NO146058B - ANALOGUE PROCEDURE FOR THE PREPARATION OF SUBSTITUTED BENZAMIDES. - Google Patents

Description

The present invention relates to an analogous process for the production of new substituted benzamides with the general formula (I)3, their quaternary ammonium salts, oxides, pharmaceutically acceptable acid addition salts, dextrorotatory and levorotatory isomers thereof.

The benzamides produced according to the invention

has the formula:

there:

A denotes an alkyl group with 1-4 carbon atoms; W denotes an alkylene group of 1-4 carbon atoms; B denotes a group with the formula

where FL denotes an alkyl group with 1-5 carbon atoms and R ? a hydroxyalkyl group with 1-5 carbon atoms

IN

or a 4-hydroxyalkyl-1-piperazinyl group,

or a group with the formula

in

where R is a hydroxyalkyl group with 1-5 carbon atoms, an acetyl group or a benzhydryloxyalkyl group;

Y represents a hydrogen atom, a nitro group or an amino group; and

Z denotes a hydrogen atom, a halogen atom, an alkylsulfonyl group with 1-5 carbon atoms or a group SC^NR^R^ where R 3 and R^ which may be the same or different denote hydrogen or a lower alkyl group with 1-5 carbon atoms.

The benzamides produced according to the invention can be produced by reacting a compound with the formula:

-where D denotes a hydroxy group or an organic residue and A and Y as well as Z have the above meaning, with an amine of the general formula (III):

where W and B have the above meaning, or by reacting their reactive derivatives.

In the starting compound (II), the organic residue includes groups capable of forming reactive acid derivatives. These can be lower alkyl esters such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl esters, etc., reactive acid esters such as cyanomethyl or methoxymethyl esters or N-hydroxyimide esters, or optionally substituted aromatic esters and acid halides; acid hydrazides; acid azides; symmetrical anhydrides; mixed anhydrides, e.g. formed with carboxylic acid esters or haloformic acid esters; azolides such as triazolides, tetrazolides or imidazolides; acid isothiocyanates; substitute

pea w-trihaloacetophenones; substituted α-oxobenzeneacetonitriles; benzamides substituted in the core.

The amine can participate in the reaction in the form of one of its reactive derivatives which can possibly be isolated. As exem-

should be mentioned the reaction products of the amine with phosphorus chloride

der, phosphorus oxychloride, dialkyl, diaryl or orthophenylene chlorophosphites, alkyl or aryl dichlorophosphites, amine isothiocyanate,

the symmetric or unsymmetrical sulfamide of the amine,

the corresponding symmetrical urea, and the corresponding enami-

down. The above-mentioned reactive derivatives can be reacted with the acid in situ or after previous isolation.

It is also possible to carry out the reaction between

the free acid and free amine in the presence of a condensing agent

such as e.g. silicon tetrachloride, phosphoric anhydride, a carbodiimide such as dicyclohexylcarbodiimide, or alkoxyacetylenes such as methoxy or ethoxyacetylene.

The amidation reaction according to the invention can be carried out in the presence or in the absence of a solvent. The systems used as solvents are purposefully inert

on the amidation reaction and is e.g. alcohols, polyols, benzene, toluene, dioxane, chloroform or diethylene glycol dimethyl ether. It is also possible to use an excess of the amine used as starting material as a solvent. It may be preferred to heat the reaction mixture during the amidation, e.g. to the boiling point of the above solvent.

The compounds obtained according to the invention can

if necessary, react with a pharmaceutically acceptable mineral acid or an organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid or methanesulfonic acid to obtain acid addition salts.

They can also, if necessary, be reacted with an alkyl halide or a sulfate to obtain the corresponding quaternary ammonium salt.

To illustrate the invention, a is given below

share execution examples.

Example 1: N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide. 48 g of ethyl 2-methoxy-5-sulfamoylbenzoate, 17 g of water and 32 g of 1-(2-hydroxyethyl)-2-aminomethylpyrrolidine were added to a 250 ml flask. The mixture was heated on a water bath until a sample was found to be completely soluble in dilute acetic acid. The solution was cooled and then diluted with 300 ml of water. The formed crystals were filtered by suction, washed with water and dried at 40°C. The benzamide obtained was purified by conversion to acetate followed by liberation of the base.

