(19) TZZ_ ¥_T (11) EP 1 778 234 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/501 (2006.01) A61K 31/4412 (2006.01) 05.10.2011 Bulletin 2011/40 A61K 31/4427 (2006.01) A61K 31/444 (2006.01) A61K 31/4166 (2006.01) A61P 9/00 (2006.01) (21) Application number: 05716238.0 (86) International application number: (22) Date of filing: 19.03.2005 PCT/EP2005/002957 (87) International publication number: WO 2005/092343 (06.10.2005 Gazette 2005/40) (54) PIMOBENDAN TO BE USED FOR THE REDUCTION OF HEART SIZE IN MAMMALS SUFFERING FROM HEART FAILURE PIMOBENDAN ZUR VERWENDUNG ZUR VERRINGERUNG DER HERZGRÖSSE VON SÄUGETIEREN MIT HERZINSUFFIZIENZ PIMOBENDAN UTILISE POUR LA REDUCTION DE LA TAILLE DU COEUR CHEZ DES MAMMIFERES SOUFFRANT D’INSUFFICANCES CARDIAQUES (84) Designated Contracting States: • KLEEMANN, Rainer AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 55218 Ingelheim (DE) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR Designated Extension States: (74) Representative: Hammann, Heinz BA HR LV Boehringer Ingelheim Pharma GmbH & Co. KG Binger Strasse 173 (30) Priority: 25.03.2004 EP 04007179 55216 Ingelheim am Rhein (DE) (43) Date of publication of application: (56) References cited: 02.05.2007 Bulletin 2007/18 US-A- 4 361 563 US-A- 4 654 342 US-A- 4 868 182 US-A- 4 906 628 (73) Proprietor: Boehringer Ingelheim Vetmedica US-A- 5 151 420 US-A- 5 569 657 GmbH 55216 Ingelheim am Rhein (DE) • BEERS, M.H. ET AL.: "Merck Manual of Diagnosis and Therapy, 17th Edition" 1999, MERCK (72) Inventors: RESEARCH LABORATORIES , WHITEHOUS • DAEMMGEN, Juergen STATION, N.J., USA , XP002331318 page 1688 - 88416 Ochsenhausen (DE) page 1692 • JÖNS, Olaf 55218 Ingelheim (DE) 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 1 778 234 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 778 234 B1 Description BACKGROUND OF THE INVENTION 5 1. TECHNICAL FIELD [0001] The invention relates to the use of pimobendan for the preparation of a medication for the reduction of the heart size of a patient suffering from heart failure. 10 2. BACKGROUND INFORMATION [0002] Intravenous positive inotropic agents play a vital role in the management of acute heart failure, and will often result in a short-term improvement in dogs with dilated cardiomyopathy (DCM). Many dogs with DCM have a very guarded prognosis (Monnet et al., 1995), with Dobermanns in particular generally experiencing only short survival times 15 (Calvert et al., 1982; Calvert et al., 1997). There have been few studies examining the influence of treatment on survival in dogs with DCM, although a subanalysis of the dogs with DCM in the LIVE study showed an improvement in time to treatment failure in those dogs receiving enalapril compared with placebo (142.8 versus 56.5 days, respectively) (Ettinger et al., 1998). On the whole, oral positive inotropic agents have lost favour in the treatment of chronic heart failure in human patients in recent years, after a number of trials revealed adverse effects on survival despite short-term hemo- 20 dynamic benefits (Packer et al., 1991; Cowley and Skene, 1994). Recently it has been suggested that calcium sensitising agents may result in positive inotropic effects without producing some of the adverse effects (including calcium overload) associated with more traditional positive in otropes such as dobutamine, amrinone and milrinone. [0003] Pimobendan is an inodilator compound with calcium sensitising effects, as well as some phosphodiesterase type III inhibitory effects. Rather than increasing calcium entry into cardiac myocytes, calcium sensitisers achieve their 25 positive inotropic effect by sensitising the contractile proteins to existing cytosolic calcium, by altering the binding of calcium with troponin-C. Producing a positive inotropic effect by calcium sensitising thereby avoids some of the adverse effects of cytosolic calcium overload. Increased cytosolic calcium levels have been associated with an increased tendency for arrhythmias and sudden death. Clinical trials of long-term use of oral pimobendan in human patients with heart failure have demonstrated an improvement in exercise tolerance and quality of life without significantly adverse effects on 30 survival (Kubo et al., 1992; Katz et al., 1992). [0004] US 4 361 563 discloses pimobendan to be used to increase the strength of myocardial contraction. [0005] US 5 151 420 reports about the treatment of congestive heart failure with pimobendan. [0006] US 4 868 182 discloses the use of α-adrenoceptor antagonists in admixture with pimobendan etc. in the treatment of congestive heart failure. 