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WO 2010/059119 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 2 7 May 2010 (27.05.2010) WO 2010/059119 Al (51) International Patent Classification: (74) Agent: ASTRAZENECA INTELLECTUAL PROP¬ A61K 31/5386 (2006.01) A61K 31/343 (2006.01) ERTY; AstraZeneca AB, SE-15 1 85 Sδdertalje (SE). A61P 9/06 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/SE2009/05 13 12 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 20 November 2009 (20. 1 1.2009) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (30) Priority Data: SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, 61/1 16,688 2 1 November 2008 (21 . 1 1.2008) U S TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): AS- (84) Designated States (unless otherwise indicated, for every TRAZENECA AB [SE/SE]; SE-151 8 5 Sδdertalje (SE). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (75) Inventors/Applicants (for US only): ANTZELEVITCH, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Charles [US/US]; Masonic Medical Research Laborato¬ ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, ry, 2150 Bleecker Street, Utica, New York 13501-1787 MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (US). BURASHNIKOV, Alexander [US/US]; Masonic TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Medical Research Laboratory, 2150 Bleecker Street, Uti¬ ML, MR, NE, SN, TD, TG). ca, New York 13501-1787 (US). CARLSSON, Leif [SE/ SE]; AstraZeneca R&D M δlndal, SE-431 8 3 M δlndal Published: (SE). SICOURI, Serge [FR/US]; Masonic Medical Re¬ — with international search report (Art. 21(3)) search Laboratory, 2150 Bleecker Street, Utica, New York 13501-1787 (US). (54) Title: A COMBINATION O F TERT -BUTYL (2- {7- [2- (4-CYANO-2- F LUOROPHENOXY) ETHYL] -9-OXA-3, 7-DI- AZABICYCLO [3.3. 1] NON-3- Y L } ETHYL) CARBAMATE AND CERTAIN ANTIARRHYTHMIC BENZOFURANS (57) Abstract: There is provided a combination product comprising tert-butyl (2-{7-[2-(4-cyano-2- fiuorophenoxy)ethyl]-9- ooxxaa--SSJJ--ddiiaazzaabbiiccyyccllooll^^..SS..llJJnnoonn--SS--yylljjeetthhyyllJJccaarrbbaammaattee ((II)) oorr pphharmaceutically acceptable salts thereof and certain antiarrhythmic benzofuranes (II) or pharmaceutically acceptable salts thereof. A combination of tert -butyl (2-{7- [2- (4-cyano-2- fluorophenoxy) ethyl] -9-oxa-3, 7-diazabicyclo [3.3.1] non-3- yl }ethyl) carbamate and certain antiarrhythmic benzofurans Field of the Invention This invention relates to a new combination of pharmaceutically active compounds. In particular the invention relates to a combination of tert-butyi (2-{7-[2-(4-cyano-2- fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3. l]non-3-yl}ethyl)carbamate (I) or pharmaceutically acceptable salts thereof and certain antiarrhythmic benzofurans (II) or pharmaceutically acceptable salts thereof. Background to the Invention Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)). In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New EnglandJournal of Medicine, 321, 406 (1989)) with class I antiarrhythmic drugs, acting primarily by slowing the conduction velocity of the electrical impulse, has directed drug development towards compounds delaying cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans membrane action potential duration (which can be caused by a block of outward K+ currents or from an increase of inward ion currents) and increase refractoriness, without affecting cardiac conduction. One of the key disadvantages of hitherto known drugs which act by delaying ventricular repolarization (class III or otherwise) is that they potentially induce a unique form of proarrhythmia known as torsades depointes (turning of points, TdP), which may, on occasion, be fatal. From a safety point of view, the minimisation of this drawback (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective and safe antiarrhythmic drugs. The use of tert-hvXy\ (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7- diazabicyclo[3 .3 .1]non-3-yl} ethyl)carbamate (I) in the treatment of cardiac arrhythmias is disclosed in WO 2006/135316. The combination between oxabispidine-based compounds and any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders is disclosed in WO 01/28992. (2-Butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo-phenyl]-methanone (Amiodarone) was initially developed in 1961 for the treatment of angina pectoris. Amiodarone