39 g of N-(1-(2'-hydroxyethyl)-2-pyrrolidnylmethyl)-2-methoxy-5-sulfamoylbenzamide were obtained in a yield of 59% and with a melting point of 135-136°C. Example 2: N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-■

methoxy-5-ethylsulfonylbenzamide hydrochloride.

38.8 g of 2-methoxy-5-ethylsulfonylbenzoic acid methyl ester, 13.5 ml of water and 28.4 g of 1-(3-hydroxypropyl)-2-aminomethyl-pyrrolidine were added to a 250 ml flask. The mixture was heated in

.10 hours at 85-90°C. After evaporation, the residue was dissolved in 200 ml of ethanol and the solution was acidified to a pH value of 1 with alcoholic hydrochloric acid. Tetrahydrofuran was added and the crystals formed were filtered, washed and dried in an oven at 50°C. 35 g of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-"-••''methoxy-5-ethylsulfonylbenzamide hydrochloride were obtained after recrystallization from alcohol. The yield was 55.5% and melting point 184-186°C).Example 3'-N-(1'-acetyl-2'-pyrrolidinylmethyl)-2-methoxy-5-sul famoylbenzamide. 48 g of ethyl-2-methoxy-5-sulfamoylbenzoate was reacted with 31.5 g of N-acetyl-2-amino-methylpyrrolidine in the same manner as stated above and this resulted in 3^.5 g of N-(1'-acetyl- 2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide in a yield of 52.5$ and with a melting point of 204°C.

Example 4: N,(N,-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2-methoxy-4-amino-5-chlorobenzamide.

6.1 g of 2-methoxy-4-amino-5-chlorobenzoic acid and 8 g of N-ethyl-N-2-hydroxyethylethylenediamine were added to a 250 ml flask. The mixture was heated to 100°C and it was added

6.5 g phosphoric anhydride. The mixture was gently heated to 110°C and the temperature was then rapidly raised to 150-160°C. This temperature was maintained for 1 hour and then, after cooling to 100°C, 100 ml of water was added. Soda was added after the components had completely dissolved. The mixture was cooled and the precipitate was filtered, washed with water and dried. 6.6 g of N-(N'-ethyl-N1-(2'-hydroxyethyl)aminoethyl)-2-methoxy-4-amino-5-chlorobenzamide were obtained in a yield of 69.8% and with a melting point of 111-112°C.

Example 5: N-(1-(2'-benzhydryloxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide. 99 g of 1-(2'-benzhydryloxyethyl)-2-aminomethylpyrrolidine and 500 ml of methyl ethyl ketone were added to a 4 liter flask. The mixture was cooled to 15°C and a solution of 80 g of 2-methoxy-5-sulfamoylbenzoyl chloride in 1500 ml of methyl ethyl ketone was added. The mixture was stirred for 2 hours at ambient temperature. The precipitate that formed was filtered, washed with a small amount of methyl ethyl ketone and dried. The hydrochloride obtained was made alkaline while hot with ammonia, and the product crystallized on cooling. The crystals were filtered, washed and dried in an oven at 50°C. 88 g of N-(1-(2'-benzhydryloxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide were obtained after recrystallization from ethanol, filtration through carbon black and drying. The yield was 52.6% and the melting point 124°C. Example 6: 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-hydroxyethylpiperazine. 45 g of 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine and 180 ml of chloroform were added to a 1 liter flask. A solution of 51 g of 2-methoxy-4-nitrobenzoyl chloride was poured into the mixture at a temperature of 5-10°C. At the end of the addition, the mixture was brought to ambient temperature and then heated for 1 to 1 1/4 hours to 40-45°C. Water was added and the chloroform was evaporated. The solution obtained was filtered using carbon black and the benzamide base was precipitated by adding 50g of potassium carbonate. After decantation, the product was dissolved in methyl chloride and the aqueous solution was extracted with methylene chloride.

The organic phase was dried with potassium carbonate and the methylene chloride was then distilled off in vacuo. The oil-like benzamide obtained was purified by formation of the hydrochloride and treatment with ammonia.

59 g of 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-hydroxyethylpiperazine were obtained in the form of an oil and in a yield of 67.2%. Purity analysis by quantitative determination in a non-aqueous medium with perchloric acid gave 97.8%.

