FI63938B - FRAMEWORK FOR THE FRAMEWORK OF THERAPEUTIC ANALYTICAL SUBSTITUTES OF 2,3-ALKYLENBIS (OXI) BENZENIDE - Google Patents

Abstract

2,3-Alkylenedioxybenzamides of formula (I) and their acid -addn. salts, quat. ammonium salts, oxides and optical isomers are new. In (I), A is 1-3C alkylene opt. substd by 1-4C alkyl, 2-4C alkenyl or 1-4C hydroxyalkyl. R is H, 1-4C alkyl or -B-NR1R2; B is a direct bond or a 1-3C alkylene gp. opt. substd. by 1-4C alkyl or 2-4C alkenyl; R1 is H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, substd. alkyl, or forms a heterocyclic ring with B, and R2 is H, 1-4C alkyl, 2-4C alkenyl or alkynyl, substd. alkyl, an opt. substd. heterocyclic gp., or a phenyl, adamantyl, cycloalkyl, bicycloalkyl or cycloalkenyl gp. bonded directly to the N atom or via an opt. substd. alkylene chain, or NR1R2 is a heterocycle opt. contg. other heteroatoms (including NR'', where R'' is H- 1-4C alkyl, 2-4C alkenyl or alkynyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, adamantyl, bicycloalkyl or alkyl substd by OH, SH, acyl, thioacyl, alkoxy or alkylthio). - R' is H, 1-4c alkyl, 2-4C alkenyl or alkynyl, adamantyl, pyrimidinyl, pyrazinyl, diazepinyl, quinuclidinyl, azabicycloalkyl, diazabicycloalkyl, bicycloalkyl, or opt. substd. phenyl or aralkyl, or R'+B forms an opt. substd. heterocycle contg. a single N atom, or R'+R1 forms an opt. substd. heterocycle contg. two heteroatoms, X is H, halogen, OH, 1-4C alkoxy, 1-4C alkyl, amino opt. mono- or disubstd. by 1-4C alkyl, acyl, aralkyl, furyl, pyranyl or alkoxycacarbonyl, or forms an A' chain with Y. Y is as defined for X or is NO2, 1-4C alkylsulphonyl, adamantyl-sulphonyl, cycloalkyl sulphonyl or SO2NR3R'; R3 and R4 are H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, bicycloalkyl, adamantyl, pyrimidinyl, pyrazinyl, or alkyl substd. by OH, SH, acyl, thioacyl, alkoxy or alkylthio, or NR3R4 is an opt. substd. heterocycle opt. congt. another heteroatom; or Y forms an A chain with X or Z. Z is as defined for X or is NO2, or forms an A chain with Y. A is a carbon chain opt. substd. or opt. interrupted by one or more opt. substd. heteroatoms. - Cpds. (I) have anxiolytic, antidepressant and antiemetic activity with little or no cataleptic activity. A typical cpd. of N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1, 4-benzodioxan-5-carboxamide. In an example, this is prepd. from 1,4-benzodioxan-5-carboxylic acid.

Description

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France-Frankrike (FR) 7623835 (71) Socilte d'fitudes Scientifiques et Industrielles de 1'Ile-de-France, 46, Boulevard de Latour-Maubourg, 753 ^ 0 Paris Cedex 07, France-Frankrike (FR) (72) Michel Thominet, Paris, Gerard Bulteau, Paris, Jacques Acher,

Itteville, Claude Collignon, Saint Remy Les Chevreuse, France-France (FR) (74) Oy Kolster Ab (54) Process for the preparation of new therapeutically useful substituted 2,3-alkylenebis (oxy) benzamides - Förfarande för framställning avnya terapeutiskt användbara, This invention relates to the preparation of novel substituted 2,3-alkylenebis (oxy) benzamides, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts, their oxides, their dextrorotatory and levorotatory isomers. .

More particularly, the invention relates to a process for the preparation of novel therapeutically useful substituted 2,3-alkylenebis (oxy) benzamides of the formula 63938 2

CONH- (CHn) C

AR (I) x of 2 n yV wherein A is an alkylene group having 1 to 3 carbon atoms, n is 0 or 1, R is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyl group or a cycloacyl group, X is a hydrogen atom or an alkoxy, nitro, amino or acetamino group, Y is a hydrogen or halogen atom or a sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl or alkylsulfonyl or X and Y together form an azimido group, Z is a hydrogen or halogen atom or Y and Z together form an azimido group .

U.S. Pat. No. 2,688,026 discloses 3,4-methylene-bis (oxy) benzamides which are useful as antihypertensive and diuretic drugs. FR-A-8245 M discloses 2,3-alkylenebis (oxy) benzamides which do not, however, contain a pyrrolidine ring as in the 2,3-alkylenebis (oxy) benzamides of formula (I) according to the invention, and in addition the known compounds are useful as anti-inflammatory, antipyretic and as analgesic agents, while the compounds of the invention are used as anxiolytics, psychostimulants and thymoleptics.

The invention is characterized in that the compound of formula

COD

A (III) ai x

X

wherein A, X, Y and Z have the same meaning as above and D is a hydroxy group, a halogen atom or an organic radical, is reacted with a compound of formula (IV) or a reactive derivative thereof 3 63938

NH 2 - (CHO) -P

2 2 n IT J (IV)

R

where R and n have the same meaning as above.

Suitable organic residues for the starting material III are those which form reactive acid derivatives.

These may be lower alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or isopentyl esters, reactive acid esters such as methoxymethyl esters, cyanomethyl esters, substituted or unsubstituted aromatics. N-hydroxyimide esters, acid azides, acid hydrazides, symmetrical anhydrides, mixed anhydrides such as those formed from carboxylic acid esters and halogenated other acid esters of azalithioate substitutes, azolides such as triazolides, tetrazoleides, and especially benzamides which are ring-substituted or other equivalents or a compound of the following general formula coo-c = ch-co-nh-c2h5

Y - s *. J-SO 3 H

I 0

X

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

14 63938

In the process of the invention, the amine may react in the form of its reactive derivative. Examples which may be mentioned are the reaction products between phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl or orthophenylene chlorophosphites or alkyl or aryl dichlorophosphites and an amine, or an amine isocyanate or any other equivalent or ammetric or amine symmetric or asymmetric sulfamides of the amine.

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

In addition, it is possible to carry out the reaction between the free acid and the free amine in the presence of a condensing reagent such as silicon tetrachloride, phosphoric anhydride or carbodiimide such as dicyclohexylcarbodiimide or alkoxyacetylenes such as methoxy or ethoxyacetylene.

In preparing the novel compounds according to the invention, it is highly preferable to use an acid halide when preparing compounds whose benzene ring is unsubstituted, compounds having a benzene ring monosubstituted by a halogen atom, a nitro group, an alkylsulfonyl group or an amino group, alkyl esters, activated acid esters, whose benzene ring is monosubstituted with a hydroxy group or an alkylsulfonyl group, compounds in which X and Y or Y and Z are joined together as an azimido group in the reaction of mixed anhydrides (formed in situ with benzoic acid starting material and a halogen formic acid ester, preferably chloroformic acid ester), preferably chlorine having a nitro group or an acetamino group as a monosubstitute.

