ANTIARRHYTHMIC AGENTS

Abstract: Compounds having formula (I) or (II) where R is primary or secondary amine or a group -L-Z, Y is H, halogen, alkyl, alkoxy, perfluoroalkyl, nitro or -L-Z, n is 1 to 4, L is a linker chain of 1-20 C, N, O or S atoms, and Z is a calcium channel blocker; have potassium channel blocking activity and are useful for the prophylaxis or therapy of arrhythmia.

Description: ANTIARRHYTHMIC AGENTS As a result of the outcome of a cardiac arrhythmia suppression trial in 1989, the search for drugs controlling reentrant ventricular tacyarrhythmias and sudden death has focused on agents that prolong the cardiac action potential and refractoriness (i.e. drugs that possess class III antiarrhythmic action). The prototype class III antiarrhythmic drugs currently in clinical use are amiodarone and sotalol. However amiodarone has a complex pharmacological profile and its precise mechanism of action is unclear; and sotalol, in addition to prolonging action potential duration, is a β adenoreceptor antagonist that may cause cardiac depression and negative inotropism. Selective block of cardiac potassium current will prolong action potential duration and hence the refractory period, an effect believed to contribute to the antiarrhythmic actions of existing drugs derived from sotalol derivatives. However, prolongation of action potential duration in such a manner may be pro-arrhythmic under certain conditions occurring as a result of disturbances of calcium balance in the heart. In consequence, one group has sought to develop an antiarrhythmic agent that shows both calcium channel and potassium channel blocking activity (A Bril et al, J Pharmacol. Exp. Ther. 276 (2), 637-646 (1996)). This invention results from the discovery of a family of compounds which show potassium channel blocking activity and which are structurally quite different from previous compounds known to have this property. Some compounds have been modified by the attachment of known groups having calcium channel blocking activity, and properties of these modified compounds are reported. The invention provides, for use as a potassium channel blocker, a compound comprising a planar electron-deficient ring structure of at least two fused 6-membered rings containing at least one ring N atom. Ring structures of two or more fused 6-membered rings are generally planar or achiral as a result of having aromatic unsaturation. This ring structure may have substituents that extend out of the plane of the ring system; but comparable ring systems that are not planar do not appear to have potassium channel blocking activity. The presence in the system of at least one ring N atom makes or tends to make the ring structure electron-deficient. But this effect may not be shown, or not sufficiently shown by the simple unsubstituted ring structure. The effect is greatly accentuated if the ring N atom is itself substituted. The effect is greatly accentuated by the presence, ortho or para to a ring N atom, of an electron-withdrawing substituent. Preferred compounds are based on quinoline and acridine. On the fused ring structures of these compounds may be bonded substituents designed to perform various functions: to increase the electron deficiency of the ring structure; to provide calcium channel blocking activity; to enhance the lipophilic or hydrophilic properties; to provide a zero or positive or negative charge on the compound as a whole. Preferred compounds have the formula where 1 ,2 or 3 of X 1 , X 2 , X 3 and X 4 are N or ≡N + -Q and each remaining X 1 , X 2 , X 3 and X 4 is ≡C-Y, Q is optionally substituted alkyl, Y is H, halogen, primary, secondary or tertiary amine, optionally substituted alkyl , alkoxy or perfluoroalkyl, nitro or a group -L-Z; or two adjacent Y may be joined together to form a carbocyclic ring, L is a linker chain of 1 -20 C, N, O or S atoms, Z is a calcium channel blocker, and n is 1 to 4. Preferably a primary or secondary amine group is attached to the ring structure at a position para to a ring N atom. Particularly preferred compounds of this type have the formula where R is primary or secondary amine or a group -L-Z, Y and n are as previously defined. Preferred compounds have a group -L-Z which provides calcium channel blocking activity These are included as new compounds within the scope of the invention. Preferably L is -NH(CH 2 ) 3 N(CH 2 ) 2 - and Z is phenyl or 3,4-dimethoxyphenyl. Such groups are well known and described in the literature. See R Mannhold et al, Archives of Pharmacology, 1978, 302 217-226. The compounds are expected to be useful for the prophylaxis or therapy of arrhythmia, for which purpose they are expected to be injected into the blood stream. They will also be useful as experimental tools to separate components of the potassium current in a variety of tissues. These uses constitute further aspects of the invention. Reference is directed to the accompanying drawings, in which Figures 1 -6, 8-12 and 14 are graphs of various effects against time, and Figures 7 and 13 show compound structures. Figure 1 shows the effect of 5mM E4031 on l κ . A. Mean data from 7 cells before (filled circles) and after (empty circles) exposure to E4031. B. E4031 sensitive currents. I κ was activated by step depolarisations from -40mV to +40mV for 10 to 800 ms and were measured as outward tails upon repolarisation to -40mV (switch voltage clamp; 36°C) in the presence of cytosolic BAPTA to suppress calcium transients. A similar protocol was adopted in all subsequent experiments where l κ was investigated (see Heath & Terrar, 1996, Experimental Physiology, 81 , p587-603). Figure 14 illustrates the log(dose)-response curve of l KR and l Ca inhibition by GT96/1 ,2,3&4. l Ca was activated by step depolarisations from -40mV to 0 mV for 200ms (switched voltage clamp). I κ was activated by step polarisations from -40mV to +40mV for 10-800ms (switched voltage clamp) and measured as outward tails upon repolarisation to -40mV; current at 40 ms was taken to represent l Kr (see Heath & Terrar, 1996, Experimental Physiology, 81 , p587-603). EXPERIMENTAL The delayed rectifier potassium current (l κ ) is one of the major time and voltage dependent outward potassium currents in heart cells, it plays an important role in the repolarisation of cardiac action potentials. Two components of l κ have been separated and can be distinguished by their differing