JPS6117832B2 - - 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

[Detailed description of the invention]

The present invention relates to novel substituted 2,3-alkylene bis(oxy)benzamides and methods for producing the same. The compound according to the present invention is a substituted 2,3-alkylenebis(oxy) having a structure represented by the following formula:
It is benzamide. That is, the general formula (In the formula, Z is a hydrogen atom, a mono to di-lower alkyl substituted or unsubstituted sulfamoyl group, or a lower alkyl substituted or unsubstituted sulfonyl group, A is an ethylene group or a propylene group, B is a single bond or a lower alkylene group, and R is a lower Substituted 2,3-alkylene bis(oxy)benzamide represented by (respectively means an alkyl group, lower alkenyl group, benzyl group or cycloalkyl group), a pharmacologically acceptable acid addition salt thereof, or a quaternary ammonium salt thereof. , N-oxide or the dextrorotatory or levorotatory isomer. The above-mentioned substituted 2,3-alkylenebis(oxy)benzamide (), its pharmacologically acceptable acid addition salt, quaternary ammonium salt, N-oxide or dextrorotatory or levorotatory isomer has the general formula (In the formula, Z and A have the same meanings as above.) Substituted 2,3-alkylenebis(oxy)benzoic acid or its reactive derivative represented by the general formula (In the formula, R and R' have the same meanings as above.) After reacting the amine represented by or a reactive derivative thereof, the product may be converted into a pharmacologically acceptable acid addition salt, a quaternary Obtained by leading to ammonium salt or N-oxide. Next, the definition of the above formula will be explained. In the definition of Z, each lower alkyl in the mono- to di-lower alkylsulfamoyl group and lower alkylsulfonyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
Examples include alkyl groups having 1 to 6 carbon atoms such as isobutyl and t-butyl, and preferably alkyl groups having 1 to 4 carbon atoms. Particularly preferred alkyl groups are methyl or ethyl. In the definition of B, examples of the lower alkylene group include alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, and propylene, and preferably alkylene groups having 1 to 3 carbon atoms. A particularly preferred alkylene group is a methylene group. Each lower alkyl group in the definition of R is the same as in the definition of Z above. Further, as the lower alkenyl group in the definition of R, alkenyl groups having 2 to 4 carbon atoms such as vinyl and allyl are exemplified, and an especially preferable alkenyl group is an allyl group. Furthermore, examples of the cycloalkyl group in the definition of R include cycloalkyl groups having 3 to 10 carbon atoms such as cyclopropyl and cyclohexyl, and a particularly preferred cycloalkyl group is a cyclohexyl group. Next, a method for producing the compound of the present invention will be explained. Substituted 2,3-alkylenebis(oxy)benzoic acid () or its reactive derivative is substituted with amine ()
or a reactive derivative thereof to form a substituted 2,3-
In the amidation reaction to produce alkylene bis(oxy)benzamide (), reactive derivatives of the starting material acid () include acid halide,
Lower alkyl esters, such as reactive esters such as methoxymethyl ester and cyanomethyl ester, aromatic esters, esters with N-hydroxyimides such as phthalimide esters, mixtures with symmetrical acid anhydrides such as carbonic acid esters, haloformic esters, etc. Examples include acid anhydrides, acid azides, acid hibiracides, acid azolides such as triazolides, tetrazolides and especially imidazolides, substituted ω-trihaloacetophenones, acid isothiocyanates, substituted α-oxobenzeneacetonitrile, ring-substituted benzamides, etc. Also general formula (This is produced from an acid and an isoxazolium salt. In the formula, A and Z have the same meanings as above.) A compound represented by the following can also be used. The use of acid halides, lower alkyl esters, reactive esters, aromatic esters and mixed acid anhydrides are particularly suitable for preparing the compounds of the invention. Reactive derivatives of the above amines () include reaction products of amines and phosphorus trichloride, reaction products of amines and phosphorus oxychloride, reaction products of amines and phosphorus oxychloride, and reaction products of amines and dialkylchlorophosphorus. Phite, diarylchlorophosphite,
Reaction products of dialkyl orthophenylene chlorophosphites or diaryl orthophenylene chlorophosphites, reaction products of amines and alkyl dichlorophosphites or aryl dichlorophosphites, isothiocyanates of amines,
Examples include substituted ureas, sulfamides, enamines, and the like. Note that the reactive derivatives of acid ( ) and amine ( ) in the present invention are not limited to those exemplified above. Further, the amidation reaction may be carried out without isolating the formed reactive derivative, or may be carried out after isolation. The amidation reaction can also be carried out in the presence of a condensing agent such as silicon tetrachloride, trichlorophenylsilane, phosphoric anhydride, a carbodiimide such as dicyclohexylcarbodiimide, or a lower alkoxyacetylene such as methoxy or ethoxyacetylene. The amidation reaction can be carried out either in the presence or absence of a solvent. As a solvent,
Examples of substances that do not adversely affect this reaction include alcohols, polyhydric alcohols, ketones, benzene, toluene, dioxane, chloroform, and diethylene glycol dimethyl ether. An excess of the amine () used as a raw material can also be used as a solvent. It may also be advantageous to heat the reaction mixture during the course of the amidation, for example to the boiling point of the solvent mentioned above. The substituted benzamide () obtained by the method of the present invention can be prepared by adding hydrochloric acid, hydrobromic acid,
