CA1114371A - Substituted 2,3-alkylene bis (oxy) benzamides, their derivatives and preparation process - Google Patents

Abstract

A B S T R A C T
The invention is concerned with novel substituted 2,3-alkylene bis (oxy) benzamides of the formula:

Description

~Lh~3'^~Pl The present invention concerns novel substituted 2,3-alkylene bis (oxy) benzamides having the general formula (I), their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts, their oxides, their dextrorotatory and levorotatory isorners, and processes for the preparation thereof.
: The invention also concerns the medicaments whose active principle cornprises the compounds of the invention.
The structure of the compounds of the invention can be diagrammatically shown by the following formula:

CO-N .
I \ R' Z ~\, 0 yl$~ 0/ ( I ) ' X ;' .`., - - .

in which:
A represents a Cl 3 alkylene chaini R represents hydrogen, a Cl 4 alkyl group, or a radical having the following general formula~

--B--N~ 1 ( I I ) ,` R 2 in which~
B represents a single bond or a Cl 3 alkylene chain; ;
Rl represents a Cl 4 alkyl group or can be connected ~:
~; 10 to B so as to form a pyrrolidinyl or piperidinyl group hetero-cycle;
R2 represents a Cl 4 alkyl group, a C2 4 alkenyl group, benzyl, cycloalkyl, pyrimidyl, or is linked to Rl to form a piperidinyl or 4-alkylpiperazinyl, ''' ' ~ ' ...
.
.
~.
: ~

- 2 - ~
;-C1 ~, ' :

' ~

R' represents hydrogen, a Cl 4 alkyl group, benzyl, adamantyl, pyrimidinyl, or is linked to Rl to forrn a piper-azinyl group, or is linked to Rl and R2 to form a diaza-bicycloalkyl group;
X represents hydrogen, a halogen atom, a C.l 4 alkoxy group, nitro, amino or acetamino;
Y represents hydrogen, a halogen atom, nitro, amino? acetamino, sulfamoyl, Cl 4 alkylsulfamoyl, Cl 4 alkyl-sulfonyl, adamantylsulfamoyl, C3 8 cycloalkylsulfamoyl ? Cl 4 dialkylsulfamoyl, or is linked to X to form an azimido group, Z represents hydrogen, a halogen atom, nitro, amino or acetamino, or is linked to Y to form an azimido group;
and their oxides, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts and their dextrorotatory and levorotatory isomers.
In the defin;tions mentioned in the present specification:

~, .

. ~

~' :

,:' ~, ' "4'~

alkyl Cl 4 mainly includes methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tertiobutyl, alkylene Cl 3 mainly includes methylene, ethylene, propylene, alkenyl C2 4 mainly includes vinyl, allyl, alkinyl C2 4 mainly includes ethinyl, propargyl, alkoxy Cl 4 mainly includes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, isobutoxy, t-butoxy, aralkyl mainly includes benzyl, phenethyl, substituted or unsubstituted by one or more halogen atom, alkoxy, alkyl, halomethyl, amino group, substituted phenyl mainly includes a phenyl ring substituted by one or more halogen atom, alkoxy, alkyl, halomethyl, amino group, halogen mainly includes chlorine, bromine, iodine, fluorine, substituted amino mainly includes an amino group mono or disubstituted by alkyl, acyl, aralkyl, :
; furanyl, pyranyl, alkoxycarbonyl group, acyl mainly includes formyl, acetyl, phthaloyl group.
The preferential values of the substituents are - for X : hydrogen atom, alkoxy group mainly methoxy, nitro, halogen atom mainly chlorine, amino, acylamino mainly acetamino group - for Y : hydrogen, halogen mainly bromine and chlorine atom, amino, acylamino mainly acetamino, alkylsulfonyl mainly ethylsulfonyl group, a sulfonyl group substi-tuted - by an amino group - by an amino group especially monosubstituted by an alkyl mainly methyl, by an adamantyl group - by an amino group especially disubstituted by an , ~. , . : ~ .

alkyl mainly methyl, ethyl group - for Z : hydrogen, halogen mainly bromine, ch10rirle atom, nitro, acylamino mainly acetamino, amino group.
The preferential values of the substituents in the disubsti-tuted compounds are:
~X - alkoxy mainly methoxy - ~Y sulfonyl group substituted by an amino group rx - acylamino mainly acetamino group ` LY - nitro group X and Y can be joined together through a heteroatom . mainly a nitrogen atom to form a triazole cycle X Y - amino group ¦X halogen mainly chlorine atom Y - amino group . ~X = amino group LY acylamino mainly acetamino group X = Y - acylamino mainly acetamino group Y = Z = nitro group :~ Y - 7 = acylamino mainly acetamino group Y Z halogen mainly bromine atom Y - Z amino group Y and Z can be joined together through a heteroatom mainly a nitrogen atom to form a triazole cycle.
The preferential values of the substituents in the trisubsti-tuted compounds are:
-~ {X nitro group ~ Y - Z - halogen atom mainly chlorine and bromine IX - halogen atom mainly chlorine and bromine Y = Z = nitro group ~X = nitro group Y = Z - acylamino mainly acetamino.

