DE1793836C1 - Process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide - Google Patents

Description

The invention relates to a process for the preparation of N- (diethyIaminoethyl) -2-methoxy-4-amino-5-bromobenzamide.

Benzamides are known from BE-PS 6 20 543, the general formula of which is that prepared according to the invention Benzamide includes, which, however, is not described there in detail.

The benzamide shows valuable pharmacological properties and can be used as an antiemetic in the Therapy can be used. It shows in comparison with what is known from BE-PS 6 20 543, Example 17 Metoclopramide superior properties.

The benzamide is produced according to the process outlined in the claim

Acetylation of the amino group of that which occurs as an intermediate in the process of the invention p-Aminosalicylic acid ester can be mixed with acetic anhydride take place. Suitable reagents for methylating the hydroxyl group are methyl halides, methyl sulfate, Dimethyl sulfate, benzene or toluenesulfonic acid methyl ester or the like. The deacetylation of the acetylamino group takes place by hydrolysis.

The invention is explained in more detail below using an exemplary embodiment.

example

N- (Diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide dihydrochloride

Level a
Production of p-aminosalicylic acid methyl ester

A 6 liter flask equipped with a mechanical stirrer and reflux condenser is charged with 1875 g of absolute methanol, then with cooling in small portions with 970 g of 93% sulfuric acid and finally with 383 g (2.5 mol) of p-aminosalicylic acid. The suspension is heated to reflux temperature with stirring for 5 to 6 hours. The solution is pretty quick. It is cooled to 30 ^° C. and the mixture is poured, with stirring, into a solution of 975 g of anhydrous sodium carbonate in 12.51 of water. The methyl p-aminosalicylate precipitates out as a solid precipitate. It is filtered with suction, washed free of sulfate ions with water and dried at 60 ⁰ C. 361 g of crystals are obtained; M.p. = 119 ^° C; Yield 86%.

Level B.
Production of p-acetylaminosalicylic acid methyl ester

A 2 liter flask equipped with a stirrer, thermometer and dropping funnel is charged with 361 g (2.16 mol) of methyl p-aminosalicylate and 725 ml of absolute alcohol. After the rather thick paste has been heated to 40 ° C., 225 g (2.16 mol) of acetic anhydride are added in small portions with stirring. The addition of the acetic anhydride is carried out at such a rate that the temperature of the reaction mixture did not exceed 50 ⁰ C increases. The pulpy mass gradually dissolves, and towards the end of the addition of the anhydride the solution becomes clear. ¹ A

ίο hour after the end of the addition of acetic anhydride, the acetylated ester crystallizes out in the form of a very thick crystal slurry. It is cooled to 20 ^° C., 500 ml of water are added and the reaction mixture is poured into 71% of water. The mixture is stirred for another IV2 hours, the crystals are then suction filtered and washed on the filter with 21% water. The filter residue is dried at 55 to 60 ° C. 427 g of methyl p-acetylaminosalicylate are obtained; Mp = 152-153 ° C; Yield 94%.

Level C

Production of methyl 2-methoxy-4-acetylaminobenzoate

A 5 liter flask equipped with a stirrer and reflux condenser is filled with 427 g of p-acetylaminosalicylic acid

> 3 remethyl esters and 1500 ml of acetone are charged. That Mixture is heated until solution occurs (about 48 ° C). Then quickly 276 g (2 mol) of potassium carbonate and then 277 g (2 mol + 10%) of dimethyl sulfate were added. The mixture is heated further to

jo simmering, whereupon the mixture quickly takes on an extremely thick consistency and is very difficult to stir. 15 minutes after the addition of the dimethyl sulfate, the reaction mixture becomes liquid. The mixture is heated to reflux temperature for a further 15 hours. 1.2001 acetone is then distilled off, the residue is cooled to 5O ⁰ C and diluted with water 2.5001. The methyl 2-methoxy-4-acetylaminobenzoate precipitates here. It is left to stand overnight, the precipitate is filtered off with suction and washed neutral. The filter residue is dried at 55 to 6O ⁰ C. 348 g of product are obtained; Mp = 127 ° C; Yield 78%.

Level D

Preparation of 2-methoxy-4-acetylamino-5-bromobenzoic acid methyl ester

A 2 liter flask fitted with a stirrer, thermometer and dropping funnel is filled with 117 g (0.524MoI) 2-Methoxy-4-acetylaminobenzoic acid methyl ester and 585 ml of acetic acid charged. It is heated to 40 ° C until Complete solution has occurred and then cools to 15 ° C. The cloudy solution is added within 1 hour 87 g of bromine (0.524 mol + 4% excess) were added dropwise while maintaining a temperature between 15 and 20 ° C. There is a slight evolution of hydrogen bromide and about in the middle of the reaction time the bromine derivative crystallizes out. After the addition is complete, the reaction mixture is in 5,8501 Poured water, sucked off the precipitate, washed free of bromide ions with water and im

bo drying cabinet at 40 ⁰ C dried. 152 g of methyl 2-methoxy-4-acetylamino-5-bromobenzoate are obtained; Mp = 174 ° C; Yield 96%.

Level E.