has been used as an anti-arrhythmic drug since the 1970's. Currently amiodarone is approved by the US Food and Drug Administration for refractory ventricular arrhythmias but not for the management of atrial fibrillation (AF). Nonetheless, it is widely prescribed for conversion of AF as well as maintenance of sinus rhythm (New Engl. J. Med., 356, 935 (2007), JAMA, 298, 1312 (2007)). Amiodarone has complex pharmacodynamic and pharmacokinetic characteristics. It blocks sodium, potassium and calcium currents and has anti-adrenergic effects and thus possess class I, II, III and IV antiarrhythmic effects. Furthermore, amiodarone exhibit different electrophysiological effects when administered acutely (intravenous administration) and chronically (oral administration). Amiodarone delays myocardial repolarisation (thus prolonging the QT interval) and increases refractoriness and influences thyroid function, the latter effect suggested to contribute to the antiarrhythmic action following chronic treatment. Despite pronounced QT prolongation caused by amiodarone, occurrence of ventricular proarrhythmias is rare. Experimental as well as clinical arrhythmia studies combining amiodarone with other repolarisation-delaying antiarrhythmic agents like ibutilide and sotalol suggest that the combination is equally effective and safe as when the drugs combined with amiodarone are used alone {Circulation, 103, 253 (2001), PACE, 28, 954 (2005), Pharmacotherapy, 27, 1297, (2007)). Amiodarone is a highly lipophilic compound with a large volume of distribution resulting in a delayed onset of action and long elimination half-life (up to 6 months). Consequently, there is a substantial lag between the initiation, modification, or discontinuation of treatment with amiodarone and a change in drug activity. Amiodarone is predominantly metabolised in the liver and the active metabolite N-desethylamiodarone has a longer half- life. Amiodarone interacts with the hepatic metabolism of many medications, the most common being digoxin and warfarin. Amiodarone treatment is associated with both cardiovascular and noncardiovascular side effects causing discontinuation of therapy in 13 to 18% of patients after 1 year. The potential adverse events include corneal microdeposits, ocular neuropathy/neuritis, skin discoloration, photosensitivity, altered thyroid function, pulmonary toxicity, hepatotoxicity and bradycardia. The therapeutic challenge with Amiodarone is thus to use the lowest dose possible to get benefit in order to avoid side effects. Λ/-[2-Butyl-3-({4-[3-(dibutylamino)propoxy]phenyl}carbonyl)-l-benzofuran-5- yljmethanesulfonamide (Dronedarone) is a noniodinated benzofuran derivative. Some data suggests that, in contrast to Amiodarone, Dronedarone does not alter plasma thyroid hormone levels in normal rats {Eur. J. Pharmacol, 444, 191 (2002)). The elimination half- life is 27-3 1 h, considerably shorter than Amiodarone. 1-Methylethyl 2-butyl-3-( {4-[3-(dibutylamino)propyl]phenyl} carbonyl)- 1-benzofuran-5- carboxylate (SSR-149744, Celivarone) is another noniodinated benzofuran derivative, with similar electrophysical effects to Dronedarone {Heart Rhythm, 4, S72, (2007) (abstract, AB 33-4)). (IS)- 1-Methylpropyl [3-( {4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl} carbonyl)-l - benzofuran-2-yl] acetate (ATI-2042, Budiodarone) is an iodinated benzofuran derivative, with similar electrophysical effects to Amiodarone (Europace, 11, 458, (2009). We have surprisingly found that the combination of tert-butyi (2- {7-[2-(4-cyano-2- fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3. l]non-3-yl}ethyl)carbamate (I) and certain antiarrhythmic benzofuranes (II) exhibit unexpectedly beneficial properties for use in the treatment of cardiac arrhythmias. Disclosure of the Invention According to one aspect of the invention, there is provided a combination product comprising: (a) tert-Butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non- 3-yl}ethyl)carbamate (I) or pharmaceutically acceptable salts thereof; and (b) a compound of formula (II) wherein 1 R is H, CO2(C L 4 alkyl) or NHSO 2(C L 4 alkyl); 2 R is C1-6 alkyl or CH 2CO2(CL 4 alkyl); R3, R4 are, independently, halogen or H; 5 6 R , R are, independently, Ci_6 alkyl; X is CH2 or C=O; Y is O or CH2; A is (CH2)n; n is 2 or 3; or pharmaceutically acceptable salts thereof.
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