The amidation reaction according to the invention can be carried out in the presence or absence of a solvent. Suitable inert solvents include, for example, alcohols, polyols, benzene, toluene, dioxane, chloroform, diethylene glycol, dimethyl ether and xylene. An excess of the starting amine can also be used as the solvent. During the amidation reaction, it may be advantageous to heat the reaction mixture to the boiling points of the above-mentioned solvents.

The compound prepared by the process of the invention may, if necessary, be reacted with a pharmaceutically acceptable organic or inorganic acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, acetic, tartaric, citric or methanesulfonic acid to form acid addition salts.

If necessary, the compound can also be reacted with alkyl halides or sulfates to give quaternary ammonium salts.

The compound can also be oxidized by known methods using, for example, hydrogen peroxide and manganese dioxide to give the corresponding N-oxide.

The invention is illustrated by the examples described below.

Example 1 N- (1- {1-yl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid 670 g of chlorosulfonic acid was placed in a round-bottomed flask equipped with a condenser and a thermometer, then 173 g of 1,4-benzodioxane-5-carboxylic acid was added in small portions and the temperature was maintained at 5-10 ° C throughout. The mixture was heated at 55 ° C, cooled and poured onto ice. The precipitate was collected, washed and dried to give 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid (m.p. 210-215 ° C, yield 93.5%).

7-methylsulfamoyl-1,4-benzodixane-5-carboxylic acid 139.5 g of a 40% aqueous solution of methylamine and 139.5 ml of water were placed in a round-bottomed flask equipped with a stirrer and a thermometer, and then 250 g of 7-chlorosulfonyl-1 was added in small portions. 4-benzodioxane-5-carboxylic acid and then a solution of 180 ml of 30% sodium hydroxide and 180 ml of water.

The mixture was stirred and then poured into 2200 ml of water. The solution was filtered and treated with 139 mL of concentrated hydrochloric acid.

The precipitate was collected, washed and dried to give 190.5 g of 7-methylsulfoyl-1,4-benzodioxane-5-carboxylic acid (m.p.

20 DEG-20 DEG C., yield 1 to 80 <!,).

/ -me Lyy 1. isu 1 f amoyl j -1,4-benl s od i oxane -6-carbonyl I or id I

1.76.5 g of thionyl chloride was placed in a round-bottomed flask equipped with 6,63938 condensers, and then 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was added in small portions while heating the mixture at 40 to 45 ° C. . The mixture was refluxed and then treated with 250 ml of chloroform.

The precipitate was collected 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 placed in a 1 liter round-bottomed flask equipped with a thermometer and a stirrer. 144 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added in small portions while maintaining the temperature at 5-10 ° C. The mixture was stirred for 1 hour and then treated with 1750 ml of water. The chloroform was distilled off, the pH of the mixture was adjusted to 4 by adding 4 ml of 20% sulfuric acid, filtered through activated carbon, and the sulfate solution thus obtained was basified by adding 60 ml of 20% ammonia. After crystallization, the base was collected, washed with water and dried at 40 ° C. Recrystallization from acetonitrile gave 134 g of N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 68.7%, mp 142-143 ° C). ).

The NMR spectrum was consistent with the assumed structure.

Example 2 N- (1-Ethyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 209 g of 34% ammonia and 97 g of 7 -chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was placed at 5-10 ° C in a round bottom flask equipped with a stirrer and thermometer. The mixture was stirred at ambient temperature and then the precipitate was dissolved in 415 any water. The solution was filtered and treated with 140 mL of concentrated hydrochloric acid. The crystals were collected, washed with water and dried to give 78 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid (m.p. 272-274 ° C, yield 87%).

Methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate 429 g of methanol were placed in a round-bottomed flask equipped with a condenser, followed by the addition of 54 g of 93% sulfuric acid and 111 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylate. carboxylic acid while cooling 7,63938. The mixture was refluxed and then cooled. The crystals were collected, washed with methanol and treated with a solution of 500 ml of water and 5 g of sodium carbonate.

The precipitate was collected, washed with water and dried to give 95 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate (m.p. 225-226 ° C, yield 81%).

N- (1-ethyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide 14-5 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 81.5 g of 1-ethyl-2-aminomethylpyrrolidine were placed in a round-bottomed flask equipped with a condenser and a stirrer. The suspension thus obtained was heated in a water bath until the sample proved to be 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 thus obtained was filtered through activated carbon and the base was precipitated with 20% ammonia. The crystals were collected, washed with water and dried. The benzamide was purified to form the hydrochloride (m.p. 238-240 ° C). The base was reprecipitated with 20% ammonia. There were thus obtained 120 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide (yield 61.5%, m.p. 160-161 ° C).

The NMR spectrum was consistent with the assumed structure.

Example 3 N- (1-Methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 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 placed in a round-bottomed flask equipped with a stirrer and condenser. The mixture was heated to 90 ° C, then cooled to 45 ° C and 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 collected, washed and dried to give 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid (m.p. 191-192 ° C, 90% yield).

7-Ethylthio-1,4-benzodioxane-5-carboxylic acid 166 g of 7-mercapto-1,4-benzododioxane-5-carboxylic acid, 242 ml of water, 216 ml of sodium hydroxide solution and 181 g of ethyl sulphate were placed in a round-bottomed flask. equipped with radiator.

The mixture was refluxed and then cooled. The solution was poured into 1.3 liters of water, filtered and treated with 110 ml of hydrochloric acid. The precipitate was collected, washed with water and dried to give 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid (m.p. 153-154 ° C, yield 81%).

7-Ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid and 958 ml of acetic acid were placed in a round-bottomed flask equipped with a condenser. 398 ml of hydrogen peroxide were added and then the mixture was heated. The crystals formed on cooling were collected, washed and dried to give 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid (m.p. 217-218 ° C, yield 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 placed in a round-bottomed flask equipped with a condenser. The mixture was heated and then the excess thionyl chloride was distilled off in vacuo. There were thus obtained 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride (m.p. 146-147 ° C, yield 100%).

N- (1-methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 59 g of 1-methyl-2-aminomethylpyrrolidine, 450 ml of chloroform and in small portions 150 g of 7-ethylsulfonyl-1,4 -Benzodioxane-5-carbonyl chloride was placed at 5-10 ° C in a round bottom flask equipped with a stirrer and thermometer. The mixture was stirred for 1 hour at ambient temperature and then 1850 ml of water were added. The chloroform was then distilled, the solution was filtered through activated carbon, and the benzamide was precipitated by adding 65 ml of sodium hydroxide solution. The solid was collected, washed with water and dried at 40 ° C. Recrystallization from absolute alcohol gave 151 g of N- (1-methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (yield 80.5%, m.p. 140-141 ° C).

The structure was confirmed by NMR spectrum.

63938

Example M-N- (1-Methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 500 ml of acetone and a solution of 99 g of dimethylamine in 250 ml of acetone was placed in a round-bottomed flask equipped with a stirrer and a 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, the acetone was distilled off and the residue was dissolved in 1 liter of water.

