CS216902B2 - Method of making the new anilides of the aminoalkan acids - Google Patents

Description

The invention relates to a process for the production of novel aminoalkanoic acid anilides which have proved to be effective against cardiac arrhythmias.

Many anilides are known which differ structurally from the anilides described herein. Some are described in the literature as therapeutically useful agents, cf. Swedish Pat. Nos. 147 308, 147 309 and 153 705, Swiss Pat. Nos. 318 077, 336 815 and 464 882, West German Pat. No. 967,642, French Pat. No. 1,161,363, English Pat. Nos. 705,460, 762,080, 754,413 and 809,286, Chem. Abstr. 42, 7871 d (1948), 47, 1055 g (1958), US Pat. No. 3,540,250.

Following intensive coronary therapy, attention was mainly paid to the treatment of ventricular extrasystole and other cardiac arrhythmias. No conventional means has been found to be entirely satisfactory for the treatment of such arrhythmias. Drugs used, such as quinidine, procainamide, Inderal ^R [1-isopropylamino-β- (1-naphthoxypropan-2-ol)] and diphenylhydantoin [Phenytoin (Brit. Pharm.jj), but exhibit undesirable side effects. also tested, but their effect on the central nervous system is similar to Phenytoin, cf. Proceedings of the British Pharmacological Society, vol. 39, 183 (1970).

In addition to the compounds described above, other pharmaceutical preparations also exhibit anti-arithmetic effects. For example, the local anesthetic xylocaine (lidocaine), whose chemical name is 2,6-xylidide of 2-diethylaminoacetic acid, is an effective antiarrhythmic agent suitable for intravenous or intramuscular use, Parkinson P. I. et al., Brit. Copper. J., Vol. 2, pp. 29-30 (1970) and The Marek Index, 8th edition (Merck and Company Inc., Rahway, NJ, 1968J, p. 618), but is not really effective for a small amount of the blood preparation, see Eisinger and Hellier, Lancet II, 1303, and Boyes et al., Clin Pharmacol. Therap., 12, 41, 1971. When lidocaine is administered orally, there is a noticeable loss of drug, probably due to function. Because the drug has to pass from the intestinal tract to the liver immediately after administration, the duration of lidocaine levels in the blood is very short, so longer protection is excluded.

It is also known that some 2-aminotetralins possess antiarrhythmic activity, cf. Graeff D. M. et al., J. Med. Chem., Vol. 14, pp. 60-62 (1971).

The invention relates to a process for the preparation of novel aminoalkanoic acid anilides of the general formula I, i

in which it denotes

R 6 is a hydrogen atom, a methyl group or an n-propoxy group,

R6 is methyl or ethyl,

R 7 is hydrogen or methyl; and

R @ 9 is hydrogen or methyl, and their physiologically acceptable salts.

The novel anilides of the general formula (I) are prepared according to the invention in that the alkenic acid anilide of the general formula (II),

in which

R a, R e, R 7 and R 9 are as defined above, reacted with concentrated aqueous ammonia, optionally in the presence of ammonia gas, and the anilides obtained, if desired, are converted into a physiologically acceptable salt.

Preferred anilides of the invention are as follows:

3-Aminopropionic acid 2,6-xylldide, m.p. 218-221 ° C (hydrochloride):

3-Aminobutyric acid 2,6-xylldide, m.p. 171-173 ° C (hydrochloride):

, ^CH J

ch ₂

3-aminopropionic acid 2-ethyl-6-methylanilide, m.p. 215.5-216 ° C (hydrochloride is:

3-Aminopropionic acid 2,4,6-mesidide, m.p. 272.5-273.5 ° C (hydrochloride):

3-Aminopropionic acid 2,6-dimethyl-4-propoxyanilide:

Particularly preferred are both the first two compounds and therapeutically useful salts.

As used herein, the term "therapeutically useful salt" refers to an acid addition salt that is physiologically innocuous when administered at such a dosage and interval (e.g., frequency of administration) that is effective for the indicated therapeutic use of the parent drug. compounds. Typical therapeutically useful acid addition salts of the above compounds include, but are not limited to, salts with mineral acids such as hydrochloric, phosphoric or sulfuric acid and organic acids such as succinic and tartaric acids and sulfonic acids such as methanesulfonic acid.

