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(12) United States Patent (10) Patent No.: US 6,747,020 B2 Perez Et Al

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(12) United States Patent (10) Patent No.: US 6,747,020 B2 Perez Et Al USOO6747020B2 (12) United States Patent (10) Patent No.: US 6,747,020 B2 Perez et al. (45) Date of Patent: *Jun. 8, 2004 (54) METHODS OF TREATING HEART FAILURE (62) Division of application No. 09/434,685, filed on Nov. 5, AND HYPERTENSION USING 1999, now Pat. No. 6,410,524, which is a continuation of application No. PCT/US99/26206, filed on Nov. 5, 1999 COMBINATIONS OF EPLERENONE AND AN (60) Provisional application No. 60/107,398, filed on Nov. 6, ANGOTENSIN CONVERTING ENZYME 1998, provisional application No. 60/122,977, filed on Mar. INHIBITOR 5, 1998, and provisional application No. 60/122,978, filed on Mar. 5, 1998. (75) Inventors: Alfonzo T. Perez, Lake Forest, IL (US); Debra J. ASner, Morton Grove, IL (51) Int. Cl. .............................................. A61R 311585 (US); Richard J. LaChapelle, (52) U.S. Cl. ....................................................... 514/175 Wilmette, IL (US); John C. Alexander, (58) Field of Search .......................................... 514/175 Princeton, NJ (US); Barbara Roniker, Chicago, IL (US) (56) References Cited (73) Assignee: Pharmacia Corporation, St. Louis, U.S. PATENT DOCUMENTS MO (US) 3.257,390 A * 6/1966 Patchett ...................... 540/118 4,129,564 A * 12/1978 Wiechert et al............. 514/175 (*) Notice: Subject to any disclaimer, the term of this 4,559,332 A * 12/1985 Grob et al. ................. 514/175 patent is extended or adjusted under 35 4,789,668 A * 12/1988 Nickisch et al. ............ 514/173 U.S.C. 154(b) by 0 days. * cited by examiner This patent is Subject to a terminal dis Primary Examiner James H. Reamer claimer. (74) Attorney, Agent, or Firm-Joseph R. Schuh; J. Timothy Keane (21) Appl. No.: 10/077,134 (57) ABSTRACT (22) Filed: Feb. 15, 2002 Methods of using eplerenone, an angiotensin converting (65) Prior Publication Data enzyme inhibitor and optionally a diuretic are described for US 2003/004.0484A1 Feb. 27, 2003 treatment of heart failure and hypertension. Related U.S. Application Data 39 Claims, 8 Drawing Sheets U.S. Patent Jun. 8, 2004 Sheet 2 of 8 US 6,747,020 B2 U.S. Patent Jun. 8, 2004 Sheet 4 of 8 O"/ 2.‘O O"O U.S. Patent Jun. 8, 2004 Sheet 5 of 8 US 6,747,020 B2 Aa177/ AAM/ AZA CalASAS ause AMAAA/WAGA res 7 yar moulmar See 7 Yap amala A/ AAC/OWAAAC77OW C26 % ammammo 226 2. campaanamo AAAA7 AA//d/AA WOWSOHAMMO. a-a-arm WSCAMC ammome-mm MMA2/4/W CAEAVAWWA (ASA Of A/6/74/AS WO -o-Hi YAS mammam (ASA OAAOA/W/AS/7OA AMO amasunamgaarmammammam YAS Hampm-re SAY AW4/A - Ma/A mannpm MAA/4/V AO724.SSWW : C2.2/7/77O//7/7A77 - e 4.2/77/77O//7/7A77 ammermammo MVYA C/4SS A// mirro-am ?/ - A72-A/OO.277 ASA WO monume dASA OA YAS AO74SSA/SAAWA/W7S : WO YAS ------------ O.2 O.4 O6 O.9 A.O /.2 A.4 SAAOWOZAC/OMWA AACAAO A77AA AA77AAp A767. 4 U.S. Patent Jun. 8, 2004 Sheet 6 of 8 US 6,747,020 B2 WOO OSA/AOWOZAC72WE 2 AACAAO 75 AAPOWAGA 25 O ASOAMVC WOWSOAMC ASOAM70 WOWASCA74/ AA C26% AA 2.26% Mya, 62/ Ays agaO AAs AAC77OAV AA7A07/OW A79.5 MOO O SPAMMOLAC/MWE 2 AACAAO 75 AACE/W726A OAA477EW7S W/O AWAA) 5O 25 OAASS /// 674SS, A/ Myar//75 M/s 463 A77. 6 US 6,747,020 B2 1 2 METHODS OF TREATING HEART FAILURE dependent factors (such as K, ACTH) that promote ALDO AND HYPERTENSION USING Synthesis. Hepatic blood flow, by regulating the clearance of COMBINATIONS OF EPLERENONE AND AN circulating ALDO, helps determine ALDO plasma ANGOTENSIN CONVERTING ENZYME concentration, an important factor in heart failure charac INHIBITOR terized by reduction in cardiac output and hepatic blood flow. CROSS-REFERENCE TO RELATED The renin-angiotensin-aldosterone system (“RAAS”) is APPLICATIONS one of the hormonal mechanisms involved in regulating preSSure/volume homeostasis and also in the development of This application is division of Ser. No. 09/434,635 filed hypertension, a precursor condition implicated in the pro Nov. 5, 1999, now U.S. Pat. No. 6,410,524, which is a gression of more Serious cardiovascular diseaseS Such as continuation of PCT/US 99/26206 filed Nov. 5, 1999, which congestive heart failure. Activation of the renin-angiotensin claims priority from U.S. provisional patent application Ser. aldosterone System begins with Secretion of the enzyme No. 60/107,398 filed on Nov. 6, 1998; U.S. provisional renin from the juxtaglomerular cells in the kidney. The patent application Ser. No. 60/122,977 filed on Mar. 5, 1998; 15 enzyme renin acts on a naturally-occurring Substrate, U.S. provisional patent application Ser. No. 60/122,978 filed angiotensinogen, to release a decapeptide, Angiotensin I. on Mar. 5, 1998. Each of these priority applications is This decapeptide is cleaved by angiotensin converting Specifically incorporated herein by reference. enzyme (“ACE) to provide an octapeptide, Angiotensin II, the primary active Species of this System. This octapeptide, FIELD OF THE INVENTION angiotensin II, is a potent vasoconstrictor and also produces Combinations of an angiotensin converting enzyme other physiological effects Such as