The solution was basified, filtered and treated with 70 ml of hydrochloric acid. The precipitate was collected, washed and dried to give 128 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid (m.p. 220-221 ° C, yield 89%).

7-Dimethylsulfamyl-1,4-benzodioxane-5-carbonyl chloride 190 g of thionyl chloride and 153 g of N-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were placed in a round-bottomed flask equipped with a condenser. When the mixture was heated and excess thionyl chloride was distilled off, 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride (m.p. 160-162 ° C, 100% yield) was obtained.

N- (1-Methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzoyloxane-5-carboxamide 61 g of 1-methyl-2-aminomethylpyrrolidine and 560 ml of chloroform were placed in a round-bottomed flask equipped with a stirrer and a thermometer, and the temperature was maintained at 0-5 ° C while 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. The chloroform was distilled off, the remaining solution was filtered, and the carboxamide was precipitated by adding 30% sodium hydroxide solution.

The crystals were filtered, washed with water and dried.

Recrystallization from absolute alcohol gave 157 g of N- (1-methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 76.9%, m.p. 165-166 ° C). .

The NMR spectrum was consistent with the assumed structure.

10 63938

Example 5 N- (1-Benzyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide phosphate 440 ml of chloroform and 110 g of 1-benzyl-2-aminomethylpyrrolidine were placed in a round-bottomed flask equipped with a stirrer and a thermometer, and then the temperature was maintained at 5-10 ° C while 110 g of 1,4-benzodioxane-5-carbonyl chloride was added. The mixture was stirred, 3 liters of water were added and the chloroform was removed.

The solution was treated with ammonia and the precipitate was extracted with methylene chloride. The organic solution was dried and the solvent was removed.

The compound thus obtained was dissolved in absolute ethanol and treated with 30 ml of 85% phosphoric acid. The precipitate formed was collected, washed with ethanol and dried. There were thus obtained 153 g of N- (1-benzyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide phosphate (yield 61%, m.p. 165 ° C).

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 placed in a round-bottomed flask equipped with a condenser. The mixture was heated on a water bath until the sample proved to be soluble in dilute acids and then 1 liter of water was added. The precipitated carboxamide was redissolved by forming acetate. The resulting solution was filtered through activated carbon and then the base was precipitated with 20% ammonia. The crystals thus obtained were collected, washed with water, dried and purified by forming the hydrochloride (m.p. 228-230 ° C) and basifying with 20% ammonia. There were thus obtained 131 g of N- (1-allyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide (yield 64.8%, m.p. 143-144 ° C). 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 11,63938 750 ml of methanol were placed in a round-bottomed flask equipped with a condenser and then cooled while 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1 , 4-benzodioxan-5-carboxylic acid. The mixture was refluxed, cooled and poured into a solution of water and sodium carbonate. The precipitate was collected, washed and dried.

There were thus obtained 143 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate (m.p. 159-160 ° C, yield 85%).

N- (1-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 l -ethyl-2-aminomethylpyrrolidine was placed in a round bottom flask equipped with a stirrer and reflux condenser. The mixture was heated in a water bath until the sample proved to be completely soluble in dilute acids. The carboxamide obtained by cooling was purified by forming acetate into a solution of 100 ml of acetic acid in 950 ml of water. The solution thus obtained was filtered through activated carbon and the base was precipitated with 20% ammonia. The crystals thus obtained were collected, washed with water, dried and recrystallized from boiling isopropyl alcohol. There were thus obtained 121 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 66.2%, m.p. 139-14 ° C). The structure was confirmed by NMR analysis. The corresponding hydrochloride was prepared by treating the carboxamide with hydrochloric acid (specific gravity 1.18) (m.p. 186-188 ° C).

Example 8 N- (1-ethyl-2-pyrrolidylmethyl) -2,3-methylenedioxybenzamide.

In a similar manner, 34.9 g of ethyl 2,3-methylenedioxybenzoate was reacted with 1-ethyl-2-aminomethylpyrrolidine (24.2 g) to give, after work-up and purification, 28.3 g of N- (1-ethyl-2- pyrrolidyylimetyyli) -2,3-methylenedioxybenzene-amide. The NMR spectrum was consistent with the assumed structure.

Example 2

Left-turning N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 65 g of left-turning 1-ethyl-2-aminomelylpyrrolidine were dissolved in 430 ml of chloroform in a round-bottomed flask equipped with τ 1 .

i2 6 3 9 3 8 with stirrer and thermometer. The solution thus obtained was cooled to 5 ° C. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were added as a fine powder, and the temperature was kept at 5-10 ° C throughout. After the addition, the mixture was stirred for 1 hour and then treated with 1 liter of water. The chloroform was distilled off, the solution was filtered through activated carbon and the base was precipitated with an excess of 30% sodium hydroxide solution. The formed crystals were collected, dried and recrystallized from isopropyl alcohol. There was thus obtained 151.5 g of levorotatory N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (yield 77.7%, m.p. 111-112 ° C). , (¢ 0 = -54.2 ° (5% in dimethylformamide solution).

Example 10 Right-rotating N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide In a similar manner, 64.5 g of right-rotating 1-ethyl-2-aminomethylpyrrolidine was reacted With 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride (146 g) to give, after treatment and purification, 133.5 g of dextrorotatory N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1, 4-benzodioxane-5-carboxamide (yield 69.8%, m.p. 111-112 ° C), (C 1 H = 55.5 ° (5% as dimethylformamide solution)).

Example 11 N- (1-Ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide

Similarly, 58 g of 1-ethyl-2-aminomethylpyrrolidine and 131 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were reacted with each other to give 103.5 g of N- (1-ethyl-2-benzodioxane-5-carbonyl chloride) after treatment and purification. -pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (yield 60.2%, m.p. 118-119 ° C). 100 g of the base thus obtained were dissolved in 220 ml of acetone, then the solution was filtered through activated carbon, and a solution of 9.5 g of hydrochloric acid in acetone was added thereto. The hydrochloride crystals thus obtained were separated, washed with acetone and dried. There were thus obtained 96 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride (yield 88.2%, m.p. 148-150 ° C).

63938

For example? 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 was placed in a round-bottomed flask equipped with a reflux condenser. The mixture was heated in a water bath until the sample proved to be completely soluble in dilute acids. The carboxamide formed on cooling was purified by treating it with a solution of 50 ml of acetic acid and 1250 ml of water. The solution thus obtained was filtered through activated carbon and the base was precipitated by adding 20% ammonia. The formed crystals were separated, washed with water, dried and purified by recrystallization from boiling methanol. There was thus obtained 119.5 g of N- (1-methyl-2-pyrrodylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide (yield 70.1%, m.p. 187-188 ° C).

