NO137500B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF 2-AMINO-2`, 6`-PROPION-XYLIDIDE FOR USE AS A MEDICINE FOR HEART ARRYTHMIA - Google Patents

Description

The present invention relates to the preparation of the new compound 2-amino-2<1>,6'-propion-xylidide for use as a drug against cardiac arrhythmia in mammals.

Ever since the emphasis was placed on cardiac treatment, great emphasis has been placed on the treatment of ventricular extrasystoles and other cardiac arrhythmias. No known drug is completely satisfactory for the long-term treatment and regulation of such arrhythmias. Substances such as quinidine, procainamide, propranolol and diphenylhydantoin (phenytoin (Brit. Pharm)) have been used, but exhibit undesirable side effects. Certain phenoxy derivatives of aminopropane have also been studied, but their action on the central nervous system is similar to that of phenytoin, Proceedings of the British Pharmacological Society, Vol. 39,

pp. 183P, (1970). In addition to the above-mentioned substances, other pharmaceutical preparations exhibit antiarrhythmic properties. For example, the local anesthetic compound lidocaine with the chemical name 2-diethylamino-2<1>,6'-acetoxylidide is an antiarrhythmic drug suitable for intravenous or intramuscular use, Parkinson, P.I., et al., Brit. With. J., Vol. 2, pp. 29-30, (1970) and The Merck Index, 8th ed., (Merck & Company, Inc., Rahway, New Jersey, 1968), p. 618, but is not effective orally

due to the low substance levels in the blood. Eisinger and Hellier, Lancet, 1969, II, 1303 and Boyes et al, Clin. Pharmacol. Therapy. 12, No. 1, pp. 105-116 (1971). When lidocaine is given orally, there is a pronounced loss of the drug, which is probably due to the liver functions that most of the substance must pass immediately after absorption from the digestive tract. The duration of

these concentrations in the blood with lidocaine are also rather low, which excludes long-term protection.

Certain 2-aminotetralins are also known to have antiarrhythmic properties. D.M. Graeff et al, Journal of Medicinal Chemistry, Vol. 14, pp. 60-62 (1971). Furthermore, from Archiv der Pharmacie, vol. 301 (1968), pages 780-785, a compound related to the compound produced according to the invention is known, namely 2-dimethylamino-2<1>,6<1->propionxylidide and with similar therapeutic effect.

According to the present invention, the antiarrhythmically active compound 2-amino-2',6'-propionxylidide is produced with the formula:

as well as the compound's pharmaceutically acceptable salts, and the method for producing this compound is characterized by reacting 2-chloro-2<1>,6<1->propionxylidide, 2-iodo-2<1>,6<1->propionxylidide or 2-bromo-2',6<1->propionxylidide with ammonia, after which, if desired, the product obtained is converted into a therapeutically acceptable salt thereof by reaction with a pharmaceutically acceptable acid.

The manufactured compound and its salts have, as mentioned, anti-arrhythmic action and even with oral administration, a high level of the drug in the blood is achieved. The duration of this high level is also relatively long.

The term "therapeutically acceptable salt" denotes in the field an acid addition salt which is physiologically innocuous when administered in such a dose and at such intervals (eg administration intervals) that the compound is effective for the indicated therapeutic use of the parent compound. Typical therapeutically applicable addition salts of 2-amino-2<1>,6'-propionxylidide include salts of mineral acids such as hydrochloric acid, phosphoric acid or sulfuric acid and of organic acids such as succinic acid and tartaric acid, as well as sulphonic acids such as methanesulphonic acid•

In clinical practice, the active compounds will normally be given orally or by injection in the form of pharmaceutical preparations containing the compound in the form of a free base or as one of the usual therapeutically usable salts, e.g. the hydrochloride, in connection with pharmaceutically usable carriers which can be solid, semi-solid or liquid, or as a digestible capsule.' Usually the active compound will make up from 0.1 to 10% by weight of the preparation, e.g. in aqueous solution in the form of the soluble acid salt, although when the compound is in the form of solid preparations such as tablets or capsules, it can have a concentration of up to 100 percent by weight of the tablet or capsule.

