GB1578421A - Antiarrhythmic quinuclidine carboxylic acid xlidide - Google Patents

Description

(54) ANTIARRHYTHMIC QUINUCLIDINE CARBOXYLIC ACID XYLIDIDE (71) We, MUNDIPHARMA A.G., a body corporate organised under the Laws of Switzerland, of St. Alban-Vorstadt 94, Postfach CH-4006, Basel, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to an antiarrhythmic quinuclidine carboxylic acid xylidide.

Lidocaine and similar compounds have been used for the treatment of cardiac arrhythmias. Although these compounds are used in coronary intensive care units, they cannot be used in the prophylaxis of the sudden death syndrome because the biological half life is only about 75 minutes. Furthermore, the absorption of lidocaine from the intestinal tract is unsatisfactory and the substance produces undesirable side effects such as hypotension, neurotoxicity and low therapeutic index. Still further, due to the rapid metabolism thereof, the lidocaine must be administered by continuous intravenous infusion in order to maintain adequate plasma concentrations.

Consequently, there has been continuous research in the field to try to provide agents with improved antiarrhythmic action.

French patent No. 1,565,045 to Aktibolaget Astra described the general group of compounds of the formula:

wherein R1 and R2 are hydrogen, halogen or lower alkyl. The patent also describes the production of these compounds by converting the quinuclidine carboxylic acid to its methyl ester followed by treatment with a mixture of methylmagnesium iodide and the selected aniline. However, yields are low and are contaminated with undesired side products.

The French patent specifically discloses the 2,6,-xylidide of quinuclidine-2carboxylic acid and the compound is indicated as having antiarrhythmic and local anaesthetic action. However, our tests have proved that this compound is neurotoxic and is completely devoid of any useful antiarrhythmic action.

The article of Dahlbom and Dolby in Acta Pharma. Suecica 65. 277 (1969) describes various derivatives of quinuclidine-3-carboxylic acid including the compound N-(quinuclidine-3-carbonyl)-2,6-dimethylaniline, which compounds were tested for various pharmacological and microbiological activities and were found to have no pharmacological effect except for a weak local anaesthetic action.

The compounds are produced according to the article in Acta Pharm. Suecica by reacting the quinuclidine carboxylic acid hydrochloride with the aniline e.g. 2,6dimethylaniline under refluxing in the presence of thionyl chloride. However, this reaction causes extensive discoloration of the reaction mixture and in the formation of sulphur-containing material of unknown composition which contaminates the desired product. The yield of partially purified product by this procedure can rarely exceed 60% of the theoretical yield.

In general, it has been found according to the present invention that, contrary to the teaching in Acta Pharm. Suecica, the 2,6-xylidide of quinuclidine-3carboxylic acid, and the pharmaceutically acceptable salts thereof such as the hydrochloride, have a highly pronounced antiarrhythmic action without undesirable side effects, which is most surprising in view of the fact that comparative tests have shown that the 2,6-xylidide of quinuclidine-2-carboxylic acid of French patent 1,566,045 is neurotoxic and devoid of any useful antiarrhythmic effect.

A method for the preparation of quinuclidine carboxylic acid and aniline derivatives of the formula:

in which R and R2 represent hydrogen, halogen our lower alkyl, is described and claimed in our co-pending application No. 21014/79 (Serial No. 1578422). It is therefore an object of the present invention to provide new and effective antiarrhythmic compositions.

It is a further object of the present invention to provide for the treatment of cardiac arrhythmia utilizing the antiarrhythmic compositions of the present invention.

The present invention therefore comprises, as an antiarrhythmic pharmaceutical composition, a pharmaceutical carrier or diluent and an antiarrhythmic effective amount of the 2,6-xylidide of quinuclidine-3-carboxylic acid or a physiologically acceptable acid addition salt thereof.