Example 13 N- (1-Allyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,2,4-benzodioxane-5-carboxamide 58 g of 1-allyl-2-aminomethylpyrrolidine and 360 ml of chloroform were placed in a round-bottomed flask equipped with a stirrer and a thermometer. , and then the temperature was maintained at 5-10 ° C while 120 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added. The mixture was stirred, one liter of water was added, and chloroform was distilled off. The solution thus obtained was filtered through activated carbon and then the base was precipitated by adding 40 ml of 30% sodium hydroxide. The formed crystals were separated, washed with water and dried. There were thus obtained 152 g of N- (1-allyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (yield 93.4%, m.p. 78-80 ° C). 146 g of base were dissolved in 290 ml of hot absolute ethanol, the resulting solution was filtered through activated carbon and acidified by adding a solution of 13.5 g of hydrochloric acid in 100 ml of absolute ethanol. The crystals formed on cooling were separated, washed with absolute ethanol, dried and purified by recrystallization from absolute ethanol. There was thus obtained 119.5 g of N- (1-allyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride (yield 75%, m.p. 138-140 ° C).

W 63938

Example 14, Ν- (1-Ethyl-2-pyrrolidylmethyl) -2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide

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 placed in a round-bottomed flask which was equipped with a stirrer and a thermometer. The mixture was heated to 40 ° C and 182 g of potassium carbonate was added. The mixture was refluxed and 2 L of water was added, the oily phase was decanted, extracted with ether and the ether solution was washed with 10% sodium carbonate and dried. Distillation of the ether in vacuo gave 86.5 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate (b.p. 166-176 ° C, 8 mm Hg, 63% yield).

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 sodium carbonate solution were placed in a round-bottomed flask equipped with radiator. The mixture was refluxed, then poured into 1 liter of water and treated with 5 g of sodium metabisulfite. The solution was filtered and treated with 77 mL of concentrated hydrochloric acid. The precipitate was separated, washed with water and dried. There were thus obtained 120 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (m.p. 65-67 ° C, yield 80.5%).

2H-3,4-Dihydro-1,5-benzodioxepine-6-carbonyl chloride 246 g of thionyl chloride and 134 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were placed in a round-bottomed flask equipped with a condenser. The mixture was refluxed followed by an additional 147 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride (m.p. 35-37 ° C, 100% yield).

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 placed in a round-bottomed flask equipped with with a stirrer and a thermometer, and then the temperature was maintained at 5-10 ° C while 152 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride was added. The mixture was stirred for 1 hour while allowing the temperature to rise, then 145U ml of water was added and the chloroform was distilled off. The solution was filtered through activated carbon and the base was precipitated by adding 75 ml of 20% ammonia. The formed crystals were separated, washed with water and dried. There was thus obtained 191 g of N- (1-ethyl-2-pyrrolidylmethyl) -2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide monohydrate (yield 82.4%, m.p. 51-52 ° C). .

173.5 g of product were dissolved in 750 ml of absolute ethanol.

The solution was filtered through activated carbon and a solution of 62 g of 85% phosphoric acid in 100 ml of absolute ethanol was added. The formed crystals were collected, washed with absolute ethanol, dried and recrystallized from ethanol. There were thus obtained 198 g of N- (1-ethyl-2-pyrrolidylmethyl) -2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide phosphate (yield 92%, m.p. 189-190 ° C).

Example 15 N- (1-Methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-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 placed in a round-bottomed flask equipped with a reflux condenser. The mixture was heated in a water bath until the sample proved to be completely soluble in dilute acids. The formed crystals were dissolved in a solution of 50 ml of acetic acid and 1250 ml of water, and then the solution was filtered through activated carbon and the base was reprecipitated by adding 100 ml of 20% ammonia. The crystals were separated, washed with water and dried. There was thus obtained 182 g of N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 83.6%, m.p. 189-190 ° C).

16 63938

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, 30 ml of tetrahydrofuran and 13 g of g of carbonyldiimidazole was placed in 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 in vacuo. The formed crystals were washed with water and dried. There were thus obtained 14 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboximide (yield 73.8%, m.p. 118-119 ° C).

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 was first placed in a round-bottomed flask equipped with a stirrer, thermometer and condenser, and then a solution of 3.5 g of phosphorus trichloride was stirred dropwise at 0-5 ° C. In 20 ml of pyridine. Stirring was continued first at 0-5 ° C and then at ambient temperature. 14.5 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were then added. The mixture was stirred while heating. The mixture was cooled, the solvent was evaporated, the residue was dissolved in chloroform, the solution was washed with aqueous sodium carbonate solution and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 12.5 g of N- (1-methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 64.5%, m.p. 155-166 ° C).

Example 18 N- (1-cyclohexyl-3-pyrrolidinyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide N - 84 g 1 - cyclohexyl-3-aminopyrrolidine, 430 ml of chloroform and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were placed in a round-bottomed flask equipped with a stirrer and a thermometer. The mixture was stirred, the base was extracted with methylene chloride and the solvent was evaporated. The formed crystals 17,63938 were dissolved in boiling absolute alcohol, and the resulting solution was filtered through activated carbon. The crystals formed on cooling were dissolved in an aqueous solution of acetic acid, the resulting solution was filtered through activated carbon, and the base was reprecipitated by adding 20% ammonia. There was thus obtained 129.5 g of N- (1-cyclohexyl-3-pyrrolidyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 61.2%, m.p. 160-161 ° C).

Example 19 N- (1-Ethyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide 64 g of 1-ethyl-2-aminomethylpyrrolidine and 530 ml of chloroform were placed in a round-bottomed flask equipped with a stirrer and a thermometer. , and then the temperature was maintained at 0-5 ° C while 153 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. The chloroform was distilled off, the solution was filtered and the carboxamide was precipitated by adding 30% sodium hydroxide solution. The formed crystals were collected by filtration, washed with water and dried. Recrystallization from absolute ethanol gave 144.5 g of N- (1-ethyl-2-pyrrolidinylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 72.8%, m.p. 14-1-1). * 4 8 ° C).

_Example 20

Right-rotating N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,2,4-benzodioxane-5-carboxamide A round-bottomed flask equipped with a stirrer and a thermometer was charged with 82 g of right-rotating 1-ethyl-2-aminomethyl. -lipyrrolidine, 600 ml of chloroform and 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride in small portions at 5-10 ° C. Then, 1 liter of water was added, the chloroform was distilled off, and the remaining solution was filtered. The base was precipitated by adding 60 ml of 20% ammonia. The formed crystals were separated, washed with water and dried. There was thus obtained 162 g of dextrorotatory N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 66%, m.p. 136-137 ° C).

18 63938

Example 21

Left-turning N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide When 82 g of left-turning 1-ethyl-2-aminomethylpyrrolidine and 195 g of 7-methylsulfamoyl- 1,4-Benzodioxane-5-carbonyl chloride was reacted with each other as described in the previous example to give 151 g of levorotatory N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5 -carboxyamide (yield 62%, mp 136-137 ° C).

.Example 2 2

Left-handed N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide _ In a round-bottomed flask equipped with a stirrer and a thermometer, 85 g of left-handed 1 -allyl-2-aminomethylpyrrolidine, 610 ml of chloroform and at least 178 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride.

The mixture was stirred, 1.2 liters of water were added, and chloroform was distilled off. The remaining solution was filtered and the base was precipitated by adding 70 ml of 20% ammonia. The formed crystals were separated and washed with water. Recrystallization from ethyl acetate gave 117 g of levorotatory N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 49%, m.p. 101-102 ° C).

