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.

According to another 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, CO2CH(CHs)2 OrNHSO2CH3; R2 is n-butyl or 3-{[(15)-l-methylpropyl]oxy}-3-oxopropyl; R3, R4 are, independently, I or H; R5, R6 are, independently, ethyl or n-butyl; X is C=O;

Y is O or CH2;

A is (CH2)n; n is 2 or 3; or pharmaceutically acceptable salts thereof.

According to a further 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) which is (2-butylbenzofuran-3-yl)-[4-(2- diethylaminoethoxy)-3 ,5-diiodo-phenyl]-methanone (Amiodarone)

wherein R1 is H; R2 is n-butyl; R3, R4 are I; R5, R6 are ethyl; X is C=O; Y is O;

A is (CH2)2; or pharmaceutically acceptable salts thereof.

According to a further aspect of the invention, there is provided a combination product comprising: (a) r -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) which is iV-[2-butyl-3-({4-[3- (dibutylamino)propoxy]phenyl}carbonyl)-l-benzofuran-5-yl]methanesulfonamide (Dronedarone)

wherein

1 R is NHSO2CH3; R2 is n-butyl; R3, R4 are H; R5, R6 are n-butyl; X is C=O; Y is O;

A is (CH2)3; or pharmaceutically acceptable salts thereof.

or pharmaceutically acceptable salts thereof; and (b) a compound of formula (II) which is 1-methylethyl 2-butyl-3-({4-[3- (dibutylamino)propyl]phenyl}carbonyl)-1-benzofuran-5-carboxylate (Celivarone)

wherein

1 R is CO2CH(CHs)2; R2 is n-butyl; R3, R4 are H; R5, R6 are n-butyl; X is C=O;

Y is CH2;

A is (CH2)2; or pharmaceutically acceptable salts thereof.

or pharmaceutically acceptable salts thereof; and (b) a compound of formula (II) which is (15)-l-methylpropyl [3-({4-[2- (diethylamino)ethoxy]-3,5-diiodophenyl}carbonyl)-l-benzofuran-2-yl]acetate (Budiodarone)

wherein R1 is H; R2 is 3-{[(15)-l-methylpropyl]oxy}-3-oxopropyl; R3, R4 are I; R5, R6 are ethyl; X is C=O; Y is O;

A is (CH2)2; or pharmaceutically acceptable salts thereof. The compounds named were named using ACD/Name 10.04 from ACD/Labs.

For the avoidance of doubt it is to be understood that in this specification "Ci " means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C1 4" means a carbon group having 1, 2, 3 or 4 carbon atoms. In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i- hexyl or t-hexyl.

The combination product according to the invention provides for the administration of (I) in conjunction with (II), wherein at least one of those formulations comprises (I) and at least one comprises (II), or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including (I) and (II) (or pharmaceutically- acceptable salts thereof)).

Thus, there is further provided: (1) a pharmaceutical formulation including (I) and (II), in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation"); and (2) a kit of parts comprising components: (a) a pharmaceutical formulation including (I), in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including (II), in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. According to a further aspect of the invention, there is provided a method of making a kit of parts as defined above, which method comprises bringing a component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.

By bringing the two components "into association with" each other, we include that components (a) and (b) of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

Thus, there is further provided a kit of parts comprising: (i) one of components (a) and (b) as defined herein; together with (ii) instructions to use that component in conjunction with the other of the two components.

The kits of parts described herein may comprise more than one formulation including (I) (or pharmaceutically-acceptable salts thereof), and/or more than one formulation including an appropriate quantity/dose of (II) (or pharmaceutically-acceptable salts thereof), in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of (I) (or pharmaceutically-acceptable salts thereof) and (II) (or pharmaceutically- acceptable salts thereof), chemical composition and/or physical form. With respect to the kits of parts as described herein, by "administration in conjunction with", we include that respective formulations comprising (I) (or pharmaceutically- acceptable salts thereof) and (II) (or pharmaceutically-acceptable salts thereof), are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition, which condition may be acute or chronic. Thus, in respect of the combination product according to the invention, the term "administration in conjunction with" includes that the two components of the combination product ((I) (or pharmaceutically-acceptable salts thereof) and (II) (or pharmaceutically- acceptable salts thereof)) are administered (optionally repeatedly), either (in the case of a combined preparation) together, or (in the case of a kit of parts) sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising (I) (or pharmaceutically-acceptable salts thereof), or a formulation comprising (II) (or pharmaceutically-acceptable salts thereof), are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition, will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.

