DK152366B - METHOD OF ANALOGUE FOR THE PREPARATION OF 2,3-ALKYLENE-BIS- (OXY) -BENZAMIDES OR DERIVATIVES THEREOF, AND 2,3-ALKYLENE-BIS (OXY) BENZOIC ACID FOR USE AS INTERMEDIATE FRENCH PRODUCT - Google Patents

Description

in

DK 152366B

The present invention relates to an analogous process for the preparation of novel 2,3-alkylene-bis (oxy) -benzamides having the general formula I or derivatives of claim 1 set forth in claim 1.

The analogous method according to the invention is characterized by the characterizing part of claim 1. The invention further relates to the 2,3-alkylene-bis (oxy) benzoic acids for use as intermediates in the preparation of the benzamide derivatives according to the process according to claim 1.

The benzamides in question exhibit a strong antiemetic effect which is not accompanied by a cataleptic effect.

U.S. Patent No. 3,370,066 discloses structurally related N-substituted methylene (bis) oxybenzamides. However, the two compounds described, as demonstrated below, exhibit a higher toxicity and generally a lower antiemetic effect resulting in a significantly lower therapeutic index DL ^ q / DE ^ q. They also exhibit some cataleptic effect. The compounds further differ from those of the present invention by containing a 2-methoxy group and an N- (2-diethylaminoethyl group). It could not be foreseen that the said structural differences would cause the compounds of the present invention to exhibit the aforementioned improved therapeutic effects over the known ones.

The starting compounds of formula II, as defined in claim 1, contain a reactive group -COD wherein D is halogen, hydroxy or alkoxy, and is thus a free acid, an acid halide or an alkyl ester such as methyl, ethyl, propyl, isopropyl, , butyl, isobutyl, tert-butyl, pentyl or isopentyl ester.

The reaction with the amine of formula III may e.g. is carried out in the presence of an alkyl halide formate which will form a mixed anhydride with the carboxylic acid ester group, phosphorus halides which will activate the amine (III), or carbonyldiimidazole which acts as a condensing agent.

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DK 152366B

The amide formation reaction by the analogous process of the invention may be carried out in the presence or absence of a solvent. As solvent inert to the reaction may be mentioned alcohols, polyols, benzene, toluene, dioxane, chloroform or diethylene glycol dimethyl ether and xylene.

As a solvent, it is also possible to use an excess of the amine (III) used as a starting material. It may be advantageous to heat the reaction mixture during the amidification reaction, e.g. up to the boiling point of the above solvents.

The compounds of this invention may, 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 give acid addition salts.

The compounds of this invention may also be reacted with C 1-6 alkyl halides or sulphates to produce quaternary ammonium salts if desired.

The compounds may also be oxidized in known manner, e.g. using hydrogen peroxide and manganese dioxide to obtain corresponding N-oxides.

The present intermediates of the invention having the formula II as claimed in claim 2 may be prepared from the corresponding compounds wherein Y is chlorosulfonyl by reaction with ammonia, C1-2 alkylamines, C1-2 dialkylamines, or via the corresponding mercapto and alkylthio compound.

The invention is further illustrated by the following examples.

DK 152366B

EXAMPLE 1 3 5z2§E322 £ 5 5 in £ 7-Chlorosulfonyl 1-1,4-benzodioxane-5-carboxylic acid 670 g of chlorosulfonic acid was poured into a round-bottomed flask equipped with a condenser and a thermometer. 173 g of 1,4-benzodioxane-5-carboxylic acid was added in portions, keeping the temperature at 5-10 ° C. The mixture was heated to 55 ° C and then cooled and poured into ice. The precipitate was filtered off, washed and dried. Clay was obtained 250 g of the above compound, m.p .: 210 - 215 ° C, yield: 93.5 $.

7-methylsulfamoyi-1,4-benzodioxane-5-carboxylic acid (intermediate of the invention) 13995 g of a 40 per cent. aqueous methylamine solution and 139.5 ml of water were added to a round bottom flask equipped with a stirrer and a thermometer, after which 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was added portionwise and a solution of 180 ml of 30 per cent. soda solution in 180 ml of water. The mixture was stirred and poured into 2200 ml of water. The solution was filtered and treated with 139 ml of concentrated hydrochloric acid. The precipitate was filtered off, washed and dried and 190.5 g of the above compound were obtained, mp 208-209 ° C, yield: 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, and then 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was added portionwise. heating to 40-45 ° 0. The mixture was heated. at reflux and then 250 ml of chloroform was added. The precipitate was filtered off and washed with chloroform.

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

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to a 1 liter round bottom flask equipped with a thermometer and a stirrer. 144 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride "were added in portions, maintaining the temperature of 5-10 ° C. Stirring of the mixture was continued for 1 hour, after which the mixture was treated with 1750 ml of water. of chloroform, the mixture was acidified to pH 4 by the addition of 4 ml of 20 per cent sulfuric acid, then filtered through activated carbon. The sulfate solution formed was made alkaline by the addition of 60 ml of 20 per cent ammonia. After crystallization the base was filtered off, washed with water and dried at 40 ° C. After recrystallization from acetonitrile, 134 g of the above compound was obtained, mp 142-145 ° C, yield: 68.7 ° C · NMR spectrum corresponded to the structure indicated.

EXAMPLE 2 N- (2,6-Methyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 209 g 54%. ammonia and 97 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were poured into a round bottom flask equipped with a stirrer and a thermometer at a temperature of 5-10 ° C. The mixture was stirred at room temperature and the precipitate dissolved in 415 ml of water. The solution was filtered and treated with 140 ml of concentrated hydrochloric acid. The crystals were filtered off, washed with water and dried. 78 g of the above product was obtained in a yield of 87 per cent. Melting point: 272 - 274 ° C.

Methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate 429 g of methanol was introduced into a round bottom flask equipped with a condenser, and 54 g of 93 per cent were added under cooling. sulfuric acid and 111 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid. The mixture was heated at reflux and then cooled. The crystals were filtered off, washed with methanol and dried

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was then treated with 500 ml of water and 5 g of sodium carbonate. The precipitate was filtered off, washed with water and dried. 95 g of the above product was obtained with a melting point of 225 -226 ° C, yield 81%.

N- (1-ethyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide 145 gmethyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 81.5 g of 1-ethyl-2-aminomethylpyrrolidine were introduced into a flask equipped with a stirrer and a condenser. The resulting suspension was heated in a water bath until a sample was dissolved in dilute acid. The reaction mixture was added with 1 liter of water and acidified with 70 ml of acetic acid. The acetate solution formed was filtered on activated charcoal and the base precipitated by 20%. ammonia. The crystals were filtered off, washed with water and dried. The benzamide was purified by conversion to the hydrochloride salt, mp 258-240 ° C. The base was precipitated by the addition of 20 per cent. ammonia. 120 g of the above compound with a melting point 160 - 161 ° C and a yield of 61.5 1 ° were obtained.

The NMR spectrum corresponded to the structure indicated.

EXAMPLE 5 N- (1- [ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,1,4-benzodioxane-5β-β-boxamide 7-mercapto-1,4-benzodioxane-5-carboxylic acid 243 g of 7-chlorosulfonyl 1,4-Benzodioxane-5-carboxylic acid and 654 ml of acetic acid were introduced into a flask equipped with stirrer and condenser. The mixture was heated to 90 ° C and cooled to 45 ° C, then 389 g of tin and 1744 ml of hydrochloric acid were added. The mixture was heated to 55 - 60 ° C, cooled and poured into water. The precipitate was filtered off, washed and dried. 166 g of the above product were obtained with a melting point of 191 - 192 ° C and a yield of 90 per cent.

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7-Ethylthio-1,4-benzodioxane-5-carboxylic acid 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 ml of water, 216 ml of soda solution and 181 g of ethyl sulfate were introduced into a flask containing condensers. The mixture was heated at reflux and then cooled. The solution was poured into 1.3 liters of water, filtered off and treated with 110 ml of hydrochloric acid. The precipitate was filtered off, washed with water and dried.

152 g of the above product with a melting point of 153 - 154 ° C in a yield of 81 pot. was achieved.

7-Ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid (intermediate of the invention) 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid and 958 ml of acetic acid were introduced into a flask equipped with a condenser. 398 ml of hydrogen peroxide were added and the mixture heated. The crystals formed by cooling were filtered, washed and dried. 139 g of the above product was obtained with a melting point of 217 - 218 ° C in a yield of 81%.

7-Ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride 243 g of thionyl chloride, some drops of dimethylformamide and 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced into a flask equipped with a condenser. The mixture was heated and excess thionyl chloride was distilled off under vacuum. 148 g of the above product with a melting point of 146 - 147 ° C were obtained in a yield of 100 per cent.

N- (-1-methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 59 g of 1-methyl-2-aminomethylpyrrolidine, 450 ml of chloroform and then in portions 150 g of 7-ethyl sulfonyl-1,4-benzodioxane-5-carbonyl chloride was added to a round bottom flask equipped with a stirrer and thermometer at a temperature of 5-10 ° C. The mixture was stirred for 1 hour at room temperature and 1850 ml of water was added. After distilling off the chloroform, the solution was filtered over activated charcoal and the benzamide precipitated by the addition of 65 ml of soda solution. The solution was filtered, washed with water and dried over

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40 ° C. After recrystallization from absolute alcohol, 151 g of the above product was obtained with a melting point of 140-1410 and in a yield of 80.5 per cent.

The structure was confirmed by NMR spectrum.

EXAMPLE 4-Ill-tert-Yll-gyrrolidylmethyl-5-dimethylsulfamoyl-3-benzodioxane-5-carboxamide 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid (intermediate of the invention) 500 ml of acetone and a solution of 99 g of dimethylamine in 250 ml of acetone was introduced into a 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 room temperature, then the acetone was distilled off and the residue dissolved in 1 liter of water. The solution was made alkaline, filtered and treated with 70 ml of hydrochloric acid. The precipitate was filtered off, washed and dried. 128 g of the above product were obtained with a melting point of 220 - 221 ° C, yield 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 introduced into a flask equipped with a condenser. The mixture was heated and excess thionyl chloride was distilled off. 163 g of the above product was obtained with a melting point of 160-162 ° C, yield 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 introduced into a flask equipped with a stirrer and a thermometer, after which, while maintaining the temperature from 0 to 5 ° 0, 163 ff of 7-dimethylsulfaminyl-1 was added. Æ-benznrH nxane - ^ - narbnnvl p.hl n-

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chloride. The mixture was stirred for 1 hour under which the temperature was allowed to rise and 1 liter of water was added. After distillation of chloroform, the solution was filtered and the carboxamide precipitated by the addition of 30 per cent. soda solution. The crystals were filtered off, washed with water and dried.

After recrystallization from absolute alcohol, 157 g of the above product was obtained in a yield of 76.9 per cent. and with a melting point of 165-166 ° C.

The NMR spectrum corresponded to the structure indicated.