As indicated above, it has been found according to the present invention that, while the 2,6-xylidide of quinuclidine-2-carboxylic acid is neurotoxic and devoid of useful antiarrhythmic action, the isomer thereof, namely 2,6-xylidide of quinuclidine-3-carboxylic acid of the formula:

exhibits pronounced antiarrhythmic activity with a minimum of side effects. In effecting antiarrhythmic action, it is preferred to utilize an antiarrhythmic effective amount of the hydrochloride of the 2,6-xylidide of quinuclidine-3-carboxylic acid although it is possible to use any physiologically acceptable salt thereof. The hydrochloride is both highly soluble and easily obtainable and is therefore most preferred.

In establishing the effective antiarrhythmic action of the present invention, the hydrochloride of 2,6-xylidide of quinuclidine-3-carboxylic acid, hereinafter referred to as "Compound I", was compared with previously known antiarrhythmic agents for evaluation, and was also compared with the hydrochloride of 2,6-xylidide of quinuclidine-2-carboxylic acid, hereinafter referred to as "Compound II".

The following examples are given to illustrate the present invention.

EXAMPLE 1.

This example illustrates the production of 2,6-xylidide of quinuclidine-3carboxylic acid hydrochloride, Compound I, utilizing the method described and claimed in our co-pending application number 29014/79 (Serial No. 1578422).

2.5 g of quinuclidine-3-carboxylic acid hydrochloride (0.013 mole) was dissolved in anhydrous, alcohol-free chloroform (150 cc). Oxalyl chloride (10 ml) was added and the mixture was refluxed for 3 hours in a glass assembly protected from atmospheric moisture. The solvent was evaporated off.

Following this, the mixture was treated with a solution of 3 g (0.025 mole) of 2,6-dimethylaniline in 100 ml anhydrous, alcohol-free chloroform and refluxed for 6 hours. All volatile solvents were removed by distillation (oil bath at 800 C) and the residue was treated with 25 ml of cold 3N aqueous hydrochloride acid.

The clear acid solution was decanted from a little insoluble residue and its pH was adjusted to 4.5 with 5% aqueous sodium hydroxide, it was extracted once with ether (25 ml) and the ether extract was discarded. The pH was raised to pH 8 and the aqueous solution was again extracted with 25 ml ether. The ether extract contained recovered 2,6-dimethylaniline. The aqueous solution was rendered strongly alkaline, whereupon the desired compound was obtained as a precipitate.

this was extracted with 50 ml chloroform: the chloroformic solution was evaporated to dryness under reduced pressure, the residue was dissolved in 200 ml 5% methanolic hydrogen chloride and the resulting solution again evaporated to dryness. The residue was recrystallized from a mixture of methanol and ether (1:1).

The yield was 3 g of the hydrochloride, Compound I, having a melting point of 234236 ; a further quantity (0.5 g) was recovered from the mother liquor upon concentration. The combined yield of the pure compound was 91% of the theoretical yield.

Carrying out the above method, however, utilizing thionyl chloride in place of oxalyl chloride results in extensive discoloration of the reaction mixture and the formation of sulphur-containing materials of unknown composition, which contaminate the desired product, resulting in a yield of the partially purified product of not more than 60% of the theoretical yield.

EXAMPLE 2.

This example illustrates the production of 2,6-xylidide of quinuclidine-2carboxylic acid hydrochloride, Compound II, utilizing the method described and claimed in our co-pending application No. 21014/79 (Serial No. 1578422).

1.5 g of quinuclidine-2-carboxylic acid hydrochloride (0.0078 mole) was dissolved in 100 ml anhydrous alcohol-free chloroform. Oxalyl chloride (7 ml) was added and the clear mixture was refluxed for 3 hours in a glass assembly protected from atmospheric moisture, and the solvent was then evaporated off. The mixture was treated with a solution of 1.5 g (0.0125 mole) of 2,6-dimethylaniline in 50 ml anhydrous, alcohol-free chloroform and reflux resumed for 6 hours.

The volatile solvents were removed by distillation on an oil bath at 800C and the residue was dissolved in cold, 3N aqueous hydrochloric acid and decanted from a little insoluble residue. The clear solution was adjusted to pH 5.5 by the addition of 5% aqueous sodium hydroxide, then extracted with 25 ml ether. The ether extract contained recovered 2,6-dimethylaniline. The aqueous phase was made strongly alkaline with sodium hydroxidethen extracted with 100 ml chloroform.