Example 7: N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide hydrochloride.

39 g of 1-(2-hydroxyethyl)-2-aminomethylpyrrolidine, 250 ml of methyl ethyl ketone and, maintaining the temperature, between 5 and 10°C, 70 g of 2-methoxy-5-ethylsulfonylbenzoyl chloride were added to a 500 ml flask. After stirring overnight, the crystalline product was filtered under reduced pressure, washed with methyl ethyl ketone and dried at 45°C. The crude product was recrystallized in 200 ml of alcohol at 95°C. 73 g of N-(1-(-2'-hydroxyethyl)-2- pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide hydrochloride in a yield of 66.5% and with a melting point of 175-178°C. Example 8: N-(N'-ethyl-N'-(2'-hydroxyethyl)-aminoethyl)-2-methoxy- 5-sul-f amoylbenzamide. 78 g of ethyl-2-rne<t>ox<y>-5-sulfamoylbenzoate, 27 ml of water and a 51 g of N-ethyl-1-N-hydroxyethylethylenediamine were added to a 250 ml" flask. The mixture was heated for 10 hours at a water bath. The solution was diluted and the benzamide base then crystallized. This ..was purified by formation of the hydrochloride and precipitation of the base with ammonia. The crystals obtained were filtered by suction, washed with water until the chloride ions were all removed, and dried in a oven at 40°C.

66 g of N-(N'-ethyl-N'-(2'-hydroxy-ethyl)aminoethyl)-2-methoxy-5-sulfamoylbenzamide were obtained in a yield of 64% and with a melting point of <:>149 -150°C.

Example 9: N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide hydrochloride.

38.9 g of ethyl 2-methoxy-5-sulfamoylbenzoate, 13.5 ml of water and 28.4 g of N-1-(3'-hydroxypropyl)-2-aminomethylpyrrolidine were added to a 250 ml flask. The mixture was heated for 10 hours at 80°C and after cooling, 100 ml of benzene was added and the solvents were distilled off. The mixture was cooled and 500 ml of water was then added. The formed crystals were fil-

stripped, washed with water and dried in an oven at 50°C.

40 g of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide were obtained with a yield of 72%.

The benzamide was converted to the hydrochloride by dissolution in absolute alcohol and treatment with 50 ml of 25% ethanolic hydrochloric acid. The solid obtained was recrystallized from methyl alcohol.

38 g of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide hydrochloride were obtained in a

yield of .62.2% and with a melting point of 226-229°C. Example 10: 1-(2'-methoxy-4'-amino-benzamidopropyl)-4-hydroxyethylpiperazine diphosphate.

2.8 g of 2-methoxy-4-aminobenzoic acid, 3.5 g of 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine and 60 ml of pyridine were added to a 250 ml flask and 2, 3 g of silicon tetrachloride was added. death.news. The mixture was heated for 3 hours at reflux temperature.

The pyridine was distilled off in vacuo. 30 ml of water was added followed by hydrochloric acid until the pH was 1. The mixture was heated to the boiling point, filtered after checking that the pH was still acidic, after which ammonia was added while the mixture was still hot.

After cooling, the liquid was decanted from the precipitate. 3.9 g of 1-(2'-methoxy-4'-aminobenzamidopropyl)-4-hydroxyethylpiperazine were obtained in . a dividend of 69.65.

Purity examination by quantitative determination in a non-aqueous medium showed 97.5%.

The base obtained was dissolved in alcohol and then converted to the corresponding phosphate with phosphoric acid. The phosphate obtained was a double phosphate which crystallized with 3 mol of water.

'There' was obtained 3.2 g of 1-(2'-methoxy-4'-aminobenzamidopropyl)-4-hydroxyethylpiperazine diphosphate with a melting point of 144-145°C.

The benzamides produced according to the invention

has valuable therapeutic properties, especially as an antiemetic. Their low toxicity allows use in human therapy without the risk of side effects.

The acute toxicity of the manufactured products was determined in mice parenterally (endovenously or intraperitoneally). The LD^ values, calculated according to Behrens et

Carbs, are listed in the following table:

The antiemetic effect of the products which are prepared in the form of apomorphine - was investigated in dogs according to Chen and Ensor as this technique was developed by Ducrot

and Decourt.

