NO152133B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2,3-ALKYLENE-BIS-OXYBENZAMIDES - Google Patents

Description

The present invention relates to the preparation of new substituted 2,3-alkylene-bis-oxybenzamides of the general formula I, pharmaceutically acceptable acid addition salts thereof, their quaternary ammonium salts, oxides, dextro- and levorotatory isomers.

US-PS 2,688,026 and NO-PS 112,728 describe methylenedioxybenzamides with therapeutic activity.

Thus, US-PS 2,688,026 describes benzamides with antihypertensive and diuretic action, i.e. effects on areas that are different from the action of the compounds described below.

NO-PS 112,728 describes benzamides which are particularly effective as antiemetic agents. The antiemetic effect is however, not as good as the antiemetic action of the compounds described below.

The structure of the compounds prepared according to the invention can generally be shown; by the following formula:

there:

A is C 1 -C 4 -alkylene;

R is C1-C4 alkyl; C 1 -C 4 -alkenyl, -C 8 -cycloalkyl or

benzyl;

X is hydrogen, C₁-C₁ alkoxy, nitro, amino or acetamino;

Y is hydrogen, halogen, sulfamoyl, C₁-C₄ alkylsulfamoyl,

C1-C3-dialkylsulfamoyl, C-1-C3-alkylsulfonyl or X and Y are linked together to form an azimido group;

Z is hydrogen, halogen or Y and Z are interconnected

and forms an azimido group; and

n is 0 or 1.

Within the definitions set out in the description include: C1-C4-alkyl methyl,, ethyl, propyl, isopropyl, butyl, isobutyl,

tert-butyl;

C 1 -C 4 -alkylene methylene, ethylene, <p>ropylene;

C2-C4-alkenyl mainly vinyl, allyl;

C-^-C4-Alkoxy methoxy, ethoxy, propoxy, isoprop-

oxy, butoxy, isobutoxy, t-butoxy;

halogen chlorine, bromine, iodine, fluorine.

The preferred meanings of the substituents are: for X: hydrogen, alkoxy and mainly methoxy, nitro,

amino, acetamino;

for Y: hydrogen, halogen and mainly bromine and chlorine, alkyl-sulfonyl and mainly ethylsulfonyl, sulfamoyl, alkylsulfamoyl and especially methylsulfathioyl, dialkylsulfamoyl

and especially dimethyl and diethylsulfamoyl,

for Z: hydrogen, halogen and mainly bromine and chlorine,

and where the preferred meanings of the substituents in the disubstituted compounds are:

' X = alkoxy and especially methoxy

Y = sulfamoyl

X and Y are joined together to form an azimido group.

Y = Z = halogen and especially bromine

Y and Z may be linked together to form an azimido group, and the preferred meanings of the substituents in the tri-substituted compounds are:

f X = nitro

\_Y = Z = halogen and especially chlorine and bromine.

According to the invention, the compounds can be produced

by reacting one compound with the general formula:

there:

A, X, Y and Z are as indicated above, D denotes a hydroxy group, a halogen atom or an organic residue, with an amine of the general formula:

there:

R and n are as stated above, or by reaction between reactive derivatives.

In the starting compounds, the organic residue comprises groups capable of forming reactive acid derivatives. These may be lower alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl; reactive acid esters, such as methoxymethyl ester, cyanomethyl ester, substituted or unsubstituted aromatic esters or N-hydroxyimide esters; acid azides; acid hydrazides; symmetrical anhydrides; mixed anhydrides, such as those formed from carboxylic acid esters and haloformic acid esters; azolides, such as triazolides, tetrazolides and especially imidazolides; substituted a)-trihaloacetophenones; acid isothiocyanates; substituted α-oxobenzeneacetonitrile; benzamides, which are substituted on the ring, or other equivalents, or the compound of the general formula:

(formed from the acid and an isoxazolium salt). In the above formula, A, X, Y and Z are as above. However, the invention is not limited to the use of the above-mentioned derivatives.

According to the invention, the amine can react in the form of one of its reactive derivatives. For example, mention may be made of the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl and orthophenylene chlorophosphites, alkyl or aryldichlorophosphites or isothiocyanate of the amine or the amine's symmetrical or asymmetrical sulfamides, the corresponding symmetrical urea, the corresponding enamines or any other equivalent.

The above-mentioned reactive derivatives can react with the acid in situ or after previous isolation. However, the invention is not limited to the use of the reactive derivatives described above.

In addition, it is also possible to carry out the reaction

on the free acid and the free amine in the presence of a condensing agent, e.g. silicon tetrachloride, phosphoric anhydride, or a carbodiimide, such as dicyclohexylcarbodiimide, or alkoxyacetylenes, such as methoxy- or ethoxyacetylene.

Among the synthesis processes, which are described for the production according to the invention of the compounds of formula I, are:

- the use of an acid halide particularly suitable for

- compounds that are unsubstituted in the benzene ring - compounds that are monosubstituted with a halogen atom, a nitro group, an alkylsulfonyl group, a sulfamoyl group, alkyl or dialkylsulfamoyl group; - the use of alkyl esters, activated acid esters or

aromatic esters particularly suitable for

- compounds in which the benzene ring is substituted with an amino group, an acetamino group, an alkylsulfonyl group, a sulfamoyl group, an alkylsulfamoyl or dialkylsulfamoyl group - compounds in which two of the X and Y or Y and Z residues are linked together to form an azimido group; - the use of mixed anhydrides (formed in situ by reaction of the starting benzoic acid on haloformic acid esters, preferably chloroformic acid esters) is particularly suitable for compounds substituted with a nitro group, an acetamino group, a sulfamoyl group, alkylsulfamoyl or dialkylsulfamoyl group.

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, which are inert with regard to the amidation reaction, are e.g. alcohols, polyols, benzene, toluene, dioxane, chloroform or diethylene glycol, dimethyl ether, xylene. It is also possible to use an excess of the amine, which is used as starting material f. It may be preferred to warm up the reaction mixture during the amidation reaction, e.g. to the boiling point of the above-mentioned solvents.

The compounds, which are produced by the method according to the invention, can, if desired, be reacted with pharmaceutically acceptable organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid, methanesulfonic acid, to obtain the acid addition salts.

One can also react with alkyl halides or sulfates to obtain quaternary ammonium salts.

The compounds can also be oxidized in a manner known per se, e.g. using hydrogen peroxide and manganese dioxide,

to obtain the corresponding N-oxide.

The invention shall be illustrated in more detail by the following examples.

Example 1

N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide

7- chlorosulfonyl- 1, 4- benzodloxane- 5- carboxylic acid

670 g of chlorosulfonic acid was added to a round bottom flask equipped with a condenser and a thermometer, 173 g of 1,4-benzodioxane-5-carboxylic acid was added in portions while the temperature was maintained at 5-10°C. The mixture was heated to 55°C and then cooled and poured onto ice. The precipitate was separated,

washed and dried and 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 210-215°C were obtained

in a yield of 93.5%.

7- methylsulfamoyl- 1, 4- benzodioxane- 5- carboxylic acid

139.5 g of a 40% aqueous methylamine solution and 139.5 cm 3 of water were added to a round flask equipped with a stirrer and a thermometer, after which, in portions, 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and a solution of 180 cm 3 of 30% soda ash solution in 180 cm 3 of water was added. The mixture was stirred and then poured into 2200 cm 3 of water. The solution was filtered, then treated with 13 9 cm 3 of concentrated hydrochloric acid. The precipitate was separated, washed and dried, and 190.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 208-209°C was obtained in a yield of 80%.