The chloroformic extract was evaporated to dryness and the residue was layered on top of a column of chromatography grade neutral alumina of activity 1 and having the following dimensions: diameter, 2 cm: length, 50 cm. Impurities were flushed out first by eluting with about 1 litre benzene. The Compound II was the eluted with chloroform (500 cc). The chloroformic solution was evaporated to dryness and the residue was dissolved in 5% methanolic hydrqgen chloride (100 cc).

Evaporation of this solution and recrystallization of the residue from a mixture of methanol + ether, 1:1, resulted in the hydrochloride Compound II. The yield was 1 g, equivalent to 50% of theoretical yield and had a melting point of 216"C.

The above method of producing Compound II is far superior to the method described in French patent No. 1,566,045 wherein quinuclidine-2-carboxylic acid is converted to its methyl ester which is treated with a mixture of methylmagnesium iodide and 2,6-dimethylaniline. The process produces a higher yield and the product is of greater purity. On the other hand, if it is attempted to produce Compound II utilizing thionyl chloride in place of oxalyl chloride as in the present method, Compound II cannot be obtained in any measurable yield because of extensive decomposition of quinuclidine-2-carboxylic acid and the formation of sulphur-containing tarry products of unknown composition.

Evaluation of the antiarrhythmic action of Compound I, including evaluation of its other pharmacological characteristics and side effects, as compared to known antiarrhythmic agents, and also as compared to Compound II are detailed below.

The toxicity of Compound I was determined by i.p. injection of a'0.5% solution of the drug into male, albino ICR mice weighing 20-25 g each. A group of six mice was used for each dose. The LDso derived by probit analysis was found to be 60+5 mg/kg.

The lack of interaction of Compound I with other centrally active drugs may also be taken as an indication of its lack of activity in the CNS. The following examples may be cited: Compound I did not affect metrazole-induced convulsions (metrazole, 100 mg/kg) when injected i.p. 30, 60 and 90 minutes prior to metrazole.

It did not affect oxotremorine-induced tremors (oxotremorine, 20 eLg/kg, i.p.) when given i.p. 30 minutes prior to oxotremorine. It was equally ineffective against Indoklon-induced seizures when the latter was administered 30 minutes later by inhalation, or electro shock-induced seizure, at a voltage of 30 volts.

Observations on conscious, healthy dogs that had received Compound I as a bolus intravenous injection over a period of 15-30 seconds and at a dose of 5 mg/kg revealed no significant change in posture, behaviour or mood from control.

The effect of Compound I on the normal heart was determined by the administration of the compound as a bolus intravenous injection to conscious healthy dogs for which the lead of the electrocardiogram positioned on the right fore leg and the left hind leg of the dog was monitored for as long as 2 hours after injection. In a total of 6 animals, a single dose of 3 mg/kg and a cumulative dose of 6 mg/kg, administered in divided doses of 3 mg/kg, 2 mg/kg and 1 mg/kg over a period of 3060 minutes, elicited no change in the ECG.

In one case, a single dose of 5 mg/kg was administered rapidly in order to achieve a high but transient concentration in the heart. Broadening of the QRS complex was observed, but there were no other signs of overt toxicity in the animal.

The ECG record reverted to normal within 15 minutes.

In one Nembutal-anesthetized dog (Nembutal, 25 mg/kg) a cumulative intravenous dose of 6 mg/kg, administered in divided doses of 3, 2 and I mg/kg over a period of 30 minutes, elicited no change in the ECG. (Nembutal is a Registered Trade Mark.) Nembutal anesthetized cats responded differently. After a total dose of 3 mg/kg of Compound I given in small increments over 34 minutes, there was a leftward shift of the QRS complex. With a cumulative doses of 6 mg/kg, and 10.5 mg/kg broadening of the QRS occurred but sinus rhythm was maintained. At a still higher dose, e.g. 16.5 kg/kg (cumulative), second degree AV block occurred. A trial conduction slowed down as seen from the widening of the P wave. If drug administration was discontinued at this stage, then the severe toxic effects would disappear after 40 minutes, the heart reverting to normal sinus rhythm. A futher massive dose, e.g., 7.5 mg/kg (total cumulative dose: 23.5 mg/kg) resulted in a high degree AV block, followed by cardiac standstill.