In clinical practice serves derivatives made according to the invention is usually orally or ¹ injefcčně in the form of pharmaceutical preparations which contain the active component as free base or as one therapeutically acceptable salts, such as hydrochloride together with a pharmaceutically acceptable carrier which may be solid, semi or a liquid diluent or edible capsule. Typically, the composition comprises between 0.1 and 10% by weight of the composition. the active compound, for example in an aqueous solution in the form of its soluble acid salt, although in solid preparations, i.e. in tablets or capsules, the concentration of the compounds produced according to the invention can reach up to 100% by weight. tablets or capsules.

Pharmaceutical compositions in unit dosage form for oral use may be prepared by mixing either the base or the acid salt with a solid powder carrier. Examples are lactose, sucrose, serhitol, mannitol and starches, for example potato starch, cereal starch or amylopektih, cellulose derivatives and gelatin. The carrier may also consist of glidants, for example magnesium stearate or calcium stearate, carboswax or other polyethylene wax, compressed into tablets or grains, which may either be coated with a concentrated sugar solution, which may also contain gum arabic, gelatin, talc and / or titanium dioxide or which may be coated alternately with a varnish dissolved in a slightly volatile organic solvent or in a mixture of organic solvents. Dyestuffs may be added to these coating materials. Tablets with a depot effect are obtained by using multiple layers of the active drug separated from each other by slowly dissolving coating substances. Another method for producing depot-effect tablets is by dividing the dose of active drug into granules with coatings of different thicknesses and compressing the granules together with the carrier into tablets. The active ingredient may also be contained in slow-dissolving tablets which are made from fatty and waxy substances, or it may be uniformly dispersed in a tablet or insoluble substance, for example, in the physiologically inert plastic described in U.S. Pat. No. 3,317,304.

Soft gelatin capsules (sealed pearl capsules) and other sealed capsules consisting, for example, of a mixture of gelatin and glycerin, and may contain mixtures of the active ingredient with a vegetable oil. Hard gelatine capsules contain granules of the active ingredient with solid powdered carriers, for example lactose, sucrose, sorbitol, mannitol or starches, for example potato starch, cereal starch or amylopectin, or with cellulose derivatives or with gelatin, as well as magnesium stearate or acid. stearovou.

For injectable parenteral use, the compositions preferably contain an aqueous solution of a water-soluble pharmaceutically acceptable acid-salt of the active ingredient and optionally a stabilizing agent and / or a buffering agent. The solutions may be isotonized by the addition of sodium chloride.

In clinical use, the amount of active substance administered to patients must be carefully determined according to the individual needs of each case. As an example to elucidate suitable requirements, for the treatment of acute cases of ventricular arrhythmia, intravenous administration of about 100 mg to about 1000 milligrams of 3-aminobutyric acid 2,6-xylidide hydrochloride to a human weighing 70 to 80 kg. Orally administered daily requirement may range from about 0.8 to about 8 g. The unit dose of the compounds produced according to the invention contains at least 10 mg for tablets, capsules and similar solid dosage forms, preferably ranging from 50 to 500 mg.

The antiarrhythmic effect of the compounds of the invention was demonstrated by observing the protection they provide against chloroform-induced fibrillation in mice. Experiments in mice were performed according to a variation of the procedure described by J. W. Lawson "Antiarrhymic activity of some isoquinolina derivatives determined by a rapid screahing procedure in the mouse", J. Pharm. Exp. Therap., Vol. 160i, pp. 22-31 (1968 J.) This procedure is based on the observation that when an unaesthetized, unpremedicated mouse is exposed to chloroform vapors, its breathing will soon cease, and at this point both electrophcardiographic and visual investigations show that they atrialize the atria When the mouse is appropriately pre-treated with an anti-arrhythmia agent, respiratory failure is not accompanied by ventricular fibrillation.

Groups of 10 female Swiss white mice (HAM / ICRJ, each weighing 18-25 g) were transformed with four different doses of the compounds of the invention at a standard time of 20 minutes before being placed in a 200 ml beaker containing 50 ml of chloroform and cotton immediately after stopping breathing, each mouse was removed from the beaker, thorax opened, and the heart examined for ventricular fibrillation or cardiac rhythm was confirmed by an electrocardiographic record. fibrillation, the heart was stimulated by a touch of tweezers The heart was considered 'fibrillating' when there were gentle trembling movements on the atrial surface and lasted at least 5 seconds after thoracotomy or mechanical stimulation. the status of those animals which have been co - ordinated after the events referred to above The dose-response curve was plotted from these values and the ED 50 value thus obtained was compared to the ED 50 value for lidocaine as a standard. The relative potency is the ED 50 of the test compound / ED 50 of lidocaine. The route of administration was subcutaneous.