7- methylsulfamoyl- 1, 4- benzodioxane- 5- carbonyl chloride

176.5 g of thionyl chloride was added to a round bottom flask equipped with a condenser after which 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was added in portions while heating to 40-45°C. The mixture was heated under reflux and then treated with 250 cc of chloroform. The precipitate was separated and washed with chloroform.

N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide

69 g of 1-allyl-2-aminomethylpyrrolidine and 432 ml of chloroform were added to a 1 liter round bottom flask equipped with a thermometer and stirrer. 144 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added in Dorsinnpimens t-pmnprflt-nrpti hie vprl 5-10°C. Stirring of the mixture was continued for 1 hour and then the mixture was treated with 1750 ml of water. After distilling off the chloroform, the mixture was acidified to a pH value of 4 using 4 ml of 20% sulfuric acid and then filtered over carbon black, the solution of the sulphate formed was made alkaline using 60 ml of 20% ammonia. After crystallization, the base was separated, washed with water and dried at 40°C. After recrystallization from acetonitrile, 134 g of N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 142-143°C were obtained in a yield of 68.7 %.

The obtained NMR spectrum corresponded to the assumed structure.

Example 2

N-(l- ethyl- 2- pyrrolidylmethyl)- 7- sulfamoyl- 1, 4- benzodioxane- 5- carboxamide

7- sul. f amoyl- 1, 4- benzodioxane- 5- carboxylic acid

209 g of 34% ammonia and 97 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added to a round flask equipped with a stirrer and thermometer at a temperature of 5-10°C. The mixture was stirred at ambient temperature and then the precipitate was dissolved in 415 cm 3 of water. The solution was filtered and treated with 140 cm <3>concentrated hydrochloric acid. The crystals were separated, washed with water and dried, and 78 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 272-274°C were obtained in a yield of 87%.

Methyl- 7- sulfamoyl- 1, 4- benzodioxane- 5- carboxylate

429 g of methanol was added to a round bottom flask equipped with a condenser and then, with cooling, 54 g of 93% sulfuric acid and 111 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux and then cooled. The crystals were separated, washed with methanol and then treated with 500 cm 3 of water and 5 g of sodium carbonate. The precipitate was separated, washed with water and dried, and 95 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate with a melting point of 225-226°C were obtained in a yield of 81%.

N-(l- ethyl- 2- pyrrolidylmethyl)- 7- sulfamoyl- 1, 4- benzodioxane- 5-carboxamide

145 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 81.5 g of 1-ethyl-2-aminomethylpyrrolidine were added to a round bottom flask equipped with a reflux condenser and a stirrer. The resulting suspension was heated on a water bath until a sample was soluble in dilute acids. The reaction mixture was then treated with 1 liter of water and acidified with 70 ml of acetic acid. The acetate solution,

which was formed, was filtered on carbon black, and the base was precipitated with 20% ammonia. The crystals were separated, washed with water and dried. The benzamide was purified by transfer to the hydrochloride (m.p. 238-240°C). The base was reprecipitated by adding 20% ammonia. 120 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 160-161°C were obtained in a yield of 61.5%.

The obtained NMR spectrum corresponded to the assumed structure.

Example 3

N-(1- methyl- 2- pyrrolidylmethyl)- 7- ethylsulfonyl- 1, 4- benzodioxane- 5- carboxamide

7- mercapto-l, 4- benzodioxane- 5- carboxylic acid

243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and 654 cm<3> of acetic acid were added to a round bottom flask equipped with a stirrer and a condenser. The mixture was heated to 90°C and then cooled to 45°C. 398 g of tin and 1744 cm<3> of hydrochloric acid were then added. The mixture was heated to 55-60°C, cooled and poured into water. The precipitate was separated, basted and dried, and 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid with a melting point of 191-192°C was obtained in a yield of 90%. 7- ethylthiol, 4- benzodioxane- 5- carboxylic acid

166 g 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242

3 3

cm of water, 216 cm of soda solution and 181 g of ethyl sulphate were added to a round bottom flask equipped with a condenser. The mixture was heated under reflux and then cooled. The mixture was poured into 1.3 l of water, filtered and treated with 110 cm 3 of hydrochloric acid. The precipitate was separated, washed with water and dried, and it remained

obtained 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid with a melting point of 154-154°C in a yield of 81%.

7- ethylsulfonyl- 1, 4- benzodioxane- 5- carboxylic acid

152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid and

958 cm 3 of acetic acid was added to a round bottom flask equipped with a condenser. 398 cm<3> of hydrogen peroxide was then added and the mixture was heated. The crystals formed on cooling were separated, washed and dried, and 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 217-218°C were obtained in a yield of 81 %.

7- ethylsulfonyl- 1, 4- benzodioxane- 5- carbonyl chloride

243 g of thionyl chloride, a few drops of dimethylformamide and 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid were added to a round bottom flask equipped with a condenser. The mixture was heated and then excess thionyl chloride was distilled off

vacuum. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride with a melting point of 146-147°C were obtained in a yield of 100%.

N-(1-methyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 59 g of l-methyl-2-aminomethylpyrrolidine, 450 ml of chloroform and then in portions 150 g of 7-ethylsulfonyl-1, 4-benzodioxane-5-carbonyl chloride was added at a temperature of 5-10°C to a round flask equipped with a stirrer and thermometer. The mixture was then stirred for 1 hour at ambient temperature after which 1850 ml of water was added. After distilling off the chloroform, the solution was filtered over carbon black and the benzamide was precipitated by adding 65 ml of soda solution. The solid was separated, washed with water and dried at 40°C. After recrystallization from absolute alcohol, 151 g of N-(1-methyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide with a melting point of 140-141°C were obtained in a yield of 80, 5%.

The presumed structure was confirmed by NMR spectroscopy.

Example 4

N-(l- methyl- 2- pyrrolidylmethyl)- 7- dimethylsulfamoyl- 1, 4- benzodioxane- 5- carboxamide

7- dimethylsulfamoyl- 1, 4- benzodioxane- 5- carboxylic acid

500 cm<3> of acetone and a solution of 99 g of dimethylamine in

250 cm 3 of acetone was added to a round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 0°C, and then 139 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was added. The mixture was stirred at ambient temperature, acetone distilled off and. the remainder dissolved in 1 liter of water. The solution was made alkaline, filtered and treated with 70 cm 3 of hydrochloric acid. The precipitate was separated, washed and dried, and 128 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 220-221°C was obtained in a yield of 89%.

7- dimethylsulfamoyl- 1, 4- benzodioxane- 5- carbonyl chloride

190 g of thionyl chloride and 153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added to a round bottom flask equipped with a condenser. The mixture was heated and then excess thionyl chloride was distilled off. 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride with a melting point of 160-162°C were obtained in a yield of 100%.

N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide 61 g of 1-methyl-2-aminomethylpyrrolidine and 560 ml of chloroform were added to a round-bottomed flask equipped with a stirrer and thermometer and then while maintaining the temperature at 0-5°C, 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added. The mixture was stirred for 1 hour while allowing the temperature to rise, and then 1 liter of water was added. After distilling off the chloroform, the solution was filtered and the carboxamide was precipitated by adding a 30% soda solution.

The crystals produced were filtered, washed with water and

dried.

After recrystallization from absolute alcohol, 157 g of N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 165-166°C were obtained

in a yield of 76.9%.

The structure was confirmed by NMR spectra.