Pharmaceutical preparations in the form of dosage units of 100 to 250 mg each for oral use can be prepared by mixing either the base or the acid salt with a solid powdered carrier. Examples are lactose, sucrose, sorbitol; mannitol and starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin. The carrier can also be lubricants such as magnesium or calcium stearate, a "Carbovox" or other polyethylene glycol waxes which are pressed into tablets or cores which can then be coated with either a concentrated sugar solution which can also contain gum arabic, gelatin, talc and/or titanium dioxide or which can optionally be coated with a varnish dissolved in a volatile organic solvent or a mixture of such solvents. Dyes can be added to these coatings. Slow-dissolving tablets can be prepared using multiple layers of the active compound separated by slow-dissolving coatings. Another way of producing slow-dissolving tablets is to divide the dose of active substance into granules with coatings that have different thicknesses and press the granules into tablets together with the carrier. the substance. The active compound can also be incorporated into slow-dissolving tablets of fat or wax or can be distributed evenly in a tablet or an insoluble compound such as e.g. a physiologically inert plastic substance f, for example as shipped in the U.S. patent 3,317,394.

Soft gelatin capsules (bead-shaped closed capsules) and other closed capsules consist, for example, of a mixture of gelatin and glycerol and may contain mixtures of the active compound and a vegetable oil. Hard gelatin capsules contain granules of the active compound with solid powdered carriers such as lactose, sucrose, sorbitol, mannitol or starch such as potato starch, corn starch or amylopectin or cellulose derivatives or gelatin, possibly magnesium stearate or stearic acid. The dosage units for all these capsules can be between 100 and 250 mg for either the base or the acid addition salt.

For parenteral use by injection, the preparations preferably consist of an aqueous solution of a water-soluble, pharmaceutically usable acid salt of the active compound, possibly with the addition of a stabilizer and/or a buffer compound. The solutions can be made isotonic by adding sodium chloride. The preferred dosage unit for these solutions is also 100 to 250 mg of 2-amino-2<1>,6<1->propionxylidide

or its therapeutic salt.

The ability of 2-amino-2<1>,6<1->propionxylidide to suppress cardiac arrhythmia has been demonstrated in both mice and dogs.

The experiments on mice were carried out according to a modification of the method described by J.W. Lawson, "Anti-arrhytmic activity of some isoquinoline derivatives determined by a rapid screening procedure in the mouse", J. Pharm. Exp. Therap., Volume 160,

pp. 22-31, (1968) . The method is based on the observation that when an unanesthetized and untreated mouse is exposed to chloroform vapor,

breathing soon stops and at this point both electrocardiographic and visual examination show that the heart chambers are fibrillating. If the mouse is treated in a suitable way with known antiarrhythmics before the chloroform treatment, the respiratory arrest will not be followed by

ventricular fibrillation.

Groups of 10 Swiss Albinotype (HAM/ICR) female mice, each weighing 18 to 25 g, were pretreated with a dose (approximately LD , - the dose that kills one in a thousand mice) of

0, 1

2-amino-2<1>,6<1->propionxylidide for 10, 20, 40, 80 and/or 160 minutes, respectively, before being placed in a 2 liter beaker containing cotton and 50 ml of chloroform. Immediately after the animals had ceased breathing, they were taken out of the beaker, the thorax was opened and the heart examined to determine whether the heart chamber was fibrillating or not. The heart rhythm was confirmed by

electrocardiographic measurements. If no fibrillation was found, the heart was touched with forceps. The heart is considered to be fibrillating if there are fine trembling movements on the surface of the heart muscle that last for at least 5 seconds after the opening of the tor axis or the mechanical stimulus. The heart is considered to be free of ventricular fibrillation in animals where an organized ventricular activity was evident after the above intervention.

The following table shows the effects of administration of lidocaine, quinidine, procainamide and 2-amino-2',6<1->propionxylidide.