kinetics and pharmacology. The rapidly activating component (l Kr ) exhibits rapid activation, being maximal within 50ms and is sensitive to the class IN antiarrhythmic drug E4031. The more slowly activating component (l κs ) exhibits a slower, sigmoidal activation and even at very long and very positive potentials it does not become maximally activated. This component is sensitive to the general anaesthetics propofol and thiopentone. EXAMPLE 1 Using the known class III antiarrhythmic drug E4031 which is believed to be a selective blocker of l Kr , the two components of the delayed rectifier potassium current can be separated. Figure 1A illustrates that following exposure of guinea pig isolated ventricular heart cells to 5μM E4031 , a reduction in l κ was observed, especially l κ activated by short pulses of less than 200ms. Since E4031 is reported to selectively block l Kr , the current remaining in the presence of E4031 represents l κs and in accordance with this, the drug-insensitive l κ is slow to activate and exhibits a sigmoidal activation. Subtraction of the E4031 insensitive current from control current produced the E4031 -sensitive current, or l Kr (Figure 1B), exhibiting a rapid activation, being maximal within 50ms. The actions of E4031 on l κ illustrated in Figure 1A are representative of a typical response to a selective I Kr blocker, and similar actions on l κ were recorded with the novel l Kr blockers of this invention. The initial experiments which led to the characterisation of the novel chemical group exhibiting l Kr blocking activity followed from the observations that exposure of guinea pig isolated ventricular heart cells to methylene blue (10 μM), an inhibitor of the cytosolic enzyme guanylate cyclase, enhanced cell contraction amplitude (Figure 2A), with an associated increase in action potential duration. These actions appeared not to be related to the inhibition of guanylate cyclase activity since exposure of cells to a structurally dissimilar guanylate cyclase inhibitor, LY83583 (10 μM) did not produce such responses (Figure 2B). The prolongation of action potential duration and hence increase in cell contractility observed following exposure to methylene blue was not associated with effects on either L-type calcium currents (Figure 3) or inwardly rectifying potassium currents (Figure 4). In contrast, a decline in the rapidly activating component of the delayed rectifier potassium current was observed following exposure to 10 μM methylene blue (Figure 5). The structurally dissimilar guanylate cyclase inhibitor LY83583 (10 μM) had no effects on l Kr (Figure 6), it therefore seems likely that methylene blue inhibits l Kr through a direct action on the channel rather than through inhibition of guanylate cyclase activity. Further support for such a view is that compounds such as quinacrine (Figure 7), chloroquine (Figure 7) and 9-aminoacridine (Figure 7), which do not exhibit guanylate cyclase inhibiting activity, but possess a flat planar electron deficient ring structure similar to that of methylene blue (Figure 7) also exhibit potent l Kr blocking activity (Figure 8). In a separate set of experiments the inventors have also investigated the l κs blocking activity of one of these compounds, 9-aminoacridine which appears to be negligible at 10 μM, demonstrating that these compounds are selective for l Kr . In the next set of experiments the inventors investigated whether the positive charge and/or the flat planar structure of such compounds is required for l Kr blocking activity. Acridine hydrochloride (Figure 7) possesses a flat planar electroneutral ring structure but did not exhibit l Kr blocking activity (Figure 9). In contrast the structurally similar methylacridine sulphonate (Figure 7) which possesses a weakly positively charged flat planar ring structure exhibited l Kr blocking activity (Figure 10); hence it appears that an electron deficient ring structure is required for l Kr blocking activity. 9-aminotetrahydroacridine (Figure 7) has 2 unsaturated electron deficient rings which lie in the same plane (although the saturated ring introduces a kink at the end of the compound) and this exhibits l Kr blocking activity (Figure 11). In contrast 1 ,2,3,4-tetrahydroquinoline (Figure 7) does not possess a flat planar structure and although it is electron deficient it does not exhibit l Kr blocking activity (Figure 12); hence it appears that at least 2 rings must lie in a plane and that this flat planar portion of molecule must be electron deficient for a compound to exhibit l Kr blocking activity. EXAMPLE 2 In addition the inventors have synthesised a novel set of compounds which incorporate both the chemical group exhibiting l Kr blocking activity and an additional chemical group conferring calcium channel blocking activity (Figure 13). Both the calcium channel and potassium channel blocking activity has been investigated in these newly synthesised compounds (Figure 14). Compound GT96/4 appears to show the greatest difference in potency between block of l Kr and of calcium channels. Antiarrhythmic Properties of GT 96/4 Guinea-pig hearts were mounted on a Langendorff apparatus, and perfused through the aorta with a solution at pH 7.4, 36°C as described in Heath B M and Terrar D A, Experimental Physiology, Vol 81 , p 587-603 (1996). Ischaemia was induced by stopping the inflow of perfusing solution for 30 minutes. Arrhythmias were provoked following reperfusion. Arrhythmias were quantified by:- • taking a signal from a tension transducer (attached to the heart by a hook at its apex and therefore measuring ventricular contraction), and • feeding this signal to a device which measured the interval between contractions (the reciprocal of heart rate). The output of this device was proportional to the interval between beats so that a steady level reflected a steady rate and fluctuations in this level reflected disturbances in rhythm. The possible effect of novel compounds on arrhythmias was tested by switching the inflow of the perfusion apparatus to a solution containing the compound of interest GT 96/4, at 10 "7 M. Reversibility of effect was tested by switching back to drug-free solution. Arrhythmia was quantified from a recording of the intervals between heart contractions in such a manner that a large variation in rhythm gave rise to a large value (arbitrary units). Results are reported below.