Further, in the context of a kit of parts according to the invention, the term "in conjunction with" includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include that individual doses of (I) (or pharmaceutically-acceptable salts thereof) and (II) (or pharmaceutically-acceptable salts thereof), are administered within 48 hours (e.g. 24 hours) of each other.

Suitable doses of (I) (or pharmaceutically-acceptable salts thereof) and (II) (or pharmaceutically-acceptable salts thereof), in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients may be determined routinely by the medical practitioner or other skilled person.

In the case of (I) (or pharmaceutically-acceptable salts thereof), typical daily doses of (I) or pharmaceutically-acceptable salts thereof are in the range 10 to 2000 mg, e.g. 25, such as 30, to 1200 mg of free base (i.e., in the case of a salt, excluding any weight resulting from the presence of a counter ion), irrespective of the number of compositions (e.g. tablets) that are administered during the course of that day. Preferred daily doses are in the range 50 to 1000 mg, such as 100 to 500 mg, for example 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg. Typical doses in individual compositions of the invention

(e.g. tablets) are thus in the range 15 to 500 mg, for example 40 to 400 mg e.g. for example 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg.

In the case of (II), suitable doses of active compound, in the therapeutic and/or prophylactic treatment of mammalian, especially human, may be in the range 0.1 mg once daily to 25 mg three times daily, and/or up to 100 mg infused parenterally over a 24 hour period, and in the range 0.1 mg once daily to 100 mg three times daily.

Specifically claimed herein are specific fixed dose combinations where any dose stated for (I) is combined with any dose stated for (II), including the doses stated as limits for the ranges described.

In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the condition that is to be treated, as well as the age, weight, sex and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

When separate formulations are administered, the sequence in which the formulations comprising (I) (or pharmaceutically-acceptable salts thereof) and (II) (or pharmaceutically-acceptable salts thereof), may be administered (i.e. whether, and at what point, sequential, separate and/or simultaneous administration takes place) may be determined by the physician or skilled person. For example, the sequence may depend upon many factors that will be evident to the skilled person, such as whether, at any time during the course or period of treatment, one or other of the formulations cannot be administered to the patient for practical reasons (e.g. the patient is unconscious and thus unable to take an oral formulation comprising either (I) (or pharmaceutically-acceptable salts thereof )or (II) (or pharmaceutically-acceptable salts thereof)).

The method described herein may have the advantage that, in the treatment or prophylaxis of cardiac diseases, it may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have other useful pharmacological properties over, similar methods known in the prior art for the treatment of such conditions.

Preferred modes of delivery are systemic. Preferred modes of administration are intravenous and oral.

The invention encompasses pharmaceutically acceptable salts of the compounds of formula (I) and (II). Where the compounds are sufficiently acidic, pharmaceutically-acceptable salts include, but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, TV-methylpiperidine, iV-ethylpiperidine, procaine, dibenzylamine, N, JV-dibenzylethylamine or amino acids for example lysine. Where the compounds are sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate salt. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. For a review on suitable salts, see Berge et al., J. Pharm. ScL, 66, 1-19 (1977).The invention further encompasses pharmaceutically acceptable solvates of the compounds of formula (I) and (II). The combinations of the present invention are useful in both the treatment and the prophylaxis of cardiac arrhythmias, in particular atrial and ventricular arrhythmias (such as atrial fibrillation and atrial flutter).

The combinations of the invention are thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischemic heart disorders, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.

According to a further aspect of the invention, there is provided a method of treatment of arrhythmia which method comprises administration of a combination of the invention to a person suffering from, or susceptible to, such a condition.

According to a further aspect of the invention, there is provided a method of treatment of atrial fibrillation which method comprises administration of a combination of the invention to a person suffering from, or susceptible to, such a condition.

According to a further aspect of the invention, there is provided a method of treatment of atrial flutter which method comprises administration of a combination of the invention to a person suffering from, or susceptible to, such a condition.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the prophylaxis, of a condition.

It is expected that the combinations of the present invention may provide one or more of the following advantages. Synergy between the components in terms of: - response rate - patient survival rate - time to disease progression - dose/response effects leading to lower doses with same efficacy. Alternatively, it is expected that the combinations of the present invention may provide one or more of the following advantages: lower toxicity/reduced side effects with similar/improved efficacy; improved physical properties, e.g. storage stability, flow properties etc.; ease of formulation for example, reduced drug/drug incompatibility problems; reduced drug/drug interaction problems on administration, for example possible changes in metabolism of one drug caused by the effect of the other drug; improved patient compliance; improved quality of life; convenient dosing regimes; and/or lack of diminishing effects of one drug caused by the presence of the other drug.