;

The preferential values of A are alkylene Cl 3 such as methylene, propylene and mainly ethylene.
The preferential values of R' are:
- a hydrogen atom - an alkyl mainly ethyl, butyl group - an aralkyl group, mainly benzyl group which can be substi-tuted with a halogen atom pre~erably bromine or fluorine or with a trifluoromethyl group - an adamantyl group, a pyrimidinyl group -;10 - a saturated di-nitrogen heterocycle when linked to Rl, ~;
preferably a piperazine ring which can be substituted.
The preferential values of R are:
- a hydrogen atom - an alkyl group mainly ethyl group - a radical according to the formula II3 in which the prefer- :
ential values of B are:
- a single bond, - an alkylene group mainly ethylene3 propylene, - a di-nitrogen heterocycle when linked to Rl, such :
as defined hereafter.
The preferential values of Rl are:
- an alkyl group mainly ethyl group ~:~
- a saturated nitrogen heterocycle when linked to B, mainly pyrrolidine, piperidine group - a nitrogen heterocycle when linked to R2 - mainly a pyrrolidine, a piperidine - or containing another hetero atom, mainly a nitrogen atom~ preferably a piperazine substituted with an alkyl group, mainly methyl, ethyl group - a saturated di-nitrogen heterocycle when linked -to R', mainly a substituted piperazine group.

When at -the same time Rl is linked to R2 such as to ~orm a nitrogen heterocycle, mainly a pyrrolidine group, and Rl is linked to R' such as to form a saturated di-nitrogen hetero-cycle, mainly a piperazine group, the whole constitutes a bicyclic radical, mainly a diazabicyclononane group.
The compounds of the invention can be prepared by the reaction of a compound having the following general formula:
COD

Z ~ \A (111) in which:
A, X, Y and Z are as defined above;
D represents a hydroxy group, a halogen atom or an organic residue, on an amine having the general formula:
: R
: HN / (IV) \~
in ~hich R and R' are as defined aboveg or by the reaction of their reactive derivatives.
In the starting compound, the organic residue comprises groups which are capable of forming reactive acid derivatives. These can be lower alkyl esters such as methyl, :~ ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, or isopentyl; reactive acid esters such as methoxymethyl ester, cyanomethyl ester, substituted or unsubstituted aromatic esters, or N-hydroxyimide esters; acid azides, acid hydrazides;
symmetrical anhydrides; mixed anhydrides such as those formed ~ from carboxylic acid esters and haloformic esters, azolides such as triazolides, tetrazolides, and especially imiclazolides;
substituted ~-trihaloacetophenones; acid isothiocyanates;

L3~7;~

substituted ~-oxo benzeneacetonitriles; benzamides which are substituted on the ring, or other equivalents, or the compound having the follow~ng general formula:

Y~ ;OO--~ C ~ C2~15 (formed from the acid and an isoxazol1um salt). In the above formula, A, X, Y and Z are as defined above. However, the invention is not limited to the reactive derivatives mentioned above.
According to the process of this invention, the amine 10 can react in the form of one of its reactive derivatives. By ~ .
way of example, ment;on can be made of the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl, and orthophenylene chlorophosphites, alkyl or ;aryl dichlorophosphites or isothiocyanate of the amine or the symmetrical or asymmetrical sulfamides of the amine, the corre-- sponding symmetrical urea, the corresponding enamines, or any other equivalent.
The above-mentioned reactive derivatives can react with the acid 'in situ' or after preliminary isolation. How-ever, the invention is not limited to the reactive derivativesdescribed above.
In addition, it is also possible to perform the reaction of the free acid and the free amine in the presence of a condensing agent, for example silicon tetrachloride, phos-phoric anhydride or a carbodiimide such as dicyclohexyl carbo-diimide or alkoxyacetylenes such as methoxy or ethoxyacetylene.
Among the synthesis processes described for the preparation of

3'7~L

':
the compounds according to the invention:
- the use of an acid halide is particularly suitable For - compounds which are unsubstituted on the benzene ring - compounds which are monosubstituted with a halogen atom, a nitro group, an alkylsulfonyl group, an adamantylsulfonyl group, a cycloalkylsulfonyl group~ a sulfonyl radical substituted with:
- an amino group - an amino group mono or di-substituted with an alkyl group, an adamantyl group, a cycloalkyl group - the use of alkyl esters, activated acid esters, or aromatic esters~ is particularly suitable for - compounds having the benzene ring substituted with . a hydroxy group, an amino group3 an acylamino ~ ~
group, an alkylsulfonyl group, an adamantylsulfonyl :
group, a cycloalkylsulfonyl group, a sulfonyl group substituted with: ~
- an amino group ` . :
- an amino group mono or di-substituted with an . alkyl group, an adamantyl group, a cycloalkyl group - compounds having two of X and Y or Y and Z radicals linked together so as to form a cycle, - the use of mixed anhydrides (formed 'in situ' by reaction of -the starting benzoic acid on haloformic esters, preferably . chloroformic acid esters) is particularly suitable for com-pounds substituted with a nitro group, an acylamino group, a sulfonyl group substituted with:
- an amino group ~ 3'7 - an amino group mono or di-substitute~ with an alkyl group, an adamantyl group, a cycloalkyl group - the use of reactive derivatives of amines, preferably formed with phosphorus chlorides, and particularly the phosphorus trichloride, with alkyl and aryl chlorophosphites, is par-ticularly suitable for primary amines and specially aliphatic amines.
The amidification reaction of the invention can be carried out in the presence or in the absence of a solvent. The systems used as a solvent, which are inert with respect to the amidifi~
cation reaction, are for example alcohols, polyols, benzene, ;~ toluene, dioxane, chloroform, or diethylene glycol dimethyl ether, xylene. It is also possible to use, as the solvent, an excess of the amine used as the prime material. It may be preferable to heat the reaction mixture during the amidi-fi-cation operation, for example up to the boiling temperature o~
the above-mentioned solvents.
The compound produced by the process of the invention can react if necessary with pharmaceutically acceptable organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, tartric acid, citric acid, methane sulfonic acid, to give acid addition salts.
It can also react if necessary with alkyl halides or sulFates to give quaternary ammonium salts.
It can also be oxidized in a manner known pe~ se, for instance by means of hydrogen peroxide and manganese bioxide, to obtain the corresponding N-oxide.
In order to illustrate the technical features of the present invention, some embodimen~s will be described hereina-fter, it being understood that these are not limiting as regards the mode of operation and the uses to which they can be put.