Example 23. Right-rotating N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide When 84 g of right-rotating 1-allyl-2-aminomethylpyrrolidine and 175 g of 7 -methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was reacted with each other as described in the previous example to give, after purification, 125 g of dextrorotatory N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane -5-carboxamide (yield 52.6%, mp 104-105 ° C).

JSample 24

Dextrorotatory N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 61 g dextrorotatory 1-methyl-2-aminomethylpyrrolidine, 465 ml chloroform and in small portions 155 g 7 -methylsulfamoyl-19,63938 1,4-benzodioxane-5-carbonyl chloride was placed at 5-10 ° C in a round bottom flask equipped with a stirrer and thermometer. The mixture was stirred, 1850 ml of water was added, chloroform was distilled off, and the remaining solution was filtered. The base was precipitated by adding 65 ml of 20% ammonia. The crystals were collected, washed and dried to give 154 g of dextrorotatory N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (yield 78.5%, m.p. 187-188 ° C).

Example 25

Left-turning N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide When 71 g of left-turning 1-methyl-2-aminomethylpyrrolidine and 180.5 g of 7- methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was reacted with each other, carbonyl chloride was reacted with each other to give 175 g of levorotatory N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl, 4-benzodioxane-5-carboxamide (yield 77%, m.p. 187-187.5 ° C).

Example 26 N- (1-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 ml of chlorosulfonic acid were placed in a round-bottomed flask equipped with a stirrer, condenser and thermometer, and then 106 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid was added in small portions while maintaining the temperature. 5-lo ° C. The mixture was stirred at ambient temperature and then poured onto ice. The crystals were collected, washed with water and dried. There were thus obtained 146 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (m.p. 114-115 ° C, yield 91%).

8-Methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 233 g of an aqueous solution of methylamine were placed in a round-bottomed flask equipped with a stirrer and a thermometer, and then the temperature was maintained at 5-10 ° C while 146 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-20,63938 6-carboxylic acid were added in small portions. The mixture was stirred and then the precipitate was dissolved in water. The solution was filtered and treated with 150 mL of concentrated hydrochloric acid. The crystals were collected, washed and dried.

There were thus obtained 112 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (m.p. 145-146 ° C, yield 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 placed in a rotary evaporator. to a flask equipped with a condenser. The mixture was heated and then the excess thionyl chloride was distilled off in vacuo. There was thus obtained 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride (m.p. 93-94, 100% yield).

N- (1-ethyl-2-pyrrolidylmethyl) -8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide 79 l of 1-ethyl-2-aminomethylpyrrolidine, 750 ml of methyl ethyl ketone and in small portions 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride was placed at 5-10 ° C in a round bottom flask equipped with a stirrer and a thermometer. The hydrochloride precipitate was collected, washed with methyl ethyl ketone and dried. The hydrochloride was recrystallized from methanol and then dissolved in 850 ml of water. The solution was filtered and the base was precipitated by the addition of 60 ml of 20% ammonia. The formed crystals were collected, washed with water and dried. There were thus obtained 180 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxyamide (yield 63.8%, m.p. 144-145 ° C).

Example 27 N- (1-Ethyl-2-pyrrolidinylmethyl) -2,3-methylenedioxybenzamide hydrochloride 134 g of 1-ethyl-2-aminomethylpyrrolidine, 950 ml of chloroform and 183 g of 2,3-methylenedioxybenzoyl chloride in small portions were placed at 5-10 °. In C to a round-bottomed flask equipped with a stirrer and a thermometer. To the mixture was added 1 liter of water, chloroform was distilled off, and the remaining solution was filtered. Then 120 ml of 20% ammonia were added, extracted with ether, the ether solution was dried over potassium carbonate and the ether was distilled off. The obtained base was dissolved in 300 ml of acetone, and a solution of 34 g of hydrochloric acid in 330 ml of acetone was added thereto. The hydrochloride precipitate was collected, washed with acetone and dried. Recrystallization from isopropanol gave 154 g of N- (1-ethyl-2-pyrrolidylmethyl) -2,3-methylenedioxybenzamide hydrochloride (yield 49.7% m.p.

127.5-128.5 ° C).

Example 28 N- (1-Ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide dioxate 8-methoxy-1,4-benzodioxane-5-carboxylic acid 171.5 g of 2,3- dihydroxy-4-methoxybenzoic acid, 515 ml of ethanol, 280 ml of sodium hydroxide solution and 175 g of ethylene bromide were placed in a round-bottomed flask equipped with a stirrer, a thermometer and an inlet tube for nitrogen. The mixture was refluxed and then cooled and poured into 2.8 liters of water. The solution was filtered and treated with 85 mL of concentrated hydrochloric acid. The precipitate was separated, washed and dried. Recrystallization from dimethylformamide gave 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid (m.p. 224-226 ° C, yield 57%).

8-Methoxy-1,4-benzodioxane-5-carbonyl chloride 391 g of thionyl chloride and 138 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were placed in a round-bottomed flask equipped with a condenser. The mixture was heated to 50-55 ° C: and the excess thionyl chloride was distilled off in vacuo. There were thus obtained 151 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride (yield 100%).

N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide dioxalate 87 g of 1-ethyl-2-aminomethylpyrrolidine and 775 ml of methyl ethyl ketone were placed in a round-bottomed flask equipped with a stirrer and with a thermometer, and then the temperature was maintained at 5-10 ° C while 155 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride were added in small portions.

The mixture was stirred, dissolved in 1500 ml of water, and the methyl ethyl ketone was distilled off. The remaining solution was filtered and treated with sodium hydroxide. The oil was decanted

__ · I

22 6 3 9 3 8 separated and extracted with methylene chloride. The solution was dried over potassium carbonate and the methylene chloride was distilled off in vacuo. There was thus obtained 224.5 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide.

197.5 g of the obtained base were dissolved in 760 ml of absolute ethanol, and then a solution of 67 g of oxalic acid in 195 ml of absolute ethanol was added. The formed crystals were separated, washed with absolute ethanol and dried. There was thus obtained 208.5 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide dioxalate (yield 82%, m.p. 129-130 ° C).

Example 29 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 ml of chlorosulfonic acid was placed in a round-bottomed flask equipped with a stirrer, thermometer and condenser, and then the temperature was maintained at 5-10 ° C while 110 g of 8-methoxy-1,4-benzodioxab-5 was added in small portions. -carboxylic acid. The mixture was stirred at room temperature and then poured onto ice. The precipitate was separated, washed and dried. There was thus obtained 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid (yield 98%).

8-Methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 300 g of 35% ammonia were placed in a round-bottomed flask equipped with a stirrer and a thermometer, and then the temperature was maintained at 0-5 ° C at the same time. when 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in small portions. The mixture was stirred and the precipitate was dissolved in water. The solution was filtered and treated with 280 mL of concentrated hydrochloric acid. The precipitate was separated, washed and dried. There were thus obtained 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid (m.p. 247-248 ° C, yield 82%).