Example 5

N-(l- benzyl- 2- pyrrolidylmethyl)- 1, 4- benzodioxane- 5- carboxamide phosphate

440 ml of chloroform and 110 ml of 1-benzyl-2-aminopmethylpyrrolidine were added to a round-bottomed flask equipped with a stirrer and thermometer, and then, at a temperature of 5-10°C, 110 g of 1,4-benzodioxane-5- carbonyl chloride added. After stirring the mixture and adding 3 1 of water, the chloroform was removed.

The solution was treated with ammonia and then

the precipitate was extracted with methylene chloride. The organic solution was dried, and then the solvent was removed. The resulting compound, dissolved in absolute ethanol, was treated with 30 ml of 85% phosphoric acid. The precipitate formed was separated, washed with ethanol and dried. 153 g of N-(1-benzyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide phosphate with a melting point of 165°C were obtained in a yield of 61%.

Example 6

N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide

145 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 89 g of 1-allyl-2-aminomethylpyrrolidine were added to a round bottom flask equipped with a condenser. The mixture was heated on a water bath until a sample was soluble in dilute acids, and then 1 liter of water was added. The precipitated carboxamide was redissolved by acetate formation. The solution obtained was filtered over carbon black, and then the base was precipitated by adding 20% ammonia. The resulting crystals were separated, washed with water, dried and purified by transfer to the hydrochloride (m.p. 228-230°C), followed by conversion to base by treatment with 20% ammonia. 131 g of N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 143-144°C were obtained in a yield of 64.8%.

The structure was confirmed by NMR analysis.

Example 7

N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide

Methyl- 7- methylsulfamoyl- 1, 4- benzodioxane- 5- carboxylate

750 ml of methanol was added to a round bottom flask equipped with a condenser, and then, with cooling, 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux, cooled and poured into water and sodium carbonate. The precipitate was separated, washed and dried.

143 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate with a melting point of 159-160°C were obtained in a yield of 85%.

N-(l- ethyl- 2- pyrrolidylmethyl)- 7- methylsulfamoyl- 1, 4- benzodioxane-5- carboxamide

137 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 43 g of water and 73 g of 1-ethyl-2-aminomethylpyrrolidine were added to a round bottom flask equipped with a stirrer and a reflux condenser. The mixture was heated on a water bath until a sample was completely soluble in dilute acids. The carboxamide, which was obtained on cooling, was purified by transfer to acetate and then treatment with 100 ml of acetic acid into 950 ml of water. After the resulting solution was filtered over carbon black, the base was precipitated by the addition of 20% ammonia. The resulting crystals were separated, washed with water, dried and purified by recrystallization from boiling isopropyl alcohol. 121 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 139-140°C were obtained

in a dividend of 66.2%.

The structure was confirmed by NMR analysis.

The corresponding hydrochloride was prepared by treating the carboxamide with hydrochloric acid (specific gravity: 1.18) (melting point: 186-188°C).

Example 8

N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxybenzamide In the same way, 34.9 g of ethyl-2,3-methylenedioxybenzoate were reacted with 24.2 g of l-ethyl-2-aminomethylpyrrolidine, and after treatment there was and purification obtained 28.3 g of N-(1-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxybenzamide.

The obtained NMR spectra are comparable with the expected structure.

Example 9

Levo-rotating N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 65 g of levo-rotating l-ethyl-2-aminomethylpyrrolidine were dissolved in 430 ml of chloroform in a round flask equipped with a stirrer and thermometer . The resulting solution was cooled to 5°C, and then 148 g of finely powdered 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added while maintaining the temperature at 5-10°C. At the end of the addition of this substance, the mixture was stirred for 1 hour and then treated with 1 liter of water. After distilling off the chloroform, the solution was filtered over carbon black, and the base was precipitated by an excess of 30% soda ash. The resulting crystals were separated, washed with water, dried and recrystallized from isopropyl alcohol. 151.5 g of levorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide with a melting point of 111-112°C were obtained in a yield of 77.7% . (a)j^ = -54.2° in 5% solution in dimethylformamide.

Example 10

Dextrorotating N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide In the same way, 64.5 g of dextrorotating l-ethyl-2-amino-methylpyrrolidine were reacted with 146 g of 7- ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride for. after treatment and purification, to give 133.5 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide with a melting point of 111-112°C in a yield of 69.8%.

(ot)^ = 55.5° in a 5% solution in dimethylformamide.

Example li

N-(l- ethyl- 2- pyrrolidylmethyl)- 7- ethylsulfonyl- 1, 4- benzodioxane- 5- carboxamide

In the same way, 58 g of 1-ethyl-2-aminomethylpyrrolidine were reacted with 131 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride, and after treatment and purification, 103.5 g of N-(l-ethyl -2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide with a melting point of 118-119°C in a yield of 60.2%.

100 g of the base obtained was dissolved in 220 ml of acetone, and then the solution was filtered on carbon black, and a solution of 9.5 g of hydrochloric acid in acetone was added. The resulting

hydrochloride crystals were separated, washed with acetone and dried, and 96 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride with a melting point of 148-150°C were obtained in a yield of 88.2%.

Example 12-N-(1-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide

131 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 43 g of water and 66 g of 1-methyl-2-aminomethylpyrrolidine were added to a round bottom flask equipped with a reflux condenser. The mixture was heated on a water bath until a sample was completely soluble in dilute acids. The carboxamide, which formed on cooling, was purified by treatment with a solution of 50 ml of acetic acid in 1250 ml of water. After the resulting solution was filtered over carbon black, the base was precipitated by the addition of 20% ammonia. The resulting crystals were separated, washed with water, dried and purified by recrystallization from boiling methyl alcohol. 119.5 g of N-(1-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 187-188°C were obtained in a yield of 70.1%.

Example 13

N-(1-ally1-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide

58 g of 1-allyl-2-aminomethylpyrrolidine and 360 ml of chloroform were added to a round bottom flask equipped with a stirrer and a thermometer and then, while maintaining the temperature at 5-10°C, 120 g of 7-ethylsulfonyl-1,4- benzodioxane-5-carbonyl chloride added. After stirring the mixture and adding 1 liter of water, chloroform was distilled off. The resulting solution was filtered through carbon black, and then the base was precipitated by adding 40 ml of 30% soda ash solution. The resulting crystals were separated, washed with water and then dried. 152 g of N-(1-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide with a melting point of 78-80°C were obtained in a yield of 93.4%.

146 g of the resulting base was dissolved in 219 ml of hot absolute ethanol and then the solution was filtered through carbon black and acidified by adding a solution of 13.5 g of hydrochloric acid in 100 ml of absolute ethanol. After cooling, the formed crystals were separated, washed with absolute alcohol and dried, and then purified by recrystallization from absolute alcohol. 119.5 g of N-(1-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride with a melting point of 138-140°C were obtained in a yield of 75%.

Example 14

N-(l- ethyl- 2- pyrrolidylmethyl) ^ 2H- 3, 4- dihydro- l, 5- benzodioxepine- 6- carboxamide

Methyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carboxylate

111 g of methyl 2,3-dihydroxybenzoate, 660 cm 3 of methyl ethyl ketone, 167 g of 1,3-dibromopropane and 10 g of sodium iodide were added to a round bottom flask equipped with a stirrer and thermometer. The mixture was heated to 40°C and then 182 g of potassium carbonate was added. The mixture was heated under reflux and 2 L of water was added. The oily phase was decanted, extracted with ether, and the solution was washed with 10% soda ash and dried. The ether was removed by distillation under vacuum, and 86.5 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate was obtained with a boiling point of 166-176°C at 8 mm Hg and in a yield of 63%.