N~ allyl-2-pyrrolidylmethyl)-7-methylsulfanloyl-1,4-benzo-dioxane-5-carboxamide 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid 670 9 of chlorosulfonic acid were introduced into a balloon flask provided with a condenser and a thermometer. 173 g of 1,4-benzodioxane-5-carboxylic acid were added in portions, with the temperature being maintained at 5-10C. The mixture was heated at 55C then cooled and poured into ice. The pre-cipitate was dried off, washed and dried. 250 g of 7-chloro-sulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained.
(M.P. = 210 - 215C; yield = 93.5%).
7-methylsulfamo~1-194-benzodioxane-5-carboxylic acid 139.5 9 of a 40% methylamine aqueous solution and 139.5 cm3 of water were introduced into a balloon flask pro-vided with an agitator and a thermometer9 then, in port;ons, 250 9 of 7-chlorosulfonyl-1,4-benzodioxane-5-carSoxylic acid and a solution of 180 cm3 of 30% soda lye in 180 cm3 o~ water were added. The mixture was agitated then poured into 2200 cm3 of water. The solution was filtered, then treated with 139 cm3 of concentrated hydrochloric acid. The precipitate was dried offl washed and dried. 190.5 9 of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. = 208 -209C; yield ~ 80%).
7-methylsulfamoyl-1~4-benzodioxane-5-carbonyl chloride 176.5 9 of thionyl chloride were introduced into a balloon flask provided with a condenser, then~ in portions, 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added under heating at 40-45C. The mixture was heated under reflux then treated by 250 cm of chloroform. The precipitate was dried off and washed with chloroform.
, - 1 1 - ' ' ' . .

~ ~ ~f~'7~

N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo dioxane-5-carboxamide 69 9 of 1-allyl-2-aminomethyl pyrrolidine and 432 ml of chloroform were introduced into a 1 litre balloon flask pro-vided with a thermometer and an agitator. 144 9 of 7-methyl-sulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added in portions, with the temperature being maintained at from 5 to 10C. Agitation of the mixture was continued for one hour, and then the mixture was treated with 1750 ml of water. After distillation of the chloroform, the mixture was acidified to a pH-value of 4, by 4 ml of 20% sulfuric acid, and then filtered on carbon black; the solution of the sulfate formed was render-ed alkaline by 60 ml of 20% ammonia. After crystallization, the base was dried off, washed with water and dried at 40C.
After recrystallization from acetonitrile9 134 g of N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (yield: 68.7%; Melting point: 142 -143C).
The Nuclear Magnetic Resonance spectra are compatible with the proposed structure.

N-(l-ethyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide ` 7-sulfamoyl-1,4-benzodioxane-5-carbox~lic acid . .
209 9 of 34% ammonia and 97 g of 7-chlorosulfonyl-ly4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometera at a temperature of 5-10C. The mixture was agitated at ambient temperature, then the precipitate was dissolved in 415 cm3 of water. The solution was filtered and treated with 140 cm3 of concentrated hydrochloric acid. The crystals were dried off, washed with water and dried. 7~ g of 7-sulfamoyl-1,4-benzo-.~

dioxane-5-carboxylic acid were obtained. (M.P. - 272 - 274C;
yield - 87%).
Methyl 7-sulfamoyl--1,4-benzodioxane-5-carboxylate 429 g of methanol were introduced into a balloon flask provided with a condenser, then, under cooling, 54 g o-f 93% sulfuric acid and 111 g of 7-sulfamoyl l,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux then cooled. The crystals were dried off~ washed with methanol then treated with 500 cm3 of water and 5 9 o-f sodium carbonate. The precipitate was dried off, washed with water and dried. 95 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained. (M.P. ~ 225 - 226C; yield - 81%).
N-(l-ethyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide .. ..
145 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 4~ g of water and 81.5 g of l-ethyl-2-aminomethyl pyrrolidine were introduced into a balloon flask provided with a reflux condenser and an agitator. The resulting suspension was heated on a water bath until a test sample is soluble in dilute acids. The reaction mixture was then treated with 1 litre of water and acidified by 70 ml of acetic acid. The acetate solution formed was filtered on carbon black and the base was precipitated by 20% ammonia. The crystals were dried off, washed with water and dried. The ben~amide was purified by passage over hydrochloride (melting point: 238 - 240C).
The base was reprecipitated by the addition of 20% ammonia.
120 g of N-(l-ethyl-2-pyrrolidylmethyl)-7 sulfamoyl-1,4-benzo-dioxane-~-carboxamide was produced (yield: 61.5%, melting point 160 - 161C).
The NMR spectra are compatible with the proposed structure.