35 [0007] It is known that the progress of heart failure is associated with an increase of the size of the heart. In dilated cardiomyopathy (DCM) the ratio of left ventricular wall thickness to chamber diameter is decreased and the circumfer- ences of the annuluses of the mitral and tricuspid valves are increased in proportion to the magnitude of chamber dilation. DCM may either be caused primarily by e.g. genetic abnormalities ar secondarily e.g. due to valvular insufficiency both resulting in cardiac volume overload. However, it involves usually cardiac remodeling that may be defined as genome 40 expression, molecular, cellular, and interstitial changes manifested clinically as changes in size, shape, and function of the heart. Cardiac remodelling is generally an adverse sign and linked to heart failure progression. Reverse cardiac remodelling is a goal of the treatment of heart failure therapy. [0008] Heart failure therapy has traditionally focussed largely on symptomatic relief rather than on addressing under- lying disease problems. 45 [0009] The problem underlying the present invention was to provide a medication, which allows to remodel the size of the heart to reduce the risk of death in patients with coronary diseases. In particular, the problem underlying the present invention was to provide a medication, which allows to reduce the size of the heart to reduce the risk of death in patients suffering from heart failure. 50 BRIEF DESCRIPTION OF THE INVENTION [0010] It has been found surprisingly that pimobendan can be used for the preparation of a medication for the reduction of the heart size of a patient suffering from heart failure. [0011] Moreover, the invention relates to a use for reduction of the heart size in a patient suffering from heart failure, 55 which use comprises administering to said patient an effective amount of pimobendan. [0012] Furthermore, the invention relates to an article of manufacture comprising packaging material contained within which is a composition effective to reduce of the heart size of a patient suffering from heart failure and the packaging material comprises a label which indicates that the composition can be used to reduce of the heart size of a patient 2 EP 1 778 234 B1 suffering from heart failure, wherein said composition comprises pimobendan BRIEF DESCRIPTION OF THE DRAWINGS 5 [0013] Figure 1 shows the lateral thoracic radiograph of an English cocker spaniel with dilated cardiomyopathy, showing alveolar pulmonary oedema and cardiac enlargement. 10 Figures 2a and 2b show the thoracic radiograph of the same dog in Fig. 1, following four months treatment with furosemide, enalapril, digoxin, and pimobendan. Figure 3 shows the Heart Insufficiency Score (ISACHC) in dogs treated with pimobendan (each left black column) or benazepril (each right grey column) on days 0, 7 and 56. 15 Figure 4 shows the Overall Clinical Effect in dogs treated with pimobendan (left black column) or benazepril (right grey column) on day 56. Figure 5 shows the survival function (56-day period) in dogs treated with pimobendan (upper-s-curve) orbenazepril 20 (lower-h-curve). Figure 6 shows the survival function in dogs treated with pimobendan (430-day period / upper-s-curve) or benazepril (228-day period / lowe-h-curve). 25 Figure 7 shows reduction in mean heart size for pimobendan treated dogs (-0.15 v) versus benazepril treated dogs (+0.22 v). DETAILLED DESCRIPTION OF THE INVENTION 30 [0014] The invention relates to the use of pimobendan for the preparation of a medication for the reduction of the heart size of a patient suffering from heart failure. [0015] Pimobendan, known to the public as 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3 (2H)-pyridazone, is for example disclosed in EP 008 391 B1. Levosimendan is a pyridazone-dinitrile derivative. In particular, levosimendan is known to the public as (R)-[[4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydra 35 zono]propanedini trile and has been described earlier for example in GB 2228004, US 5,151,420 and US 5,569,657. [0016] The term "patient" as used hereinabove and hereinbelow relates to an animal or a person suffering from heart failure. The term "patient" embraces mammal such as primates including humans. [0017] In addition to primates, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals, including but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats 40 or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species. [0018] Preferred are human patients, dogs, cats and horses. Human patients are female or male person who are suffering from heart failure.