EXAMPLE 5 N- [1-Allyl] - gyrrolidylmethyl ^ - N -sulfamoyl-1'-benzodioxane-S-22ik25§5} id 145 gmethyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g water and 89 g of 1-allyl-2-aminomethylpyrrolidine were introduced into a flask equipped with a condenser. The mixture was heated on a water bath until a sample was obtained. soluble in dilute acid and 1 liter of water was added. The precipitated carboxamide was redissolved by acetate formation. The resulting solution was filtered on activated charcoal and then the base precipitated by the addition of 20 per cent. ammonia. The resulting crystals were filtered off, washed with water and dried and purified by converting the product to the hydrochloride (m.p. 228-230 ° 0) followed by conversion to the base by treatment with 20 per cent. ammonia. 131 g of the above product was obtained with a melting point of 143-144 ° C in a yield of 64.8%.

The structure was confirmed by NMR analysis.

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EXAMPLE 6) 7-Methylsulf amoyl-1β-benzodioxane-1β-1β

Methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate 750 ml of methanol was introduced into a flask fitted with a condenser. 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 to reflux, cooled and poured into water and sodium carbonate. The precipitate was filtered off, washed and dried. 143 g of the above product were obtained with a melting point of 159-160 ° and in a yield of 85%.

N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane 5-carboxamide 1,137 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 43 g of water and 73 g of 1 -ethyl-2-aminomethylpyrrolidine was introduced into a flask equipped with a stirrer and a condenser. The mixture was heated in a water bath until a sample was completely dissolved in dilute acid. The carboxamide formed by cooling was purified by conversion to the acetate and then treated with 100 ml of acetic acid in 950 ml of water. After the resulting solution was filtered on activated charcoal, the base precipitated by the addition of 20 per cent. ammonia. The resulting crystals were dried, washed with water, dried and purified by recrystallization from boiling isopropyl alcohol.

121 g of the above product was obtained in a yield of 66.2 per cent. and had a melting point of 139 - 140 ° 0. The structure was confirmed by NMR analysis. The corresponding hydrochloride was formed by treating the carboxamide with hydrochloric acid (density 1.18) (mp: 186 - 188 ° C).

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EXAMPLE 7 Ϊ222522522ΐ2252_ ~ ί.1ι2552ΐ :: 2ιΕ2222ΐ152 ^225 ^ 2ΐ) ιΖιθ1 ^ 2ΐ81: ι11οη21-1λ1ι52222512522ι5ι2225252215 65 g left in a 1-ethyl-2-aminomethylpyric step with 1-ethyl-2-aminomethylpyric acid. 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 keeping the temperature of 5-10 ° C. After the addition of this product, the mixture was stirred for 1 hour and treated with 1 liter of water. After chloroform distillation, the solution was filtered on activated charcoal and the base precipitated at an excess of 30 per cent. soda. The resulting crystals were filtered off, washed with water, dried and recrystallized from isopropyl alcohol. 151.5 g of the above product were obtained in a yield of 77.7 per cent; mp: 111-112 ° C); (a) + = -54.2 ° (in solution in dimethylformamide).

EXAMPLE 8 5222252212252-5 :: 11 :: 2552111 :: 22222115212255212 :: 2 :: 255212215222111.11- 5222 ° 512522z5zc§rboxamide In a similar manner to Example 7, 64.5 g of right-turning l-ethyl-2-aminomethylpyrrolidine was reacted with 146 g -ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give after treatment and purification of 133.5 g of the above product with a melting point of 111 - 112 ° C and a yield of 69.8%. (a) + = 55.5 ° (in 5% solution in dimethylformamide).

EXAMPLE 9 N- (1-Ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,1,4-benzodioxane-5z2a25052m11 In a similar manner to Example 7, 58 µl of 1-ethyl-2-amino-methylpyrrolidine was reacted with 131 g of 7-ethylsulfonyl l, 4-benzodioxan-5-carboxylic

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bonyl chloride to obtain after treatment and purification of 103.5 g of the above product in a yield of 60.2 per cent. and with a melting point of 118 - 119 ° C. 100 g of the product was dissolved in 220 ml of acetone and the solution was filtered on activated charcoal and a solution of 9.5 g of hydrochloric acid in acetone was added. The resulting hydrochloride was filtered off, washed with acetone and dried. 96 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride were obtained, m.p. 148-150 ° C and in 88.2% yield. .

EXAMPLE 10 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 introduced into a flask equipped with a condenser. The mixture was heated on a water bath until a sample was completely dissolved in dilute acid. The carboxamide formed by cooling was purified and treated with a solution of 50 ml of acetic acid in 1250 ml of water. After the resulting solution was filtered on activated charcoal, the base precipitated by the addition of 20 per cent. ammonia. The resulting crystals were filtered off, washed with water, dried and purified by recrystallization from boiling methyl alcohol. 119.5 g of the above product was obtained in a yield of 70.1 per cent. and with a melting point of 187-188 ° C.

EXAMPLE 11 N- (1-Allyl-β-pyrrolidylmethyl-β-ethylsulfonyl-1β-benzodioxane-β-carb2xamide 58 g of 1-allyl-2-aminomethylpyrrolidine and 360 ml of chloroform were introduced into a flask with a stirrer and a thermometer, after which 120 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were added while maintaining the temperature of 5-10 ° C. After stirring the mixture and adding 1 liter of water, the chloroform was distilled off. Bone obtained solution was filtered on activated charcoal,

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and then the phase precipitated by the addition of 40 ml of 30 per cent. soda solution. The resulting crystals were filtered off, washed with water and dried. 152 g of the above product were obtained with a yield of 93.4%, m.p. 78-80 ° 0. 146 g of the resulting base was dissolved in 290 ml of warm absolute alcohol and then the solution was filtered on activated charcoal and acidified by adding a solution of 13.5 g of hydrochloric acid in 100 ml of absolute alcohol. After cooling, the crystals were filtered off, washed with absolute alcohol and dried, then purified by recrystallization from absolute alcohol. 119.5 g of N- (1-allyl-2-pyrrolidylmethyl) -7-ethylsulfony-1, 1,4-benzodioxane-5-carboxamide, hydrochloride having a melting point of 138-140 ° O were obtained and in a yield of 75 per cent.