3 ~

N~ methyl-2~pyrrolidylmethyl)~7-ethylsulfonyl-1,4-benzo-dioxane-5-carboxamide _ 7-mercapto-1,~-benzodioxane~5~carboxy1ic acid 243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carbox-y1ic acid and 654 cm3 of acetic acid were introduced into a balloon flask provided with an agitator and a condenser. The mixture was heated at 9~C then cooled at 45C. 389 ~ of tin and 1744 cm3 of hydrochloric acid were then added. The mixture was heated at 55-60C, cooled and poured into water. The pre-cipitate was dried off, washed and dried. 166 9 of 7-mercapto-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. ~
191 - 192C; yield - 90%).
7-ethylthio-1,4-benzodioxane-5-carboxylic acid 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 cm3 of water, 216 cm3 of soda lye and 181 g of ethyl-sulfate were introduced into a balloon flask provided with a condenser. The mixture was heated under reflux, then cooled.
The solution was poured into 1.3 1 of water, filtered and treated with 110 cm of hydrochloric acid. The precipitate was dried off, washed with water and dried. 152 9 of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. ~
153 - 154C; yield = 81%).
7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid 152 9 of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid and 958 cm3 of acetic acid were introduced into a balloon flask provided with a condenser. 398 cm3 of hydrogen peroxide were then added and the mixture was heated. The crystals formed by cooling were dried off, washed and dried. 139 g of 7-ethylsulfonyl-1,4~benzodioxane-5-carboxylic acid were obtain-- ed. (M.P. - 217 - 218C; yield - 81%).
, 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride 243 y of thionyl chloride, some drops oF dimethyl-formamide and 139 g of 7-ethylsulfonyl-1~4-benzodioxane-5-car~oxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated~ then the thionyl chloride in excess was distilled off under vacuum. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were obtain-ed. (M.P. - 146 - 147C; yield - 100%).
N-(l-methyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-dioxane-5-carboxamide . . . ~
59 g of 1-methyl-2-arninomethyl pyrrolidine, 450 ml of chloroform and then, in portions, 150 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride, were introduced, at a temper-ature of from S to 10C, into a balloon flask provided with an agitator and a thermometer. The mixture was then agitated for one hour at ambient temperature, and then 1850 ml of water was added. After distillation of the chloroform, the solution was filtered over carbon black and benzamide was precipitated by the addition of 65 ml of soda lye. The solid was dried off, washed with water and dried at 40C. After recrystallization from absolute alcohol, 151 g of N-(l-methyl-2-pyrrolidyl-methyl)-7-ethylsulfonyl-1~4-benzodioxane-5-carboxamide was obtained. (Yield: 80.5%; melting point: 140 - 141C). ;~
The structure was confirmed by NMR.

1-(2,3-ethylenedioxy-5-sulfamoyl benzoyl)-4-(2-pyrimidinyl)-piperazine 146 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of dioxane and then 57 g of triethylamine were introduced into a 1 litre 3-neck flask provided with an agi-tator, a thermometer and an introduction funnel. The mixture was heated at 40 to 50C and ~30 ml of water was added. The solution was cooled to a temperature of from 5 to 10C and 61.5 g of ethyl chloroformiate was added. Agitation of the mixture was maintained for 1 hour at 10C and 93 g of 1-(2-pyrimidinyl)piperazine was added, without the temperature rising above 15C. Agitation of the mixture was continued for 1 hour at ambient temperature and then, after the addition of 1500 ml of water, the mixture was rendered alkal~ne to a pH-value of 10, by ammonia. The crystals produced after distil-lation under vacuum of the solvents and cooling, were dried off, washed with water, dried in a drying oYen at 50C and then purified by treatment with 120 ml of chloroform. After fil-tration and drying, 92 g of 1-(2,3-ethylenedioxy-5-sulfamoyl-benzoyl)-4-(2-pyrimidinyl)piperazine was produced. (Yield 40.2%; melting point: 239C).
The structure was confirmed by NMR analysis.

N-(l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide 7-dimethylsulfamoyl-1,~-benzodioxane-5-carbox~lic acid 500 cm3 of acetone and a solution of 99 9 of dimethylamine in 250 cm3 of acetone were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled at 0C, then, 139 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was agitated at ambient temperature, the acetone distilled off and the residue dissolved in 1 1 of water. The solution was rendered alkaline, filtered and treated with 70 cm3 of hydro-chioric acid. The precipitate was dried off, washed and dried.
128 g of 7-dimethylsulfamoyl~ -benzodioxane-5-carboxylic acid were obtained. ~M.P. - 220 - 221C; yield - 89~).

7-dimethylsulfamoyl-l,4-benzodioxane-5-carbonyl chloride 190 g of thionyl chloride and 153 g of 7-dimethyl-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated, then the thionyl chloride in excess was distilled off. 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were obtained. (M.P. - 160 - 162C, yield = 100%).
N-(l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide _ _ 61 g of 1-methyl-2-aminomethyl pyrrolidine and 560 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, and then, with the temper-ature being kept at from 0 to 5C, 163 g of 7-dimethyl-sulfamoyl-1,4-benzodioxane-5-carbonyl chloride was introduced.
The mixture was agitated for 1 hour, allowing the temperature to rise, and then 1 litre of water was added. After distil-lation of the chloroform the solution was filtered and the carboxamide was precipitated by the addition of 30% of soda lye. The crystals produced were filtered, washed with water and dried.
After recrystallization from absolute alcohol, 157 9 of N-(l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide was obtained. (Yield: 76.9%, ~; melting point: 165 - 166C).
The NMR spectra are compatible with the proposed structure.