Test compound 3-Aminopropionic acid 2-ethyl-6-methylanilide

2.4.6- mesidid 3-aminopropionitrile 2.6- ^{1 L} of di methyl-4-n-propoxyanilld acid

3-Aminopropionic acid 2,6-xylidide 3-Aminopropionic acid 2,6-xylidide

*) The value outside the parentheses indicates the statistical mean value. Numbers in parentheses are confidence limits.

A number of compounds prepared according to the invention were tested to determine protection against chloroform-induced fibrillation in guinea pigs. Guinea pigs (250-350 g) were individually placed in a row of 4000 ml beakers containing cotton wool and 100 ml chloroform. After respiratory arrest, the animal was removed from the beaker, the thorax was opened, and the heart examined for ventricular fibrillation. The type of heart rhythm was confirmed by electrocardiography. Whenever fibrillation was not apparent, the test compound was

3-Aminobutyric acid 2,6-xilidide

3-Aminopropionic acid 2,6-dimethyl-4-propoxyanilide

The compound 3-aminobutyric acid 2,6-xylidide was also tested in dogs by the modified procedure described by A. S, Harris, "Delayed Development of Ventricular Ectopic Rhytms Following Experimental Coronary Occlusions," respectively. St. 1, pp. 1318-1328 (1950). In this procedure, the dogs were anesthetized, the heart relaxed, and the forward downstream branch of the left coronary artery was ligated in two stages. Thorax was closed and the dogs left until they came to consciousness. After such intervention, during the first 2 to 3 days of the electrocardiogram, they showed the presence of ventricular arrhythmias and it was shown that such arrhythmias were suppressed by known antiarrhythmic agents. Clark, B.R., and Cummings, J.R., "Arrhytmias Following Experi'Relative Efficacy * i

0.29 (0.00 to 0.81)

0.30 (0.2 to 0.6)

0.20 (0.12 to 0.34)

0.4 (0.2 to 0.8)

0.99 (0.6 to 1.9) 'heart stimulated by tweezers. Fibrilation was considered when there was a gentle trembling movement on the atrial surface and lasted at least 5 seconds after thoracotomy or mechanical stimulation. Fibrillation that did not occur was considered to be the condition in those animals in which coordinated ventricular activity was maintained after these events.

A single intraperitoneal dose (about 1 to 5 ml) of each test compound was administered using a 25 gauge needle, twenty minutes before the animals were placed in chloroform.

The following table shows the protection observed after two compounds produced according to the invention:

% of protected animals dose (mg / kgj

326 100%

200 313% 'mental Goronary Occlusion and their Response to Drugs', Annals New York Academy of Sciences, Vol. 65, pp. 543-551 (1956). In order to test the effect of 3-amino-2,6-butyroxylidide on these arrhythmias, non-sleeping dogs were tied and given the drug intravenously or orally. Electrocardlographic, cardiovascular and other drug effects have been reported. These experiments showed that intravenous doses significantly suppressed ventricular arrhythmias, with no discernible side reactions. Other dogs were dosed orally, which produced marked suppression of ventricular arrhythmias.

The following table summarizes the results of intravenous treatment.

Reaction of non-anesthetized dogs to intravenous doses of 3-amino-2 ‘, 6‘-butyroxylidide on day 1 after coronary artery ligation

Dog number

Power of arrhythmia Ventricular dose (beats / min)

Ventricular ectopia (%)

Antiarrhythmic efficacy Dose Dose acting partially * totally **

Duration (min) mg / kg mg / kg

559 216 100 ALIGN! 30 50 75 none none 547 222 100 ALIGN! 7.5 32 330 none none 543 195 '100 15 Dec 18 96 none none 544 198 '96 15 Dec 22nd 30 none none

dropped to less than 50% of the total

*) Incidence of abnormal ventricular heart rate counts **) Incidence of abnormal ventricular heart rate counts

Experiments using isolated cardiac tissue (e.g. Purkinje fibers) show the advantageous properties of the compounds prepared according to the invention.

The compounds prepared according to the invention exhibit unexpected antiarrhythmic effects. Compared to lidocaine ¹ , a known anesthetic and natarrhythmic drug, they have a weak local anesthetic effect.