EXAMPLE 12 5-Carb2xamide 169 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a condenser flask.

The mixture was heated on a water bath until a sample was completely soluble in dilute acid. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1250 ml of water and the solution was filtered over activated charcoal and the base was re-precipitated by the addition of 100 ml of 20 per cent. ammonia. The crystals were filtered off, washed with water and dried. 182 g of the above product was obtained in a yield of 83.6 per cent, m.p .: 189 - 190 ° C.

EXAMPLE 13 N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,2,4-benzo dioxane-5-cartoxamide 13 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of tetrahydrofuran and 13 g of carbonyl diimidazole were introduced into a flask equipped with a stirrer, a thermometer and a condenser. The mixture was stirred

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at room temperature and 9.5 g of 1-ethyl-2-aminomethyl-pyrrolidine were added. Stirring was carried out at room temperature and then the solvent was evaporated under vacuum. The crystals formed were washed with water and dried. 14 g of the above product were obtained in a yield of 75.8 pot. M.p .: 118-199 ° C.

EXAMPLE 14 N- (1-methyl-5-pyrrolidylmethyl-T-dimethylsulfamoyl-1'-henzo-dioxane - ^ - carhoxamide

A solution of 6 g of 1-methyl-2-aminomethylpyrrolidine in pyridine was added dropwise with stirring at a temperature of 0 - 5UC to a solution of 3.5 g of phosphorus trichloride in 20 ml of pyridine and the whole was in a flask equipped with a stirrer. thermometer and a condenser. Stirring was continued at a temperature of from 0 to 5 ° C, and then the temperature rose to room temperature. 14.5 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were 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 the above product was formed in a yield of 64.5%, m.p .: 165-166 ° C.

EXAMPLE 15 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 introduced into a flask equipped with a stirrer and a thermometer. After stirring the mixture, the base was extracted with methylene chloride and the solvent was evaporated. The crystals formed were dissolved in boiling absolute alcohol and the resulting solution was filtered on activated charcoal. The crystals formed by cooling were dissolved in a solution of acetic acid in water, after which the solution was filtered over activated carbon, and

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the base was re-precipitated by the addition of 20 per cent. ammonia. 129.5 g of the above product was obtained in a yield of 61.2 per cent, with a melting point of 160 - 161 ° C.

EXAMPLE 16 IsillaziZizarEHSHiiiiiSiiiiZiizirrii iiiZisulfamoyl-Iji ^ -benzodioxane-5-carboxyamide 64 g of 1-ethyl-2-aminomethylpyrrolidine and 530 ml of chloroform are introduced into a flask with a stirrer, a thermometer and a thermometer, was maintained at 0 to 5 ° C, with 153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride added. The mixture was stirred for one hour, then the temperature was allowed to rise and 1 liter of water was added. After distillation of chloroform, the solution was filtered and the carboxamide precipitated by the addition of 30 per cent. soda. The crystals formed were filtered off, washed and dried. After recrystallization from absolute alcohol, 144> 5 g of the above product was obtained in a yield of 72.8%, mp 146-148 ° C.

EXAMPLE 17 High-end N-1-ethyl-2-pyrrolidylmethyl 2-7-methylsilphamoyllizil2S52Ei22§: 5-carboxamide 82 g of right-turn 1-ethyl-2-aminomethylpyrrolidine, 600 ml of chloroform was introduced into a flask with a flask equipped with a flask equipped with a stirrer. . At 5 ° 10 ° O, 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was gradually added.

After adding one liter of water, the chloroform was distilled off and the remaining solution was filtered. The base was precipitated by the addition of 60 ml of 20%. ammonia. The crystals formed were filtered off, washed with water and dried. 162 g of the above product was obtained in a yield of 66 per cent. and with a melting point of 136 - 137 ° C.

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EXAMPLE 18 Y§2§Three_N = a = ethyl = 2 = 2yrrolidylmethyl2i7-methylsulfamoyl-1 in 4-¾ and zo di o xan-5 - c ar bo xami d In a similar manner to Example 17, 82 g of left-turn 1 were reacted. -ethyl-2-aminomethylpyrrolidine with 195 g of 7-methylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give 151 g of the above product in a yield of 62 pot, m.p. 136-137 ° C .

EXAMPLE 19

Left-N-1-allyl-2-gyrrolidylmethyl] -37-methylsulf amoyllic acid §5 52Ei22§Bl5-carboxamide 85 g of left-turning l-allyl-2-aminomethylpyrrolidine and 610 mq chloroform were introduced into a flask and a flask provided and thermometer. Per, 178 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were gradually added at 5-10 ° C. After stirring the mixture, 1.2 liters of water were added and the chloroform distilled off. Pen-obtained solution was filtered off and the base precipitated by the addition of 70 ml of 20 pot. ammonia. Pe crystals formed were filtered off and washed with water. After recrystallization from ethyl acetate, 117 g of the above product was obtained in a yield of 49 per cent. with a melting point of 101-102 ° C.