N-(l-benzyl-2-pyrrolidylmethyl)-1,~-benzodioxane-5-carboxamide, 440 ml of chloroform and 110 g of 1-benzyl-2-amino-methyl pyrrolidine were introduced into a balloon flask pro-vided with an agitator and a thermometer, and then, at a . - ~

temperature of from 5 to 10C, 110 g of 1,4-benzodioxane-5-carbonyl chloride was added. After agitation of the mixture and addition of 3 litres of water, chloroform was removed.
The solution was treated with ammonia and then the precipitate was extracted by means of methylene chloride. The organic solution was dried and then the solvent was removed.
The resulting compound, dissolved in absolute ethanol, was treated with 30 ml of 85% phosphoric acid. The precipitate formed was dried off, washed with ethanol and dried. 153 g of N-(l-benzyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-oarboxamide phosphate was produced. (Yield: 61%; melting point: 165C).

N-(l-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-aminomethyl pyrrolidine were introduced into a balloon flask provided with a condenser. The mixture was heated on a water bath until a test sample was soluble in dilute acids, and then 1 litre of water was added. The precipitated carboxamide was redissolved, by acetate formation. The solution formed was filtered on carbon black and then the base was precipitated by the addition of 20% ammonia. The resulting crystals were dried off, washed with water, dried and purified by passing over hydrochloride (melting point: 228 - 230~C), followed by transformation into a base by treatment with 20% ammonia. 131 g of N-(l-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 64.8%; melting point: 143 - 144C).
The structure was confirmed by NMR analysis.

N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo-dioxane-5-carboxamide i Methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate 750 ml of methanol were introduced into a balloon flask provided with a condenser, then, under cooling, 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux, cooled and poured into water and sodium carbonate. The precipitate was dried off, washed and dried.
143 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxyl-ate were obtained. (M.P. - 159 - 160C; yield - 85%).
N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo-dioxane-5-carboxamide 137 9 of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 43 g of water and 73 g of 1-ethyl-2-aminomethyl ;~
pyrrolidine, were introduced into a balloon flask provided with an agitator and a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The carboxamide produced by cooling was purified by passing it over acetate, and then treatment with 100 ml of acetic acid in 950 ml of water. After the resulting solution was filtered on carbon black, the base was precipitated by the addition of 20% ammonia. The resulting crystals were dried off, washed with water, dried and purified by recrystalli~ation from boiling isopropyl alcohol. 121 g of N-(l-ethyl-2-pyrrol-idylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 66.2%; melting point: 139 - 140C).
The structure was confirmed by NMR analysis. The corresponding hydrochloride was produced by treatment of the carboxamide with hydrochloric acid ~specific gravity: 1.18) (melting point: 186 - 188C).

; N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide In a similar manner, 34.9 9 of ethyl 2,3-methylene-3~ L

dioxy benzoate was reacted with 24.2 g of 1-ethyl-2-aminomethyl pyrrolidine, to give, after treatment and purification, 28.3 g of N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide.
The NMR spectra are compatible with the expected structure.

Levorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 65 9 of levorotatory 1-ethyl-2-aminomethyl pyrroli-dine9 was dissolved in 430 ml of chloroformg in a balloon flask provided with an agitator and a thermometer. The resulting solution was cooled to 5C and then 148 g of finely pulverised 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5 to 10C. At the end oF the operation of introducing this substance, the -, mixture was agitated for 1 hour and then treated with 1 litre : .
of water. After distillation of the chloroform, the solution was filtered on carbon black and the base was precipitated by an excess o~ 30% soda. The resulting crystals were dried off, washed with water, dried and recrystallized from isopropyl alcohol.
151.5 g of levorotatory N-~l-ethyl-2-pyrrolidyl-methyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide was produced. ~Yield: 77.7%; melting point: 111 - 112C), ~D0 -54.2 (in 5% sGlution in dimethylformamide).

Dextrorotatory N~ ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl~
1,4-benzodioxane-5-carboxamide .~
In a similar manner, 64.5 g of dextrorotatory 1-ethyl-2-aminomethyl pyrrolidine was reacted on 146 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give, a~ter treatment and purification, 133.5 g of dextrorotatory N-~;

3~7:~

(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide. (Yield: 69.8%; melting point: 111 - 112C);
- 55.5 (in 5% solution in dimethylformamide).
EXAMPLE 1?
N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-dioxane-5-carboxamide , In a similar manner, 58 9 of 1-ethyl-2-aminomethyl pyrrolidine was reacted on 131 g of 7-ethylsulfonyl-1,4-benzo-dioxane-5-carbonyl chloride to give, after treatment and puri-fication, 103.5 9 of N-(l-ethyl-2-pyrrolidylmethyl)-7-ethyl- -sulfonyl-1,4-benzodioxane-5-carboxamide. (Yield: 60.2%;
melting point: 118 - 119C). 100 9 of the base prodwced was dissolved in 220 ml of acetone, then the solution was filtered on carbon black, and a solution of 9.5 9 of hydrochloric acid in acetone was added. The resulting hydrochloride crystals were dried off, washed with acetone and then dried. 96 9 of N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride was produced. (Yield: 88.2%i melting point: 148 - 150C).

