USE OF 5-HT4 RECEPTOR ANTAGONISTS IN THE TREATMENT OF ARRYTHMIAS AND STROKE

Abstract: The use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrythmias and for reducing the occurrence of stroke.

Description: 1USE OF 5-H 4 ΕmΕX SSWRt RQOmSIS IN THE TREATMENT OF ARRHYTHMIAS AND STROKE The present invention relates to a novel method of medical treatment, in particular the treatment and prevention of human atrial arrhythmias and the prevention of stroke. Compounds which antagonise the effects of 5-HT 4 receptors in the central nervous system, and gastro- intestinal system are known in the art (see for example European Journal of Pharmacology, 146 (1988), 187-88, Naunyn-Schmiedeberg's Arch.Pharmacol. (1989) 340:403-410) and Br. Journal of Pharmacology 96:247p. 1989) . In addition, 5-HT receptors which may resemble those known to exist in the CNS, have been identified in the human atrium [Br. Journal of Pharmacology, 98, 664p, (1989) and Br. Journal of Pharmacology, 100, 879-885 (1990)]. These M 5-HT 4 -like n receptors located in the atrium are hereinafter referred to as cardiac 5-HT receptors. However, in spite of these disclosures there is no indication as to the potential clinical usefulness of compounds which block cardiac 5-HT receptors. It has now been found that the compound (3-α-tropanyl)-lH-indazole-3-carboxylic acid ester antagonises cardiac 5-HT 4 receptors and is expected, as a consequence, to be of use in the treatment of atrial arrhythmias. The present invention therefore provides the use of cardiac 5-HT 4 receptor antagonists in the treatment of human atrial arrhythmias. Cardiac arrhythmias have been associated with symptomatic cerebral embolism. Cerebral embolism is the most common cause of ischaemic stroke and the heart, the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation (Harrison's Principles of Internal Medicine, 11th Edition) . Up to 9% of individuals over the age of 60 have atrial fibrillation (Sirna et al. 1990, Stroke 21; 14-22) . Atrial fibrillation in combination with rheumatic valvular heart disease is associated with a 17-fold increased risk of stroke, whereas chronic atrial fibrillation without rheumatic valvular heart disease is associated with a 5-fold increased risk of stroke. Only arrhythmias which encourage atrial stasis, such as atrial fibrillation and atrial disorders cause cerebral and systemic embolism. Thus, specific cardiac 5-HT 4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke. The present invention therefore provides in a further aspect, the use of cardiac 5-HT receptor antagonists for reducing the occurrence of stroke. As indicated above, the compound (3-α-tropanyl)- lH-indazole-3-carboxylic acid ester has been found to be a cardiac 5-HT 4 receptor antagonist and is expected to be of use in the treatment of the conditions hereinbefore defined. When used in therapy, the cardiac 5-HT 4 receptor antagonists are usually formulated in a standard pharmaceutical composition. The present invention therefore provides pharmaceutical compositions comprising a cardiac 5-HT 4 receptor antagonist in association with a pharmaceutically acceptable carrier. The compositions can be prepared by methods well known in the art of pharmacy, for example, compounds which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions., tablets, capsules and lozenges. Liquid formulations will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) , for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycols, oils, or water with a suspending agent, preservative, flavouring or colouring agent. Tablet compositions can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. Compositions in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. Preferably, the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. DATA (3-α-Tropanyl)-lH-indazole-3-carboxylic acid ester can be prepared by the procedures described in EP-200444-A. PIGLET SPONTANEOUS BEATING ATRIA SCREEN Method (See A. J. Kaumann, 1990, Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622). Piglets of either sex, 2 to 5 days old, were obtained from local farms. Usually 2 piglets were from the same litter. The piglets were anaesthetised with halothene; their hearts rapidly removed and washed free of blood with warm solution containing (mM):120 Na +, 5 K+, 2.25 Ca2+, 0.5 Mg 2+ , 98.5 Cl " , 0.5 SO^ " , 34 HC0 3 " , 1 HP0 4 2" , 0.04 EDTA, deionised and double distilled water in glass, equilibrated with 95% 0 2 and 5% C0 2 . After dissection of the right atrium in warm solution, the tissue was set up in an apparatus with a 50 ml. bath (Blinks, 1965 J. Appl. Physiol. 20, 755-757), containing the solution described above supplemented with (mM) :15 Na + , 5 fumarate, 5 pyruvate, 5 L-glutamate, 10 glucose. Experiments were carried out at 37°C. For the study of positive chronotropic effects, the spontaneously beating right atrium was suspended at a resting tension just sufficient for measurable development of tension (to avoid tachycardia induced by stretching the sinoatrial node - Blinks, 1956 Amer. J. Physiol. 186, 299-303) . The tissue was attached to a Swema SG4-45 strain gauge transducer by means of a stainless steel wire and force recorded on a Watanabe polygraph. To avoid possible indirect β-adrenoceptor-mediated effects due to release of noradrenaline all experiments were carried out in the presence of 400 nM (+)-propranolol (about 100 x K B for (+)-propranolol) . To reduce tissue capture of 5-HT, all experiments were carried out in the presence of 6 μM cocaine; cocaine potentiates the effects of 5-HT on human atrium [Kaumann et al., Br. J. Pharmacol. 100, 879-885, (1990)]. To decrease oxidation of 5-HT the physiological solution and all dilutions of 5-HT contained 0.2 mM ascorbate. A single cumulative concentration-effect curve was determined by the sequential addition of 5-HT or other agonists to the bath in amounts that increased the total concentration in steps of log unit. Enough time was allowed for each effect to reach equilibrium. The experiments were terminated by the administration of a saturating concentration of (-)-isoprenaline (0.2 mM) . The time of incubation with an antagonist was at least 1 hr before a concentration-effect curve for an agonist was determined. Results In the above screen, the potency of a number of known agonists was found to be similar to that published for human atrium [Kaumann et al., Br. J. Pharmacol. 100, 879-885, (1990)]. These results are consistent with the hypothesis that the 5-HT receptors of porcine sinoatrial node and of human right atrial appendage are the same. The preliminary screening results shown in Table 1 indicate that (3-α-tropanyl)-lH-indazole-3-carboxylic acid ester is a competitive antagonist of cardiac 5-HT 4 receptors. TABLE 1 Comparison of blocking potencies of antagonists on right atrial preparations Porcine (rate) Human (force) pK n pK n (3-α-tropanyl)- lH-indazole-3- carboxylic acid ester 7.1 6 ND Granisetron ineffective 3 ineffective (EP-200444-A) (1 μM) (20 μM) pK -log M equilibrium dissociation constant ND not determined n number of individuals

Claims: Claims . 1. A cardiac 5-HT 4 receptor antagonist for use in the treatment of atrial arrhythmias. 2. A cardiac 5-HT 4 receptor antagonist or use in reducing the occurrence of stroke. 3. The use according to claim 1 or 2 in which the 5-HT 4 receptor antagonist is (3-α-tropanyl)-1H- indazole-3-carboxylic acid ester.

Inventors: KAUMANN ALBERTO JULIO, KAUMANN, ALBERTO, JULIO
Applicants: SMITH KLINE FRENCH LAB, SMITH KLINE & FRENCH LABORATORIES LIMITED
Application year: 1991
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K45, A61P9, C07D451