The following describes tests which were carried out to determine the effect of ouabain-induced arrhythmias.

Cats of both sexes (1.8-3.4 kg) were anesthetized with Nembutal (40 mg/kg, i.p.). The trachea was cannulated to insure a potent airway. Artificial respiration was used only when difficulties in respiration were observed after nembutal administration and before the administration of any other drug (2 cases out of 10).

A femoral artery and vein were cannulated to record blood pressure and to administer drugs, respectively. Lead II of the electrocardiogram (ECG) was monitored throughout the experiment by means of a Grass Model 7 polygraph. All solutions were in saline. Arrhythmia was induced with oubain in two ways: either by injection of small doses of this drug every 30 minutes or by constant infusion.

Usually, ventricular tachycardia (VT) set in after administration of a total dose of 75-80 ,ug/kg.over a period of one hour at least.

After induction of arrhythmia, Compound I was administered as a bolus intravenous injection at a dose of I mg/0.2 ml/kg over a period of 30 seconds. In a number of cases, this treatment was repeated once, but at the reduced dose of 0.5 mg/kg this, if arrhythmia reappeared within one hour. For comparison, lidocaine was administered by the same procedure.

In other experiments using mongrel dogs, the animals were anesthetized by an i.v. injection of Nembutal (25 mg/kg), then arrhythmia was induced by the administration of decreasing doses of ouabain at 30 minute intervals, 40, 20 and 10 ug/kg. Treatment with Compound I was then carried out as described for cats.

Ten minutes after the establishment of constant arrhythmia in cats with a cumulative dose of 79-90 ug/kg ouabain, administration of Compound I as a single therapeutic dose of 1 mg/kg resulted in a marked improvement of the ECG that lasted much longer than any improvement achieved with lidocaine used under identical conditions. The results for Compound I treated cats are given in Table I and those for lidocaine-treated cats are given in Table 2.

In dogs, reversal of VT to normal sinus rhythm was achieved with 1 mg/kg single doses of Compound I. If arrhythmia reappeared after 45 minutes, reversal to normal sinus rhythm could be restored again with an additional dose of Compound I equal to half the initial dose (Table 3).

TABLE 1.

EFFECT OF COMPOUND I ON OUABAIN-INDUCED ARRHYTHMIA IN THE CAT After anesthesia with 40 mg/kg Nembutal, arrhythmia was induced by the administration of ouabain i.v., either in small doses or by constant infusion, to a total dose of 75-80 Mg/kg. Then Compound I was given as a bolus i.v. injection of I mg/kg. (Nembutal was given i.p.) Normal Arrhythmia Compound I treated Serial H.R. B.P. Type H.R. B.P. S.R. H.R. B.P. Duration (min) 1 160 90/70 VPB 100 80/60 + 100 80/60 10# 2 150 110/85 VPB 110 170/120 + 80 110/90 75## 3 140 130/80 VPB 140 120/100 + 110 130/90 4 hrs.

4 130 92/64 VPB 80 142/100 + 70 120/90 90 5 140 140/100 VPB 150 170/160 + 150 165/1 56 60 orVT 6 200 130/100 VT 120 120/100 + 120 120/100 120 7 180 120/80 VT 160 60/40 + 120 60/40 30## 8 100 80/55 VT 120 120/80 + 90 120/80 9 120 50/30 VT 150 100/70 + 100 100/80 180* 10 170 140/90 VPB 70 90/70 + 90 90/75 120## Abbreviations and Symbols: H.R. heart rate, per min.

B.P. blood pressure in mm.

VPB -ventricular premature beats.

VT -ventricular tachycardia.

S.R. sinus rhythm, + denotes return to this rhythm.