N-(l-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-aminomethyl pyrrolidine were introduced into a balloon flask provided with a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The carboxamide produced by cooling was purified by treatment with ; a solution of 50 ml of acetic acid in 1250 ml of water. After the resulting solution was filtered on carbon black, the base was precipitated by the addition of 2~% ammonia. The resulting crystals were dried off, washed with water, dried and purified ~$~

by recrystallization from boiling methyl alcohol. 119.5 g of N~ methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 70.1%; melting point:
187 - 188C).

N-(l-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-dioxane-5-carboxamide 58 g of 1-allyl-2-aminomethyl pyrrolidine and 360 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer and then, with the tempera-ture being maintained at 5 to 10C, 120 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added. After agi-tation of the mixture and the addition of a litre of water, chloroform was distil.led. The resulting solution was filtered on carbon black and then the base was precipitated by the addition of 40 ml of 30~ soda lye. The resulting crystals were dried off, washed with water and then dried~ 152 g of N-(l-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 93.4%; melting point:
78 - 80C). 146 g of the resulting base was dissolved hot in 290 ml of absolute alcohol and then the solution was filtered on carbon black and acidified by the addition of a solution of 13.5 g of hydrochloric acid in 100 ml of absolute alcohol.
After cooling, the crystals formed were dried off, washed with absolute alcohol and dried, and then purified by recrystalli-zation from absolute alcohol. 119.5 g of N~ allyl 2-pyrrol-idylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride was produced. tYield: 75%; melting point:
138 - 140C).
:

N-(l-ethyl-2-pyrrolidylme~hyl)-2~-3,4-dihydro-1,5-benzo-dioxepine-6-carboxamide __ Methyl 2~I-3,4-dihydro-1,5~benzodioxepine-6-carboxylate - ~2 -, - .

~ 7 111 9 of methyl 2,3-dihydroxy benzoate, 660 cm3 of methyl ethyl ketone, 167 y of 1,3-dibromopropane and 10 9 of sodium iodide were introduced into a balloon flask provided with an agitator and a therrnometer. The mixture was heated at 40C then 182 9 of potassium carbonate were added. The mixture ~-was heated under reflux and 2 1 of water were added. The oily phase was decanted, extracted by ether and the solution was washed with 10% soda and dried. The ether was removed. By distillation under vacuum, 86.5 9 of methyl 2H-3,~-dihydro-1,5-benzodioxepine-6-carboxylate were obtained. (Boiling point =
166 - 176C under 8 mm/Hg; yield ~ 63%).
2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid _ 160 9 of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate and 388 cm3 of soda were introduced into a balloon flask provided with a condenser. The mixture was heated under reflux then poured into 1 1 of water and treated with 5 g of ~ sodium metabisulfite. The solution was filtered and treated ; with 77 cm3 of concentrated hydrochloric acid. The precipitate was drained off, washed with water and dried. 120 9 of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were obtained.
(M.P. - 65 - 67C; yield - ~0.5%).
2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride 246 9 of thionyl chloride and 134 9 of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated under reflux, then the thionyl chloride in excess was distilled off under vacuum. 147 9 of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were obtained. (M.P. - 35 -37C; yield = 100~).
N-(l-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxe-pine-6-carboxamide 92 g of 1-ethyl-2-aminomethyl pyrrolidine and 458 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, and then, with the temper-ature being kept at from 5 to 10C, 152 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride was added. After agi-tation for 1 hour, with the temperature being allowed to rise, 1450 ml of water was added, then chloroform was distilled. The solution was filtered over carbon black and the base was precipitated by the addition of 75 ml of 20% ammonia. The crystals formed were dried o-Ff, washed with water and dried.
191 g of N-(l-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide monohydrate was produced. (Yield:
82.4%; melting point: 51 to 52C). 173.5 g oF the compound produced was dissolved in 750 ml of absolute alcohol. The solution was filtered over carbon black and then a solution of 62 g of 85% phosphoric acid in 100 ml of absolute alcohol was added. The crystals formed were dried oFf, washed with abso-- lute alcohol and dried, and then recrystallized from alcohol.
198 g of N-(l-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide phosphate was produced. (Yield:
92%; melting point 189 - 190C).

N-(l-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzo-dioxane-5-carboxamide 169 9 of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of l~methyl-2-aminomethyl pyrrolidine were introduced into a balloon flask provided with a reflux condenser.
The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1250 ml of water, then the solution was filtered over carbon - 2~ -, black and the base was reprecipitated by the addition of 100 ml of 20~ ammonia. The crystals were dried off, washed with water and dried. 182 g of N~ methyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield:
83.6%; melting point 189 - 190C).

N-(diethylaminoethyl)-1,4-benzodioxane-5-carboxamide,hydro-chloride 21 9 of die~hylaminoethylamine and 85 ml of acetone 10 were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 0C, then 36 9 of 1,4-benzodioxane-5-carbonyl chloride were added. The crystals formed at ambient temperature were dried off, washed with acetone, dried and purified by recrystalli~ation from isopropyl alcohol. 36.5 9 of N-(diethylaminoethyl)-1,4-benzodioxane-5-carboxamide hydrochloride were obtained. (M.P. - 120C~
yield _ 64%).