23 6 3 9 3 8

Methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate 396 g of methanol were placed in a round-bottomed flask equipped with a condenser, followed by the addition of 51 g of sulfuric acid and 114.5 g of 8-methoxy-7-sulfamoyl. 1,4-benzodioxane-5-carboxylic acid with cooling. The mixture was refluxed and then poured into a solution of 485 ml of water and 40 g of sodium carbonate. The precipitate was separated, washed and dried. There was thus obtained 110.5 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate (m.p. 202-203 ° C, yield 92%).

N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide 150 g methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane -5-carboxylate and 750 ml of ethylene glycol were placed in a round bottom flask. After dissolution, 127 g of 1-ethyl-2-aminomethylpyrrolidine was added and the mixture was heated at 50 ° C. The solution thus obtained was mixed with 2 liters of water and acidified by adding 120 ml of acetic acid. The precipitate formed was separated, washed with water and dried. The precipitate was then redissolved in hot water. The solution was filtered and the base was precipitated with ammonia. The precipitate was separated, washed with water and dried. There were thus obtained 144 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide (yield 73%, m.p. 110-115 ° C). .

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 of water, 100 ml diethylamine and 200 ml of triethylamine were placed in a round-bottomed flask equipped with a stirrer and a thermometer, and then the temperature was maintained at 20-30 ° C while 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in small portions .

2 4 63 9 3 8

The mixture was stirred at ambient temperature and then 500 ml of water were added. The solution was filtered and treated with 300 ml of hydrochloric acid. The precipitate was separated, washed and dried. There were thus obtained 117 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid (m.p. 149 ° C, yield 74%).

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 placed in a round-bottomed flask equipped with a stirrer and a thermometer, and then the temperature was maintained at 15-20 ° C while 17.2 g of isobutyl chloroformate was added. The mixture was stirred and then the temperature was maintained at 15-20 ° C while 25 g of 1-benzyl-2-aminomethylpyrrolidine was added. The mixture was stirred at ambient temperature and then the solvents were removed. The residue was dissolved in a mixture of 200 ml of methylene chloride and 300 ml of water. After stirring, the solvent was decanted and dried over magnesium sulfate. The solution was filtered and the solvent was removed. The residue was dissolved in boiling ethanol and 18 g of 85% phosphoric acid was added. The formed crystals were separated, washed with ice-cold ethenol and dried. There were thus obtained 56 g of N- (1-benzyl-2-pyrrolidylmethyl) -7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide phosphate (yield 79.6%, m.p.

180 ° C).

Example 31 N- (1-Ethyl-2-pyrrolidylmethyl) -8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide hydrochloride 8-mercapto-2H-3,4-dihydro-1 , 5-benzodioxepin-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 placed in a round-bottomed flask equipped with a stirrer and a thermometer. The mixture was stirred at 40-45 ° C and then 705 ml of concentrated hydrochloric acid were added. Mix the mixture. .

was passed at 55-60 ° C and then cooled. The precipitate was separated, washed and dried. There were thus obtained 65 g of 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (m.p. 99.5-100 ° C, yield 80%).

8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 86 g of d-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid, 162 ml of water, 76 ml of sodium hydroxide solution and 58.5 g of ethyl sulfate were placed in a round-bottomed flask equipped with a condenser. The mixture was refluxed, then cooled and 150 ml of water were added, the solution was filtered and treated with 60 ml of hydrochloric acid. The precipitate was separated, washed and dried.

There were thus obtained 88 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (m.p. 66-67 ° C, yield 91%).

8-Ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-cartoxylic 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-bottomed flask equipped with a condenser, and then 210 ml of hydrogen peroxide was added in small portions. The solution was heated and the acetic acid was removed in vacuo. The residue was dissolved in 180 ml of water and cooled. The precipitate was separated, washed and dried. There was thus obtained 90 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid (m.p. 142-143 ° C, yield 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 placed in a round-bottomed flask. , which was equipped with a radiator. The mixture was heated at 45-5 ° C and then the thionyl chloride was removed in vacuo. The residue was treated with petroleum ether, separated, washed and dried. There were thus obtained 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride (m.p. 105-110 ° C, yield 98%).

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 Lii to a 11th round bottom flask equipped with a stirrer 26 63938 and a thermometer, and then the temperature was maintained at 5-10 ° C while 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5 was added in small portions. -bentsodioksepiini-6-carbonyl chloride. The mixture was heated and then poured into water. The aqueous phase was cooled, filtered and treated with 30 ml of sodium carbonate solution. 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 isopropanol and treated with a solution of hydrochloric acid in isopropanol. The precipitate was separated, washed with ethanol and dried.

There were thus obtained 98 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide.

(m.p. 141-142 ° C, 73% yield).

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 placed in a round-bottomed flask equipped with a stirrer, an inlet tube and a condenser. The mixture was heated to 55 ° C and then a solution of 700 g of bromine in 360 ml of acetic acid was added in small portions. The mixture was heated to 120 ° C and then cooled to 15 ° C. The precipitate was separated, washed with acetic acid and dried. There were thus obtained 332 g of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid (m.p. 212 ° C). The structure was confirmed by NMR analysis.

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 were placed in a round bottom flask. The mixture was heated to 37 ° C and a solution of 60 ml of nitric acid (density 1.49) in 60 ml of acetic acid and sulfuric acid were added as a catalyst. The mixture was heated at 50 ° C and then poured into cold water with stirring. The precipitate was separated, washed with water and dried. There were thus obtained 107 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid (m.p. 237 ° C). The acid was purified by first treating with a solution of 50 g of sodium bicarbonate in 500 ml of water and then precipitating with hydrochloric acid. Precipitate 27 63938 was separated, washed and dried. There was thus obtained a crystalline product (m.p. 238 ° C, yield 51%). The structure was confirmed by NMR analysis.

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 placed in a round-bottomed flask which was equipped with a stirrer and a thermometer. The mixture was refluxed and then the excess thionyl chloride was distilled off in vacuo. The residue was dissolved in 100 ml of isopropyl ether, the solvent was removed and the product was air-dried. There was thus obtained 91 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride (m.p. 215 ° C, yield 91%).

N- (1-ethyl-2-pyrrolidylmethyl) -6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide 18 g of 1-ethyl-2-aminomethylpyrrolidine and 500 ml of methyl ethyl ketone were placed in a 1 liter round-bottomed flask. , equipped with a stirrer and a thermometer. The mixture was cooled to 10 ° C and then 50 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride was added in small portions, taking care not to exceed 20 ° C. The mixture was then stirred for 1 1/2 h at room temperature and the precipitate was filtered off with suction, washed with 100 ml of methyl ethyl ketone, dried and dissolved in 400 ml of water at room temperature. After adding 7 g of carbon black and filtering, the filtrate was treated with 50 ml of 20% ammonia. The formed crystals were filtered off with suction, washed with water and dried to give 40 g of N- (1-ethyl-2-pyrrolidinylmethyl) -6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide, yield 65%. , sp. 213 ° C.

Example 33 N- (1-Ethyl-4-pyrrolidylmethyl-N-amino-1H-benzodioxane-5-carboxamide 8-Amino-1,4-benzodioxane-5-carboxylic acid 400 ml of water, 98.5 g 6.7 -dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml of sodium carbonate solution and 10 g

The Pd / C was placed in an autoclave and the mixture was heated at 50 ° C at the same time as hydrogen was introduced into the autoclave at a pressure of 40 kg / cm. The mixture was filtered and treated with 95 ml of hydrochloric acid. The precipitate was separated, washed and dried. There was thus obtained 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid (m.p. 186 ° C, yield 83.7%).