Duratiowperiod of observation from onset of reversal of arrhythmia.

# -0.5 mg/kg of EC-122 used.

## -Arrhythmia reappeared but was suppressed again with an additional dose of EO-122, 1 mg/kg for 2, 7 and 8 and 0.5 mg/kg for 10.

* -with stimulation of the vagus.

TABLE 2.

EFFECT OF LIDOCAINE ON OUABAIN-INDUCED ARRHYTHMIA IN CATS.

Conditions are the same as those given in Table 1.

Normal Arrhythmia Lidocain-treated# Serial H.R. B.P. Type H.R. B.P. S.R. H.R. B.P. Duration 11 180 120/80 VT 160 60/40 - 150 60/40 none 12 140 85/70 VPB 120 140/100 + 110 120/80 2min** 13 130 92/64 VPB 80 130/100 + 80 130/100 3min** Abbreviations are the same as given in Table 1.

# -Lidocaine HCI was given as a single i.v. injection at the rate of 4 mg/kg in 11 and 12 and 1.6 mg/kg in 13.

4# -Arrhythmia reappeared.

TABLE 3.

EFFECT OF COMPOUND I ON OUABAIN-INDUCED ARRHYTHMIA IN DOGS.

Conditions are those described in Table 1.

Normal Arrhythmia Compound I treated Serial H.R. B.P. Type H.R. B.P. S.R. H.R. B.P. Duration 14 130 125/90 VT 180 100/80 + 170 100/80 40 min 15 110 130/100 VT 200 140/110 + 170 140/110 25 min Abbreviations are same as given in Table 1.

# -Arrhythmia reappeared after this period but was suppressed by one i.v. injection of 0.25 mg/kg EO-122.

The effect of parenteral administration of Compound I on occlusion-induced arrhythmias in conscious dogs was determined. Occlusion was achieved by ligation of the left anterial descending coronary artery on 5 dogs. The animals developed arrhythmia but recovered spontaneously after 3 or 4 days.

Compound I was administered once within 24 hours and once within 48 hours after ligation. Within the 24 hours period, one bolus i.v. injection of 3 mg/kg restored full, uninterrupted sinus rhythm for as long as 20 minutes, followed by mixed stretches of SR, VT and VPB's for 2 to 3 hours. Treatment within the next 24 hours required a lower effective dose, e.g., 1.5 mg/kg, with similar results.

Therapeutic blood levels were 5 and 2.5 Mg/cc blood, accordingly.

In the same animals, lidocaine was either completely ineffective or of ultra short duration, when applied as a bolus i.v. injection of 3 mg/kg. The tests with lidocaine were performed either 2 hours before treatment with Compound I or 2 hours following such treatment, with the assumption that the effect is not cumulative at such an interval.

Tests were also carried out to determine the effect of oral administration of Compound I on occlusion induced arrhythmias in conscious dogs.

Arrhythmia was induced by occlusion of the left anterior descending artery, as above described. Following this, Compound I was administered orally to the animals at the rate of 15-20 mg/kg, the dose being divided among 4 to 6 gelatin capsules, without prior treatment such as micronization or admixture with a diluent or carrier. In all cases, the drug was fully effective in the restoration of normal sinus rhythm, but with a delay of 11 to 60 minutes after administration, depending on the severity of the condition.

The pharmacokinetic parameters of Compound I were determined in conscious dogs suffering from occlusion-induced arrhythmia. After intravenous injection of a single therapeutic dose, venous blood samples were withdrawn at given intervals, heparinized and analyzed for their content of Compound I by gas chromatography. The following data were derived: Biological half-life (t"2) 4 to 5 hours t"2 for distribution 5 minutes volume of distribution 0.2 litre/kg body weight Therapeutic body levels 2.5-5 ug/ml The biological availability of Compound I administered by the oral route was determined first in conscious, healthy dog that received a dose of 7.5 mg/kg subdivided in 6 gelatin capsules that were slipped down its throat. Peak blood concentration was reached within one hour after ingestion and was of the order of 1.5-2 Rug/ml blood. Within 4 hours after ingestion, about 30 percent of the ingested dose had been absorbed and could be accounted for by measurement of the AUC (area under curve) of the combined absorption-elimination kinetics. In conscious arrhythmic dogs, bioavailability of the drug appears to be of the same order.