_r Preparation of N- (diethylaminoethyl) -2-methoxy-4- ^bJ amino-5-bromobenzamide

A 2 liter flask equipped with a reflux condenser is filled with 152 g of 2-methoxy-4-acetylamino-5-bromobene-

zoesäuremethylester, 460 ml of ethylene glycol and 174 g (three times the theoretical amount) Ν, Ν-diethylethylenediamine charged. The mixture is heated to 120 ° C. under nitrogen in an oil bath for 2 hours. At the start of heating, complete dissolution occurs. After 2 hours, the hot reaction mixture is transferred, without cooling, to a 5 liter flask equipped with a reflux condenser, and 460 ml of 2.5N sodium hydroxide solution previously heated to 95 to 100 ° C. are added. The mixture is refluxed for 30 minutes under nitrogen. Two layers form, of which the oily amine layer is deposited at the bottom of the flask. This layer solidifies when it is stirred while cooling. The mixture is diluted with 460 ml of water and stirred for a ^{further 1 hour.} The precipitate is filtered off with suction, washed with water and dried at 50 ° C. in a drying cabinet. 140 g of N- (diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide are obtained; Mp = 149 ° C; Yield 81%. _, "
Level F

Preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide dihydrochloride monohydrate

140 g of the base obtained in stage E are dissolved in 420 ml of alcohol near the boiling point. The cloudy solution is filtered rapidly cooled to 5O ⁰ C where it partially crystallized, and treated with a solution of 30 g of dry hydrogen chloride in 120 ml of absolute alcohol and 10 ml water. Complete solution takes place here. It is cooled to 20 ° C., whereupon crystallization begins. After standing in a refrigerator overnight, the precipitate is filtered off, washed on the filter with 70 ml of absolute alcohol and dried at 4O ⁰ C. 132 g of dihydrochloride are obtained, which crystallizes with 1 mol of water of crystallization; M.p. = 134 to 136 ° C; Yield 74%.

In the following, comparative experiments are reported, those with metoclopramide as a comparative compound were used. In the following description is the connection of the above embodiment referred to as bromopride.

1. Antiemetic effect
(Chen and Ensor technique)

Emetizing agents

Metoclopramide
DE ₅₀

(Hg / kg / dog)

Bromopride

DE ₃₀

^ g / kg / dog)

Apomorphine 26.8 (s.c.) 17.4 (s.c.) 100μg / kg / s.c. 42 (p.o.) 35 (p.o.) Hydergin 207 (s.c.) 106 (s.c.) 90 μg / kg / i.v. Lanatoside 4600 210 100 µg / kg / i.v.

The test compound was administered subcutaneously to male Wistar rats in geometrically increasing doses. After 30 minutes, the test animals were subcutaneously with polymyxin in treated at a dosage of 10 mg / kg.

The antiulcer activity was measured 2 hours after the administration of the product prepared according to the invention determined. The following values were obtained for the effective dose 50 (DE50; mg / kg).

Metoclopramide: DE ₅₀ (sc 102 mg / kg) Bromopride: DE ₅₀ (S. c. 56 mg / kg)

4. Analgesic activity (mouse)

The pain sensation was induced in the test animals by three different stimulus categories. In each case, the effective dose 50 (DE50; mg / kg) was determined at the peak of the effect.

As can be seen from the following list, bromopride shows an improvement over metoclopramide analgesic effect.

Mechanical stimulus Haffner test

Metoclopramide: 84 (i.p.); 230 (ρ. Ο.) Bromopride: 42 (lp.); 102 (ρ. Ο.)

Chemical stimulus phenylbenzoquinone test

Metoclopramide: 30.7 (i.p.); 115 (ρ. Ο.) Bromopride: 31 (i.p.); 65 (ρ. Ο.)

Thermal stimulus

Heating plate (technique according to

Jacob Woolfe and MacDonald)

Metoclopramide: 69.2 (see α); 149 (ρ. Ο.) Bromopride: 19% at 50 mg / kg (see α); 114 (ρ. Ο.)

5. Anti-arithmic activity

It turns out that bromopride behaves similarly to metoclopramide in terms of ventricular tachycardia however, two to five times more effective in reducing the maximum frequency of atrial actuation.

These experiments were carried out on the isolated auricle of the guinea pig according to the technique of Alles and Ellis carried out. The comparison values of the maximum actuation frequency were determined. The results correspond to a percentage inhibition, determined 12 minutes after contact with the person to be examined Product, based on the comparative value.

It was found that bromopride caused a significant reduction in the maximum actuation frequency, in proportion to the dosage:

2. Toxicity (DL50, mg / kg, iv .; mouse)

Metoclopramide 36.8
Bromopride 36.4

A more favorable therapeutic index for bromopride can already be derived from the above results recognize.

3. Anti-ulcer effect in the rat

The antiulcer activity was determined against polymyxin as an ulcerogenic agent. As can be seen from the The table below shows that bromopride is twice as effective as metoclopramide.

27% at 9 ^ mol / l
%bi

The clinical advantages of bromopride over metoclopramide can be outlined as follows:

1. The local anesthetic activity of bromopride allows better treatment of various hyperalgic or gastric digestive syndromes.

2. The anti-lanatoside activity enables an improved therapy for symptoms of vomiting, caused by digitalis derivatives.

5 6

3. Bromopride acts faster and with more constant gene in symptoms of colic origin (colic effectiveness for nausea and vomiting pain, spasmodic colopathy, terminal nings. Ileitis, hemorrhagic rectocolitis and the like

4. The peripheral zone of action is larger than with chen), where metoclopramide is no longer Metoclopramide. The product is still effective.

Claims (1)

Claim: Process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-bromobenzamide, characterized in that p-aminosalicylic acid is esterified in a manner known per se, the Amino group of the ester obtained is acetylated, the hydroxyl group is alkylated, the aromatic ring in 5-position brominated, the ester function by heating with a suitably asymmetrically substituted Amidated diamine, deacetylated the acetylamino group and optionally the one thus obtained Compound converted into a pharmaceutically acceptable acid addition salt.