The compound 2-amino-2<1>,6<1->propionxylidide was also tested on dogs following a modification of the method described by A.S. Harris in "Delayed Development of Ventricular Ectopic Rhythms Following Experimental Coronary Occlusions"

(Delayed induction of ventricular ectopic rhythms after experimental cardiac occlusions), Circ. volume 1, pp. 1318-1328

(1950). In this procedure, the dogs were anesthetized, the heart was opened and the anterior descending branch of the left coronary artery was ligated in two steps. The chest was closed and the dog was allowed to recover from the anaesthetic. During the first 2 to 3 days after this surgical procedure, the electrocardiograms showed ventricular arrhythmia and these irregular rhythms were found to be suppressed or abolished by the known antiarrhythmics. B.B. Clark and J.R. Cummings, "Arrhytmias Following Experimental Coronary Occlusion and Their Response to Drugs" Annals of the New York Academy of Sciences, vol. 65, pp. 543-551

(1956). To investigate the effect of 2-amino-2<1>,6'-propionxylidide on these arrhythmias, unanesthetized dogs were placed in straps and treated intravenously or orally with the drug. The electrocardiographic, cardiovascular or other effects of the drug were read and written down. The experiments showed that intravenous doses induced a clear suppression of or reduction of the cardiac arrhythmia, without any adverse side effects being found. Other dogs were given oral doses which also produced marked reductions in the ventricular arrhythmia.

Table II summarizes the results of the oral treatment.

The response of unanesthetized dogs to intravenous infusion of lidocaine and 2-amino-2',6'-propionxylidide on the first day after coronary artery ligation is shown below in Table III. The dosage schedule was: 1st hour: 15 mg/kg/hour, 2nd hour: 30 mg/kg/hour, 3rd hour: 60mg/kg/hour. The infusion was stopped at the first sign of toxicity other than vomiting.

The ligation was made close to the distal edge of the left ventricular appendage. A double ligature was passed under the detached artery and cut across so that two ligatures were obtained in the same position on the artery. The first was tightened around, the artery with the interposition of a No. 20 needle which was then pulled up. After 30 minutes, the second ligature was tightened to close the artery.

The compound 2-amino-2<1>,6<1->propionxylidide unexpectedly shows antiarrhythmic effects. The substance has a very weak local anesthetic effect compared to lidocaine, a well-known anesthetic and antiarrhythmic drug. To show this, was

20 ml solutions of 2-amino-2<1>,6'-propionxylidide and lidocaine compared-in vitro by measuring the effect on the sciatic nerve of frog according to the method described by Camougis and Takman, "Nerve and Nerve-Muscle Preparations (As Applied to Local Anesthetics), Chapter 1, in Methods of Pharmacology, A. Schwartz, ed., Appleton-Century-Crofts, New York, New York (.1970). Mon

found that the lidocaine solution blocked 78% of the nerve's normal action potential after 5 minutes, while the compound of the invention did not block the action potential at all after the nerve was exposed to the solution for 96 minutes.

In order to demonstrate what is achieved by the compound produced according to the invention in relation to said known compound, namely 2-dimethylamino-2',6'-propionxylidide, comparative experiments were carried out with these compounds (the racemates) as follows: By continuous infusion in dogs, a successively increased content in the blood plasma (venous blood) was achieved with the compound in the present application. In contrast, a plateau value was achieved with the previously known compound, which suggests a shorter pharmacological half-life and thus less good possibilities for use as an orally administrable antiarrhythmic agent.

By continuous infusion of 0.5 mg/kg/min. of the compound produced according to the invention, a blood level of 40.1 ug/ml was thus obtained after 160 min. The level increased linearly during the entire period.

By continuous infusion of 2-dimethylamino-2-', 6'-propionxylidide (0.25 mg/kg/min), a plateau value of 7 Mg/ml was achieved after 30 min. When the infusion rate was increased to 0.5

mg/kg/min., a new plateau value of 10 ;ig/ml was obtained after

10 minutes By further increasing the infusion rate to

1 mg/kg/min. blood level rose to 20 pg/ml (plateau value) after 30

my. This suggests a rapid metabolism and/or elimination of the substance with subsequent difficulty in maintaining pharmacologically effective blood levels.

The results from comparison tests of CNS toxicity and protective effect against chloroform-induced arrhythmias (cf. page 5 of the application) in mice are shown in the table below:

The numerical values stated above imply a relative therapeutic index of 2 for ataxia, 2 for convulsion and 3 for loss of corrective reflex, for the new compound produced according to the present invention compared to said previously known compound.

