The compounds belonging to the group of heterocyclic aminoalkyl benzamides of general formula I are also used in treatment of parkinsonism, for contraceptive mixtures, in treatment of sterility, as fungicides, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins.

According to international patent classification (Int. Cl. 5) the invention can be classified into classes : C 07D 207/00, C 07D 207/06 and C 07D 207/08.

Teclznicalproblem There was a need to come to the new, technically more perfect process for obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides and/or salts and/or hydrates and/or optical isomers thereof, which are used in human medicine as antipsychotics, antidepressives and antiemetics, fungicides, for contraceptive mixtures, in treatment of sterility, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins, as well as in treatment of parkinsonism. The suggested invention of the synthesis procedure is technically more convenient, more ecconomical, with higher yield and purity. Contemporary pharmaceutical technology sets the more strict demands for increasingly higher purity of the products, in comparison with already existing patents from the eighties, which had lower criteria.

The suggested original invention, in completely new way, solves the problem of obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides using cheaper starting substances, by reaction of 2-alcoxy-5-sulphamoyl-alkyl benzoate with (RS, R+ or : S-) heterocyclic amine, with higher degree of their exploitation, which enables obtaining of the entire pallet of pharmaceutically acceptable compounds.

Advantages of the present invention are: simple procedure of performing, lower reaction temperature and work at atmospheric pressure, without use of catalysts, performing of the reaction in cheaper and safer organic solvents, with obtaining of final product without subsequent purification, achieving of good yield and high quality of the final product, which makes the procedure cheaper for industrial use. In this way, disadvantages of the procedures mentioned in known patents, are avoided, for example: use of catalysts, high reaction temperatures, use of expensive and unsafe dangerous organic solvents, as well as obtaining of the product which requires an additional purification, which lowers the yield and raises the costs of the production.

Background of the invention In professional and patent literature, there are number of ways for obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides and/or salts and/or hydrates and/or optical isomers thereof.

It is known from before that the compounds belonging to the group of heterocyclic aminoalkyl benzamides of general formula I, possess antipsychotic, antidepressive and antiemetic properties (Annals of the New York Academy of Science, 96,315, (1962) ).

French patent Fr 73 35 601 describes the procedure, according to which, the reaction between 2-methoxy-5-sulphamidobenzoic acid with N-ethyl-2- aminomethylpirrolidon in dioxane, in the presence of catalyst PhSiCI3, gives sulpiride of formula II.

In another French patent Fr 22 45 628, synthesis is carried out at temperature of 165°C, and as a catalyst, P205 is used.

Yugoslav patent YU 35 118 describes the procedure according to which 2-methoxy- 5-sulphamoylbenzoic acid ester in presence of hydrazin hydrate at 60°C in aqueous medium, is converted into 2-methoxy-5-sulphamoylbenzoyl hydrazid, and it is in aqueous medium, in presence of sodium nitrite converted into 2-methoxy-5- sulphamoylbenzoylazide, which is in presence of 1-ethyl-2-aminomethyl pirrolidon in dioxane at temperature of 10°C gives sulpiride of formula II.

Yugoslav patent YU 35 119 describes the procedure according to which 1-ethyl-2- aminomethyl pyrrolidon in presence of phosphorous oxychloride in pyridine, is converted into N, N', N"-(l-ethyl-2-aminomethyl) phosphorous amide, which in reaction with 2- methoxy-5-sulphamoyl methylbenzoic acid in pyridine gives sulpiride of formula II.

German patent DE 27 21 643 describes the procedure for obtaining of sulpiride of formula II, starting with 5-chlorosulphonyl-2-metoxybenzoyl chloride in chloroform at temperature of 10°C, N-ethyl-2-aminomethylpyrrolidon is instillated, and afterwards, that solution is added to the ammonium solution, and heated under reflux.

German patents DE 15 95 925 and DE 17 95 723, as well as Yugoslav patent YU 29 097, describe the procedures for obtaining of heterocyclic aminoalkyl benzan ? ides by reaction of 2-alcoxybenzoic acid with suitable amines using various ways of converting of carboxylic group into active acylating agent. As the acylating agent, N-acyl imidazole has priority, and it is obtained by reaction of an acid with 1, 1'-sulphinyldiimidazole, but, also with 1, 1'-carbonyldiimidazole.

Common disadvantages of the procedures described in the mentioned patents are: use of catalysts, high temperatures of reactions, use of expencive and dangerous organic solvents, as well as obtaining of a product which requires an additional purification, which lowers the yield and increases costs of the production.