28,63938 N- (1-ethyl-2-pyrrolidylmethyl) -8-amino-1,4-benzodioxane-5-carboxamide

Following the procedure of Example 2, 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid was treated with methanol, the compound thus obtained was first treated with 33 g of 1-ethyl-2-aminomethylpyrrolidine and then with a solution of 13 g of g of hydrochloric acid in absolute ethanol. There were thus obtained 49 g of N- (1-ethyl-2-pyrrolidinylmethyl) -8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride (m.p. 173 ° C, yield 69%).

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 placed in a round bottom flask and then 24.5 ml of acetic anhydride were added in small portions. The mixture was heated to 60-70 ° C and then cooled. The precipitate was separated, washed with acetic acid and water and dried. There was thus obtained 44 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid (m.p. 233 ° C, yield 84%).

N- (1-ethyl-2-pyrrolidylmethyl) -8-acetamino-1,4-benzodioxane-5-carboxamide 8-Acetamino-1,4-benzodioxane-5-carboxylic acid was treated according to the procedure described in Example 30 with isobutyl chloroformate and l-ethyl-2-aminometyylipyrrolidiinillä. There was thus obtained N- (1-ethyl-2-pyrrolidylmethyl) -8-acetamino-1,4-benzodioxane-5-carboxamide, m.p. 152 ° C. 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 8- acetamino-1,4-benzodioxane-5-carboxylic acid, 75 ml of acetic acid and 75 ml of acetic anhydride were placed in a round-bottomed flask, and then the temperature was allowed to rise while a solution of 17.5 ml of nitric acid (density 1.49) was added to 17 ml: in acetic acid. After dissolution and crystallization

II

29 63938 was added 50 ml of acetic acid. The mixture was stirred at 40-45 ° C and then cooled to 20 ° C. The precipitate was separated, washed with acetic acid and water and dried. There was thus obtained 13.5 g of a mixture of half of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and half of 6-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid.

This mixture, together with 90 ml of water, 4.5 ml of sodium hydroxide and some Raney nickel, was placed in an autoclave and 2 hydrogens were introduced at a pressure of 50 kg / cm. When the absorption of hydrogen ceased, the nickel was filtered off from the solution and the solution was first treated with 12 ml of hydrochloric acid and then at 20-25 ° C with a solution of 3.5 g of sodium nitrite and 10 ml of water. The resulting precipitate was separated, washed and treated with aqueous sodium hydroxide solution. After acidification, the precipitate was separated, washed and dried to give 3 g of 7,8-azimido-1,4-benzodioxane-5-carboxylic acid (m.p. 260 ° C, yield 59%).

N- (1-allyl-2-pyrrolidylmethyl) -7,8-azimido-1,4-benzodioxane-5-carboxamide 7,8-azimido-1,4-benzodioxane-5-carboxylic acid was treated with N-hydroxyphthalimide and dicyclohexylcarbodi -imide mixture. The phthalimide carboxylate thus obtained was treated with 1-allyl-2-aminomethylpyrrolidine. There was thus obtained N- (1-allyl-2-pyrrolidylmethyl) -7,8-azimido-1,4-benzodioxane-5-carboxamide, the structure of which was confirmed by NMR analysis.

Example 36 N- (1-Allyl-2-pyrrolidylmethyl) -6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride 1,4-Benzodioxane-6,7-dinitro-5-carboxylic acid 165 ml of nitric acid ( density 1.49) was placed in a 500 mL round bottom flask equipped with a stirrer and thermometer.

90 g of 1,4-benzodioxane-5-carboxylic acid were added at -10 ° C. The mixture was kept at room temperature for 2 hours and then 1 liter of water was added. The precipitate was filtered off, washed with water, dried at 50 ° C and purified by recrystallization from acetic acid. There were thus obtained 87 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid (m.p. 211 ° C).

30 6 3 9 3 8 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, 50 ml of sodium hydroxide solution were placed in a 1 liter autoclave. and the mixture was hydrogenated at 80 kg using Raney nickel as a catalyst. The mixture was heated at 100 ° C for 2 hours, then cooled and filtered, the nickel was washed with 200 ml of water and the filtrates were combined. A sample was taken which was acidified with hydrochloric acid to give 1,4-benzo-dioxane-6,7-diamino-5-carboxylic acid dihydrochloride (m.p. 153 ° C).

1,4-Benzodioxane-6,7-azimido-5-carboxylic acid The filtrate obtained above was placed in a 2-liter round-bottomed flask equipped with a stirrer and a thermometer. A solution of 35 g of sodium nitrite in 70 ml of water was added dropwise at 20-25 ° C. The crystallized product was filtered off, washed with water and dried at 50 ° C. There was thus obtained 96 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid (yield 87%). The structure was confirmed by NMR analysis.

1,4-Benzodioxane-6,7-azimido-5-N-phthalimidicarboxylate A mixture of 74 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid, 1 liter of dimethylformamide, 57 g of N-hydroxyphthalimide and 74 g of , 5 g of dicyclohexylcarbodiimide, was heated at 90 ° C for 30 minutes. The mixture was cooled to 20 ° C, the crystals were filtered off and washed with 150 ml of dimethylformamide. The filtrates were evaporated in vacuo and the residue was treated with 400 ml of methanol. The solid was filtered, washed and dried. There was thus obtained 80 g of 1,4-benzodioxane-6,7-azimido-5N-phthalimidicarboxylate (m.p. 250 ° C, yield 65.5%).

N- (1-allyl-2-pyrrolidylmethyl) -6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride 92 g of 1,4-benzodioxane-6,7-azimido-5-N-phthalimidicarboxylate and 500 ml of dimethylformamide was placed in a 1 liter round bottom flask equipped with a stirrer and thermometer. 45 g of 1-allyl-2-aminomethylpyrrolidine was stirred in the mixture, and the mixture was kept at room temperature for 2 hours. The solvent was then evaporated and the residue was treated with 500 ml of hot acetone.

The mixture was filtered, and 50 ml of ethanolic hydrochloric acid solution was added to the filtrate. The product was filtered off, washed and recrystallized. There was thus obtained 50 g of N- (1-allyl: L-2-pyrrolidylmethyl) -6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride (m.p.

255 ° C). The structure was confirmed by IR and NMR analysis.

31 63938

Example 37 N- (1-Ethyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide hydrochloride

When 1,4-benzodioxane-5-carbonyl chloride was reacted with 1-ethyl-2-aminomethyl-pyrrolidine as described in Example 26, N- (1-ethyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide hydrochloride ( mp 149-150 ° C).

Table I summarizes the compounds whose syntheses are described in the above examples.

The compounds of the invention are used in various forms of administration such as capsules, tablets, pills, granules or syringes, the preparation of which is known per se. As carriers, substances which do not react with the compounds of the invention, such as lactose, magnesium stearate, starch, talc, cellulose modifications, levilite, alkali metal lauryl sulfates, sucrose or other carriers suitable for pharmaceutical preparations, can be used.