Despite the generally accepted previous teaching that antiarrhythmic action and local anesthetic action are closely linked and that primary amines are much weaker local anesthetics than the corresponding secondary amines, the very weak local anaesthetic, 2-amino-2<1>, shows 6'-propionxylidide strong antiarrhythmic properties that have a long duration. A. P. Truant and B. Takman, "Local Anesthetics", Drills, Pharmacology and Medicine, J.R. DiPalma, ed., McGraw-Hill Book Co., New York, N.Y.,

(1965) and F.F. Doerge, "Local Anesthetic Agents", Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th edition of CO. Wilson et al., Lippincott, Philadelphia, Pa., pp. 597-598 (1966). 2-amino-2',6'-propionxylidide is synthesized as mentioned by reacting the corresponding 2-chloro-, 2-bromo- or 2-iodo-2',6'-propionxylidide with ammonia in alcoholic-aqueous solution or alcoholic solution . The ammonia is added as gas either continuously or intermittently at a low temperature. A mixture of ammonium hydroxide, alcohol and gaseous ammonia can also be used. The reaction participants can be kept at room temperature or a higher temperature in a closed vessel. The mixture is stirred in

4-9 days if used at room temperature.

The invention is further illustrated by the following example:

Example:

Synthesis of 2-amino-2', 6'-propionxylidide. The compound 2-amino-2',6'-propionxylidide was synthesized by saturating with gaseous ammonia and at room temperature a suspension of 50 g (0.195 mol) of 2-bromo-2',6<1->propionxylidide in a mixture of 500 ml of 95% alcohol and 400 ml of concentrated aqueous ammonia. The saturation was carried out under mechanical stirring. After 25 hours, the mixture was saturated again with ammonia gas. Stirring at room temperature was continued for a total of 116 hours and a sample was taken at this time. Gas chromatographic analysis showed that approx. 95% of the bromine compound was converted to the desired product. The solutions were evaporated in vacuo and the residue taken up in 80 ml of 3 molar hydrochloric acid. After adding 220 ml of water, insoluble matter was filtered off, washed with 100 ml of water and dried. The insoluble matter weighed 9.5 g and consisted mainly of unreacted bromine compound. The filtrate was reacted with 50 ml of 7 molar NaOH, extracted three times with methylene chloride (50 ml + 2 x 25 ml portions), dried over potassium carbonate and evaporated. The yield was 26.8 g, which was 71.4% of the theoretical yield. This residue was a colorless solidifying oil which was dissolved in 200 ml of chloroform. Hydrogen chloride was bubbled through until a sample of the solution showed an acidic reaction on moist pH indicator • paper. A precipitate was obtained which was filtered off. This was washed with chloroform and dried. The melting point was determined to be 246-247.5°C. Gas chromatographic analysis of the substance showed only one component. The calculated values for 2-amino-2',6<1->propionxylidide hydrochloride (C^H^<C>11^O with a molecular weight equal to 228.5) are:

C, 57.8; H, 7.49; N, 12.2; Cl, 15.5; and the analysis values were:

C, 57.7; H, 7.69; N, 12.2; Cl, 15.5. IR analysis (KBr disc, hydrochloride). showed: 0 2000-1850 (a broad band with shoulder, NH3+), 1670 (amide I), 1540 (amide II), 1386, 1375 (symmetric methyl groups), 760-1 (three neighboring hydrogens on phenyl).

The compound 2-amino-2<1>,6'-propionxylidide and its therapeutic salts have been shown to have antiarrhythmic effects when administered to dogs at oral doses of from 50 to 100 mg/kg, and a cumulative dose of 75 mg /kg to mice in a maximum oral dose of approx. 380 mg/kg and should be effective in humans in a dose of approx. 6 g per day orally.

Claims (1)

Analogous process for the preparation of anti-arrhythmic active 2-amino-2<1>,6<1->propionxylidide with the formula: as well as the compound's pharmaceutically acceptable salts, characterized by reacting 2-chloro-2',6'-propionxylidide, 2-iodo-2<1>,6<1->propionxylidide or 2-bromo-2<1>, 6'-propionxylidide with ammonia, after which, if desired, the product obtained is converted to a therapeutically acceptable salt thereof by reaction with a pharmaceutically acceptable acid.