DK145155B - METHOD OF ANALOGUE FOR THE PREPARATION OF AN N-M-METHOXYBENZYL-N, N-DIMETHYL-N-ETHYLAMMONIUM SALT OR N-M-METHOXYBENZYL-N-NIMETHYL-N-2-HYDROXYTHYLMETHYL - Google Patents

Description

MÉm (19) DENMARK \ J3 /

| J | (12) PUBLICATION OF 1451 55 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 3224/70 (51) | nt.CI.3 C 07 C 93 / 1A

(22) Filing day 22 Jun. 1970 (24) Race day 22 Jun. 1970 (41) Aim. available Dec 24 1970 (44) Presented 20 Sep. 1982 (86) International application # - (86) International filing day - (85) Continuation day - (62) Master application no -

(30) Priority Jun 23 1969, 31686/69, GE Dec 4 1969 * 39230/69, GB

(71) Applicant THE WELLCOME FOUNDATION LTD., London N.W.T, GE.

(72) Inventor Robert Arthur Maxwell, US: Frederick Charles

Copp, GE.

(74) International Patent Bureau.

(54) Analogous process for frerrp = position of an N-m-methoxybenzyl-N, N-dimethyl-N-ethylammonium salt or N-m-methoxybenzyl-N, N-dimethyl-N-2-hydroxy = ethyl-ammonium salt.

It has been suggested previously to use the potent hypotensive drug bretylium (No-bromobenzyl-N-ethyl-N, N-dimethylammonium) p-toluene sulfonate in the treatment of cardiac arrhythmia (see "Anti-arrhythmic Action of Bretylium", NATURE , Vol. 207, No. 4993, pages 203-204, July 10, 1965, and "Treatment of Ventri- gular Cell Fibrillations and Other Acute Arrhythmias with Bretylium Tosylate," The American Journal of Cardiology, April 1968, Vol. 21, No. 4, pages 530-543). This drug has powerful antiarrhythmic properties, but the hypotensive effect,

Lf) attributable to sympathetic blockage causes an undesirable significant lowering of blood pressure. Thus, it is essential when this drug is used that patients be in hospital wards where careful care is taken for them.

It has now surprisingly been found that Nm-methoxybenzyl-N, N-dimethyl-N-2,215,155 ethylammonium salts and Nm-methoxybenzyl-N, N-dimethyl-N-2-hydroxyethylammonium salts have unexpected advantages over this drug in the treatment of arrhythmia. These salts not only have anti-arrhythmic properties that can be met with bretylium, but also significantly less sympathetic blocking effect, enabling treatment of cardiac disorders with little or no ugly effect on blood pressure.

The pharmaceutically acceptable of these salts, hereinafter referred to as the salts of this invention, are effective in treating and suppressing venous fibrillations and atrial fibrillations in mammals such as humans, dogs and cats.

The pharmacological effect lies in the quaternary ammonium cation, the nature of the anion being of significance only as regards the administration requirements of medical use. The salts in question will often be administered over a prolonged period of time and in such cases the anion must be pharmaceutically acceptable, i.e. non-toxic in the sense that it has no harmful effect on the patient after prolonged treatment. Bromides and iodides of quaternary ammonium compounds have a pharmacological effect in mammals which may be undesirable, especially by prolonged administration, but such salts are useful intermediates in the preparation of pharmaceutically acceptable salts.

The invention thus relates to an analogous process for the preparation of a novel Nm-methoxybenzyl-N, N-dimethyl-N-ethylammonium salt or Nm-methoxybenzyl-N, N-dimethyl-N-2-hydroxyethylammonium salt of general formula I ( see claim 1) wherein R represents an ethyl or a hydroxyethyl group and Z '' is the anion of a non-toxic acid, characterized in that (a) is reacted with a tertiary amine of formula II (see claim 1 ) wherein R is as defined above with a compound of formula III (see claim 1) wherein Z represents a nucleophilic atom or nucleophilic group, (b) reacting an amine of formula IV (see claim 1) wherein R has and X represents a hydrogen atom or a methyl group, with a methylating agent, CH 2 Z, wherein Z represents a nucleophilic atom or nucleophilic group, or (c) translates a tertiary amine of formula V (see claim 1) with a compound RZ wherein R is as defined above and Z represents a nucleophilic atom or a nucleophilic group, after which, if desired or necessary, a formed salt is transferred into a salt of a non-toxic acid.

A convenient embodiment of process (b) consists in the formation of the tertiary amines of formula IV, wherein X represents a methyl group, in situ as intermediates from amines of formula IV, wherein X represents a hydrogen atom.

Thus, in this embodiment, two equivalents of the methylating agent CH3Z are used.

Furthermore, according to the invention, it is convenient that the salt of formula I be the chloride, sulfate or sulfonate, such a salt being particularly preferred for therapeutic use, and for the direct preparation of such a salt it is further advantageous that Z is a chidratome or a sulfate or sulfonate group.

A further convenient embodiment of the process according to the invention consists in the reaction being carried out in a solvent, in particular a solvent selected from acetone, methyl ethyl ketone, ethyl acetate, methanol, benzene and ether.

In process (b), when starting from an amine of the parent IV, wherein X represents a hydrogen atom, it is preferable that the acidification is carried out in the presence of an acid-binding agent, the acid-binding agent being preferably an alkaline salt, and the alkaline salt in particular is sodium or potassium carbonate.