The combination product of the present invention can be used both in conversion of atrial fibrillation into normal sinus rhythm and maintenance of said sinus rhythm.

The combination product of the present invention can be used to treat both symptomatic and asymptomatic atrial fibrillation.

The combination product of the present invention can be used to treat paroxysmal atrial fibrillation, persistent atrial fibrillation and permanent atrial fibrillation.

The ratios of the active compound in the combination product of the present invention can be in the range of 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10, 1:50 or 1:100.

The present invention therefore provides the additional advantage that it allows tailoring of treatment to the needs of a particular patient population. Examples of such particular patient population are; 1) elderly patients, especially over the age of 60, preferably over the age of 70, more preferably over the age of 80; 2) female patients; 3) patients suffering from any of the following conditions; hypertension, heart failure, and diabetes, 4) patients undergoing open heart surgery.

The combination product of the present invention, is either additive or synergistic in effect in the treatment of atrial fibrillation, in particular paroxysmal atrial fibrillation, persistent atrial fibrillation and permanent atrial fibrillation of a particular patient population.

Examples of such particular patient population are; 1) elderly patient, especially over the age of 60, preferably over the age of 70, more preferably over the age of 80; 2) female patients; 3) patients suffering from any of the following conditions; hypertension, heart failure, and diabetes.

Experimental part

Left atrial pulmonary vein (PV) sleeve preparations were isolated from untreated dogs or from dogs chronically administered (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)- 3,5-diiodo-phenyl]-methanone (Amiodarone). The preparations were placed in a small tissue bath and superfused with conventional Tyrode's buffered with 95% O2/5% CO at 35°C) and stimulated at a basic cycle length (BCL) of 1000 ms during the equilibration period ( 1 h) using electrical stimulation delivered through silver bipolar. Transmembrane potentials were recorded using glass microelectrodes connected to a high input-impedance amplification system. Electrophysiological effects of (I) were assessed in pulmonary vein sleeve preparations at increasing concentrations. The assessments were carried out in tissue samples excised from untreated dogs and from dogs chronically treated with (2- butylbenzofuran-3 -yl)-[4-(2-diethylaminoethoxy)-3 ,5-diiodo-phenyl] -methanone (Amiodarone) for 6 weeks.

Results Superfusion with (I) was associated with a concentration-dependent increase in excitability. Likewise, chronic treatment with (2-butylbenzofuran-3-yl)-[4-(2- diethylaminoethoxy)-3,5-diiodo-phenyl]-methanone (Amiodarone) markedly depressed PV excitability. Addition of (I) to PV preparations from dogs chronically treated with (2- butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo-phenyl]-methanone (Amiodarone) further depressed excitability giving rise to activation failure at much longer

BCLs than in preparations treated with either compound alone (Figure 1).

Brief description of the drawings Figure 1 displays the effects of (I) on basic cycle length at which activation failure occurred in pulmonary vein sleeve preparations isolated from untreated dogs or dogs chronically treated with (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo- phenyl]-methanone (Amiodarone).

1: Control (n=6) 2: 1 µmol/L t rt-Butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7- diazabicyclo[3.3.1]non-3-yl}ethyl)carbamate (I) (n=6) 3: 3 µmol/L t rt-Butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7- diazabicyclo[3.3 .1]non-3-yl} ethyl)carbamate (I) (n=6)

4: 10 µmol/L tert-Butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7- diazabicyclo[3.3.1]non-3-yl}ethyl)carbamate (I) (n=6)

5: Chronic (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo-phenyl]- methanone (Amiodarone) (n=5)

6: Chronic (2-butylbenzofuran-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodo-phenyl]- methanone (Amiodarone) + 1 µmol/L ert-Butyl (2-{7-[2-(4-cyano-2- fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3. l]non-3-yl}ethyl)carbamate (I) (n=5) Claims

1. A combination product comprising: (a) t-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(C1-4 alkyl) OrNHSO2(Ci -4 alkyl); 2 R is Ci-6 alkyl or CH2CO2(Ci -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; Dis 2 or 3; or pharmaceutically acceptable salts thereof.

2. A combination product according to Claim 1 comprising: (a) t t-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, CO2CH(CH3)2 OrNHSO2CH3; R2 is n-butyl or 3-{[(l S)-l -methylpropyl]oxy}-3-oxopropyl;

R3, R4 are, independently, I or H; R5, R6 are, independently, ethyl or n-butyl; X is C=O; or pharmaceutically acceptable salts thereof.