2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carboxylic acid

160 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate and 388 cm 3 of soda were added to a round bottom flask equipped with a condenser. The mixture was heated under reflux and then poured into 1 liter of water and treated with 5 g of sodium metabisulphite. The solution was filtered and treated with 77 cm<3 >concentrated hydrochloric acid. The precipitate was separated, washed with water and dried, and 120 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid with a melting point of 65-67°C was obtained in a yield of 80.5% .

2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carbonyl chloride

246 g of thioneyl chloride and 134 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added to a round bottom flask equipped with a condenser. The mixture was heated under reflux and then the excess thionyl chloride was distilled off under vacuum. 14 7 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride with a melting point of 35-37°C were obtained in a yield of 100%.

N-(1-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide 92 g of 1-ethyl-2-aminomethylpyrrolidine and 458 ml of chloroform were added to a round bottom flask equipped with a stirrer and thermometer, and then, while maintaining the temperature from 5-10°C, 152 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride was added. After stirring for 1 hour, while the temperature was allowed to rise, 1450 ml of water was added, and then chloroform was distilled off. The solution was filtered over carbon black, and the base was precipitated by adding 75 ml of 20% ammonia. The formed crystals were separated, washed with water and dried, and 191 g of N-(1-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide monohydrate with a melting point of at 51-52°C and in a yield of 82.4%..

173.5 g of the compound produced was dissolved in

750 ml absolute alcohol. The solution was filtered over carbon black, and then a solution of 62 g of 85% phosphoric acid in 100 ml of absolute alcohol was added. The crystals formed were separated, washed with absolute alcohol and dried and then recrystallized from alcohol. 198 g of N-(1-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide phosphate with a melting point of 189-190°C were obtained in a yield of 92%.

Example 15

N-(1-methyl,1-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxam-5-carboxamide

169 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were added to a round bottom flask equipped with a reflux condenser.

The mixture was heated on a water bath until a sample was completely soluble in dilute acids. The resulting cry-

staller was dissolved in a solution of 50 ml of acetic acid in 1250

ml of water, then the solution was filtered over carbon black, and the base was precipitated by adding 100 ml of 20% ammonia. The crystals were separated, washed with water and dried. 182 g of N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 189-190 C were produced

in a yield of 83.6%.

Example 16

N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 13 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of tetrahydrofuran and 13 g of carbonyldiimidazole were added to a round bottom flask equipped with a stirrer, thermometer and condenser. The mixture was stirred at ambient temperature and then 9.5 g of 1-ethyl-2-aminomethylpyrrolidine was added. Stirring was continued at ambient temperature, and then the solvent was evaporated under vacuum. The crystals obtained were washed with water and then dried, and 14 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide with a melting point of 118-119° were prepared C in a dividend of 73.8%.

Example 17

N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide

A solution of 6 g of 1-methyl-2-aminomethylpyrrolidine in pyridine and then dropwise, with stirring and with a temperature maintained in the range of 0-5°C, a solution of 3.5 g of phosphorus trichloride in 20 ml of pyridine , was added to a round bottom flask equipped with a stirrer, thermometer and condenser. Stirring was continued at a temperature of 0-5°C and then at room temperature. 14.5 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was then added. The mixture was heated with stirring. After the mixture was cooled and the solvent removed, the residue was dissolved in chloroform, and the solution was washed with aqueous sodium carbonate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 12.5 g of N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 165-166°C were prepared in a -

change of 64.5%.

Example 18

N-(1-cyclohexyl-3-pyrrolidyl)-7-methylsulfamoyl-1,4-benzodloxane-5-carboxamide

84 g of 1-cyclohexyl-3-aminopyrrolidine, 430 ml of chloroform and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added to a round bottom flask equipped with a stirrer and thermometer. After stirring the mixture, the base was extracted with methylene chloride, and then the solvent was evaporated. The formed crystals were dissolved in boiling absolute alcohol, and the remaining solution was filtered on carbon black. The crystals, which were produced by cooling, were dissolved in a solution of acetic acid in water, the solution was filtered over carbon black, and the base was reprecipitated by adding 20% ammonia. 129.5 g of N-(1-cyclohexyl-3-pyrrolidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 160-161°C were obtained

in a dividend of 61.2%.

Example IS

N-(1-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide 64 g of l-ethyl-2-aminomethylpyrrolidine and 530 ml of chloroform were added to a round flask equipped with a stirrer and a thermometer, and then, while the temperature was maintained at from 0-5°C,

153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride added. The mixture was stirred for 1 hour while allowing the temperature to rise, and then 1 liter of water was added. After distilling off the chloroform, the solution was filtered, and the carboxamide was precipitated by adding a 30% soda solution. The crystals obtained were filtered, washed with water and dried. After recrystallization from absolute alcohol, 144.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 146-148°C were obtained in a yield of 72.8%.

Example 2 0

Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 82 g dextrorotatory l-ethyl-2-aminomethylpyrrolidine, 600 cm<3> chloroform and gradually, at a temperature in the range 5-10°C, 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added to a round bottom flask with a stirrer and thermometer.

After adding 1 liter of water, chloroform was distilled off and the remaining solution filtered. The base was precipitated by adding 60 cm 3 of 20% ammonia. The crystals obtained were separated, washed with water and dried, and 162 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 136- 137°C in a yield of 66%.

Example 21

Levorotatory N-(l- ethyl- 2- pyrrolidylmethyl)- 7- methylsulfamoyl- 1, 4- benzodioxane- 5- carboxamide

In the same manner as above, 82 g of levorotatory 1-ethyl-2-aminomethylpyrrolidine was reacted with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, and 151 g of levorotatory N-(1-ethyl-2- pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 136-137°C in a yield of 62%.

Example 22

Levo-rotating N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-bemzodioxane-5-carboxamide 85 g levo-rotating l-allyl-2-aminomethylpyrrolidine, 610 cm 3chloroform and gradually, 178 g 7-methylsulfamoyl-1 ,4-benzodioxane-5-carbonyl chloride, was added at a temperature of 5-10°C to a round flask equipped with a stirrer and thermometer.

After stirring the mixture, 1.2 L of water was added and the chloroform was distilled off.

The remaining solution was filtered, and then the base was precipitated using 70 cm 3 of 20% ammonia. The formed crystals were separated and washed with water.

After recrystallization from ethyl acetate, 117 g of levorotatory N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 101-102°C were obtained in a yield of 49 %.

Example 2 3

Dextro-rotating N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodloxane-5-carboxamide In the same way as in the example above, 84 g of dextro-rotating l-allyl-2-aminomethylpyrrolidine were reacted with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, and after purification 125 g of dextrorotating N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide were obtained with a melting point of 104-105°C in a yield of 52.6%.

Example 24

Dextrorotating N-(l-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 61 g dextrorotating l-methyl-2-aminomethylpyrrolidine, 465 cm<3> chloroform and in portions 155 g 7 -methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, while the temperature was maintained at 5-10°C, was added to a round flask equipped with a stirrer and thermometer. After stirring the mixture and adding 1850 cm<3> of water, chloroform was distilled off and the remaining solution was filtered. The base was precipitated by the addition of 6 5 cm<3 >20% ammonia. The formed crystals were filtered off, washed and dried. 154 g of dextrorotating N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 187-188°C were obtained in a yield of 78.5%.

Example 25

Levorotatory N-(1- methyl- 2- pyrrolidylmethyl)- 7- methylsulfamoyl- 1, 4- benzodioxane- 5- carboxamide

In the same way as in the above example, 71 g of levorotatory l-methyl-2-aminomethylpyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, and 175 g of levorotatory N-(l -methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 187-187.5°C in a yield of 77%.