The following is the summary of the more important properties of Compound I as compared to those of lidocaine: Parameter Compound I Lidocaine Single therapeutic dose for suppression of Ouabain-induced arrhythmia 0.5-I mg/kg, i.v. 14 mg/kg, i.v.

Duration of effect about I hour 2 to 4 minutes Onset of effect about 2 minutes about 2 minutes Occlusion-induced arrhythmia within I st 24 hr. after operation 3 mg/kg, i.v. often ineffective Duration of effect 20 min to 2 hr. 1 to 2 min. when effective Onset of effect 2 minutes 2 minutes Within 2nd 24 hr. after operation 1.5 mg/kg, i.v. I to 3 mg/kg, i.v.

Duration of effect I to 4 hr. I to 3 min.

Therapeutic blood levels 2.5-5 ,ag/ml 2-5 g/ml Bioavailability by oral route about 80% insignificant Single therapeutic oral dose for suppression of occlusioninduced arrhythmia 15-20 mg/kg not applicable side effects Hypotension none about 20% Emesis partial partial CNS-effects none extensive t"2 for distribution 5 min 5 min t1,2 for elimination 4 to 5 hr. 75-120 min.

volume of distribution 0.21/keg 0.2 I/kg It is thus clear that while Compound I of the present invention possesses the antiarrhythmic properties of lidocaine it possesses numerous pharmacological advantages, namely a longer biological half-life, reducing or obviating the need of drug administration by constant infusion; excellent bioavailability after oral administration, reducing or obviating the need of multiple injections; and absence of side effects such as hypotension and CNS stimulation. Furthermore, it appears that Compound I is not significantly degraded by the liver. It is thus clear that, in accordance with the present invention, Compound I and the free base and other pharmacologicaily effective acid addition salts thereof can be used in single or multiple intravenous dose for the management of arrhythmias after acute myocardial infraction, can be used in emergencies before and during the transfer of a patient to an intensive care unit; can be used for the management of arrhythmias due to digitalis intoxication and also can be used orally for continued management.

As indicated above, these effects can be achieved only with the compound which is the 2,6-xylidide of quinuclidine-3-carboxylic acid and the physiologically compatible acid addition salts thereof, while the isomer thereof, namely the 2,6xylidide of quinuclidine-2-carboxylic acid is both neurotoxic and devoid of useful antiarrhythmic properties. This is confirmed by the tests of Compound II, namely the hydrochloride of 2,6-xylidide of quinuclidine-2-carboxylic acid, which was produced both by the method of French patent No. 1,566,045, and by the method of the present invention. Administration of Compound II to albino mice by the intraperitoneal route induced the following symptoms: Dose range Effects 20-30 mg per kg increased locomotion, excitation 40--60 mg per kg pronounced neutroxicity, ataxia, partial paralysis 100 mg. per kg lethal dose. Cause of death seems to be due to respiratory failure.

EFFECT OF COMPOUND II IN DRUG-INDUCED ARRHYTHMIA: Arrhythmia was induced in 2.7 kg cat, previously anesthetized with Nembutal, by the slow infusion of ouabain over a period of one hour and to a total dose of 70 ,ug per kg. At this stage, the electrocardiogram showed clear signs of arrhythmia, mainly ventricular premature beats and ventricular tachycardia. An intravenous injection of Compound II at the rate of 1.1 mg per kg precipitated ventricular fibrillation and death.

EFFECT OF COMPOUND II IN ARRHYTHMIA INDUCED BY CORONARY OCCLUSION: Arrhythmia was induced in a dog of 15 kg body weight, by ligation of the left anteria descending coronary artery with a silk thread number 000. Twenty-four hours after surgery, the electrocardiogram showed clear signs of arrhythmia, mainly ventricular tachycardia. An intravenous injection of Compound II at the rate of 3 mg per kg produced only a fleeting response in the electrocardiogram with only a few signs of improvement. On the other hand, the animals exhibited clear signs of neurotoxicity such as undue excitement and lateral movements of the head.