It may be converted into an acid addition salt with a pharmacologically acceptable inorganic or organic acid such as sulfuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid, or methanesulfonic acid. It may be led to a quaternary ammonium salt by reaction with sulfuric acid or the like. Furthermore, if desired, the substituted benzamide () may be oxidized to lead to the corresponding N-oxide. This oxidation reaction is usually carried out in a solvent. Examples of the oxidizing agent include hydrogen peroxide and manganese dioxide. Although this reaction temperature is not particularly limited, it is often carried out with or under heating. Some examples are described below to illustrate the technical features of the invention. However, these examples are not intended to limit the invention. Measured on the final product in each example
Both IR and NMR spectra were consistent with the predicted structure. Example 1 N-(1-allyl-2-pyrrolidinylmethyl)-
7-Methylsulfamoyl-1,4-benzodioxane-5-carboxamide a 670 g of chlorosulfonic acid are placed in a spherical flask equipped with a condenser and a thermometer. 173 g of 1,4-benzodioxane-5-carboxylic acid are added in small portions, maintaining the temperature at 5-10°C. The mixture is heated to 55°C, then cooled and poured into ice. The precipitate is filtered off, washed and dried. 7-
250 g of chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid are obtained (melting point = 210
~215°C, yield = 93.5%). b 139.5g of 40% aqueous solution of methylamine to 139.5g of water
ml of 7-chlorosulfonyl-1,4- into a spherical flask equipped with a stirrer and a thermometer.
Add 250 g of benzodioxane-5-carboxylic acid little by little, and add 180 g of 30% aqueous sodium hydroxide solution.
Add ml. Stir the mixture and then add 2200ml of water.
Inject inside. The solution was filtered, then concentrated hydrochloric acid
Process with 139ml. The precipitate formed is filtered off, washed and dried. 7-methylsulfamoyl-
1,4-benzodioxane-5-carboxylic acid
190.5 g are obtained (melting point = 208-209°C, yield = 80%). c Thionyl chloride in a spherical flask equipped with a condenser.
Then, 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was added little by little while heating to 40-45°C. The mixture is heated under reflux and then treated with 250 ml of chloroform. The resulting precipitate is collected by filtration and washed with chloroform. Thus 7-
Methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride is obtained. d 1-allyl-2-aminomethylpyrrolidine 69
g and 432 ml of chloroform into a spherical flask equipped with a thermometer and a stirrer. 7-Methylsulfamoyl-1,4-benzodioxane-
144 g of 5-carbonyl chloride was heated to 5.
Add little by little while keeping the temperature at ~10°C. Continue stirring the mixture for 1 hour, then add 1750ml of water to the mixture.
Process with. After distilling off the chloroform, the mixture is acidified to a pH value of 4 with 4 ml of 20% sulfuric acid and then filtered with activated carbon. Make the generated sulfate alkaline with 60 ml of 20% ammonia water. After crystallization,
The base is filtered off, washed with water and dried at 40°C. Recrystallization from acetonitrile gave N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-
134 g of 5-carboxamide is obtained (melting point -
142-143°C, yield = 68.7%). Example 2 N-(1-ethyl-2-pyrrolidinylmethyl)-
7-Sulfamoyl-1,4-benzodioxane-5-carboxamide a 209 g of 34% ammonia water was added to 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid at a temperature of 5 to 10°C with a stirrer and Place in a spherical flask equipped with a meter. The mixture is stirred at room temperature and the precipitate is then dissolved in 415 ml of water. The solution is filtered and treated with 140 ml of hydrochloric acid. The formed crystals are collected by filtration, washed with water, and dried. 78 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid are obtained (melting point = 272-274°C,
Yield = 87%). b Methanol in a spherical flask equipped with a condenser.
Add 429g of sulfuric acid, then add 54g of 93% sulfuric acid while cooling.
and 111 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid. The mixture is heated to reflux and then cooled. The crystals formed are collected by filtration, washed with methanol, and then treated with 500 ml of water containing 5 g of sodium carbonate.
The precipitate after treatment is collected by filtration, washed with water, and dried.
95 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate are obtained (melting point = 225-226°C, yield = 81%). c Put 145 g of this product, 48 g of water, and 81.5 g of 1-ethyl-2-aminomethylpyrrolidine into a spherical flask equipped with a reflux condenser and a stirrer. The resulting suspension is heated on a water bath until a portion of the sample is completely dissolved in the dilute acid. The reaction solution is then treated with 1 portion of water and acidified with 70 ml of acetic acid. The resulting acetate-containing solution is filtered with activated carbon and the base is precipitated from the filtration by addition of 20% aqueous ammonia. The crystals are collected by filtration, washed with water, and dried. Purification is carried out by converting the base into a hydrochloride salt (melting point 238-240°C) which is then treated with 20% aqueous ammonia to convert it back to the base. N-
(1-ethyl-2-pyrrolidinylmethyl)-7-
Sulfamoyl-1,4-benzodioxane-
120 g of 5-carboxamide are obtained. (Melting point=
160-161°C, yield = 1.5%). Example 3 N-(1-methyl-2-pyrrolidinylmethyl)-
7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide a 243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and 654 ml of acetic acid,
Place in a spherical flask equipped with a stirrer and condenser. The mixture is heated to 90°C and then cooled to 45°C. Next, add 389 g of tin and 1744 ml of hydrochloric acid.
Heat the mixture to 55-60 °C, cool and pour into water. The precipitate formed is filtered off, washed and dried. 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid are obtained (melting point = 191 DEG -192 DEG C., yield = 90%). b Put 166 g of this product, 242 ml of water, 216 ml of 30% aqueous sodium hydroxide solution, and 181 g of ethyl sulfate into a spherical flask equipped with a condenser. The mixture is heated to reflux and then cooled. The solution is poured into 1.3 liters of water, filtered and treated with 110 ml of hydrochloric acid. The resulting precipitate is collected by filtration, washed with water, and dried. 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid are obtained (melting point = 153-154°C,