Description of the invention with examples The suggested invention is related to the procedure of obtaining of the compounds of high pharmacopoeic purity, belonging to the group of heterocyclic aminoalkyl benzamides of general formula I and/or salts and/or hydrates and/or optical isomers thereof : wherein Ri and R2 denote Cl-C4 an alkyl group, R3 denotes amino-sulphonyl group, R4 denotes a hydrogen atom or an amino group, Rs denotes a hydrogen or a halogen atom, and the coefficients m and n have value of 1 and/or 2.

Accoring to the new, original invention, the synthesis is carried out through the following series of reactions, and it starts when 2-alcoxy benzoic acid of formula IV: in presence of chlorosulphonic acid, at temperature of reaction mixture in the range between 30-80°C, for 1-4 hours, at atmosperic pressure, is converted into 2-alcoxy-5- chlorosulphonyl benzoic acid of formula V: which is afterwards, in presence of ammonium hydroxide, with. heating at temperature in range between 20-50°C, for 1-5 hours, at atmospheric pressure, as well as, with neutralization with HCI aqueous solution, converted into 2-alcoxy-5-sulphamoyl benzoic acid of formula VI, which is, afterwards, in presence of alcohol, for example methanol, ethanol, at temperature of reflux of reaction mixture for 2-9 hours, at atmosperic pressure, is converted into 2- alcoxy-5-sulphamoyl alkyl benzoate of formula VII: The synthetized 2-alcoxy-5-sulphamoyl benzoate of formula VII and (R, R+ or S-) 1-alkyl- 2-aminoalkyl heterocyclic derivative of formula VIII react in an organic solvent, belonging to the group of alcohols, such as: methanol, ethanol, ethylene glycol, for 10 to 90 hours, at atmosperic pressure and at temperature of reaction mixture of 20 to 100°C, primarily at temperature of 35-85°C, which gives a compound belonging to the group of heterocyclic aminoalkyl benzamides of general formula I, in the form of pharmaceutically acceptable salt and/or hydrate of pharmacological purity.

Obtained compound is afterwards transformed into form of a tablet, pill, dragee, capsule, or ampulla, using usual pharmaceutical additives.

The reactant of general formula VIII, that is (RS, R+ or S-) l-alkyl-2-aminoalkyl heterocyclic derivative has an asymmetric C atom, which does not alter the configuration during the synthesis. When optically pure reactant of general formula VIII is used for the synthesis, ie, (R+ or S-) 1-alkyl-2-aminoalkyl heterocyclic derivative, the mentioned procedure gives the compound belonging to the group of heterocyclic aminoalkyl benzamides of general formula I in the form of optical isomer R+ or S-.

The present invention provides a completely new, original procedure for obtaining of heterocyclic aminoalkyl benzamides, using cheaper starting substances, with higher degree of their exploitation. The advantage of the present invention is in the just the way of synthesis of heterocyclic aminoalkyl benzamides, by synthesis of 2-alcoxy-5-sulphamoyl- alkyl benzoates and their reaction with the corresponding heterocyclic amine, which avoids the disadvantages of the procedures stated in already existing patents (use of catalysts, high temperatures of reaction, use of expensive and dangerous organic solvents, as well as obtaining of product which must be additionally purified, which reduces the yield and increases the costs of the very production). Basicly new procedure is described, which, in contrast to the already known procedures, has number of advantages, such as simplicity of the procedure of performing, lower temperature of reaction and work at atmospheric pressure, without using of catalysts, performing of the reaction in the cheaper and safer organic solvents, with obtaining of the final product without subsequent purification, achieving good yield and high quality of the final procuct, which makes the procedure cheaper for industrial use.

The invention is primarily related to the synthesis of sulpiride (RS, R+ or S-) 5- (Aminosulphonyl)-N-/(l-ethyl-2-pyrrolidinyl) rnethyl/-2-methoxybenzamide, of formula II, sulmepride (RS, R+ or S-) (5-(Aminosulphonyl)-2-methoxy-N-/(l-methyl-2- pyrrolidinyl) methyllbenzamide), of formula III The compounds processed in such way, can be used in pharmaceutical form of tablets, pills, dragees, capsules, or ampullas, using usual pharmaceutical additives, for obtaining of pharmaceutical preparations used in therapy as antipsychotics, antidepressives and antiemetics, fungicides, for contraceptive mixtures, in treatment of sterility, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins, as well as in treatment of parkinsonism, obtained in usual manner.

In order to make understanding of the procedure, which is the subject of the present invention, easier, examples of different phases of the procedure are given, but should not be considered as restrictive.