EXAMPLE 20 High-Red End_N- {l_ = allYl-2-pyrr2lidyllmethyl 2-7-methylsulfamoyllil 2B222i25§Bi2z22E ^ 222; Si2 with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give after purification of 125 g of the above product in a yield of 52.6%, m.p .: 104-105 ° C.

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EXAMPLE 21 High Reduction_N - (1-2-Etl2l32-22 ££ 2li§2l5®iii2i2lIz5®i ^ 2l2HiÉSS2Zl 1 £ 4-benzodioxane-5-carboxamide 61 g of right-turn 1-methyl-2-aminomethylpyrrolidine, 465 ml Into a flask equipped with stirrer and thermometer, then portionwise while maintaining the temperature of 5-10 ° C 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride After stirring the mixture and adding 1850 ml of water the chloroform was distilled off and the resulting solution was filtered.

The base was precipitated by the addition of 65 ml of 20 per cent. ammonia. The crystals formed were filtered off, washed and dried. 154 g of the above product was obtained in a yield of 78.5%, mp 187-188 ° C.

EXAMPLE 22 Yin Threatened End ^ N- ^ Zmethyl ^ - Pyrrolidylmethyl ^ - J -methylsulfamoyl-1 '] 2e222 £ 22 £ 22z5' Carboxamide In a similar manner to Example 21, 71 g of left-hand end 1-methyl-2-aminomethylpyrrolidine was reacted with 180 g of 7-methylsulfamoyl-1,4-benzodi-oxane-5-carbonyl chloride to give 175 g of the above product in a yield of 77 per cent, m.p. 187 - 187.5 ° C.

EXAMPLE 23 N- (1-Ethyl-g-pyrrolidylmethyl-5-methylsulfamoyl-gH-J 1 -dihydro-1 ± 5ζζ 2ϋ22 ^ 252ΕΕ 2ΐ§ΐ22 £222: 2ΐ§

Methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate 111 g of methyl 2,3-dihydroxybenzoate, 660 ml of methyl ethyl ketone, 167 g of 1,3-dibromopropane and 10 g of sodium iodide were introduced into a flask equipped with a stirrer and a thermometer. The mixture was heated to 40 ° G and then 182 g of potassium carbonate was added. The mixture was heated to reflux and 2 liters of water was added

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added. The oil phase was extracted with ether and the solution washed with 10 per cent. soda and dried. The ether was removed by distillation in vacuo to give 86.5 g of the above compound, boiling point 166 - 176 ° C under 8 mmHg, yield 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 ml of soda were introduced into a flask fitted with a condenser . The mixture was heated at reflux and poured into one liter of water and treated with 5 g of sodium metabisulphite. The solution was filtered and treated with 77 ml of concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried. 120 g of the above product were obtained with a melting point of 67 - 65 ° C, yield 80.5 per cent.

8-Chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxenine-6-carboxylic acid 1092 ml of chlorosulfonic acid was introduced into a flask equipped with a stirrer, a condenser and a thermometer, and then 106 g of 2H-3,4-dihydro was added portionwise. -1,5-benzodioxepine-6-carboxylic acid, keeping the temperature at 5-10 ° C. The mixture was stirred at room temperature and poured on ice. The crystals were filtered off, washed with water and dried. 146 g of the above product was obtained in a yield of 91 per cent. and with a melting point of 114-115 ° C.

8-methylsulfamoyl-2H-5,4-dihydro-1,5-benzodioxenine-6-carboxylic acid 233 g of an aqueous methylamine solution was introduced into a flask equipped with a stirrer and a thermometer, and then 146 g of 8-chlorosulfonyl-2H was added portionwise. -3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid, maintaining the temperature of 5-10 ° C. The mixture was stirred and the precipitate dissolved in water. The solution was filtered and treated with 150 ml of concentrated hydrochloric acid. The crystals were filtered off and washed and dried. 112 g of the above product was obtained in a yield of 78 per cent. and with a melting point of 145-146 ° C.

i «DK 152366 B

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 introduced into a flask. provided with a condenser. The mixture was heated, after which excess thionyl chloride was distilled off under vacuum. 188 g of the above product was obtained in a yield of 100 per cent. and with a melting point of 93-94 ° C.

N- (1-ethyl-2-pyrrolidylmethyl) -8-methylsulfamoyl-2H-5,4-dihydro-1,5-benzodioxepine-6-carboxamide 79 g of 1-ethyl-2-aminomethyl-pyrrolidine, 750 ml of methyl ethyl ketone and 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-dibenzodioxepine-6-carbonyl chloride was introduced into a flask equipped with a stirrer and a thermometer, keeping the temperature from 5 to 10 ° C.

The hydrochloride which precipitated was filtered off, washed with methyl ethyl ketone and dried.

After recrystallization from methyl alcohol, the hydrochloride was dissolved in 850 ml of water. The solution was filtered off and the base precipitated by the addition of 60 ml of 20 per cent. ammonia. The crystals formed were filtered off, washed with water and dried. 180 g of the above product was obtained in a yield of 63.8%, mp 144-145 ° 0.

EXAMPLE 24 5-Ca, Ribosamino Plia. 7-Diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid (intermediate of the invention) 200 ml of water, 100 ml of diethylamine and 200 ml of triethylamine were introduced into a flask fitted with a flask. stirrer and a thermometer, after which 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was added portionwise, keeping the temperature between 20 and 30 ° C. Bian-

19 DK 152366 B

The mixture was stirred at room temperature and 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 the above compound was obtained in a yield of 74 per cent. and with a melting point of 149 ° C.

N- (1-benzyl-2-pyrrolidylmethyl) -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 introduced into a flask equipped with a stirrer and a thermometer, after which 17.2 g of isobutyl chloroformate was added at a temperature of 15 to 20 ° C.