3. A combination product according to claim 1 comprising: (a) ert-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) which is (2-butylbenzofuran-3-yl)-[4-(2- diethylaminoethoxy)-3,5-diiodo-phenyl]-methanone (Amiodarone)

wherein R1 is H; R2 is n-butyl;

R3, R4 are I; R5, R6 are ethyl; X is C=O; Y is O;

A is (CH2)2; or pharmaceutically acceptable salts thereof.

4. A combination product comprising: (a) tert-Butyl (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 (b) a compound of formula (II) which is -[2-butyl-3-({4-[3- (dibutylamino)propoxy]phenyl}carbonyl)-l-benzofuran-5-yl]methanesulfonamide (Dronedarone)

wherein

R2 is n-butyl; R3, R4 are H; R5, R6 are n-butyl;

X is C=O; Y is O;

A is (CH2)3; or pharmaceutically acceptable salts thereof.

5. A combination product comprising: (a) ert-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) which is 1-methylethyl 2-butyl-3-({4-[3- (dibutylamino)propyl]phenyl}carbonyl)-l-benzofuran-5-carboxylate (Celivarone)

wherein

1 R is CO2CH(CH3)2; R2 is n-butyl; R3, R4 are H; R5, R6 are n-butyl; X is C=O;

Y is CH2;

A is (CH2)2; or pharmaceutically acceptable salts thereof.

6. A combination product comprising: (a) er -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) which is (15)-l-methylpropyl [3-({4-[2- (diethylamino)ethoxy]-3,5-diiodophenyl}carbonyl)-l-benzofuran-2-yl]acetate (Budiodarone)

wherein R1 is H; R2 is 3-{[(15)-l-methylpropyl]oxy}-3-oxopropyl;

R3, R4 are I; R5, R6 are ethyl; X is C=O; Y is O;

A is (CH2)2; or pharmaceutically acceptable salts thereof.

7. A combination product according to any one of Claims 1-6 which comprises a kit of parts comprising components: (a) a pharmaceutical formulation including (I) or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including (II) or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

8. A method of making a kit of parts as defined in Claim 7, which method comprises bringing a component (a), as defined in Claim 7, into association with a component (b), as defined in Claims 7, thus rendering the two components suitable for administration in conjunction with each other.

9. A kit of parts comprising:

(i) one of components (a) and (b) as defined in Claim 7; together with (ii) instructions to use that component in conjunction with the other of the two components.

I5 10. A combination product according to any one of Claims 1 to 6 or a kit of parts as defined in Claim 7 for use in antiarrhythmic therapy.

11. A method of treatment for arrhythmia, which comprises administration of a

20 combination product according to any one of Claims 1 to 6 or a kit of parts as defined in Claim 7 to a patient suffering from, or susceptible to, such a condition.

12. The use of a combination product according to any one of Claims 1 to 6 or a kit of parts as defined in Claim 7 for the manufacture of a medicament for the treatment or

25 prophylaxis of a condition where antiarrhythmic therapy is indicated.

INTERNATIONAL SEARCH REPORT International application No. PCT/SE2009/051312 A. CLASSIFICATION OF SUBJECT MATTER

IPC: see extra sheet According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols)

IPC: A61K, A61P Documentation searched other than minimum documentation to the extent that such documents are included m the fields searched

SE, DK, FI , NO classes as above

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-INTERNAL, WPI DATA, PAJ C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2006135316 A l (ASTRAZENECA AB), 1-12 21 December 2006 (21.12.2006), combination, see page 43

RU 2292885 C2, 000 NPOB FARMATRON NPO FARMATR 1-12 et al, 2007-02-10: (abstract) Retrieved from: EPODOC database

WO 03050102 Al (ARYX THERAPEUTICS), 19 June 2003 1-12 (19.06.2003), see claim 16

WO 2005123748 Al (ASTRAZENECA AB), 1-12 29 December 2005 (29.12.2005), see claim 43

Further documents are listed in the continuation of Box C. See patent family annex.

