WO2010059119A1

WO2010059119A1 - A combination of tert -butyl (2-{7- [2- (4-cyano-2- f luorophenoxy) ethyl] -9-oxa-3, 7-diazabicyclo [3.3.1] non-3- yl } ethyl) carbamate and certain antiarrhythmic benzofurans

Info

Publication number: WO2010059119A1
Application number: PCT/SE2009/051312
Authority: WO
Inventors: Charles Antzelevitch; Alexander Burashnikov; Leif Carlsson; Serge Sicouri
Original assignee: Astrazeneca Ab
Priority date: 2008-11-21
Filing date: 2009-11-20
Publication date: 2010-05-27

Abstract

There is provided a combination product comprising 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 certain antiarrhythmic benzofuranes (II) or pharmaceutically acceptable salts thereof.

Description

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 England Journal 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 transmembrane 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 27-31 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

R¹ is H, CO₂(C_L4 alkyl) or NHSO₂(C_L4 alkyl); R² is C_1-6 alkyl or CH₂CO₂(CL₄ alkyl);

R³, R⁴ are, independently, halogen or H;

R⁵, R⁶ 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:

wherein

R¹ 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) 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 iV-[2-butyl-3-({4-[3-

(dibutylamino)propoxy]phenyl}carbonyl)-l-benzofuran-5-yl]methanesulfonamide

(Dronedarone)

wherein

R¹ 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

R¹ 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_-6" means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C ₁.₄" 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% CO₂ 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 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)

3: 3 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)

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 tert-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:

wherein

R¹ is H, CO₂(C_1-4 alkyl) Or NHSO₂(Ci_-4 alkyl);

R² is Ci_-6 alkyl or CH₂CO₂(Ci_-4 alkyl);

R³, R⁴ are, independently, halogen or H; R⁵, R⁶ are, independently, Ci_-6 alkyl;

X is CH₂ or C=O;

Y is O or CH₂;

A is (CH₂)_n;

D is 2 or 3; or pharmaceutically acceptable salts thereof.

2. A combination product according to Claim 1 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)

wherein

R¹ is H, CO₂CH(CH₃)₂ Or NHSO₂CH₃;

R² is n-butyl or 3-{[(liS)-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:

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 N-[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:

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

R¹ 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:

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.

5

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.

10

9. A kit of parts comprising:

(i) one of components (a) and (b) as defined in Claim 7; together with

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.