The compounds of the invention may be administered in doses of 50-900 mg / d. The recommended dose is 50-300 mg / d and the preferred one is about 100-150 mg / d.

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The compounds according to the invention have interesting anxiolytic, psychostimulant, revitalizing and indeed also thymoanaleptic properties, which make them suitable for therapeutic use in the psychofunctional area and in particular e.g. in gastroenterology, cardiology, urology, rheumatology and gynecology.

Due to their low level of toxicity, they are well suited for human use without the risk of side effects.

The acute toxicity of the new compounds was determined by administering them to Swiss mice parenterally (intravenously, intraperitoneally and subcutaneously) and orally. Table II shows the LD50 doses. The numbering of the compounds used in the table corresponds to the numbers of the examples.

37 6 3 9 3 8

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The compounds of the invention have virtually no cataleptic effect. · They were administered subcutaneously to rats. The criterion for the cataleptic condition was considered to be that the animal remained stationary for 30 seconds, even though it was placed in an unusual and uncomfortable position with its forelegs separated by 4 cm high wooden blocks. The cataleptic effect was measured as the maximum effect. The results are shown in Table III.

Table III. Cataleptic effect Compound ED, -q (mg / kg) administered subcutaneously to rats 1 Efficacy up to 40% at 200 mg / kg 2 Ineffective between 0-200 mg / kg 3,325 4 Efficacy up to 30% at 200 mg / kg 6 Effect between 0-200 mg / kg 7 Efficacy up to 10% at a dose of 200 mg / kg 9 No effect between 0-200 mg / kg 10 No effect between 0-200 mg / kg 11 No effect between 0-200 mg / kg 12 No effect between 0-200 mg / kg 13 Your effect 10% at a dose of 200 mg / kg 14 No effect between 0-200 mg / kg 15 No effect between 0-200 mg / kg 18 No effect between G-200 mg / kg 19 No effect between 0-200 mg / kg 22 Efficacy up to 30% at a dose of 200 mg / kg / kg 23 No effect between 0-200 mg / kg 26 No effect between 0-200 mg / kg

From the above results, it can be seen that the compounds of the invention have virtually no cataleptic effect in rats. Thus, the new compounds can be used clinically because they are very well tolerated by the extrapyramidal system. The new compounds have also been found to be highly active in dogs against key antiemetics such as apomorphine. The experiments used an experimental design by Ohen and Ensor. According to the invention the compounds were administered subcutaneously 30 minutes prior to the apomorphine (100 mcg / kg subcutaneously) and the animals were observed for 39 63938 after half an hour alkaloidiruiskeen administration. The results are shown in Table IV.

Table IV: Anti - emetic effect

Compound ^ D50 / u§ / kg subcutaneously in dogs 1 3 2 Efficacy to 81% at a dose of 5 μg / kg subcutaneously 3 5.5 M- 10 7 1.5 9 2 10 40 11 3.5 12 9 13 3.9 14 30 15 2.3 18 3.5 19 4

The interest generated by the results obtained in animal experiments was found to be highly justified when the compounds of the invention were tested clinically. By way of example, the following cases may be mentioned.

A 38-year-old patient with Hodgkins disease received chemotherapy in outpatient therapy once a week, and each treatment session was associated with nausea and then severe vomiting that lasted 24 hours despite standard treatment procedures. Nausea and vomiting no longer occurred at all when the patient was administered 50 mg of N- (1-ethyl-2-pyrrolidinylmethyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 24 hours before and 4 hours after perfusion. very well and no side effects could be observed.

The 28-year-old computer engineer suffered from natural neurosis, the pain conditions of which had escalated into three suicide attempts. 18 months of analytical treatment allowed a return to normal life, but. it had little effect on anxiety. When the patient was administered 50 mg * = 63938 N- (1-methyl-2-pyrrolidinylmethyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide three times daily), the anxiety disappeared within a few days and no sedative effect was observed. well and no side effects could be observed.

The 78-year-old had suffered from severe reactionary depression (imminent death) for 8 months. The prostate tumor prevented the use of tricycles. The carrier was treated with 50 mg of N- (1-methyl-2-pyrrolidinylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide three times daily for three weeks, substantially improved, and was able to leave hospital. After continuing treatment at home for three months, the mental balance has remained excellent and the person of retirement age has been able to live a normal life.

The patient has tolerated the drug very well and no side effects have been observed.

A 42-year-old person underwent hysterectomy for connective tissue tumor 5 months ago. A few days after the surgery, sudden feelings of warmth (10-20 times a day) began to appear, accompanied by sweating, which woke the patient up at night and made them feel unwell at work. When treated with 100 mg of N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide once daily, the symptoms disappeared in 4 days. Only once every two or three days did the feeling of hotness remain. The patient tolerated the drug very well and no side effects were observed at all.

A 47-year-old patient developed frequent and malignant cystitis at the onset of menopause at the onset of menopause, which made it impossible to participate in normal life. The patient contacted general practitioners and specialists. All experiments were negative and no treatment helped with this classic case of cystitis. After treatment with 150 mg of N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide once daily, the symptoms completely disappeared and the patient's psychological state returned to normal.

Claims (1)

A process for the preparation of new therapeutically useful substituted 2,3-alkylenebis (oxy) benzamides of the formula CONH- (CHO) -C I 2 n \ A | (I) "Vs · 7 * wherein A is an alkylene group having 1 to 3 carbon atoms, n is 0 or 1, R is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyl group or a cycloalkyl group, X is a hydrogen atom or an alkoxy , a nitro, amino or acetamino group, Y is a hydrogen or halogen atom or a sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl or alkylsulfonyl or X and Y together form an azimido group, Z is a hydrogen or halogen atom or Y and Z together form an azimido group, characterized in that a compound of the formula COD A (III) X in which A, X, Y and Z have the same meaning as above and D is a hydroxy group, a halogen atom or an organic radical, is reacted with a compound of formula (IV) or with its reactive derivative NH2- (CH2) n-- (χγ) R wherein R and n have the same meaning as above.-1 .. 42 63938 For the preparation of a therapeutic agent, substituted with 2,3-alkylenbis (oxy) benzamide in the form of CONH-C CH0) _r- I 2 n r γ_! R (I) X color A is an alkyl group having 1-3 cholatomers, n is 0 or 1, R is an alkyl group having 1 to 4 cholatomers, an alkenyl group having 2 to 4 cholatomers, a benzyl group or a cycloalkyl group, X is -atom or alkoxy, nitro, amino or acetamino, Y or en halogen or sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl or alkylsulfonyl or X and Y bildar tillsmams en azimido, Z or en halogen or Y and Z bildar tillsammans en azimido group, kanne-t ecknat därav, att en förening med formeln COD 2 - <^ γ '\ (III) X color A, X, Y and Z har den ovan angivna betydelsen och D är en hydr -oxy group, which is a halogen atom or an organic radical, is formed with a compound of formula (IV) or a reactive derivative of MH2- (CH2> n-FI (IV) R color R och n is denied anhydrous.