Yield = 81%). c Put 152 g of this product and 958 ml of acetic acid into a spherical flask equipped with a condenser. Then 40% hydrogen peroxide solution
Add 398ml and heat the mixture. The crystals formed on cooling are collected by filtration, washed and dried. 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid are obtained (melting point = 217-218 DEG C., yield = 81%). d Place 139 g of this product, 243 g of thionyl chloride, and a few drops of dimethylformamide in a spherical flask equipped with a condenser. The mixture is then heated and excess thionyl chloride is distilled off under reduced pressure. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride are obtained (melting point =
146-147°C, yield = 100°C). e. Place 150 g of this product, 59 g of 1-methyl-2-aminomethylpyrrolidine, and 450 ml of chloroform in small portions at a temperature of 5 to 10°C into a spherical flask equipped with a stirrer and a thermometer. The mixture is stirred for 1 hour at room temperature and then 1850 ml of water are added. After distilling off the chloroform, the solution was filtered with activated carbon and 30%
Add 65 ml of aqueous sodium hydroxide solution. The resulting solid is collected by filtration, washed with water, and dried at 40°C.
Recrystallization from absolute alcohol gives N-(1
-Methyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-
151 g of 5-carboxamide are obtained (melting point =
140-141℃, yield 80.5%). Example 4 N-(1-methyl-2-pyrrolidinylmethyl)-
7-Dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide a 500 ml of acetone and a solution of 99 g of dimethylamine in 250 ml of acetone are placed in a spherical flask equipped with a stirrer and a thermometer. Mixed liquid to 0
℃ and then 7-chlorosulfonyl-
1,4-benzodioxane-5-carboxylic acid
Add 139g. The mixture is stirred at room temperature, the acetone is distilled off, and the residue is dissolved in 1 part of water. The solution is made alkaline, filtered and treated with 70 ml of hydrochloric acid. The precipitate formed is filtered off, washed and dried. 128 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid are obtained (melting point = 220 DEG -221 DEG C., yield = 89%). b Place 153 g of this product and 190 g of thionyl chloride in a spherical flask equipped with a condenser. The mixture is heated and then the excess thionyl chloride is distilled off.
7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride 163g
is obtained (melting point = 160-162℃, yield = 100
%). c 1-methyl-2-aminomethylpyrrolidine 61
g and 560 ml of chloroform are placed in a spherical flask equipped with a stirrer and a thermometer, then the temperature is adjusted to 0-
While maintaining the temperature at 5°C, 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added. Stir the mixture for 1 hour while increasing the temperature, then add 1 part of water. After distilling off the chloroform, the solution is filtered and 30% aqueous sodium hydroxide solution is added. The formed crystals are collected by filtration, washed with water, and dried. By recrystallization from absolute alcohol, N-
(1-methyl-2-pyrrolidinylmethyl)-7-
157 g of dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 165-166°C, yield = 76.9%). Example 5 N-(1-ethyl-2-pyrrolidinylmethyl)-
7-Methylsulfamoyl-1,4-benzodioxane-5-carboxamide a Add methanol to a spherical flask equipped with a condenser.
Add 750ml. Then, while cooling, 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid are added. The mixture is heated under reflux, cooled and the aqueous sodium carbonate solution is filtered off, washed and dried. 143 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate are obtained (melting point = 159-160°C, yield = 85%). b Place 137 g of this product, 43 g of water, and 73 g of 1-ethyl-2-aminomethylpyrrolidine into a spherical flask equipped with a stirrer and a reflux condenser. the mixture,
Heat the aliquot on a water bath until the sample is completely dissolved in the dilute acid. The carboxamide formed on cooling is purified by passing through the acetate salt and then treated with 100 ml of acetic acid in 950 ml of water. After filtering the resulting solution with activated carbon,
Add 20% aqueous ammonia to precipitate the base. The crystals thus obtained were collected by filtration, washed with water,
Purify by drying and recrystallizing from boiling isopropyl alcohol. 121 g of N-(1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide is obtained (melting point = 139-140°C, yield = 66.2%) . The corresponding hydrochloride salt is obtained by treating this carboxamide with hydrochloric acid (specific gravity = 1.18) (melting point = 186-188°C). Example 6 Levorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide In a spherical flask equipped with a stirrer and a thermometer, the levorotatory 1-ethyl-2-aminomethylpyrrolidine 65
Dissolve g in 430 ml of chloroform. Solution at 5℃
Then, 148 g of finely powdered 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride are added while maintaining the temperature at 5-10°C. After introduction of this substance, the mixture is stirred for 1 hour and treated with 1 part of water. After distilling off the chloroform, the solution is filtered on activated carbon and the base is precipitated by an excess injection of 30% aqueous sodium hydroxide.
The crystals are filtered off, washed with water, dried and then recrystallized from isopropyl alcohol. dextrorotatory N-(1
-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-
151.5 g of carboxamide is obtained (melting point = 111 ~
112°C, yield = 77.7%) (α)20/d = 54.2° (5
% in dimethylformamide solution). Example 7 Devoratory N-(1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide In the same manner as in Example 6, dextrorotary 1-ethyl -2
- Reacting 64.5 g of aminomethylpyrrolidine with 146 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride gives rise to dextrorotatory N-(1-ethyl-2-pyrrolidinylmethyl) after treatment and purification. )-7-ethylsulfonyl-1,
