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N-Hydroxylsulfonamide Derivatives As New Physiologically Useful Nitroxyl

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N-Hydroxylsulfonamide Derivatives As New Physiologically Useful Nitroxyl (19) TZZ ¥Z_T (11) EP 2 489 350 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/18 (2006.01) A61P 9/04 (2006.01) 04.12.2013 Bulletin 2013/49 C07D 207/36 (2006.01) C07D 213/71 (2006.01) C07D 213/74 (2006.01) C07D 231/18 (2006.01) (2006.01) (2006.01) (21) Application number: 12155608.8 C07D 233/84 C07D 239/38 C07D 241/18 (2006.01) C07D 249/12 (2006.01) C07D 261/10 (2006.01) C07D 277/36 (2006.01) (22) Date of filing: 16.03.2007 C07D 285/12 (2006.01) C07D 295/096 (2006.01) C07D 307/64 (2006.01) C07D 307/82 (2006.01) C07D 333/34 (2006.01) C07D 333/62 (2006.01) C07D 263/58 (2006.01) C07D 285/125 (2006.01) (54) N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors N-Hydroxylsulfonamidderivate als neue physiologisch nützliche Nitroxyl-Spender Dérivés de N-hydroxylsulfonamide en tant que nouveaux donateurs de nitrozyle physiologiquement utiles (84) Designated Contracting States: • Courtney, Stephen, Martin AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Oxfordshire, OX14 4SA (GB) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • Frost, Lisa, Marie SI SK TR Oxfordshire, OX14 4SA (GB) • Kalish, Vincent, Jacob (30) Priority: 17.03.2006 US 783556 P Annapolis, MD 21401 (US) (43) Date of publication of application: (74) Representative: Sexton, Jane Helen 22.08.2012 Bulletin 2012/34 J A Kemp 14 South Square (60) Divisional application: Gray’s Inn 12195114.9 / 2 586 433 London WC1R 5JJ (GB) 12195118.0 / 2 586 434 12195124.8 / 2 586 435 (56) References cited: 12195128.9 / 2 596 785 WO-A-2005/074598 WO-A-2007/002444 US-A- 3 751 255 US-A1- 2004 038 947 (62) Document number(s) of the earlier application(s) in US-B2- 6 936 639 accordance with Art. 76 EPC: 07753345.3 / 1 998 761 (73) Proprietors: • Johns Hopkins University School of Medicine Baltimore, MD 21201 (US) • Cardioxyl Pharmaceuticals, Inc. Towson, Maryland 21204 (US) (72) Inventors: • Toscano, John, P. Glen Arm, MD 21057 (US) • Brookfield, Frederick, Arthur Oxfordshire, OX14 4SA (GB) • Cohen, Andrew, D. Mamaroneck, NY 10543 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 489 350 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 489 350 B1 • A. SCOZZAFAVA, ET AL.: "Carbonic anhydrase • DATABASE CAPLUS [Online] CHEMICAL and matrix metalloproteinase inhibitors: ABSTRACTS SERVICE, COLUMBUS, OHIO, US; sulphonylated amino acid hydroxamates with 1956, Z. Talik, et al.: "Syntheses of MMP inhibitory properties act as efficient pyridinesulfohydroxamic acids", XP002679818, inhibitors of CA isozymes I, II, and IV, and N- Database accession no. 1956: 64557 -& Z. TALIK, hydroxysulfonamides inhibit both of these zinc ET AL.: "Syntezy kwasów enzymes", JOURNAL OF MEDICINAL pirydynosulfohydroksamowych", ACTA CHEMISTRY, vol. 43, no. 20, 13 September 2000 POLONIAE PHARMACEUTICA, vol. 12, no. 4, (2000-09-13), pages 3677-3687, XP002394373, 1955, pages 219-222, XP008153461, Polskie AMERICAN CHEMICAL SOCIETY, Towarzystwo Farmaceutyczne, Warsaw, PL WASHINGTON, DC, US ISSN: 0022-2623 -& A. ISSN: 0001-6837 SCOZZAFAVA, ET AL.: "Carbonic anhydrase and matrix metalloproteinase inhibitors: sulphonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N- hydroxysulfonamides inhibit both of these zinc enzymes", JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 6, 8 March 2001 (2001-03-08), page 1016, XP002445147, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US 2 EP 2 489 350 B1 Description STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 5 [0001] This invention was made in part with government support under Grant No. CHE-0518406 from the National Science Foundation. The government may have certain rights in this invention. BACKGROUND OF THE INVENTION 10 Summary of Heart Failure [0002] Congestive heart failure (CHF) is a generally progressive, life threatening condition in which myocardial con- tractility is depressed such that the heart is unable to adequately pump the blood returning to it, also referred to as decompensation. Symptoms include breathlessness, fatigue, weakness, leg swelling, and exercise intolerance. On 15 physical examination, patients with heart failure often have elevated heart and respiratory rates (an indication of fluid in the lungs), edema, jugular venous distension, and enlarged hearts. The most common cause of CHF is atherosclerosis, which causes blockages in the coronary arteries that provide blood flow to the heart muscle. Ultimately, such blockages may cause myocardial infarction with