Novel oxabispidine compounds and their use in the treatment of cardiac arrhythmias

This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.

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 tachyarrhymias (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 “traditional” antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay 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 refractoriness, without affecting cardiac conduction.

One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (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 antiarrhythmic drugs.

Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including, inter alia, J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993).

Certain oxabispidine compounds are disclosed as chemical curiosities in Chem. Ber., 96, 2872 (1963). The use of certain other oxabispidine compounds in the treatment of cardiac arrhythmias is disclosed in WO 01/28992. Methods for the preparation of such oxabispidine compounds are disclosed in WO 02/28863, WO 02/28864, WO 02/83690 and WO 02/83691. Oxabispidine compounds in which one or both of the N-atoms bears a substituent that includes an “in-chain” sulfonamide group are neither disclosed nor suggested.

We have surprisingly found that a novel group of oxabispidine-based compounds exhibit electrophysiological activity and are therefore expected to be useful in the treatment of cardiac arrhythmias. The novel group of oxabispidine-based compounds has advantageous properties compared to compounds of the prior art, such as enhanced potency, enhanced selectivity, and/or reduction of total clearance. These advantageous properties can distinguish the use of such compounds as pharmaceutical agents by lowering the daily clinical dose, lengthening the duration of action, and/or improving the side effect profile.

According to the invention there is provided compounds of formula I,

wherein

R¹ represents C_1-12 alkyl (which alkyl group is optionally substituted by one or more groups selected from halo, cyano, nitro, aryl, Het¹, —N(R^5a)R⁶, —C(O)R^5b, —OR^5c, —C(O)XR⁷, —C(O)N(R^8a)R^5d, —OC(O)N(R^8b)R^5e, —S(O)₂R^9a, —S(O)₂N(R^9b)R^9c and —N(R^9b)S(O)₂R^9d) or R¹ represents —C(O)XR⁷, —C(O)N(R^8a)R^5d or S(O)₂R^9a;

R^5a represents H or C_1-6 alkyl (which latter group is optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, —S(O)₂N(R^9b)R^9c and —N(R^9b)S(O)₂R^9d);

R^5b to R^5e independently represent, at each occurrence when used herein, H, C_1-6 alkyl (which latter group is optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, Het², —S(O)₂N(R^9b)R^9c and —N(R^9b)S(O)₂R^9d), aryl or Het³, or R^5d or R^5e, together with, respectively, R^8a or R^8b, may represent C_3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C_1-3 alkyl groups);

R⁶ represents H, C_1-6 alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O)₂N(R^9b)R^9c and —N(R^9b)S(O)₂R^9d), aryl, —C(O)R^10a, —C(O)OR^10b or —C(O)N(H)R^10c or —S(O)₂R^10d;
R^10a, R^10b, R^10c and R^10d independently represent C_1-6 alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R^10a represents H;


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