Example 2 6

N- (l- ethyl- 2- pyrrolidylmethyl)- 8- methylsulfamoyl- 2H- 3, 4-dihydro- 1, 5- benzodioxepine- 6- carboxamide 8- chlorosulfonyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepine - 6- carboxylic acid 1092 cm<3> chlorosulfonic acid was added to a round flask equipped with a stirrer, condenser and thermometer. Then 106 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added in portions, while the temperature was kept between 5 and 10°C. The mixture was stirred at ambient temperature and then poured

on ice. The crystals were separated, washed with water and dried.

146 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid with a melting point of 114-115°C were obtained in a yield of 91%. 8- methylsulfamoyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carboxylic acid

233 g of an aqueous metalamine solution was added

a round flask equipped with a stirrer and thermometer, after which 146 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added in portions, while the temperature was maintained between 5 and 10°C. The mixture was stirred, and the precipitate was then dissolved in water. The solution was filtered and treated with 150 cm 3 of concentrated hydrochloric acid. The crystals were separated, washed and dried, and 112 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid with a melting point of 145-146°C were obtained in a yield of 78% .

8- methylsulfamoyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carbonyl chloride

220 g of thionyl chloride and 177 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added to a round bottom flask equipped with a condenser. The mixture was heated, and then excess thioneyl chloride was distilled off under vacuum, and 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride with a melting point of 93-

94°C in a yield of 100%.

N-(l- ethyl- 2- pyrrolidylmethyl)- 8- methylsulfamoyl- 2H- 3, 4- dihydro-1, 5- benzodioxepin- 6- carboxamide 79 g l-ethyl-2-aminomethylpyrrolidine, 750 cm methyl ethyl ketone and gradually, 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride was, while maintaining the temperature at 5-10°C, added to a round-bottomed flask equipped with a stirrer and thermometer.

The hydrochloride precipitate was separated, washed with methyl ethyl ketone and dried.

After recrystallization from methyl alcohol, the hydrochloride was dissolved in 850 cm<3> of water. The solution was filtered, after which the base was precipitated by adding 60 cm<3> of 20% ammonia. The formed crystals were separated, washed with water and dried. 180 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide with a melting point of 144-145°C were obtained in a yield of 63.8%.

Example 2 7

N-(I- ethyl- 2- pyrrolidylmethyl)- 2, 3- methylenedioxybenzamide hydrochloride

134 g of 1-ethyl-2-aminomethylpyrrolidine, 950 cm<3> chloroform

and gradually, 183 g of 2,3-methylenedioxybenzoyl chloride, while maintaining the temperature between 5 and 10°C, was added to a round bottom flask equipped with a stirrer and thermometer.

After adding 1 liter of water, chloroform was distilled off, and then the remaining solution was filtered.

After addition of 120 cm<3> of 20% ammonia and extraction with ether, the ethereal solution was dried over potassium carbonate, and then the ether was distilled off.

The prepared base was dissolved in 300 cm 3 of acetone, and then a solution of 34 g of hydrochloric acid in 330 cm<3> of acetone was added.

The hydrochloride precipitate was dried, washed with acetone and dried again.

After recrystallization from isopropyl alcohol, 154 g of N-(1-ethyl-1-2-pyrrolidylmethyl)-2,3-methylenedioxybenzamide hydrochloride with a melting point of 127.5-128.5°C were obtained in a yield of 49.7% .

Example 28

N-(1^ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamidoxolate

8- methoxyl, 4- benzodioxane- 5- carboxylic acid

171.5 g of 2,3-dihydroxy-4-methoxybenzoic acid, 515 cc of alcohol, 280 cc of sodium hydroxide solution and 175 g of ethyl bromide were added to a round bottom flask equipped with a stirrer, thermometer and inlet tube for nitrogen. The mixture was heated under reflux, then cooled and poured into 2.8 L of water. The solution was filtered and treated with 85 cm of concentrated hydrochloric acid. The precipitate was filtered off, washed and dried. After recrystallization in dimethylformamide, 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid with a melting point of 224-226°C were obtained in a yield of 57%.

8- methoxyl, 4- benzodioxane- 5- carbonyl chloride

391 g of thionyl chloride and 138 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were added to a round bottom flask equipped with a condenser. The mixture was heated to 50-55°C, and then excess thioneyl chloride was distilled off under vacuum. 151 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride were obtained in a yield of 100%.

N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxyl, 4-benzodioxan-5-carboxamidoxalate 87 g of l-ethyl-2-aminomethylpyrrolidine and 775 cm 3 of methyl ethyl ketone were added to a round flask equipped with a stirrer and thermometer after which in portions 155 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride was added while maintaining the temperature from 5-10°C. After stirring, the mixture was dissolved in 1500 cm 3 of water, and then methyl ethyl ketone was distilled off. The remaining solution was filtered and then treated with sodium hydroxide. The oil was decanted, then extracted with methylene chloride. The solution was dried over potassium carbonate, and methylene chloride was then distilled under vacuum. 224.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide were obtained.

197.5 g of the prepared base was dissolved in 760 cm 3 of absolute alcohol, and then 67 g of oxalic acid in solution in 195 cm<3> of absolute alcohol was added. The formed crystals were filtered off, washed with absolute alcohol and then dried.

208.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamidoxate with a melting point of 129-130°C were produced in a yield of 82%.

Example 2S

N-(1-ethyl-2-^pyrrolidylmethyl)-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide

8- methoxy- 7- chlorosulfonyl- 1, 4- benzodioxane- 5- carboxylic acid

1045 cm 3 of chlorosulfonic acid was added to a round bottom flask equipped with a stirrer, thermometer and condenser, after which 110 g

8-Methoxy-1,4-benzodioxane-5-carboxylic acid was added in portions while maintaining the temperature at from 5-10°C. The mixture was stirred at ambient temperature and then poured onto ice. The precipitate was filtered off, washed and dried, and 159 g of 8-metCoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained in a yield of 98%.

8- methoxy- 7- sulfamoyl- 1, 4- benzodioxane- 5- carboxylic acid

300 g of 34% ammonia was added to a round flask equipped with a stirrer and thermometer. Then 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was added in portions while the temperature was maintained at from 0-5°C. The mixture was stirred, and then the precipitate was dissolved in water. The solution was filtered and washed with 280 cm 3 of concentrated hydrochloric acid. The precipitate was filtered off, washed and dried, and 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 247-248°C were obtained in a yield of 82%.

Methyl- 8- methoxy- 7- sulfamoyl- 1, 4- benzodioxane- 5- carboxylate

396 g of methanol were added to a round bottom flask equipped with a condenser, then 51 g of sulfuric acid and 114.5 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added while cooling. The mixture was heated under reflux and then poured into 485 cm 3 of water and 40 g of sodium carbonate. The precipitate was filtered off, washed and dried, and 110.5 g of methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 202-203°C were obtained in a yield of 92 %. N-(l- ethyl- 2- pyrrolidylmethyl)- 8- methoxy- 7- sulfamoyl- 1, 4- benzodioxane- 5- carboxamide

150 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate and 750 cm<3> of ethylene glycol were added to a round bottom flask. After dissolution, 127 g of 1-ethyl-2-aminomethylpyrrolidine was added, and the mixture was heated to 50°C. The resulting solution was dissolved in 2 L of water and acidified with 120 cm<3> of acetic acid. The precipitate thus formed was filtered off, washed with water and dried. The precipitate was then redissolved in 915 cm 3 of hot water. The solution was filtered, and then the base was precipitated with ammonia. The precipitate was filtered off, washed with water and then dried. 144 g of (N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide with a melting point of 110-115°C were obtained in a yield of 73% .