After stirring the mixture, 25 g of 1-benzyl-2-aminomethyl-pyrrolidine was added, maintaining the temperature of 15-20 °.

The mixture was stirred at room temperature and then the solvent was 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 off and the solvent removed. Bone obtained compound was dissolved in boiling ethanol and 18 g of 85 per cent. phosphoric acid was added. The crystals formed by cooling were filtered off, washed with ice-cold ethanol and dried. 56 g of the above compound was obtained with a yield of 79.6 per cent. with a melting point of 180 ° C.

EXAMPLE 25] IIl2S2] 2Yll2 :: 2Y2 E2lidylmethyl ^ S-ethylsulfonyl- ^ H ^ S ^ -dihydro-1 ^ S ^ benzodioxepine-G-carboxamide 8 Hydrochloride 8-mercapto-2H-5,4-dihydro-1 , 5-benzodioxepin-6-oarboxvlsyre

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 introduced into a flask equipped with a stirrer and a thermometer. The mixtures

20 DK 152366 B

Gene was stirred under 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 the above compound was obtained in a yield of 80 per cent. with a melting point of 99.5 - 100 ° 0.

8-Ethylthio-2H-5,4-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 and 58.5 g of ethyl sulfate were introduced into a flask fitted with a condenser. The mixture was heated to reflux and then cooled. 150 ml of water was added, then the solution was filtered off and treated with 60 ml of hydrochloric acid. The precipitate was filtered off, washed and dried.

88 g of the above product was obtained in a yield of 91 per cent. with a melting point of 66 - 67 ° C.

8-Ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (intermediate of the invention) 88 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzo di oxepin-6 carboxylic acid in 528 ml of acetic acid was introduced into a flask equipped with a condenser. Then 210 ml of hydrogen peroxide was added portionwise. 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. 90 g of the above product was obtained in a yield of 91%. and a melting point of 142 - 143 ° C.

8-ethylsulfonyl-2H-5,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride 75 g of thionyl chloride and 90 g of 8-ethylsylphonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were introduced into a flask provided with a condenser. The mixture was heated to 45-50 ° C and the excess thionyl chloride removed in vacuo. The residue was treated with petroleum ether, then filtered off, washed and dried.

94 g of the above product was obtained in a yield of 98 per cent. with a melting point of 108-110 ° C.

21 DK 152366 B

N- (1-ethyl-2-pyrrolidylmethyl) -8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide hydrochloride 39.5 g of 1-ethyl-2-aminomethylpyrrolidine in 282 ml of chloroform was introduced into a flask equipped with a stirrer and a thermometer. Then, 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxe-pin-6-carbonyl chloride was added portionwise to the flask, keeping the temperature from 5 to 10 ° C. The mixture was heated and poured into water. The aqueous phase was cooled, filtered and treated with 30 ml of soda. The precipitate was extracted with methylene chloride and the organic phase was dried over potassium carbonate. The solvent was distilled off, the residue was 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 the above product was obtained in a yield of 73 per cent. and with a melting point of 141 - 142 ° C.

The compounds prepared in the examples above are summarized in Table I.

22

DK 152366 B

TABLE I

Ex. Y m - (CHO) -F I R

2 nvi 1 SC 3 NHCH 2 2-pyrrolidylmethyl C 1-6 C 2 Cl 2 SC 3 N 1 2 2-pyrrolidylmethyl 2 2 5 3 SO 2 C 2 H 2 2-pyrrolidylmethyl CH 2 SO 4 N (CH 3) 2 2 2-pyrrolidylmethyl CH3 5 SC ^ NE ^ 2 2-pyrrolidylmethyl CE ^ -CHK ^ 6 SO2 NHCH3 2 2-pyrrolidylmethyl C2H5 7 (L) SO2C2H3 2 2-pyrrolidylmethyl ^ 2 ^ 5 8 (D) SO2C2H5 2 2-pyrrolidylmethyl C2H5 9 (R) SC > 2C2H3 2 2-pyrrolidylmethyl 2H5 SO2NH2 2 2-pyrrolidylmethyl CH3 11 SO2C2Ht-2 2-pyrrolidylmethyl CH2 -CH = CH212 SC ^ NHCH2-2-pyrrolidylmethyl CH3 13 ®0202 ^ 5 2 2-pyrrolidylmethyl C2H5 CH 3) 2 2 2-pyrrolidylmethyl CH 3 SO 2 NHCH 3 2 3-pyrrolidyl cyclohexyl 16 SO 2 N (CH 3) 2 2 2-pyrrolidylmethyl C 2 H 5 17 (D) SO 2 NHCH 3 2 2-pyrrolidylmethyl C 2 H 5 18 (L) SO 2 SC> 2NHCH3 2 2-pyrrolidylmethyl CH2-CH = CH2 20 (D) SO2NHCH3 2 2-pyrrolidylmethyl CH2-CH = CH2 21 (D) SC> 2NHCH3 2 2-pyrrolidylmethyl CH3 22 (L) SO2NHCH3 2 2-pyrrolidylmethyl CH3 23 SO2 3 2-pyrrolidylmethyl C2H5 24 SO2N (C2H, -) 2 2 2-pyrrolidylmethyl benzyl SO2C2H5 3 2-pyrrolidylmethyl C2H5 23

DK 152366B

The present compounds may be used in various forms, such as capsules, tablets, pills, granules, injectable solutions. The preparation of these is known per se. Compounds that do not react with the active compounds can be used, e.g. lactose, magnesium stearate, starch, talc, cellulose, levilite, alkali metal lauryl sulfonates, sucrose and other carriers used in the pharmaceutical industry.