In contrast to the generally known prior art that antiarrhythmic activity and local anesthetic effect are closely related and that primary amines such as local anesthetics are much less effective than the corresponding secondary amines, weak local anesthetics produced according to the invention exhibit strong antiarrhythmic properties. AP Truant and B. Takman, "Local Anesthetics", Brills, Pharmacology and Medicine, JR DiPalma, Edition McGraw-Hill Book Co., New York, (1965), and FF Doerge, "Local Anesthetic Agents", Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th edition by CO Wilson et al., Lippincott, Philadelphia, Pa., Pp. 597-598 (1966).

When administered to mammals, the compounds produced according to the invention do not produce any methemoglobin in the bloodstream of the animal. This can be attributed to the nature of the substituents having these compounds in the ortho-position of the benzene ring.

The following examples are intended to illustrate the invention without limiting it.

Example 1 a d 1

3-Aminobutyric acid 2,6-xylidide g of ammonium chloride is added to a solution of 11.8 g (0.062 mol) of crotonic acid 2,6-xylidide in 150 ml of 95% ethanol and the mixture is saturated with gaseous ammonia at 0 ° C. The mixture thus obtained was placed in a pressure vessel and heated at 80 ° C for 48 hours. The contents were transferred to a still and the solvents were evaporated in vacuo to give a residue as a solidifying oil. This was dissolved in 75 ml of 1 N acidic Toxicity

Twitching fatal cases dropped to less than 15% of total ny hydrochloric acid and extracted with ether. The ether is removed. The acidic solution is adjusted to pH 11 with sodium hydroxide until alkaline. The liberated oily base is extracted thoroughly with methylene chloride. The combined extracts were dried with potassium carbonate, filtered and concentrated in vacuo. Ethereal HCl solution was added and the resulting precipitate (10.0 g) was isolated and recrystallized from an alcohol / ether mixture. The colorless crystals were dried for 2 hours at a pressure of 0.1 mm Hg and at 100 ° C, having a melting point of 171-173 ° C.

Analysis for C12H19ClN2O calculated:

C 59.4%, H 7.89%, Cl 14.6%, N 11.5%;

found:

39.3% C, 8.01% H, 14.4% Cl,

11.4%; N.

Example 2

3-Amino-2-methylpropionic acid 2,6-xylidide

A. Methacrylic acid 2,6-xylidide

From 29.0 g of magnesium (1.2 mol), 130 g (1.2 mol) of ethyl bromide and 400 ml of absolute! of ether, a Grignard reagent solution is prepared. A solution of 121 g (1.0 mol) of 2,6-xylidine in 400 ml of absolute ether is added over 45 minutes with vigorous mechanical stirring. Add an additional 400 mL of absolute ether, then a solution of 100 ^; g (1.0 mol) of methyl methacrylate in 400 ml of absolute ether is added over 30 minutes at reflux. The reflux is maintained for 2 hours. The reaction mixture is cooled and 700 ml of 9 N hydrochloric acid are added carefully with stirring and cooling. The ether phase was separated, washed with water, 0.2 M sodium bicarbonate and water, dried

216802 over or out of anhydrous magnesium sulphate and alcohol (boiling point 60 to 110 ° C). The ether was evaporated to leave a solid mixture of ethanol and water. Yield: 35%. Point to which can be recrystallized from petroleum ether: 10.1 to 105 ° C.

A small amount of isopropyl may be prepared in the same manner.

S-amino-N, N-propionoxylidide, mp 218-221 ° C (HCl-salt)

NH-CO-C

S-amino-4-ethyl-4-methylpropionanilide. Mp 215.5-216 ° C (HCl-salt)

3-amino-, 2 2, 4‘, 6‘-propionomesidide B. mp 272.5-273.5 ° C (HCl-salt)

3-Amino-2 ', 6'-dimethyl-4'-n-propoxypropionanilide. Mp 208-210.5 ° C (HCl-salt)

Claims (1)

A process for the preparation of the novel aminoalkanoic acid anilides of the general formula (I) in which it is labeled R4 is hydrogen, methyl or n-propoxy, A methyl or ethyl group, R 7 is hydrogen or methyl; and R9 is a hydrogen atom or a methyl group of the invention and their physiologically acceptable salts, characterized in that the anild of the alkenoic acid of the formula II in which: R1, R6, R7 and R9 are as defined above, reacted with concentrated aqueous ammonia, optionally in the presence of ammonia gas, and, if desired, the anilides obtained are converted into a physiologically acceptable salt.