Example 30

N-(1- benzyl- 2- pyrrolidylmethyl)- 7- diethylsulfamoyl- 1, 4- benzodioxane- 5- carboxamide phosphate

7- diethylsulfamoyl- 1, 4- benzodioxane- 5- carboxylic acid

200 ml water, 100 ml diethylamine and 200 ml triethylamine

was added to a round bottom flask equipped with a stirrer and thermometer. Then 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, while the temperature was kept at 20-30°C. The mixture was stirred at ambient temperature, and then 500 ml of water was added. The solution was filtered and treated with 300 ml of hydrochloric acid. The precipitate was filtered off, washed and dried. 117 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 149°C were obtained in a yield of 74%.

N-(1-benzyl-2-pyrrolidyl-methyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide phosphate. 40 ml of water, 37.8 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 12.5 g of triethylamine and 120 ml of methyl ethyl ketone were added to a round bottom flask equipped with a stirrer and thermometer, after which 17.2 g of isobutyl chloroformate was added at a temperature of 15-20°C.

After stirring the mixture, 25 g of 1-benzyl-2-amino-methylpyrrolidine was added, while the temperature was maintained at 15-20°C.

The mixture was stirred at ambient temperature, after which the solvents were removed. The residue was dissolved in 200 ml of methylene chloride and 300 ml of water. After stirring, the solvent was decanted and then dried over magnesium sulfate. The solution was filtered, and then the solvent was removed. The resulting compound was dissolved in ethanol at boiling temperature, and 18 g of 85% phosphoric acid were added. The crystals, which formed on cooling, were filtered off, washed with ice-cold ethanol and then dried. 56 g of N-(1-benzyl-2-pyrrolidylmethyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide phosphate with a melting point of 180°C were obtained in a yield of 79.6%.

Example 31

N-(l- ethyl- 2- pyrrolidylmethyl)- 8- ethylsulfonyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepln- 6- carboxamide hydrochloride 8- mercapto- 2H- 3, 4- dihydro- 1, 5- benzodioxepine - 6- carboxylic acid

A solution of 106 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 273 ml of acetic acid and 159.5 g of tin was added to a round flask equipped with a stirrer and thermometer. The mixture was stirred while heating to 40-45°C, and then 705 ml of concentrated hydrochloric acid was added. After heating to 55-60°C, the solution was cooled. The precipitate was filtered off, washed and dried. 65 g of 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid with a melting point of 99.5-100°C were obtained in a yield of 80%.

8- ethylthio- 2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carboxylic acid

86 g of 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid, 152 ml of water, 76 ml of soda ash and 58.5 g of ethyl sulphate were added to a round flask equipped with a condenser. The mixture was heated under reflux and then cooled. 150 ml of water was added, and then the solution was filtered and treated with 60 ml of hydrochloric acid. The precipitate was filtered, washed and dried. 88 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid with a melting point of 66-67°C were thus obtained in a yield of 91%. 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 88 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 528 ml of acetic acid were added to a round bottom flask equipped with a condenser, after which 210 ml of hydrogen peroxide was added in portions. The solution was heated and the acetic acid removed under vacuum. The residue was dissolved in 180 ml of water and cooled. The precipitate was filtered off, washed and dried, and 90 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid with a melting point of 142-143°C were obtained in a yield of 91 %.

8- ethylsulfonyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepine- 6- carbonyl chloride

75 g of thionyl chloride and 90 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added to a round bottom flask equipped with a condenser. The mixture was heated to 45-50°C and excess thionyl chloride was removed under vacuum. The residue was treated with petroleum ether, then filtered, washed and dried. 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride with a melting point of 108-110°C were obtained

in a yield of 98%.

N-(l- ethyl- 2- pyrrolidylmethyl)- 8- ethylsulfonyl- 2H- 3, 4- dihydro- 1, 5- benzodioxepin- 6- carboxamide hydrochloride

39.5 g of 1-ethyl-2-aminomethylpyrrolidine in 282 ml of chloroform was added to a round-bottomed flask equipped with a stirrer and thermometer, after which 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxapine-6-carbonyl chloride was added in portions while the temperature was maintained at 5-10°C. The mixture was heated and then poured into water. The aqueous phase was cooled, filtered and treated with 30 ml of soda ash. The precipitate was extracted with methylene chloride, and the organic phase was dried over potassium carbonate. The solvent was distilled off, the residue dissolved in isopropyl alcohol and treated with a solution of hydrochloric acid in isopropyl alcohol. The precipitate was filtered off, washed with alcohol and dried. 98 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide hydrochloride with melting point 141-142°C were obtained in a yield of 73 %.

Example 32

"N-(1-ethyl-2-pyrrolidylmethyl)-6,7-dibromo-8-nitro-1,4-:benzodioxane-5-carboxamide".

6, 7- dibromo- 1, 4- benzodioxane- 5- carboxylic acid

1440 ml of acetic acid and 360 g of 1,4-benzodioxane-5-carboxylic acid were added to a round bottom flask equipped with a stirrer, introduction funnel and condenser. The mixture was heated to 55°C, after which a solution of 700 g of bromine in 360 ml of acetic acid was added in portions. The mixture was heated to 120°C and then cooled to 15°C. The precipitate was filtered off, washed with acetic acid and dried, and 332 g of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid with a melting point of 212°C were obtained. The structure was confirmed by NMR analyses.

6, 7- dibromo- 8- nitro- 1, 4- benzodioxane- 5- carboxylic acid

166 g of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid and 500

ml of acetic acid was added to a round bottom flask. The mixture was up-

heated to 37°C, after which a solution of 60 ml nitric acid (d=1.49) in 60 ml acetic acid and sulfuric acid was added as a catalyst. After heating to 50°C, the mixture was poured into cold water with stirring. The precipitate was filtered off, washed with water and dried. 107 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid with a melting point of 237°C were obtained.

The acid was purified by treatment with a solution of

50 g of sodium bicarbonate in 500 ml of water and precipitation using hydrochloric acid. The precipitate was filtered off, washed and dried, and crystals with a melting point of 238°C were obtained in a yield of 61%. The structure was confirmed by NMR analyses. 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride 96 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid and 200 ml of thionyl chloride were added to a round bottom flask equipped with with stirrer and thermometer. The mixture was heated under reflux, after which excess thionyl chloride was removed under vacuum. The residue was dissolved in 100 ml of isopropyl ether, then the solvent was removed, and the product was air-dried. 91 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride with a melting point of 215°C were obtained in a yield of 91%.

N-(1-ethyl1-2-pyrrolidylmethyl)-6,7-dibromo-8-nitro-1,4-benzodioxan-5-carboxamide

In a flask equipped with a stirrer and thermometer is introduced

500 ml of methyl ethyl ketone and 18 g of 1-ethyl-2-aminomethylpyrrolidine.

It is cooled to 10°C and then introduced in portions without exceeding 20°C, 50 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride. The obtained solution is stirred for 1 hour at ambient temperature, after which the crystals formed are separated, washed with methyl ethyl ketone and dried. The product obtained is dissolved in 400 ml of water at ambient temperature. 7 g of activated charcoal is added, filtered and the base is precipitated by adding

50 ml of 20% ammonia. The formed crystals are separated,

washed with water and dried and 40 g of N-(1-ethyl-2-pyrrolidinylmethyl)-6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide with melting point 213°C are obtained in a yield of 65%.