4-benzodioxane-5-carboxamide
133.5 g is obtained (melting point = 111-112 °C, yield =
69.8% (α)20/D = 55.5° (in 5% dimethylformamide solution). Example 8 N-(1-ethyl-2-pyrrolidinylmethyl)-
7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide In the same manner as in Example 6, 58 g of 1-ethyl-2-aminomethylpyrrolidine was converted to 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride. React with 131g. After processing and purification,
N-(1-ethyl-2-pyrrolidinylmethyl)-7
103.5 g of -ethylsulfonyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 118-119°C, yield = 60.2%). 100 g of this base are dissolved in 220 ml of acetone, the solution is then active filtered and a solution of 9.5 g of hydrochloric acid in acetone is added. The hydrochloride crystals thus formed are filtered off, washed with acetone and dried. N-(1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-
Benzodioxane-5-carboxamide hydrochloride 96
g (melting point = 148-150°C, yield = 88.2
%). Example 9 N-(1-methyl-2-pyrrolidinylmethyl)-
7-Sulfamoyl-1,4-benzodioxane-5-carboxamide 131 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 43 g of water, and 1-
66 g of methyl-2-aminomethylpyrrolidine are placed in a spherical flask equipped with a reflux condenser. The mixture is heated on a water bath until a portion of the sample is completely dissolved in the dilute acid. The carboxamide precipitated by cooling was mixed with 50 ml of acetic acid and 1250 ml of water.
redissolve by treating with a solution dissolved in After filtering the solution with activated carbon, the base is precipitated by addition of 20% aqueous ammonia. The crystals thus obtained are filtered, washed with water, dried, and purified by recrystallization from boiling methyl alcohol. N-(1-methyl-
119.5 g of 2-pyrrolidinylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 187-188°C, yield = 70.1%). Example 10 N-(1-allyl-2-pyrrolidinylmethyl)-
7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 1-allyl-2-aminomethylpyrrolidine 58g
and 360 ml of chloroform were placed in a spherical flask equipped with a stirrer and a thermometer, and then the temperature was adjusted to 5-10°C.
7-ethylsulfonyl-1,4-
Benzodioxane-5-carbonyl chloride
Add 120g. After stirring the mixture and adding 1 part of water, the chloroform is distilled off. The resulting solution is filtered with activated carbon, and then 40 ml of 30% aqueous sodium hydroxide solution is added to precipitate the base. The crystals are collected by filtration, washed with water, and then dried. 152 g of N-(1-allyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 78-80°C, yield = 95.4%). 146 g of the base thus formed are dissolved in 290 ml of absolute alcohol while still hot, the solution is then filtered with activated carbon and acidified by adding a solution of 13.5 g of hydrochloric acid in 100 ml of absolute alcohol.
After cooling, the formed crystals are collected by filtration, washed with absolute alcohol, dried, and then recrystallized from absolute alcohol for purification. N-(1-allyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,
119.5 g of 4-benzodioxane-5-carboxamide hydrochloride are obtained (melting point = 138-140°C, yield = 75%). Example 11 N-(1-ethyl-2-pyrrolidinylmethyl)-
7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 13 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid and tetrahydrofuran
Place 300 ml and 13 g of carbonyldiimidazole in a spherical flask equipped with a stirrer, thermometer and condenser. The mixture was stirred at room temperature and then 1-ethyl-
Add 9.5 g of 2-aminomethylpyrrolidine. Stirring is carried out while maintaining the temperature at room temperature, and then the solvent is distilled off under reduced pressure. The formed crystals are washed with water and then dried. 14 g of N-(1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 118-119°C, yield = 73.8%). Example 12 N-(1-methyl-2-pyrrolidinylmethyl)-
7-Methylsulfamoyl-1,4-benzodioxane-5-carboxamide 169 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate and 53 ml of water
and 81g of 1-methyl-2-aminomethylpyrrolidine
into a spherical flask equipped with a reflux condenser.
The mixture is heated on a water bath until a portion of the sample is completely dissolved in the dilute acid. The formed crystals are dissolved in a solution of 50 ml of acetic acid dissolved in 1250 ml of water, and then the solution is filtered with activated carbon, and 100 ml of 20% aqueous ammonia is added to reprecipitate the base. The crystals are collected by filtration, washed with water, and dried. 182 g of N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 189-190
°C, yield = 83.6%). Example 13 N-(1-Acyclohexyl-3-pyrrolidinyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 1-Cyclohexyl-3-aminopyrrolidine 84
g, 430 ml of chloroform and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride are placed in a spherical flask equipped with a stirrer and a thermometer. After stirring the mixture, the base is extracted with methylene chloride and the solvent is then distilled off. The formed crystals are dissolved in boiling absolute alcohol, and the resulting solution is filtered with activated carbon. After cooling, the formed crystals are dissolved in an aqueous solution of acetic acid, the solution is then filtered with activated carbon, and the base is reprecipitated by addition of 20% aqueous ammonia. 129.5 g of N-(1-cyclohexyl-3-pyrrolidinyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point = 160-161°C, yield = 61.2%). Example 14 N-(1-ethyl-2-pyrrolidinylmethyl)-
7-Dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide 1-ethyl-2-aminomethylpyrrolidine 64g
and 530 ml of chloroform were placed in a spherical flask equipped with a stirrer and a thermometer, and then, while maintaining the temperature between 0 and 5°C, 7-dimethylsulfamoyl-1,
Add 153 g of 4-benzodioxane-5-carbonyl chloride. Stir the mixture for 1 hour while increasing the temperature, then add 1 part of water. After distilling off the chloroform, the solution is filtered and 30% aqueous sodium solution is added to precipitate the carboxamide. The crystals are collected by filtration, washed with water, and dried.