subsequent decline in heart function and resultant heart failure. Other causes of CHF include valvular heart disease, hypertension, viral infections of the heart, alcohol consumption, and diabetes. Some 20 cases of CHF occur without clear etiology and are called idiopathic. The effects of CHF on a subject experiencing the condition can be fatal. [0003] There are several types of CHF. Two types of CHF are identified according to which phase of the cardiac pumping cycle is more affected. Systolic heart failure occurs when the heart’s ability to contract decreases. The heart cannot pump with enough force to push a sufficient amount of blood into the circulation leading to a reduced left ventricular 25 ejection fraction. Lung congestion is a typical symptom of systolic heart failure. Diastolic heart failure refers to the heart’ s inability to relax between contractions and allow enough blood to enter the ventricles. Higher filling pressures are required to maintain cardiac output, but contractility as measured by left ventricular ejection fraction is typically normal. Swelling (edema) in the abdomen and legs is a typical symptom of diastolic heart failure. Often, an individual experiencing heart failure will have some degree of both systolic heart failure and diastolic heart failure. 30 [0004] CHF is also classified according to its severity. The New York Heart Association classifies CHF into four classes: Class I involves no obvious symptoms, with no limitations on physical activity; Class II involves some symptoms during or after normal activity, with mild physical activity limitations; Class III involves symptoms with less than ordinary activity , with moderate to significant physical activity limitations; and Class IV involves significant symptoms at rest, with severe to total physical activity limitations. Typically, an individual progresses through the classes as they live with the condition . 35 [0005] Although CHF is generally thought of as a chronic, progressive condition, it can also develop suddenly. This type of CHF is called acute CHF, and it is a medical emergency. Acute CHF can be caused by acute myocardial injury that affects either myocardial performance, such as myocardial infarction, or valvular/chamber integrity, such as mitral regurgitation or ventricular septal rupture, which leads to an acute rise in left ventricular and diastolic pressure resulting in pulmonary edema and dyspnea. 40 [0006] Common treatment agents for CHF include vasodilators (drugs that dilate blood vessels), positive inotropes (drugs that increase the heart’s ability to contract), and diuretics (drugs to reduce fluid). Additionally, beta-antagonists (drugs that antagonize beta-adrenergic receptors) have become standard agents for treating mild to moderate heart failure. Lowes et al, Clin. Cardiol., 23:III11-6 (2000). [0007] Positive inotropic agents include beta-adrenergio agonists, such as dopamine, dobutamine, dopexamine, and 45 isoproterenol. However, use of a beta-agonist has potential complications, such as arrhythmogenesis and increased oxygen demand by the heart. Additionally, the initial short- lived improvement of myocardial contractility afforded by these drugs is followed by an accelerated mortality rate resulting largely from a greater frequency of sudden death. Katz, HEART FAILURE: PATHOPHYSIOLOGY, MOLECULAR BIOLOGY AND CLINICAL MANAGEMENT, Lippincott, Wil- liams & Wilkins (1999). 50 [0008] Beta-antagonists antagonize beta-adrenergic receptor function. While initially contra- indicated in heart failure, they have been found to provide a marked reduction in mortality and morbidity in clinical trials. Bouzamondo et al., Fundam. Clin. Pharmacol., 15: 95-109 (2001). Accordingly, they have become an established therapy for heart failure. However, even subjects that improve under beta- antagonist therapy may subsequently decompensate and require acute treatment with a positive inotropic agent. Unfortunately, as their name suggests, beta- antagonists block the mechanism 55 of action of the positive inotropic beta-agonists that are used in emergency care centers. Bristow et al., J. Card. Fail., 7: 8-12 (2001). [0009] Vasodilators, such as nitroglycerin, have been used for a long period of time to treat heart failure. However, the cause of nitroglycerin’s therapeutic effect was not known until late in the last century when it was discovered that 3 EP 2 489 350 B1 the nitric oxide molecule (NO) was responsible for nitroglycerin’s beneficial effects. In some subjects experiencing heart failure, a nitric oxide donor is administered in combination with a positive inotropic agent
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