Example 33

N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride

8- amino- 1, 4- benzodioxane- 5- carboxylic acid

400 ml of water, 98.5 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml of soda and 10 g of Pd/C were added to an autoclave followed by hydrogen, under a pressure of 40 kg/cm 2 was added while heating to 50°C. The mixture was filtered and then treated with 95 ml of hydrochloric acid. The precipitate was filtered off, washed and dried, and 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid with a melting point of 186°C was obtained

in a yield of 83.7%.

N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride

According to the method described in ex. 2, became

42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid heated with methanol and the resulting compound treated with 33 g of 1-ethyl-2-aminomethylpyrrolidine and then with a solution of 13 g of hydrochloric acid in absolute alcohol. 49 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride with a melting point of 173°C were obtained in a yield of 60%.

Example 34

N-(1-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide

8-acetamino-1,4-benzodioxane-5-carboxylic acid

43 g of 8-amino-1,4-benzodioxane-5-carboxylic acid and 72 ml of acetic acid were added to a round bottom flask after which 24.5 ml of acetic anhydride were added in portions. The mixture was heated to 60-70°C and then cooled. The precipitate was filtered off, washed with acetic acid and water and then dried. 44 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid with a melting point of 233°C were obtained in a yield of 84%.

N-(1-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide,

According to the procedure described in ex. 30, 8-acetamino-1,4-benzodioxane-5-carboxylic acid was heated with isobutyl chloroformate and 1-ethyl-2-aminomethylpyrrolidine. N-(1-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide was obtained. The structure was confirmed by NMR analysis.

Example 35

N-(1-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzodioxane-5-carboxamide

7, 8-azimido-1,4-benzodioxane-5-carboxylic acid

42 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid, 75 ml of acetic acid and 75 ml of acetic anhydride were added to a round flask after which a solution of 17.5 ml of nitric acid (d=1.49)

in 17 ml of acetic acid was added, while the temperature was allowed to rise. After dissolution and crystallization, 50 ml of acetic acid was added. The mixture was stirred at 40-45°C and then cooled to 20°C. The precipitate was filtered off, washed with acetic acid and water and dried, and 13.5 g of a 50% mixture of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and 6-nitro -8-acetamino-1,4-benzodioxane-5-carboxylic acid. 13 g of this 50% mixture of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid, 90 ml of water, 4.5 ml of sodium hydroxide, some Raney nickel and hydrogen under a pressure of 50 kg/cm<o>were fed into an autoclave. At the end of the hydrogen absorption, nickel was filtered off and the solution was treated with 12 ml of hydrochloric acid and then with a solution of 3.5 g of sodium nitrite in 10 ml of water at a temperature of 20-25°C. The resulting precipitate was filtered off, washed and then treated with an aqueous sodium hydroxide solution. The mixture was acidified, and then the precipitate was filtered off, washed and dried, and 30 g of 7,8-azimido-1,4-benzodioxane-5-carboxylic acid with a melting point of 2 60°C was obtained, with decomposition, in a yield of 59%.

N-(1-ally1-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzodioxane-5-carboxamide

The 7,8-azimido-1,4-benzodioxane-5-carboxylic acid was treated with N-hydroxyphthalimide together with dicyclohexylcarbodiimide. The phthalimide carboxylate obtained was treated with 1-allyl-2-amino-methylpyrrolidine. N-(1-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzodioxane-5-carboxamide was obtained, the structure of which was confirmed by NMR analysis.

Example 3 6

N-(1-allyl-2-pyrrolidylmethyl)-6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride

1, 4- benzodioxane- 6, 7- dlnitro- 5- carboxylic acid

165 ml of nitric acid (d=1.49) was added to a 500 ml round flask equipped with a stirrer and thermometer. 90 g of 1,4-benzodioxane-5-carboxylic acid was added at 10°C. The mixture was kept for 2 hours at room temperature, after which 1 liter of cold water was added. The precipitate was filtered off, washed with water and dried at 50°C and then purified by recrystallization in acetic acid. 87 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid with a melting point of 211°C were obtained.

1, 4- benzodioxane- 6, 7- diamino- 5- carboxylic acid

135 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid,

500 ml of water and 50 ml of caustic soda were added to a 1 liter autoclave and hydrogenated under a pressure of 80 kg/cm 2 in the presence of Raney nickel. The mixture was heated to 100°C for 2 hours

and then cooled and filtered. The nickel was washed on the filter with 200 ml, and the filtrates were combined. A sample was acidified with hydrochloric acid to form 1,4-benzodioxane-6,7-diamino-5-carboxylic acid dihydrochloride which was filtered, washed and dried. The melting point was 153°C.

1, 4- benzodioxane- 6, 7- azimido- 5- carboxylic acid

The filtrate obtained above was added to a 2 liter round bottom flask equipped with a stirrer and thermometer. A solution of 35 g of sodium nitrite in 70 ml of water was added dropwise at a temperature of 20-35°C. The crystallized product was filtered off, washed with water and dried at 50°C, and 96 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid were obtained in a yield of 87%. The structure was confirmed by NMR analysis.

1, 4- benzodioxane- 6, 7- azimido- 5N- phthalimide carboxylate

74 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid, 1 liter of dimethylformamide, 57 g of N-hydroxyphthalimide, 74.5 g of dicyclohexylcarbodiimide were heated at a temperature of 90°C for 30 min. After cooling to 20°C, the crystals were filtered off, washed with 150 ml of dimethylformamide. The filtrate was evaporated under vacuum and the residue was heated with 400 ml of methanol. The solid was filtered off, washed and dried. 80 g of 1,4-benzodioxane-6,7-azimido-5N-phthalimide carboxylate with a melting point of over 250°C were obtained in a yield of 65.6%.

N-(1-allyl-2-pyrrolidylmethyl)-6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride 92 g of 1,4-benzodioxane-6,7-azimido-5N-phthalimide carboxylate, 500 ml of dimethylformamide were added to a 1 liter round flask equipped with a stirrer and thermometer. 45 g of 1-allyl-2-amino-methylpyrrolidine were added with stirring while maintaining room temperature for 2 hours. After evaporation of the solvent, the residue was treated with 500 ml of hot acetone. After filtration, 50 ml of an ethanolic solution of hydrochloric acid was added to the filtrate. The product was filtered, washed and recrystallized, and 50 g of N,(1-allyl-2-pyrrolidylmethyl)-6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride with a melting point of 255°C were obtained.

The structure was confirmed by IR and NMR analyses.

Example 3 7

N-(1- ethyl- 2- pyrrolidylmethyl)- 1, 4- benzodioxane- 5- carboxamide hydrochloride

In the same way, as described in ex. 28, by reaction of 1,4-benzodioxane-5-carbonyl chloride with 1-ethyl-2-amino-methylpyrrolidine, N-(1-ethyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide hydrochloride was obtained with a melting point of 149-150°C.

The compounds in the synthesis examples, which are described

above, are collected in table I.

The compounds produced according to the invention are used in various forms, such as capsules, tablets, pills, granules, injectable solutions, preparations, which are known in and of themselves. You can use substances that do not react with the compounds, e.g. lactose, magnesium stearate, starch, talc, celluloses, levilite, alkali metal lauryl sulphates, sucrose and other carriers, which are used in medicinal preparations.

The compounds produced according to the invention can be administered in doses

of 50-900 mg/day. It is advantageous to use 50-300 mg/day,

and preferably approx. 100-150 mg/day.

The compounds produced according to the invention have interesting anxiolytic, psychostimulant, disinhibitory and thymoanaleptic effects which give properties which are suitable for therapeutic use in the psychofunctional area, and especially when it comes to gastroenterology, cardiology, urology, rheumatology and gynaecology.