Recrystallization from absolute alcohol gives N-(1-
Ethyl-2-pyrrolidinylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-
144.5 g of 5-carboxide is obtained (melting point =
146-148°C, yield = 72.8%). Example 15 N-(1-benzyl-2-pyrrolidinylmethyl)-7-diethylsulfamoyl-1,4-
Benzodioxane-5-carboxamide 40 ml of water and 7-diethylsulfamoyl-1,4
-Benzodioxane-5-carboxylic acid 37.8g, triethylamine 12.5g and methyl ethyl ketone 120g
ml into a spherical flask equipped with a stirrer and a thermometer, then 17.5 g of isobutyl chloroformate at a temperature of 15
Add at ~20°C. After stirring the mixture, 25 g of 1-benzyl-2-aminomethylpyrrolidine is added while maintaining the temperature at 15-20°C. The mixture is stirred at room temperature and then the solvent is distilled off. The residue is added to a mixture of 200 ml methylene chloride and 300 ml water. After stirring, the organic solvent is decanted and dried over magnesium sulfate. The solution is filtered and the solvent is then distilled off. The resulting compound is dissolved in ethanol at boiling temperature and 18 g of 85% phosphoric acid are added. After cooling, the formed crystals are collected by filtration, washed with ice-cold ethanol, and then dried. N-(1-benzyl-2-pyrrolidinylmethyl)-7-dimethylsulfamoyl-
56 g of 1,4-benzodioxane-5-carboxamide phosphate are obtained (melting point = 180°C, yield =
79.6%). Example 16 N-(1-methyl-2-pyrrolidinylmethyl)-
7-Dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide In a spherical flask equipped with a stirrer, thermometer, and condenser, add 1-methyl-2-aminomethylpyrrolidine 6
g of pyridine solution and then lower the temperature to 0-5℃.
3.5 g of phosphorus trichloride and 20 ml of pyridine while maintaining
Add the solution drop by drop under stirring. Stirring is carried out at a temperature of 0-5° C. and then maintained at room temperature. Next, 7-dimethylsulfamoyl-1,4-
Add 14.5 g of benzodioxane-5-carboxylic acid. Heat the mixture while stirring. After cooling the mixture and distilling off the solvent, the residue is dissolved in chloroform, and the solution is then washed with aqueous sodium carbonate and dried over anhydrous magnesium sulfate. When concentrated under reduced pressure, N-(1-methyl-2-pyrrolidinylmethyl)-7-dimethylsulfamoyl-
1,4-benzodioxane-5-carboxamide
12.5 g is obtained (melting point = 165-166 °C, yield =
64.5%). Example 17 N-(1-allyl-2-pyrrolidinylmethyl)-
7-Sulfamoyl-1,4-benzodioxane-5-carboxamide 145 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate and 1-allyl-
89 g of 2-aminomethylpyrrolidine are placed in a spherical flask equipped with a condenser. The mixture is heated on a water bath until a portion of the sample is dissolved in the dilute acid, then 1 part of water is added. The precipitated carboxamide is redissolved by forming the acetate. The solution is filtered with activated carbon and then 20% aqueous ammonia is added to precipitate the base. The crystals were collected by filtration, washed with water, dried, and converted into hydrochloride (melting point = 228-230
°C) and then purified by treatment with 20% aqueous ammonia to convert it back to the base. N-
(1-allyl-2-pyrrolidinylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-
131 g of carboxamide is obtained (melting point = 143 ~
144°C, yield = 64.8%). Example 18 Dedextrorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-
Benzodioxane-5-carboxamide In a spherical flask equipped with a stirrer and a thermometer, 82 g of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine.
Add 600ml of chloroform and heat to 5~10℃.
200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride are gradually added at <RTIgt;C. After adding 1 portion of water, the chloroform is distilled off and the remaining solution is then filtered. Precipitate the base by adding 60 ml of 20% aqueous ammonia.
The crystals are collected by filtration, washed with water, and dried. dextrorotatory N-
162 g of (1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point =
136-137°C, yield = 66%). Example 19 Levorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-
Benzodioxane-5-carboxamide In the same manner as in Example 18, levorotatory 1-ethyl-2
- 82 g of aminomethylpyrrolidine is reacted with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give a levorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7
151 g of -methylsulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point =
136-137°C, yield = 62%). Example 20 Levorotatory N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-
Benzodioxane-5-carboxamide 85 g of levorotatory 1-allyl-2-aminomethylpyrrolidine, 610 ml of chloroform, and 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were prepared using a stirrer and a thermometer. Gradually pour into a spherical flask at a temperature of 5-10°C. After stirring the mixture, 1.2 parts of water is added and then the chloroform is distilled off. Filter the residual solution and then
Precipitate the base by adding 70 ml of 20% aqueous ammonia. Filter the crystals and wash with water. Recrystallization from ethyl acetate gives 117 g of levorotatory N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (melting point = 101 ~102℃, yield =
49%). Example 21 Dedextrorotatory N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-
Benzodioxane-5-carboxamide In the same manner as in Example 20, dextrorotatory 1-allyl-2
- Reaction of 84 g of aminomethylpyrrolidine with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride yields dextrorotatory N-(1-allyl-2-pyrrolidinylmethyl) after purification. -7-methylsulfamoyl-1,4-
125 g of benzodioxane-5-carboxamide are obtained (melting point = 104-105°C, yield = 52.6%). Example 22 Dedextrorotatory N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-
Benzodioxane-5-carboxamide 61 g of dextrorotatory 1-methyl-2-aminomethylpyrrolidine, 465 ml of chloroform, and 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were mixed with a stirrer and a thermometer. Pour a small amount into the spherical flask provided. After stirring the mixture and adding 1850 ml of water, chloroform is distilled off and the remaining mixture is filtered. 20% ammonia water 65