The subject compounds may be administered in doses of 50 - 900 mg / day. It is advantageous to use 50-300 mg / day and preferably 100-150 mg / day.

Tablets can be prepared by mixing the selected compound with starch and lactose by successive dilution. Granules can be prepared from the mixture and methyl cellulose. Levilite, magnesium stearate and talc are added to the granulate prior to compression. Methyl cellulose can be replaced with any suitable granulating agent such as ethyl cellulose, polyvinylpyrrolidone, starch paste, gum arabic, etc.

Starch may also be replaced by other agents such as corn starch, carboxymethylamyloids, alginates, microcrystalline cellulose, etc.

Injectable solutions can be prepared by dissolving one of the compounds of the following acids: hydrochloric acid, levulinic acid, gluconic acid or glucoheptonic acid. The solution is prepared under sterile conditions and made isotonic with alkali metal chloride, such as sodium chloride, and then preservatives are added.

The same solution can be prepared without preservatives, i.e. The vial is filled under a nitrogen atmosphere and sterilized for half an hour at 100 ° C.

The present compounds exhibit valuable attractive anxiolytic, psychostimulatory, disinhibitory and thymoanaleptic 24

DK 152366B

effects, making them suitable for therapeutic use in the psychofunctional sphere and especially in the gastroenterology, cardiology, urology, rheumatology and gynecology.

Their low toxicity makes them useful in human therapy without the risk of side effects.

The acute toxicity LDcn of the compounds of the invention determined

SU

in Swiss mice by parenteral (intravenous, intraperitoneal and subcutaneous) as well as by oral administration is shown in Table II. .

The numbering of the compounds in the following tables corresponds to the example number. In comparison, toxicity data for the two compounds are disclosed in U.S. Pat.

3,370,066, namely N-diethylaminoethyl-2-methoxy-3,4-methylene-dioxy-benzamide (Example 1) and N-diethylaminoethyl-2-methoxy-4,5-methylenedioxy-benzamide (Example 2).

The table shows that the known compounds are significantly more toxic than those disclosed herein.

DK 152366 B

TABLE II TOXICITY

Combine DL 50-Mice mg / kg (base)

Part IV IP SC PO

Ϊ 171.5 - 172 522 - 540 1344 - 1440 3515 - 3690 2 48 - 49.6 312 - 320 594 - 624 0% v.3O0O mg / kg 3 120 - 120.4 300 - 315 700 - 752 1568 - 1680 4 220.8 - 225.6 462 - 480 1300 - 1440 2755 -2900 5 96.6 - 100 555 - 567 0% v.1200 mg / kg 0% v.6000 mg / kg 6 84.6 - 90 322 - 328 1450 - 1485 35% v.2000 mg / kg 7 150 - 157.5 350 - 363 1260 - 1360 8 168 - 184 442 - 450 9 147 - 154 480 1225 - 1230 1400 - 1470 ID 64 - 67.5 234 - 240 430 - 437 O% v.3000 mg / kg Π 146 - 157 325 - 338 420 - 442 2900 - 3491 12 88 - 96 380 - 396 925 - 1014 2760 - 2900 Ϊ5 72.5 - 76 180 - 184.5 476 - 499.5 1190 - 1200 16 196 - 208 429 - 448 1540 - 1560 2001 - 2100 17 83.6 - 86 408 - 414 1000 - 1014 1748 - 1804 1158 115.5 - 126 325 - 350 1238 - 1320 2328 - 2440 219 216 - 232 465 - 494 1900 - 1980 3840 - 3850 20 160 - 168 510 - 555 1320 - 1428 2460 - 2610 21 105 - 116 441 - 480 ΪΪ25 10% v.3000 mg / kg 22 80 - 83.6 288 - 297 1092 - 1107 2100 23 l4l - 154 387.5 - 418 1620 - 1850 2100 - 2400 24 38 - 39.1 205 - 208 422 ^ 450 342 - 343 25 160 - 164 359 - 363 916 - 928 1154 - 1245 ^! Rilgn1 35 70 170

Ex. 2 2 49 “55 99-106 114 - 116 199 - 218

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26

Furthermore, the compounds of the present invention are substantially free of cataleptic action. They were administered subcutaneously in rats. The criterion for the cataleptic condition was the immobility of the animal for 30 seconds when the forelegs of the animal were spread apart and placed gently on wooden blocks 4 cm high, bringing the animal into an unusual and uncomfortable situation. The catalytic effect was measured by the maximum effect. The result is shown in Table III, from which it is seen that the known compounds exhibit some cataleptic effect at substantially lower doses.

TABLE · III

Cataleptic effect

Compound DE 50 SC - Rat - mg / kg 1 40% effect at 200 mg / kg 2 Inactive at 200 mg / kg 3 325 4 30% effect at 200 mg / kg 5 Inactive at 200 mg / kg 6 10% effect at 200 mg / kg 7 Inactive at 200 mg / kg 8 Inactive at 200 mg / kg 9 Inactive at 200 mg / kg 10 Inactive at 200 mg / kg 11 10% effect at 200 mg / kg 12 Inactive at 200 mg / kg 15 Inactive at 200 mg / kg 16 Inactive at 200 mg / kg 19 30% effect at 200 mg / kg 20 Inactive at 200 mg / kg 23 Inactive at 200 mg / kg

Ex. 1 (flush) 20% effect at 50 mg / kg

Ex. 2 (smign) 20% effect at 50 mg / kg

From these results it can be seen that the compounds of this invention are essentially free of cataleptic action in rats.

This feature makes it possible to use the present compounds.