The low toxic level is compatible with use in human therapy without the risk of secondary effects.

The acute toxicity of the compounds prepared according to the invention was determined on Swiss mice by parenteral (intravenous, intraperitoneal and subcutaneous) administration and by oral administration. The determined LD,-q are shown in Table II.

Due to the particularly high antiemetic effects, the compounds prepared in Examples 1 to 4, 6, 7, 11 to 13, 15, 18, 19 and 26 are particularly preferred.

The numbering of the compounds in the following tables corresponds to the example numbers.

The compounds produced according to the invention are furthermore free of cataleptic action. They were administered subcutaneously to rats. Criterion with regard to the cataleptic state was immobility for the animal for 30 sec. where the forelegs were spread out and arranged carefully on wooden cubes, which were 4 cm high, so that the animal was placed in an unusual and uncomfortable position.

The cataleptic activity was measured by the maximum effect. The results are given in Table III:

From these results it can be seen that the compounds produced according to the invention are free of cataleptic action in rats. This property allows the clinical use of the compounds prepared according to the invention with a high degree of tolerance with regard to the extra-pyramidal system. The compounds prepared according to the invention have also been found to be particularly active in dogs with regard to central emetic agents, such as apomorphine. The experimental procedure followed was according to Chen and Ensor. The compounds produced according to the invention were administered subcutaneously for 30 min.

before apomorphine (100 ug/kg/SC); the animal was observed 5j hours after injection of the alkaloid.

The results are given in Table IV.

The interest, which was aroused by carrying out the laboratory tests, was found to be justified by human clinical tests on the compounds produced according to the invention.

Among other things, the following examples were carried out:

- A 38-year-old patient suffered from Hodgkin's disease, and was subjected to repeated chemotherapy as an outpatient once a week. Each session was accompanied by nausea and severe vomiting, which lasted 24 hours, despite the usual treatment.

Treatment 24 hours before the start of the perfusion and

4 hours afterwards with 50 mg of N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide completely suppressed the nausea and vomiting attacks. The product was completely tolerated and no secondary effects were noted. - A 28-year-old patient suffered from a neurosis with nervous attacks that culminated in three suicide attempts. Analytical treatment for 18 months made it possible to achieve social integration, but had little effect on the nervous aspect.

The administration of 50 mg of N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide three times per day, caused in a few days a total disappearance of all nervous problems without problematic sedative effect. The product was completely tolerated, and no side effects were noted. - A 78-year-old patient had been suffering from severe reactionary depression for 8 months. The presence of a prostatic adenoma contraindicated the use of tricyclic compounds.

He was treated three times per day with 50 mg of N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, and after three weeks, when his condition had significantly improved, he was able to leave the hospital. The treatment, which was continued at home for three months, made it possible to maintain an excellent mental balance, with the resumption of the normal activities of a retired person on

this age.

The product was fully tolerated and no side effects were noted. - A 42-year-old patient underwent hystereotomy for fibroma 5 months ago. A few days after the operation, hot flashes appeared (10-20 per day) with sweat attacks, which woke the patient at night and caused disturbances in work.

She was treated with N-(1-ethyl1-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide in the form of a single dose of 100 mg per day, and the symptoms disappeared within 4 days. After 5 months, only one hot flush occurred every two or three days.

The product was perfectly tolerated and no side effects were noted. - A 47-year-old patient suffered, after the menopause, from repeated cystitis attacks with a frequency and severity that made social intercourse impossible. The patient consulted general practitioners and specialists. All tests were negative and all treatment was ineffective in this classic case of cystitis. The patient was then treated for a few days with N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide at a dose of 150 mg/day, and the symptoms completely disappeared and the normal mental state was re-corrected.

Claims (14)

1. Analogy method for the preparation of therapeutic active 2,3-alkylene-bis-oxybenzamides of formula (I) where: A is C 1 -C 4 -alkylene; R is C 1 -C 4 -alkyl; C 1 -C 4 -alkenyl, C 1 -C 8 -cycloalkyl or benzyl; X is hydrogen, C 1 -C 4 alkoxy, nitro, amino or acetamino; Y is hydrogen, halogen, sulfamoyl, C-^-C^-alkylsulfamoyl, C-^-C^-dialkylsulfamoyl, C-^-C^-alkylsulfonyl or X and Y are linked together to form an azimido group; Z is hydrogen, halogen or Y and Z are interconnected and forms an azimido group; and n is 0 or 1, or pharmaceutically acceptable acid addition salts, quaternary ammonium salts and N-oxides thereof, characterized by the reaction of a compound of the general formula where A, X, Y and Z are as indicated above and D denotes a hydroxy group, a halogen atom or an organic residue, with an amine of the general formula: where R and n are as stated above, possibly by reacting reactive derivatives of these compounds, and, if desired, converting the obtained compounds into pharmaceutically acceptable acid addition salts, quaternary ammonium salts or N-oxides. 2. Method according to claim 1 for the production of N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating 7-methylsulfamoyl-1,4- benzodioxane-5-carbonyl chloride with 1-allyl-2-aminomethylpyrrolidine. 3. Method according to claim 1 for the production of N-(1-ethyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating methyl-7-sulfamoyl-1, 4-benzodioxane-5-carboxylate with 1-ethyl-2-aminomethylpyrrolidine. 4. Process according to claim 1 for the production of N-(1-methyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating 7-ethylsulfonyl-1,4- benzodioxane-5-carbonyl chloride with 1-methyl-2-aminomethylpyrrolidine. 5. Process according to claim 1 for the production of N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating 7-dimethylsulfamoyl-1,4- benzodioxane-5-carbonyl chloride with 1-methyl-2-aminomethylpyrrolidine. 6. Process according to claim 1 for the production of N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating methyl-7-sulfamoyl-1, 4-Benzodioxane-5-carboxylate with 1-allyl-2-aminomethylpyrrolidine. 7. Method according to claim 1 for the production of N-(1-ethyl-1-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating methyl-7-methylsulfamoyl-1, 4-benzodioxane-5-carboxylate with 1-ethyl-2-aminomethylpyrrolidine. 8. Process according to claim 1 for the production of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating 7-ethylsulfonyl-1,4- benzodioxane-5-carbonyl chloride with 1-ethyl-2-aminomethylpyrrolidine. 9. Process according to claim 1 for the production of N-(1-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating methyl-7-sulfamoyl-1, 4-benzodioxane-5-carboxylate with 1-methyl-2-aminomethylpyrrolidine. 10. Method according to claim 1 for the production of N-(1-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating 7-ethylsulfonyl-1,4- benzodioxane-5-carbonyl chloride with 1-allyl-2-aminomethylpyrrolidine. 11. Process according to claim 1 for the production of N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it comprises treating methyl-7-methylsulfamoyl-1, 4-benzodioxane-5-carboxylate with 1-methyl-2-aminomethylpyrrolidine. 12. Process according to claim 1 for the production of N-(1-cyclohexyl-3-pyrrolidy-1-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it consists in treating 7-methylsulfamoyl-1,4- benzodioxane-5-carbonyl chloride with 1-cyclohexyl-3-aminopyrrolidine. 13. Process according to claim 1 for the production of N-(1-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide, characterized in that it consists in treating 7-dimethylsulfamoyl-1,4 -benzodioxane-5-carbonyl chloride with 1-ethyl-2-aminomethylpyrrolidine. 14. Process according to claim 1 for the production of N-(1-ethyl-2-pyrrolidylmethyl)-8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide, characterized in that it comprises treating 8-Methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride with 1-ethyl-2-aminomethylpyrrolidine.