Precipitate the base by adding ml. The formed crystals are collected by filtration, washed and dried. dextrorotatory N-(1-
Methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5
- 154 g of carboxamide are obtained (melting point = 187 ~
188°C, yield = 78.5%). Example 23 Levorotatory N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-
Benzodioxane-5-carboxamide In the same manner as in Example 22, levorotatory 1-methyl-2
- 71 g of aminomethylpyrrolidine was reacted with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, and levorotatory N-(1-methyl-2-pyrrolidinylmethyl)-7
175 g of -methylsulfamoyl-1,4-benzodioxane-5-carboxamide are obtained (melting point =
187-187.5°C, yield = 77%). Example 24 N-(1-ethyl-2-pyrrolidinylmethyl)-
7-Methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide a 1092 ml of chlorsulfonic acid was placed in a spherical 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 at a temperature of 5 to
Add little by little while keeping the temperature at 10°C. The mixture is stirred at room temperature and then poured onto ice. The resulting crystals are collected by filtration, washed with water, and dried. 14 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid are obtained (melting point = 114 DEG -115 DEG C., yield = 91%). b. Place 233 g of a 40% aqueous solution of methylamine in a spherical flask equipped with a stirrer and thermometer, then
146 g of -chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid are added in small portions while maintaining the temperature at 5-10°C. Stir the mixture and then dissolve the precipitate in water. The solution is filtered off and treated with 150 ml of hydrochloric acid. The crystals are filtered, washed and dried. 8
112 g of -methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid are obtained (melting point = 145-146°C,
Yield = 78%). c Put 177 g of this product and 220 g of thionyl chloride into a spherical flask equipped with a condenser. The mixture is heated and then the excess thionyl chloride is distilled off under reduced pressure. 8-Methylsulfamoyl-2H-
188 g of 3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride are obtained (melting point = 93-94°C, yield = 100%). d In a spherical flask equipped with a stirrer and a thermometer, add 1
- Add 79 g of ethyl-2-aminomethylpyrrolidine and 750 ml of methyl ethyl ketone, and add 8-
188 g of methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride are gradually added while maintaining the temperature at 5-10°C. The resulting hydrochloride precipitate is filtered off, washed with methyl ethyl ketone and then dried. After recrystallization from methyl alcohol, the hydrochloride salt is dissolved in 850 ml of water. The solution is filtered and the base is then precipitated by addition of 60 ml of 20% aqueous ammonia. The crystals are collected by filtration, washed with water, and then dried. N-(1-ethyl-2-pyrrolidinylmethyl)-8-methylsulfamoyl-
180 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide are obtained (melting point = 144-145°C, yield = 63.8%). Example 25 N-(1-ethyl-2-pyrrolidinylmethyl)-
8-Ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide a 8-Chlorsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6- A solution of 10g of carboxylic acid dissolved in 273ml of acetic acid and tin
Place 159.5 g into a spherical flask equipped with a stirrer and thermometer. The mixture is heated to 40-45°C and stirred, then 705 ml of concentrated hydrochloric acid is added. 55~60℃
After heating to , the solution is cooled. Filter the precipitate,
Wash and dry. 8-Mercapto-2H-
65 g of 3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid are obtained (melting point =
99.5-100°C, yield = 80%). b Put 86 g of this product, 152 ml of water, 76 ml of 30% sodium hydroxide solution, and 58.5 g of ethyl sulfate into a spherical flask equipped with a condenser. The mixture is heated to reflux and then cooled. 150 ml of water are added, then the solution is filtered and treated with 60 ml of hydrochloric acid. The precipitate formed is filtered off, washed and dried. 8-ethylthio-2H-3,4-dihydro-1,5-
88 g of benzodioxepine-6-carboxylic acid are obtained (melting point = 66-67°C, yield = 91%). c Dissolve 88 g of this product in 528 ml of acetic acid, place in a spherical flask equipped with a condenser, and then add 210 ml of 40% hydrogen peroxide solution little by little. The solution is heated and the acetic acid is distilled off under reduced pressure. Pour the residue into 180ml of water.
Dissolve and cool. The precipitate is filtered off, washed and dried. 8-ethylsulfonyl-2H-
90 g of 3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid are obtained (melting point =
142-143°C, yield = 91%). d Place 90 g of this product and 75 g of thionyl chloride in a spherical flask equipped with a condenser. Heat the mixture to 45-50℃
The excess thionyl chloride is distilled off under reduced pressure. The residue is treated with petroleum ether, then filtered off, washed and dried. 8-Ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride 94
g (melting point = 108-110°C, yield = 98
%). e 1-ethyl-2-aminomethylpyrrolidine
39.5 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride was dissolved in 282 ml of chloroform and placed in a spherical flask equipped with a stirrer and a thermometer. Add 94g little by little while keeping the temperature between 5 and 10°C. The mixture is heated and then poured into water. Cool the aqueous phase, filter,
Treat with 30 ml of 30% aqueous sodium hydroxide solution.
The precipitate is extracted with methylene chloride cm ² and the organic phase is dried over potassium carbonate. The solvent is distilled off, the residue is dissolved in isopropyl alcohol and treated with a solution of hydrochloric acid in isopropyl alcohol. The resulting precipitate is filtered, washed with alcohol and dried.
N-(1-ethyl-2-pyrrolidinylmethyl)-
98 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide hydrochloride are obtained (melting point = 141~
142°C, yield = 73%). The compounds obtained in Examples 1 to 25 above are summarized in the table below. general formula