DK 152366 B

27 clinical trials with a high tolerance to the extrapyramidal system.

The compounds of the present invention have also been found to be particularly active on dogs against central emetic agents such as apo-morphine. The experimental procedure followed was the method described by Chen and Ensor. The subject compounds were administered subcutaneously 30 minutes before apomorphine (100 µg / kg / SC). The animal was observed half an hour after the injection of apomorphine.

The results are set forth in Table IV, compared to the two known compounds of U.S. Patent No. 3,370,066.

Furthermore, therapeutic indices have been calculated from the toxicity data listed in Table II.

28 DK 152366 B

TABLE IV

Conn. DE, -nantiemethi so-called DL-nIV DUnSC

fBg / ks / s.c.i _5L_ _J £ _

DE50SC DE50SC

_ 3 570 x 10 ^ 464 x "10 * 2 675 75 x 102 93 x 103 3 575 2lS X 10έ 132 x 10 * 4 Ϊ0 223 x Ϊ02 137 x lO3 5 Ϊ6 61 x 102> 75 x 10s 6 Ϊ75 580 x 102 978 χ 103 _ _ 765 x 10 * —g 40 44 x Ϊ02 - 375 428 x 102 350 x 103 _ 72 x 102 48 x 103 Π 379 387 x 102 110 x 103: 272 273 400 x 102 420 x 103 15 375 20STP 139 x 103 _ _ 505 χ "Ίθέ 387 x 10 * —Ϊ7 Ϊ2 70" X Ϊ0 * 84 x ΙΟ3 18 Π5 800 χ ΙΟ2 850 χ ΙΟ3 __ _ 2240 χ ΙΟ2 1940 χ ΙΟ3 20 ΪΟ 164 χ 10 * 137 χ ΙΟ3 i

29 DK 152366B

TABLE IV (continued)

FOR 'DE% gAg /? C) 1Sk' DL50SC

DE50SC DE50SC

2x 22 50 x 102 51 x 103 _ _ 405 x 10 * 550 x 103 23 475 326 x 10 * 385 x 103 ^ 24 973 4Ϊ x 102 25 5 324 x 102 J.S. 3370066 _ (smlan) ___: Ex. 1 18.5 19 x 102: "Ex. 2 240 2 x 102 0.5 x 103

It is clear from the table that the compounds of the present invention exhibit a stronger antiemetic effect (lower DE, _q) and an improved therapeutic index over the known compounds.

The interesting experimental data obtained from performing laboratory-scale experiments on animals have been found to hold when human clinical trials of the compounds are performed. In this connection, the following may be cited as an example:

A 38-year-old patient suffered from Hodgkin's disease. The patient was repeatedly treated with chemotherapy once a week.

Each treatment was accompanied by bouts of nausea and very vomiting that lasted for 24 hours despite the usual treatments.

30

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Treatment 24 hours before the onset of perfusion and 4 hours after with 50 mg of N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfonamyl-1,4-benzodioxane-5-carboxamide completely suppressed nausea and vomiting experiments. The compound was perfectly tolerated and no side effects were observed.

A 28-year-old patient suffered from a distinctive neurosis with anxiety attacks, culminating in three attempted suicides. Analytical treatment for 18 months made it possible to achieve social reintegration but had little effect on the anxiety aspect.

Administration of 50 mg of N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4'-benzodioxane-5-carboxamide three times daily caused any anxiety to disappear within a few days without any sedative effect. The compound was perfectly tolerated and no side effects were observed.

For eight months, a 78-year-old patient suffered from a severe depression (death in the immediate family). The existence of a prostatic adenoma contraindicated the use of tricyclic agents.

The patient was treated three times daily with 50 mg of N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, and in three weeks his condition was significantly improved so that he could leave. the hospital. The treatment, which was continued at home for 3 months, allowed an excellent mental balance to be maintained and the patient could resume normal activity for a person of this age. The compound was perfectly tolerated and no side effects were observed.

A 42-year-old patient had had a hysterectomy for a fibroma 6 months earlier. A few days after surgery, heath attacks (10-20 a day) occurred with sweat attacks that woke the patient at night and caused discomfort at work.

She was treated with N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsul-famoyl-1,4-benzodioxane ~ 5-carboxamide at a single dose of 100 mg / day and the symptoms disappeared within 4 days. Only

Claims (2)

An analogous process for the preparation of racemic or optically active substituted 2,3-alkylene bis (oxy) benzamides of the general formula CONH (CHO) + T in which n is 0 or 1, m is 2 or 3, R represents C C2 alkyl, allyl, cyclohexyl or benzyl, Y represents sulfamoyl, C1-2 alkylsulfamoyl, C1-2 dialkylsulfamoyl or C1-2 alkylsulfonyl, DK 152366 B or their acid addition salts with pharmacologically acceptable acids, quaternary ammonium salts or C1-2 alkyl halides or N-oxides, characterized by reacting a 2,3-alkylene-bis (oxy) benzoic acid derivative of the general formula COD JUL / + wherein Y and m are as defined above and D is halogen, hydroxy or alkoxy , with an amine of the general formula: H2N - <CH2) n -II \ / (III) NR wherein n and R are as defined above, optionally in the presence of an alkyl haloformate, a carbonyl diimidazole or a phosphorus halide to which if desired, a formed compound transfers into an acid addition salt or quaternary ammonium salt of the kind specified in the preamble of the claim or an N-oxide. Substituted 2,3-alkylene-bis (oxy) benzoic acids for use as intermediates in the process of claim 1, characterized in that they have the general formula COOH ArA X. X r >>. wherein m and Y are as defined in claim 1.