The salts in question may also be prepared from other salts by double reaction. Thus, the non-toxic salts of this invention can be prepared from a salt which is not suitable for long-term administration.

The salts in question may be presented in forums of any acceptable pharmaceutical composition. Preparations for oral or parenteral administration are preferred. Parenteral administration is particularly preferred.

The dosages are preferably in the range of 1 to 10 mg / kg of the cation. The pharmaceutical compositions are conveniently presented in forums of a unit dose usually containing from 100 to 600 mg of the cation.

The process according to the invention is further elucidated by the following examples.

Example 1 80 g of N-m-methoxybenzyl-N, N-dimethylamine were mixed with 396 ml of acetone and 105 g of ethyl p-toluenesulfonate with 9 mp. 30.5 ° C and the mixture refluxed overnight. The reaction mixture was then cooled to 10 ° C and the crystal slurry filtered. A crude product of N-m-methoxybenzyl-N, N-dimethyl-N-ethylammonium p-toluenesulfonate was isolated, which was 106 g and melted at 101.5 to 102 ° C. Recrystallization of 450 ml of acetone yielded 98 g of a product of red mp. 102.5 to 104 ° C. The product appeared as white needles that were highly soluble in water and alcohol and gave the following analysis:

Calculated Found C 62.4 62.03 H 7.45 7.50 N 3.835 3.77 4 145155

Example 2 d>

A column of "Amberlite" resin exchanger IRA400 (chloride form) was prepared from approx. 25 ml resin exchanger and water. It was washed with 2 N sodium hydroxide solution until the eluate was alkaline (about 70 ml) and then with water until the wash water was neutral. A solution of 22 g of p-toluenesulfonic acid in 100 ml of water was then poured through the column, whereupon the eluate was finally acidified. This column was then washed with water until the washing water was practically neutral, requiring approx. 300 ml of water. A solution of 320 mg of N-ethyl-N-m-methoxybenzyl-Ν, Ν-dimethylammonium iodide in 5 ml of water was then poured through the column and the solution was collected in 6 ml aliquots, each of which was evaporated to dryness in a rotary evaporator. After washing with a total of 36 ml, no more product was obtained. The 300 mg solids were recrystallized from acetone to give 280 mg of N-ethyl-N-m-methoxybenzyl-N, N-dimethylammonium-p-toluenesulfonate with m.p. 101-104 ° C.

Example 3 25 g of m-methoxybenzyl chloride was slowly added to a hot stirred solution of 31 g of methylaminoethanol in 63 ml of benzene. After heating on a steam bath for 1 hour, the resulting mixture was cooled and treated with 50 ml of 5 N sodium hydroxide solution. The aqueous layer was separated and extracted with 100 ml of ether. The combined organic layers were washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. The residue was distilled in vacuo to give N-2-hydroxyethyl-N-m-methoxybenzyl-N-methylamine as a colorless oil with b.p. 116-118 ° C / 0.2 mmHg.

3 ml of methyl iodide was added to a solution of 5 g of the above base in 25 ml of ethyl methyl ketone. The mixture became spontaneously hot and an oil which then crystallized was separated. The solid formed, N-m-methoxybenzyl-N, N-dimethyl-N-2-hydroxyethylammonium iodide, was collected and recrystallized from acetone or isopropyl alcohol, m.p. 95-96 ° C and then converted to the corresponding p-toluene sulfonate, m.p. 67-68 ° G.

Example 4 5 g of N-2-hydroxyethyl-N-m-methoxybenzyl-N-methylamine and 4.7 g of methyl p-toluenesulfonate were dissolved in 50 g of ethyl methyl ketone and left at a temperature of 22 ° G for 2.5 hours. Adding ether to the reaction mixture precipitated a crystalline solid, m.p. 68-69 ° C. The solid was recrystallized from isopropyl ether to give N-2-hydroxyethyl-N-m-methoxybenzyl-N, N-dimethyl-ammonium p-toluenesulfonate, m.p. 67-68 ° C.

Claims (2)

Example 5 2 Equivalents of methyl iodide were added to a solution of N-m-methoxybenzyl-N-ethylamine in ethyl methyl ketone and the mixture heated slightly. The solid precipitate formed of N-ethyl-N-m-methoxybenzyl-N, N-dimethylammonium iodide was then converted to the corresponding p-toluenesulfonate stop. 101-103 ° C. Example 6 An excess of m-methoxybenzyl-p-toluenesulfonate was added to a solution of N-2-hydroxyethyl-N, N-dimethylamine in ethyl methyl ketone and stirred gently for 3 hours. Upon addition of ether to the reaction mixture, a crystalline solid was precipitated and then recrystallized from isopropyl ether to give N-2-hydroxyethyl-N, N-dimethylammonium p-toluenesulfonate, m.p. 68 ° C. 1. Analogous Procedures for the Preparation of a Nm-Methoxybenzyl-N, N-Dimethyl-N-Ethylammonium Salt or Nm-Methoxybenzyl-N, N-Dimethyl-N-2-Hydroxy-Ethylammonium Salt of the General Formula I CH 2 - '- ct'3' Z, 'I 0CH3 wherein R represents an ethyl or hydroxyethyl group and Z' - is the anion of a non-toxic acid, characterized in that (a) is reacted with a tertiary amine of formula II rn (ch3) 2 II wherein R has the above meaning, with a compound of formula III / 7-CH - Z III > = ^ 2 OCBj wherein Z represents a nucleophilic atom or nucleophilic group, (b) reacting an amine of formula IV