EXAMPLE 1: Synthesis of sulpiride (RS, R+ or S-) (5-(Aminosulphonyl)-N-/(l- ethyl-2-pyrrolidinyl) methyl/methoxybenzamide) of formula II Into 284 cm3 of chlorosulphonic acid, 100 gr of 2-methoxy benzoic acid is added, with constant stirring and cooling, the syntesis is being carried out for 1 hour at 50°C, and then, for half an hour at 70°C, and afterwards, the reaction mixture is effluxed into 1000 cm3 of cooled distillated water, filtered, rinsed with water, and obtained precipitate of 2- methoxy-5-chlorosulphonly benzoic acid is added, with constant stirring, to 500 cm3 of ammonium hydroxide, heated for 2 hours at 30°C. Into cooled reaction mixture, gradually is added 15% aqueous solution of HCI to pH 3, precipitate of 2-methoxy-5-sulphamoyl benzoic acid is separated by filtration, rinsed with water and suspended in 240 cm3 of methanol, in which previously, 60 cm3 of sulphuric acid was disolved, and refluxed for 6 hours. Reaction mixture is effluxed into 900 cm3 of 15% aqueous solution of sodium carbonate, filtered, rinsed with water, then with methanol, well dried on filter funnel, and 2-methoxy-5-sulphamoyl methyl benzoate is obtained. Obtained 2-methoxy-5-sulphamoyl methyl benzoate is afterwards suspended in 215 cm3of ethylene glycol, to which 62 gr of (RS) l-ethyl-2-aminomethylpyrrolidine was previously added. After heating at 62-65°C for 36 hours, filtering, rinsing with cooled distilled water and drying at 45°C, 138, 6 g of <BR> <BR> <BR> <BR> sulpiride (RS) 5-(Aminosulphonyl)-N-/(1-ethyl-2-pyrrolidinyl) methyl/-2-methoxybenzamide of formula II is obtained, 90% yield.

Obtained 2-methoxy-5-sulphamoyl methyl benzoate is afterwards suspended in 215cm3 of etylene glycol to which 62 gr of (R+) l-ethyl-2-aminomethylpyrrolidin was previously added. After heating at 62-65°C for 36 hours, rinsing with cooled distilled water and drying at 45°C, 138,6 g of sulpiride (R+) 5-(Aminosulphonyl)-N-/(1-ethyl-2- pyrrolidinyl) methyll 2-methoxybenzamide of formule II is obtained, 90% yield.

Obtained 2-methoxy-5-sulphamoyl methyl benzoate is afterwords suspended in 215 cm3 of etylene glycol to which 62 gr of (S-) l-ethyl-2-aminomethylpyrrolidin was previously added. After heating at 62-65°C for 36 hours, rinsing with cooled distilled water and drying at 45°C, 138, 6 g of sulpiride (S-) 5-(Aminosulphonyl)-N-/(l-ethyl-2- pyrrolidinyl) methyl/-2-methoxybenzamide of formule II is obtained, 90% yield.

EXAMPLE 2: Synthesis of sulmepride (RS, R+ or S-) (5-(Aminosulphonyl)-2-methoxy-N- /(l-methyl-2-pyrrolidinyl) methyl/benzamide) of formula III The synthesis is carried out analogously to the procedure described in Example 1, with the difference that instead of the compound (RS) -1ethyl-2-aminomethyl pyrrolidin, (RS) l-methyl-2-aminomethyl pyrrolidin is used, and sulmepride (RS) (5- (Aminosulphonyl)-2-methoxy-N-/(1-methyl-2-pyrrolidinyl)methy l/benzamide) of formula III is obtained, 75% yield.

The synthesis is carried out analogously to the procedure described in Example 1, with the difference that instead of the compound (R+) 1-ethyl-2-aminomethyl pyrrolidin, (R+) 1-methyl-2-aminomethyl pyrrolidin is used, and sulmepride (R+) (5- (Aminosulphonyl)-2-methoxy-N-/(1-methyl-2-pyrrolidinyl)methy l/benzamide) of formula III is obtained, 75% yield.

The synthesis is carried out analogously to the procedure described in Example 1, with the difference that instead of the compound (S-) 1-ethyl-2-aminomethyl pyrrolidin, (S-) l-methyl-2-aminomethylpyrrolidin is used, and sulmepride (S-) (5-(Aminosulphonyl)- 2-methoxy-N-/(1-methyl-2-pyrrolidinyl)methyl/benzamide) of formula III is obtained, 75% yield.