[Table] Each compound according to the present invention is prepared in capsules, tablets,
They are used in various forms such as pills, granules and injection solutions, the methods of their preparation being known per se. Substances that do not react with this compound, such as lactose, magnesium stearate, starch, talc,
Celluloses, levilite, alkali metal lauryl sulfates, sucrose and other excipients used in pharmaceuticals can all be used. Each compound according to the invention can be administered in doses of 50 to 900 mg per day. 50-300mg per day,
It is advantageous to use preferably 100 to 150 mg per day. Examples 26 to 31 below relate to pharmaceutical preparations prepared in a manner known per se using the respective compounds of the invention. Example 26 Three tablets were prepared with the composition shown in the table below.

【table】 Example 27 Tablets having the composition shown in the table below were prepared.

【table】 Example 28 Two tablets were prepared with the composition shown in the table below.

【table】 Example 29 Tablets having the composition shown in the table below were prepared.

【table】 Example 30 Tablets having the composition shown in the table below were prepared.

【table】

【table】 Example 31 Capsules having the composition shown in the table below were prepared.

[Table] Tablets are prepared by mixing the selected compound with starch and lactose by serial dilution method. Granules are prepared from the mixture and methylcellulose. Levirite, magnesium stearate and talc are added to the granules before compression. Methylcellulose is ethylcellulose, polyvinylpyrrolidone,
Any suitable granulating agent such as starch paste or gum arabic may be substituted. Starch may also be replaced with other partitioning agents such as corn starch, carboxylmethylamyloids, alginates, microcrystalline cellulose, and the like. Injectable solutions can be prepared by dissolving the compounds according to the invention in the following acids. These are hydrochloric acid, levulinic acid, gluconic acid or glucoheptonic acid. Injectable solutions prepared under sterile conditions may be rendered isotonic with alkali metals, such as sodium chloride, and may be prepared without added preservatives. Ampoule filling is carried out in a nitrogen atmosphere, then the filling is held for half an hour
Sterilized at 100℃. The compounds of the invention have interesting central nervous system effects,
In particular, it has anxiolytic, psychostimulant, disinhibiting, and thymoanaleptic effects, and as a result, it has an effect on the areas of mental function and especially in dysentery, heart disease, etc. It provides properties that make it suitable for therapeutic use in urinary, rheumatic and gynecological diseases. Due to its very low toxicity, this compound is suitable for human therapeutic use without risk of side effects. The acute toxicity of compounds of the invention was determined in Swiss mice by parenteral administration (intravenous, intraperitoneal and subcutaneous administration) and oral administration. The half-lethal dose (LD ₅₀ ) is shown in the table below.
The numbers assigned to compounds in the table correspond to the numbers in Examples.

【table】

[Table] Furthermore, the compounds of the present invention have virtually no cataldpsy effect. It was administered subcutaneously to rats. The criteria for determining a tonic state are to separate the animal's forelimbs, carefully place the animal on a 4 cm high wooden measuring cube, and allow it to move for 30 seconds in this unfamiliar and uncomfortable position. There is no such thing. The tonic effect was determined at the time of maximum effect, ie 5-6 hours after administration of the substance. The accumulation is as shown in the table below. In the table, the compound numbers correspond to the example numbers.

【table】

[Table] These results demonstrate that the compounds of the present invention are virtually devoid of infarctic effects in rats. This property allows the clinical use of the compounds of the invention with a high degree of tolerance to the extrapyramidal system. The compounds of the present invention have also been found to be effective as central emetics, such as apomorphine, particularly in dogs. The experimental methods used were CHEN and
It is from ENSOR. Each compound of the present invention was administered subcutaneously before subcutaneous administration of apomorphine (100 μg/Kg). The animals were then observed for the second half of the injection of this alkaloid. The accumulation is as shown in the table below. In the table, the compound numbers correspond to the example numbers.

【table】

[Table] Next, known benzamide compounds 1-ethyl-2 having a chemical structure similar to the compound of the present invention are shown.
-(2,3-dimethoxybenzamidomethyl)pyrrolidine, i.e., N-(1-ethyl-2-pyrrolidinylmethyl)-2,3-dimethoxybenzamide (see Example 16 of Japanese Patent Publication No. 44-23496, hereinafter this compound) (hereinafter referred to as "known compound") was also measured for its toxic effect in mice, tonic effect in rats, and antiemetic effect against apomorphine in dogs, using the same method as above. The test results are as follows. a Toxicity LD ₅₀ (intravenous administration) = 54 mg/Kg LD ₅₀ (intraperitoneal administration) = 171-186 mg/Kg LD ₅₀ (subcutaneous administration) = 320-360 mg/Kg LD ₅₀ (oral administration) = 600 mg/Kg b Strong Infarct effect ED ₅₀ (subcutaneous administration) = 17.6 mg/Kg c Antiemetic effect ED ₅₀ (subcutaneous administration) = 13.4 μg/Kg As is clear from the comparison of the measured values for the compound according to the present invention and the measured values for the known compound Most of the compounds according to the present invention have lower toxicity and tonic action and higher antiemetic action than known compounds, and the rest are almost equal to known compounds. Next, the ratios of toxicity/antiemetic activity and infarction/antiemetic activity are calculated from the measured values of the compound according to the present invention and the known compound as follows.

【table】

Table: As is clear from the above table, the toxicity/antiemetic activity ratio and the infarctic/antiemetic activity ratio of the compounds according to the invention are significantly greater than those of the known compounds. This means that the lower the side effects such as toxicity and infarction (i.e. the higher the LD ₅₀ value and the ED ₅₀ value of infarction) and the greater the anti-emetic activity (i.e. anti-emetic activity). The smaller the ED ₅₀ value of the effect, the higher it becomes.Comparison of numerical values shows that the compound according to the present invention is significantly superior to known compounds. Therefore, the compounds according to the invention are also superior to known compounds in this respect. The interest thus aroused by the experiments carried out on laboratory animals was very widely realized by carrying out clinical trials in humans of the compounds according to the invention. A clinical example is given below. *38-year-old Hodgkins disease patient. He was receiving chemotherapy once a week as an outpatient. At every medical treatment,
The nausea attack was followed by extremely profuse vomiting, which lasted 24 hours despite standard treatment. 24 hours and 4 hours after the start of perfusion, N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-
Treated with 50 mg of carboxamide (compound of Example 5). Nausea and vomiting attacks disappeared, the drug was completely tolerated, and no side effects were observed. *28-year-old data processing engineer. He was a characteristically neurotic patient with anxiety attacks that at the height of his climax made him attempt suicide three times. After 18 months of psychoanalytic treatment, he was able to return to society, but had little effect on his anxiety. N-(1-methyl-2-pyrrolidinylmethyl)-
When 50 mg of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (compound of Example 12) was administered three times a day, the anxiety completely disappeared within a few days. No troublesome sedative effects were noted, the drug was completely well tolerated, and no side effects were observed. *78-year-old patient. For eight months, he suffered from severe reactive depression (due to the death of a close relative). The use of tricyclic compounds was contraindicated due to the presence of prostatic tumor. N-(1-methyl-2-pyrrolidinylmethyl)-
He was treated with 50 mg of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (compound of Example 12) three times a day. Within 3 weeks, the patient's condition had completely recovered and he was discharged from the hospital. Treatment continued for three months at home, and the patient was able to maintain good mental balance and resumed normal activities as an elderly, moderately living person. The drug was completely well tolerated and no side effects were observed. *42-year-old female patient. Six months ago, I had a hysterectomy for a fibroid tumor. A few days after the surgery, facial flushing with sweating (10-20 times a day) developed, which woke the patient up at night and interfered with work. N-(1-ethyl-2-pyrrolidinylmethyl)-
When treated with 100 mg of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (compound of Example 5) once a day, the symptoms disappeared in less than 4 days. However, the patient still had facial flushing once a day, which appeared every 2 to 3 days. The drug was completely well tolerated and no side effects were observed. *47-year-old female patient. She suffers from repeated attacks of cystitis after menopause. This was so frequent and sudden that social life became impossible. Patients were seen by general practitioners and specialists. In this classic case of cystitis, all tests were negative and all treatments were ineffective. N-(1-methyl-2-pyrrolidinylmethyl)-
After several days of treatment with 7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (compound of Example 12) at a dose of 150 mg per day, the symptoms completely disappeared and the patient's psychological state improved. It returned to normal.