Stimulating aldosterone inhibitor and an aldosterone antagonist are described for use Secretion, promoting Sodium and fluid retention, inhibiting in treatment of circulatory disorders, including cardiovas renin Secretion, increasing Sympathetic nervous System cular diseaseS Such as heart failure, hypertension and con activity, Stimulating vasopressin Secretion, causing a posi gestive heart failure. Of particular interest are therapies 25 tive cardiac inotropic effect and modulating other hormonal using a Spirolactone-type aldosterone antagonist compound Systems. in combination with an angiotensin converting enzyme Emphasis has been placed on minimizing hyperaldoster inhibitor to reduce the death rate or the number of non-fatal onism as a basis for optimizing patient treatment. This hospitalizations in patients. includes the importance of ALDO-receptor antagonism both in patients treated with conventional diuretic programs and BACKGROUND OF THE INVENTION in patients treated with angiotensin-converting enzyme Myocardial (or cardiac) failure, that is, heart failure (ACE) inhibitors, who are often constrained to small doses ("HF"), whether a consequence of previous myocardial of ACE inhibitor because of orthostatic hypotension. Such infarction(s), heart disease associated with hypertension, or patients may demonstrate a recurrence of heart failure primary cardiomyopathy, is a major health problem of 35 Symptoms likely related to elevations in plasma ALDO Worldwide proportions. The incidence of Symptomatic heart levels. failure has risen Steadily over She past Several decades. Many aldosterone blocking drugs and their effects in In clinical terms, decompensated cardiac failure consists humans are known. For example, Spironolactone is a drug of a constellation of Signs and Symptoms that arise from which acts at the mineralocorticoid receptor level by com congested organs and poorly perfused tissues to form con 40 petitively inhibiting aldosterone binding. This steroidal gestive heart failure (CHF) Syndrome. Congestion is caused compound has been used for blocking aldosterone largely by increased venous pressure and by inadequate dependent Sodium transport in the distal tubule of the kidney sodium (Na") excretion, relative to dietary Na" intake, and in order to reduce edema and to treat essential hypertension is importantly related to circulating levels of aldosterone and primary hyperaldosteronism F. Mantero et al., Clin. Sci. 45 Mol. Med., 45 (Suppl 1), 219s-224s (1973). Spironolactone (ALDO). An abnormal retention of Na" occurs via tubular is also used commonly in the treatment of other epithelial cells throughout the nephron, including the later hyperaldosterone-related diseases Such as liver cirrhosis and portion of the distal tubule and cortical collecting ducts, congestive heart failure F. J. Saunders et al., AldactOne, where ALDO receptor Sites are present. Spironolactone. A Comprehensive Review, Searle, New ALDO is the body's most potent mineralocorticoid hor 50 York (1978)). Progressively-increasing doses of spironolac mone. AS implied by the term mineralocorticoid, this Steroid tone from 1 mg to 400 mg per day i.e., 1 mg/day, 5 mg/day, hormone has mineral-regulating activity. It promotes Na' 20 mg/day were administered to a Spironolactone-intolerant reabsorption not only in the kidney, but also from the lower patient to treat cirrhosis-related ascites P. A. Greenberger et gastrointestinal tract and Salivary and Sweat glands, each of al, N. Eng. Reg. Allergy Proc., 7(4), 343-345 (July-August, which represents classic ALDO-responsive tissues. ALDO 55 1986)). It has been recognized that development of myo regulates Na" and water resorption at the expense of potas cardial fibrosis is sensitive to circulating levels of both sium (K) and magnesium (Mg) excretion. Angiotensin II and aldosterone, and that the aldosterone ALDO can also provoke responses in non-epithelial cells. antagonist Spironolactone prevents myocardial fibrosis in Elicited by a chronic elevation in plasma ALDO level that is animal models, thereby linking aldosterone to excessive inappropriate relative to dietary Na' intake, these responses 60 collagen deposition D. Klug et al, Am. J. Cardiol.., 71(3), can have adverse consequences on the Structure of the 46A-54A (1993)). Spironolactone has been shown to pre cardiovascular System. Hence, ALDO can contribute to the vent fibrosis in animal models irrespective of the develop progressive nature of myocardial failure for multiple rea ment of left Ventricular hypertrophy and the presence of SOS. hypertension C. G. Brilla et al., J. Mol. Cell. Cardiol., 25(5), Multiple factors regulate ALDO synthesis and 65 563-575 (1993). Spironolactone at a dosage ranging from metabolism, many of which are operative in the patient with 25 mg to 100 mg daily is used to treat diuretic-induced myocardial failure. These include renin as well as non-renin hypokalemia, when orally-administered potassium Supple US 6,747,020 B2 3 4 ments or other potassium-Soaring regimens are considered gestive heart failure are described in PCT Application WO inappropriate Physicians' Desk Reference, 46th Edn., p.
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