The results obtained are compared with those obtained by Courvoisier for phenothiazines and with those obtained by Schallek for trimethobenzamide, and are given in the following table. The activity index is calculated subcutaneously with chlorpromazine as reference substance.

These results indicate that the compounds produced are significantly more active as antiemetics than ferridthiazines and trimethobenzamide.

Claims (11)

1. Analogy process for the production of therapeutically active substituted benzamides, quaternary ammonium salts, oxides, acid addition salts with pharmaceutically acceptable acids and dextrorotatory and levorotatory isomers thereof, with the formula: where: A denotes an alkyl group with 1-4 carbon atoms; W denotes an alkylene group of 1-4 carbon atoms; ' B denotes a group with the formula where R^ denotes an alkyl group with 1-5 carbon atoms and Yi^ a hydroxylalkyl group with! 1-5 carbon atoms or a 4-hydroxyalkyl-1-piperazinyl group, or' a group with the formula where R is a hydroxylalkyl group with 1-5 carbon atoms, an acetyl group or a benzhydryloxylalkyl group; Y represents a hydrogen atom, a nitro group or an amino group; and Z represents a hydrogen atom, a halogen atom, an alkylsulfonyl group with 1-5 carbon atoms or a group SO^NR^R^ where R^ and R^ which may be the same or different denote hydrogen or a lower alkyl group with 1-5 carbon atoms, characterized in that a compound mad. the formula: where D denotes a hydroxy group or an organic residue and A, Y and Z have the meaning given above, is reacted with an amine of the general formula: in which W and B have the meaning indicated above, or by conversion of the corresponding reactive derivatives. 2. - Analogous method according to claim 1 for the production of N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide, characterized in that ethyl 2-methoxy-5-sulfamoylbenzoate is reacted with 1- (2-hydroxyethyl)-2-aminomethylpyrrolidine. ..<.>..<...>. 3. Analogous process according to claim 1 for the production of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide hydrochloride, characterized in that 2-methoxy-5-ethylsulfonylbenzoic acid methyl ester is reacted with 1-(3 -hydroxypropyl)-2-aminomethyl-pyrrolidine with subsequent conversion to hydrochloride. 4. Analogous method according to claim 1 for the production of N-(1'-acetyl-2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide, characterized in that ethyl 2-methoxy-5-sulfamoylbenzoate is reacted with N-acetyl-2 -amineb-methylpyrrolidine-.din. 5. Analogous process according to claim 1 for the preparation of N-(N'-ethyl-N'-hydroxyethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide, characterized in that 2-methoxy-4 -amino-5-chlorobenzoic acid is reacted with N-ethyl-N-2-hydroxyethylenediamine. 6. Analogous method according to claim 1 for the production of N-(1-(2'.-benzhydryloxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide, characterized in that 1-(2'-benzhydryloxyethyl)-2-aminomethylpyrrolidine is reacted with 2-methoxy-5-sulfamoylbenzoyl chloride. 7. Analogous method according to claim 1 for the production of 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-hydroxyethyl-piperazine, characterized in that 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine is reacted with 2-methoxy-4-nitrobenzoyl chloride. 8. Analogous process according to claim 1 for the production of N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide hydrochloridej characterized in that 1-(2-hydroxyethyl)-2-aminomethylpyrrolidine is reacted with 2 -methoxy-5-ethylsulfonylbenzoyl chloride with subsequent conversion to hydrochloride. 9- Analogous method according to claim 1 for the preparation of N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2-methoxy-5-sulfamoylbenzamide, characterized in that ethyl 2-methoxy-5-sulfamoylbenzoate is reacted with N-ethyl-N-hydroxyethylethylenediamine. 10. Analogous process according to claim 1 for the production of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide, characterized in that ethyl 2-methoxy-5-sulfamoylbenzoate is reacted with N-1- (3'-Hydroxy-propyl)-2-aminomethylpyrrolidine. 11. Analogous method according to claim 1 for the production of 1-(2'-methoxy-4'-aminobenzamidopropyl)-4-hydroxyethyl-piperazine diphosphate, characterized in that 2-methoxy-4-aminobenzoic acid is reacted with 1-(2'-hydroxyethyl)- 4-(3'-aminopropyl)piperazine with subsequent conversion to diphosphate.