Claims (1)

[Claims] 1. General formula (In the formula, Z is a mono to di-lower alkyl substituted or unsubstituted sulfamoyl group or a lower alkylsulfonyl group, B is a single bond or a lower alkylene group,
R means a single bond or a lower alkylene group, R means a lower alkyl group, a lower alkenyl group, a benzyl group or a cycloalkyl group, respectively. ), a pharmacologically acceptable acid addition salt, quaternary ammonium salt, N-oxide, or dextrorotatory or levorotatory isomer thereof. 2. The compound according to claim 1, which is 2N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide. 3. The compound according to claim 1, which is N-(1-ethyl-2-pyrrolidinylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide. 4. The compound according to claim 1, which is N-(1-methyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide. 5. The compound according to claim 1, which is N-(1-methyl-2-pyrrolidinylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide. 6. The compound according to claim 1, which is N-(1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide or a hydrochloride thereof. 7. The compound according to claim 1, which is levorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide. 8. The compound according to claim 1, which is dextrorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide. 9. The compound according to claim 1, which is N-(1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfonyl-1,4-benzodioxane-5-carboxamide or a hydrochloride thereof. 10 The compound according to claim 1, which is N-(1-methyl-2-pyrrolidinylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide. 11. The compound according to claim 1, which is N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfonyl-1,4-benzodioxane-5-carboxamide or a hydrochloride thereof. 12. The compound according to claim 1, which is N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide. 13. The compound according to claim 1, which is N-(1-cyclohexyl-2-pyrrolidinyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide. 14. The compound according to claim 1, which is N-(1-ethyl-2-pyrrolidinylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide. 15 N-(1-benzyl-2-pyrrolidinylmethyl)-7-diethylsulfamoyl-1,4-
The compound according to claim 1, which is benzodioxane-5-carboxamide or a phosphate thereof. The compound according to claim 1, which is 16 N-(1-allyl-2-pyrrolidinylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide. 17 Dedextrorotatory N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4
-Benzodioxane-5-carboxamide. 18 Levorotatory N-(1-ethyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4
-Benzodioxane-5-carboxamide. 19 Levorotatory N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4
-Benzodioxane-5-carboxamide. 20 Dedextrorotatory N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4
-Benzodioxane-5-carboxamide. 21 Dedextrorotatory N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4
-Benzodioxane-5-carboxamide. 22 Levorotatory N-(1-methyl-2-pyrrolidinylmethyl)-7-methylsulfamoyl-1,4
-Benzodioxane-5-carboxamide. 23 N-(1-ethyl-2-pyrrolidinylmethyl)-8-methylsulfamoyl-2H-3,4-
The compound according to claim 1, which is dihydro-1,5-benzodioxepine-6-carboxamide. 24 N-(1-ethyl-2-pyrrolidinylmethyl)-8-methylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide or its hydrochloride A compound according to scope 1. 25 General formula (In the formula, Z means a mono- to di-lower alkyl substituted or unsubstituted sulfamoyl group or a lower alkylsulfonyl group, and A means an ethylene group or a propylene group, respectively.) Substituted 2,3-alkylenebis(oxy)benzoic acid represented by the formula or its reactive derivatives have the general formula (In the formula, B is a single bond or a lower alkylene group, R
means a lower alkyl group, a lower alkenyl group, a benzyl group or a cycloalkyl group, respectively. ) by reacting the amine or its reactive derivative represented by the general formula (In the formula, Z, A, B and R have the same meanings as above.) A substituted 2,3-alkylenebis(oxy)benzamide represented by A method for producing a substituted 2,3-alkylene bis(oxy)benzamide, which is characterized in that it leads to a quaternary ammonium salt or an N-oxide. 26. The method of claim 25, wherein the reactive derivative of substituted 2,3-alkylenebis(oxy)benzoic acid is an acid halide. 27. The method of claim 25, wherein the reactive derivative of substituted 2,3-alkylenebis(oxy)benzoic acid is a lower alkyl ester. 28. The method of claim 25, wherein the amine is reacted in the presence of a halogenated alkyl ester of substituted 2,3-alkylenebis(oxy)benzoic acid. 29. The method of claim 25, wherein the amine is reacted in the presence of an imidazolide of substituted 2,3-alkylenebis(oxy)benzoic acid. 30. The method according to claim 25, wherein substituted 2,3-alkylenebis(oxy)benzoic acid is reacted with an amine in the presence of phosphorus halide.