Claims: CLAIMS 1. For use as a potassium channel blocker, a compound comprising a planar electron-deficient ring structure of at least two fused 6- membered rings containing at least one ring N atom. 2. A compound as claimed in claim 1 having the formula where 1 ,2 or 3 of X 1 , X 2 , X 3 and X 4 are N or ≡N + -Q and each remaining X 1 , X 2 , X 3 and X 4 is ≡C-Y, Q is optionally substituted alkyl, Y is H, halogen, primary, secondary or tertiary amine, optionally substituted alkyl , alkoxy or perfluoroalkyl, nitro or a group -L-Z; or two adjacent Y may be joined together to form a carbocyclic ring, L is a linker chain of 1-20 C, N, O or S atoms, Z is a calcium channel blocker, and n is 1 to 4. 3. A compound as claimed in claim 1 or claim 2, wherein a primary or secondary amine group is attached to the ring structure at a position para to a ring N atom. 4. A compound as claimed in claim 3 having the formula where R is primary or secondary amine or a group -L-Z, Y and n are as previously defined. 5. A compound as claimed in claim 4, wherein Y is H, chloro, primary or secondary amine or methoxy or the group -L-Z, and L is a linker chain of 1-20 carbon atoms, optionally including one or more O, N or S atoms. 6. A compound as claimed in claim 4 or claim 5, wherein R is -L-Z.. 7. A compound as claimed in any one of claims 2 to 6, wherein L is -NH(CH 2 ) 3 N(CH 3 )(CH 2 ) 2 - and Z is phenyl or 3,4-dimethoxyphenyl. 8. A compound having the formula: where 1 ,2 or 3 of X 1 , X 2 , X 3 and X 4 are N or ≡N + -Q and each remaining X 1 , X 2 , X 3 and X 4 is =C-Y, Q is optionally substituted alkyl, Y is H, halogen, primary, secondary or tertiary amine, optionally substituted alkyl , alkoxy or perfluoroalkyl, nitro or a group -L-Z; or two adjacent Y may be joined together to form a carbocyclic ring, L is a linker chain of 1-20 C, N, O or S atoms, Z is a calcium channel blocker, and n is 1 to 4, provided that at least one group -L-Z is present. 9. A compound as claimed in claim 8, wherein a primary or secondary amine group is attached to the ring structure at a position para to a ring N atom. 10. A compound as claimed in claim 8, having the formula where R is primary or secondary amine or a group -L-Z, Y and n are as previously defined. 11. A compound as claimed in claim 10, wherein Y is H, chloro, primary or secondary amine or methoxy or the group -L-Z, and L is a linker chain of 1-20 carbon atoms, optionally including one or more O, N or S atoms. 12. A compound as claimed in claim 10 or claim 11 , wherein R is -L-Z. 13. A compound as claimed in any one of claims 8 to 12, where L is -NH(CH 2 ) 3 N(CH 3 )(CH 2 ) 2 - and Z is phenyl or 3,4-dimethoxyphenol. 14. A method of preparing an anti-arrhythmic agent, which method comprises bringing a compound as claimed in any one of claims 1 to 12 into a form suitable for administration.

Inventors: GILL EDWARD, MAMAS MAMAS, TERRAR DEREK, GILL, EDWARD, MAMAS, MAMAS, TERRAR, DEREK
Applicants: GILL EDWARD, ISIS INNOVATION, MAMAS MAMAS, TERRAR DEREK, GILL, EDWARD, ISIS INNOVATION LIMITED, MAMAS, MAMAS, TERRAR, DEREK
Application year: 1998
Main classification: C07D215
IPC codes: C07D215, C07D219