It is thus clear that Compound II cannot be used as an antiarrhythmic agent.

WHAT WE CLAIM IS: An antiarrhythmic pharmaceutical composition, comprising an antiarrhythmic effective amount of the 2,6-xylidide of quinuclidine-3-carboxylic acid or a physiologically compatible acid addition salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.

2. A composition as claimed in claim 1 in which the pharmaceutically acceptable carrier is a carrier suitable for injection.

3. A composition as claimed in claim 2 in which the pharmaceutically acceptable carrier is a carrier suitable for oral administration.

3. Method of treating arrhythmia, which comprises administering to a nonhuman patient requiring antiarrhythmic treatment an antiarrhythmic effective amount of the 2,6-xylidide of quinuclidine-3-carboxylic acid or a pharmaceutically acceptable acid addition salt thereof.

4. Method according to claim 3 in which the compound administered is a pharmaceutically acceptable salt of the 2-6-xylidide of quinuclidine-3-carboxylic acid.

5. Method according to claim 4 wherein said salt is the hydrochloride.

6. Method according to any of claims 3 to 5 wherein the administration is by injection.

7. Method according to any of claims 3 to 5 wherein the administration is oral.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (7)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   intraperitoneal route induced the following symptoms: Dose range Effects 20-30 mg per kg increased locomotion, excitation 40--60 mg per kg pronounced neutroxicity, ataxia, partial paralysis 100 mg. per kg lethal dose. Cause of death seems to be due to respiratory failure.

   EFFECT OF COMPOUND II IN DRUG-INDUCED ARRHYTHMIA: Arrhythmia was induced in 2.7 kg cat, previously anesthetized with Nembutal, by the slow infusion of ouabain over a period of one hour and to a total dose of 70 ,ug per kg. At this stage, the electrocardiogram showed clear signs of arrhythmia, mainly ventricular premature beats and ventricular tachycardia. An intravenous injection of Compound II at the rate of 1.1 mg per kg precipitated ventricular fibrillation and death.

   EFFECT OF COMPOUND II IN ARRHYTHMIA INDUCED BY CORONARY OCCLUSION: Arrhythmia was induced in a dog of 15 kg body weight, by ligation of the left anteria descending coronary artery with a silk thread number 000. Twenty-four hours after surgery, the electrocardiogram showed clear signs of arrhythmia, mainly ventricular tachycardia. An intravenous injection of Compound II at the rate of 3 mg per kg produced only a fleeting response in the electrocardiogram with only a few signs of improvement. On the other hand, the animals exhibited clear signs of neurotoxicity such as undue excitement and lateral movements of the head.

   It is thus clear that Compound II cannot be used as an antiarrhythmic agent.

   WHAT WE CLAIM IS: An antiarrhythmic pharmaceutical composition, comprising an antiarrhythmic effective amount of the 2,6-xylidide of quinuclidine-3-carboxylic acid or a physiologically compatible acid addition salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.
2. 2. A composition as claimed in claim 1 in which the pharmaceutically acceptable carrier is a carrier suitable for injection.

   3. A composition as claimed in claim 2 in which the pharmaceutically acceptable carrier is a carrier suitable for oral administration.
3. 3. Method of treating arrhythmia, which comprises administering to a nonhuman patient requiring antiarrhythmic treatment an antiarrhythmic effective amount of the 2,6-xylidide of quinuclidine-3-carboxylic acid or a pharmaceutically acceptable acid addition salt thereof.
4. 4. Method according to claim 3 in which the compound administered is a pharmaceutically acceptable salt of the 2-6-xylidide of quinuclidine-3-carboxylic acid.
5. 5. Method according to claim 4 wherein said salt is the hydrochloride.
6. 6. Method according to any of claims 3 to 5 wherein the administration is by injection.
7. 7. Method according to any of claims 3 to 5 wherein the administration is oral.