* Special categories of cited documents: "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention ' E " earlier application or patent but published on or after the international "X" document o f particular relevance: the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) "Y" document o f particular relevance: the claimed invention cannot be considered to involve an inventive step when the document is 'O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled m the art ' P " document published prior to the international filing date but later than the priority date claimed "&" document member o f the same patent family Date of the actual completion of the international search Date of mailing of the international search report 1 0 -03- 2010 10 February 2010

Name and mailing address of the ISA/ Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM Eva Johansson / Eo Facsimile No. + 46 8 666 02 86 Telephone No. + 46 8 782 25 00 Form PCT/ ISA/210 (second sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No. PCT/SE2009/051312

C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

N ϊ kolaos Fragakis, et al. "Efficacy and Safety of 1-12 Ibutilide for cardioversion of Atrial Flutter and Fibrillation in Patients Receiving Amiodarone or Propafenone", PACE, vol. 28, September 2005, pages 954-960

WO 0129018 A2 (ARYX THERAPEUTICS), 26 April 2001 1-12 (26.04.2001), combination of compounds, see page 8 , claim 6

Form PCT/ISA/21 0 (continuation of second sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No. PCT/SE2009/051312

International patent classification (IPC) A61K 31/5386 (2006.01) A61P 9/06 (2006.01) A61K 31/343 (2006.01)

Download your patent documents at wvrw.prv.se The cited patent documents can be downloaded: • From "Cited documents" found under our online services at www.prv. se (English version) • From "Anforda dokument" found under "e-tjanster" at www.prv. se (Swedish version) Use the application number as username. The password is CHZNCWPZQF .

Paper copies can be ordered at a cost of 50 SEK per copy from PRV InterPat (telephone number 08-782 28 85) .

Cited literature, if any, will be enclosed in paper form.

Form PCT/ISA/210 (extra sheet) (July 2008) INTERNATIONAL SEARCH REPORT International application No. Information on patent family members PCT/SE2009/051312

WO 2006135316 Al 21/12/2006 AR 057064 A 14/11/2007 AU 2006258293 A 21/12/2006 CA 2609938 A 21/12/2006 CN 101243093 A 13/08/2008 EC SP078025 A 23/01/2008 EP 1893619 A 05/03/2008 JP 2008543750 T 04/12/2008 KR 20080021114 A 06/03/2008 MX 2007015800 A 04/03/2008 NO 20076052 A 11/03/2008 US 20090054422 A 26/02/2009

WO 03050102 Al 19/06/2003 AU 2002360582 A ,B 11/06/2009 CA 2469730 A 19/06/2003 EP 1451169 A 01/09/2004 JP 2005516010 T 02/06/2005

WO 2005123748 Al 29/12/2005 AR 049823 A 06/09/2006 AU 2005254924 A ,B 27/08/2009 AU 2009222548 A 22/10/2009 BR PI0512012 A 06/02/2008 CA 2568895 A 29/12/2005 CN 1968956 A 23/05/2007 CN 101525339 A 09/09/2009 EP 1765832 A 28/03/2007 JP 2008502678 T 31/01/2008 KR 20070039045 A 11/04/2007 MX PA06014692 A 12/02/2007 NO 20070148 A 09/01/2007 SG 153822 A 29/07/2009 US 7648985 B 19/01/2010 US 20090005558 A 01/01/2009 US 20090270383 A 29/10/2009 UY 28959 A 31/01/2006 ZA 200610418 A 30/07/2008 ZA 200710111 A 26/08/2009

WO 0129018 A2 26/04/2001 AT 369351 T 15/08/2007 AU 774873 B 08/07/2004 AU 1091201 A 30/04/2001 CA 2392016 A 26/04/2001 DE 60035888 D ,T 06/12/2007 DK 1222180 T 27/12/2007 EP 1222180 A ,B 08/08/2007 SE 1222180 T3 ES 2290054 T 16/02/2008 HK 1049829 A 22/02/2008 JP 2003512364 T 02/04/2003 PT 1222180 E 20/09/2007

Form PCT/IS A/210 (patent family annex) (April 200S) INTERNATIONAL SEARCH REPORT International application No. PCT/SE2009/051312

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

Claims Nos.: 1 1 because they relate to subject matter not required to be searched by this Authority, namely: Claim 11 relates to a method ,for treatment of the human or animal body by surgery or by therapy, as well as diagnostic

2- J Claims NOS.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:

3. I I Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:

1. ] As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims.

2. ] As all searchable claims could be searched without effortjustifying an additional fees, this Authority did not invite payment of any additional fees.

3. Q ] As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:

4. Q ] No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on Protest Q ] The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. r~j The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. I I No protest accompanied the payment of additional search fees.

Form PCMS A/2 10 (continuation of first sheet (2)) (July 2008) INTERNATIONAL SEARCH REPORT International application No. PCT/SE2009/051312 Box I I . 1 methods, see PCT rule 39.1(iv). Nevertheless, a search has been made for this claim. The search has been directed to the technical content of the claim.

Form PCT/ISA/210 (extra sheet) (July 2008)