JPH0217554B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel reserpirin quaternary salt derivative and an antiarrhythmic agent containing the same. The reserpirin quaternary salt derivative of the present invention has the following general formula: (In _the formula _, Indicates an alkyl group,
One of R ₁ and R ₂ is a lower alkyl group substituted with a tri-lower alkyl ammonium group. The reserpirin quaternary ammonium salt derivative of the present invention is a compound useful as an antiarrhythmic agent. Conventionally, this type of compound has a general formula that is not quaternary chlorinated. (In the formula, R ¹ represents hydrogen, an alkyl group and a dialkylaminoalkyl group, R ² represents an alkyl group,
It is known that reserpiline derivatives represented by morpholinoalkyl group and dimethylaminoalkyl group have antiarrhythmic effects (see JP-A-52-93799). As a result of various studies, the present inventors have discovered that by converting these conventionally known reserpirin derivatives into quaternary ammonium salts, they have unexpectedly strong antiarrhythmic effects. The reserpirin quaternary ammonium salt derivative of the present invention can be obtained by dissolving the reserpirin derivative represented by the general formula [] in an organic solvent having a polarity such as acetone, and adding lower alkyl halide in an amount ranging from equimolar to large excess. Add and stir, 0
It is produced by reacting for 2 to 24 hours at ℃ to room temperature. Since the reserpiline quaternary ammonium salt derivative of the present invention thus obtained is separated from the reaction solution, the solvent is removed, for example, by decantation, and the residue is dissolved again in a polar solvent such as acetone or ethanol. By adding a relatively non-polar solvent such as ether or benzene, it can be precipitated as crystals.
After separation, the obtained crystals can be further purified by repeating the same recrystallization as described above. The efficacy of the reserpirin quaternary ammonium salt derivative of the present invention was tested by determining whether it inhibited arrhythmia induced by adrenaline administration to guinea pigs. That is, male guinea pigs weighing 400 to 600 g are intraperitoneally injected with 1.2 g/Kg of urethane, fixed in a dorsal position, and cannulated into the external jugular vein. ECG electrodes are fixed to the limbs and the electrocardiogram is observed through the second lead. After 30 to 60 minutes of anesthesia, epinephrine is rapidly injected through the cannula, and the amount of epinephrine is determined so that the resulting arrhythmia lasts for 25 to 60 seconds. Thirty minutes after setting the amount of epinephrine to be injected, the test compound is slowly injected intravenously. A preset amount of epinephrine is rapidly injected 5, 10, 15, and 30 minutes after the intravenous injection of the test compound. After 5 minutes, 10 minutes and 15 minutes
The amount of the test compound that completely inhibits adrenaline-induced arrhythmia after one or more minutes is defined as the minimum effective dose for complete inhibition (LED). The measurement results are as follows.

[Table] Pyrinate iodide
1〓〓2〓(Dimethyl〓n〓Propy 3
5/5 10.0 3.3
ammonium)〓ethyl〓〓
Reserpirin Iodide The above test compound is shown below in relation to the general formula [].

[Table] Daedl acute toxicity (LD ₅₀ ) was measured in male ddY mice (body weight approx.
The test compound dissolved in a solvent was injected into the tail vein using ~25 g), and the test compound was measured by the Litchfield-Wilcoxon method. The above results show that the novel reserpirin quaternary ammonium salt derivative according to the present invention is a compound that has antiarrhythmia effects that are superior to known compounds. Production example 1 2-(dimethyl-n-propylammonium)-
Ethyl reserpirinate iodide Dissolve 5 g of 2-(dimethylamino)-ethyl reserpirinate in 15 ml of anhydrous acetone, and dissolve n-iodide.
17 at room temperature under nitrogen by adding 10 ml of propyl
Leave it for a while. A yellow oil separates and the solvent is removed by decantation. Add 100 c.c. of acetone to the residue again and filter out the insoluble matter. Ether is added to the solution while stirring, and the resulting powdery precipitate is filtered, washed with ether, and then dried in vacuum. yield
3.5g (yield 51.4%). IR: 3200, 1710, 1620, 1100 NMR: 10.6 (N ^a −H) 3.75 (−OCH ₃ , 6H)
7.6(

