Journal of vascular Enigma,” Journal of Cardiac Failure, vol. 6, No. 3, 2000, Pharmacology and Experimental Therapeutics, vol. 280, No. 2, pp. pp. 183-186. 866-875, 1997. U.S. Patent Jun. 26, 2007 Sheet 1 of 3 US 7,235,237 B2 FIG. 1 Decreased Renin Release NO Insufficiency Salt/Water Retention Increased Intracellular Increased Sensitivity to Sodium & Calcium Catecholamines and Angiotensin II LVH a. Increased Vascular Tone Decreased Capillary Density Myocardial Fibrosis Hypertension Microvascular Increased LV Mass Cardiac schemia Diastolic Dysfunction FIG.
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