[Formula] 1H) 0.85 (

[Formula] 3H) 6.9 (aromatic 2H) mp: 161.1-164.4°C Production Example 2 1-{2-(Dimethyl-n-propylammonium)-ethyl}-reserpiline iodide 2 used in Production Example 1 above -1- in place of (dimethylamino)ethyl reserpirinate
The title compound was prepared according to the procedure of Preparation Example 1 except that {2-(dimethylamino)-ethyl}-reserpiline was used. IR: 1680, 1600, 1190 NMR: 7.70 (

[Formula] 1H) 3.7 (- COOCH ₃ 3H) 7.10 (Aromatic 2H) 0.9
(

[Formula] 3H) 3.9 and 3.8 (-OCH ₃ 6H) mp: 212.7-214.6°C The compounds of the present invention can be administered orally or parenterally, usually in the form of a pharmaceutical preparation. Forms of pharmaceutical preparations include tablets, capsules, suppositories, troches, syrups, creams, ointments, patches, poultices, granules, powders, injections, suspensions,
There are inhalants, aerosols, etc. It can also be made into double-layer tablets or multi-layer tablets together with other drugs. Furthermore, the tablets can be made into tablets with conventional coatings, such as sugar-coated tablets, enteric-coated tablets, or film-coated tablets, if necessary. When preparing a solid preparation, additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, hydroxypropylcellulose, glycerin, polyethylene glycol, stearic acid are used. ,Magnesium stearate,
Talc etc. are used. In the case of semi-solid preparations, vegetable or synthetic waxes or fats are used. When preparing a liquid preparation, additives such as sodium chloride, sorbitol, glycerin, olive oil, almond oil, propylene glycol, and ethyl alcohol are used. The amount of active ingredient in these preparations ranges from 0.1 to 100% of the preparation
% by weight, suitably from 1 to 50% by weight in the case of formulations for oral administration and from 0.1 to 10% by weight in the case of formulations for injection. There are no particular restrictions on the administration method or dosage of the antiarrhythmic agent of the present invention, and there are various formulation forms, administration routes,
The daily dose of the active ingredient is selected depending on the patient's age, gender, degree of disease, etc.
It is 0.01-1000mg. Formulation Example 1 Tablet (1 tablet) 2-(dimethyl-n-propylammonium)
Ethyl reserpirinate iodide 1 mg Lactose 76 mg Crystalline cellulose 15 mg Corn starch 7 mg Magnesium stearate 1 mg 100 mg Each component is mixed uniformly to make a powder for direct compression. This is molded into tablets with a diameter of 6 mm and a weight of 100 mg using a rotary tablet press. Formulation example 2 Granules (1 sachet)

[Table] After the components of A are mixed uniformly, the solution of B is added and kneaded, the granules are sized using an extrusion granulation method, and then dried in a dryer at 50°C. Particle size of dried granules is 297 μm ~
The granules are sieved to 1460μm. 1
The sachet amount is 200mg. Formulation Example 3 Injection 2-(dimethyl-n-propylammonium)
Ethyl reserpirinate iodide 1 mg Sodium chloride 10 mg Distilled water Appropriate total volume 1.0 ml Add distilled water to dissolve sodium chloride and the active ingredient to make a total volume of 1.0 ml. Formulation example 4 Suppositories 2-(dimethyl-n-propylammonium)
Ethyl reserpyrinate iodide 1g Polyethylene glycol 4000 79g Glycerin 20g Total amount 100g Add glycerin to the active ingredients and dissolve. Polyethylene glycol 4000 is added thereto, heated and dissolved, poured into suppository molds, cooled and solidified to produce suppositories weighing 1.5 g each.

Claims (1)

[Claims] 1. General formula (In _the formula _, Indicates an alkyl group,
One of R ₁ and R ₂ is a lower alkyl group substituted with a tri-lower alkyl ammonium group). 2 General formula (In _the formula _, Indicates an alkyl group,
An antiarrhythmic agent characterized in that it contains a reserpiline quaternary ammonium salt derivative represented by R ₁ and R ₂ , in which one of R 1 and R 2 is a lower alkyl group substituted with a tri-lower alkyl ammonium group.