~::
N-(l-ethyl-2~pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzo-20 dioxane-5-carboxamide 13 9 of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid, 3ao ml of tetrahydrofuran and 13 9 of carbonyldiimidazole were introduced into a balloon flask provided with an agitator, - a thermometer and a condenser. The mixture was agitated at ambient temperature and then 9.5 9 of 1-ethyl-2-aminometh~l pyrrolidine was added. Agitation was maintained at ambient temperature and then the solvent was evaporated under vacuum. d The crystals produced were washed with water and then dried.
14 9 of N-(l-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-- 30 benzodioxane-5-carboxamide was produced. (Yield: 73.8%;
mPlting poin~ 118 - 119C).
;~

- ~5 -.. . .
: , : ' N~ methyl-2-pyrrolidylmethyl)-7 dimeth~ylsulfamoyl-1,4-benzo-dioxane-5-carboxamide A solution of 6 9 of 1-methyl-2-aminomethyl pyrroli-dine in pyridine, and then, dropwise, with agitation and with the temperature being kept at from 0 to 5C, a solution of 3.5 g of phosphorus trichloride in 20 ml of pyridine~ were intro-duced into a balloon flask provided with an agitator, a thermo-meter and a condenser. Agitation was maintained at a temper-ature of from 0 to 5C and then at ambient temperature. 14.5 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was then added. The mixture was heated with agitation. After the mixture had been cooled and the solvent removed, the residue was dissolved in chloroform, then the solution was washed with aqueous sodium carbonate and dried on anhydrous magnesium sulfate. After concentration under reduced pressure, 12.5 g of N-~l-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide was produced. (Yield: 64.5%; melting point: 165 - 166C).

N-(l-cyclohexy1-3-pyrrolidyl)-7-methylsulfamoyl-1,4-ben~o-dioxane-5-carboxamide 84 9 of 1-cyclohexyl-3-aminopyrrolidine, 430 ml of chloroForm and 146 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture, the base was extracted with methylene chloride and then the solvent was evaporated. The crystals formed were dissolved in boiling absolute alcohol and the resulting solution was filtered on carbon black. The crystals produced after cooling were dissolved in a solution of acetic acid in water, then the solution was filtered over carbon black and the 3'~

base was reprecipitated by the addition of 20% ammonia. 129.5 g of N-(l-cyclohexyl-3-pyrrolidyl)-7-me~hylsulfa~oyl-1,4-benzo-dioxane-5-carboxamide was produced. (Yield: 61.2%; melting point: 160 - 161C).

N-(l-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide 64 g of 1-ethyl-2-aminomethyl pyrrolidine and 530 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, and then, with the temper-ature being maintained at from 0 to 5C, 153 9 of 7-dimethyl-sulfamoyl-1,4-benzodioxane-5-carbonyl chloride was added. The mixture was a~itated for an hour, allowing the temperature to rise, and then 1 litre of water was added. After distillation ~; of the chloroform, the solution was filtered and the carbox-amide was precipitated by the addition of 30% soda lye. The `
crystals produced were filtered, washed with water and dried.
After recrystallization from absolute alcohol, 144.5 9 of N-(l-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzo-20 dioxane-5-carboxamide was obtained. (Yield: 72.8%; melting -point 146 - 1~8C).

Dextrorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide 82 9 of dextrorotatory 1-ethyl-2-aminomethyl pyrroli-dine, 600 ccm of chloroform and, gradually, at a temperature nf from 5 to 10C, 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, were introduced into a balloon flask with an agitator and a thermometer.
After the addition of a litre of water, chloroform was distilled, then the remaining solution was filtered. The base was precipitated by the addition of 60 ccm of 20% ammonia.

- 27 ~

The crystals formed were dried off, washed with water and then dried. 162 9 of dextrorotatory N~ ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced.
. (Yield: 66%; melting point: 136 - 137C).

Levorotatory N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-194-benzodioxane-5-carboxamide In a similar manner to that of the above example, 82 g of levorotatory l-ethyl-2-aminomethyl pyrrolidine was reacted with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, to give 151 g of levorotatory N-(l-ethyl-2-pyrrol-idylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.
(Yield: 62%, melting point: 136 - 137C).

Levorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methylsul~amoyl-1,4-benzodioxane-5-carboxamide 85 g of levorotatory 1-allyl-2-aminomethyl pyrrol-idine, 610 ccm of chloroform, and gradually, 178 9 of 7-methyl-sulfamoyl-1,4-benzodioxane-5-carbonyl chloride, at a temper-ature of from 5 - 10C, were introduced into a balloon flask provided with an agitator and a thermometer.
After agitation oF the mixture, 1.2 litres of water was added, then chloroform was distilled.
The remaining solution was filtered and then the base was precipitated by 70 ccm of 20% ammonia. The crystals formed were dried off ~nd washed with water.
After recrystallization from ethyl acetate, 117 9 of levorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 49%;
melting point: 101 - 102C).

Dextrorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methyl-sulfamovl-1,4-benzodioxane-5-carboxamide ~, In a similar manner to the above example, 84 9 of dextrorotatory l-allyl-2-aminomethyl pyrrolidine was reacted with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, to give, after purification, 125 g of dextrorotatory N-(l-allyl-2-pyrrolidylmethyl)-7-methylsulFamoyl-1,4-benzo-dioxane-5-carboxamide. (Yield: 52.6%; melting point 104 -105C) Dextrorotatory N-(l-methyl-2-pyrrolidylmethyl)-7~methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide 61 g oF dextrorotatory l-methyl-2-aminomethyl pyrrol-idine, 465 ccm of chloroform, and, in portions, 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the ; temperature being maintained at 5 to 10C, were introduced into , a balloon flask provided with an agitator and a thermometer.
After agitation of the mixture and the addition of 1850 ccm of water, chloroform was distilled and the remaining solution was filtered. The base was precipitated by the addition of 65 ccm of 20% ammonia. The crystals formed were dried off, washed and dried. 154 g oF dextrorotatory N-(l-methyl-2-pyrrolidyl-methyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 78.5%; melting point: 187 - 188C).
;~ EXAMPLE 27 Levorotatory N-(l-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide In a similar manner to that of the above example, 71 g of levorotatory l-methyl-2-aminomethyl pyrrolidine was reacted with 180.5 9 of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, to give 175 9 of levorotatory N-~l-methyl-2-30 pyrrolidylmethyl)-7-methylsulfamoyl-174-benzodioxane-5-carbox-amide. (Yield: 77%; melting point: 187 - 187.5C).
, 'XAMPLE 28 N~ 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 cm3 of chlorosulfonic acid were introduced into a balloon flask provided with an agitator, a condenser and a thermometer, then, in portions, 106 9 of 2H-3,4-dihydro-1,5-benzodioxepine~6-carboxylic acid were added, with the temper-ature being maintained at from 5 to 10C. The mixture was agi-tated at ambient temperature then poured on ice. The crystals were dried off, washed with water and dried. 146 9 of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were obtained. (M.P. 114 - 115C; yield - 91%).
8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbox-ylic acid .
233 g of a methylamine aqueous solution were intro-duced into a balloon flask provided with an agitator and a thermometer, then, in portions, 146 9 of 8-chlorosulfonyl-2-H-- 20 3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added, with the temperature being maintained at from 5 to 10C. The mixture was agitated and the precipitate was then dissolved in water. The solution was filtered and treated with 150 cm3 oF
concentrated hydrochloric acid. The crystals were dried oFf, washed and dried. 112 9 of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were obtained. (M.~. -145 - 146C; yield - 78%).
8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride 220 y of thionyl chloride and 177 9 of 8-methyl-sulfamoyl-2~1-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were introduced into a balloon flask provided with a condenser.
The mixture was heated, then the thionyl chloride in excess was distilled off under vacuum. 188 9 of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzod;oxepine-6-carbonyl chloride were obtained.
~M.P. - 93 - 94C; yield ~ lOOX).
N-(1-ethyl-2-pyrrolidylmethyl )-8-methylsul famoyl -2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide 79 9 of l-ethyl-2-aminomethyl pyrrolidine, 750 ccm of methyl ethyl ketone and, gradually, 188 9 of 8-methylsul famoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride, with the temperature being maintained at from 5 to 10C, were introduced into a balloon flask provided with an agitator and a thermo-meter.
The hydrochloride precipitate was dried off, washed with methyl ethyl ketone and then dried.
After recrystallization from methyl alcohol, the '!"~
hydrochloride was dissolved in 850 ccm of water. The solution , ;~
was filtered and then the base was precip; tated by the addition of 60 ccm of 20X ammonia. The crystals formed were dried o'F'F9 washed with water and then dried. 180 9 of N-(l-ethyl-2-pyrrolidylmethyl )-8-methylsulfamoyl-2H-3,4-dihydro-lj5-benzo- , ~5 dioxepine 6-carboxamide was produced. (Yield: 63.8%; melting point: 144 - 145C). ' N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylene dioxy benzamide hYdrochloride _ _ 134 9 of l-ethyl-2-aminomethyl pyrrolidine, 950 ccm of chloroform and, gradually, 183 9 of 293-methylenedioxy benzoyl chloride, with the temperature being maintained at-from 5 to 10C5 were introduced into a balloon flask provided with an agitator and a thermome~er.
After the addition of 1 litre of water, chloroform was distilled and then the remaining solution was filtered.
After the addition of 120 ccm o~ 20% ammonia and extraction with ether, the ethereal solution was dried on potassium carbonate and thesl the ether was distilled.

37 ~

The base produced was dissolved in 300 ccm of acetone and then a solution of 34 g of hydrochloric ac;d in 330 ccm o~
ace~one was added. The hydrochloridè precipita~e was dr;ed, washed with acetone and then dried.
After recrystallization from isopropyl alcohol, 154 9 of N-(l-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide hydrochloride was produced. (Yield: 49.7%; melting point:
127.5 - 128.~C).

4-(1,4-benzodioxane-7-ethylsulfonyl-5-carbonyl)-1,4-diaza- -bicyclo (4-3-0) nonane 41.5 9 of 1,4-diazabicyclo (4-3-0) nonane and 300 ml of chloroform were introduced into a 1 litre balloon flask.
The mixture was cooled to 5, then 87 9 of 7-ethyl-sulfonyl-1,4-benzodioxane-5-carbonyl chloride was added in ~- small amounts. After agitation of ~he mixture at ambient temperature 5 g of acticarbon was added. ~;
After filtration and removal of the chloroform, the oily residue was dissolved in 200 ml of water and then 30 ml of 20% ammonia was added. The resulting residue was dried and then recrystallized from acetone. 40 g of 4-(1,4-benzodioxane-7-ethylsulfonyl-5-carbonyl)-1,4-diazabicyclo (4-3-0) nonane was ; produced. (Yield: 35Xi melting point: 147C).
Example 31 ~ . .

5- ~ 4-methyl-1-1-piperazinyl)carbony ~-7-nitro-1,4-benzodioxane, hydrochloride _ 7-nitro-1,4-ben2Odioxane-5-carboxylic acid 16~ ml of acetic acid, 160 ml of acetic anhydride and 100 9 of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermo-meter. The mixture was heated and a solution Df 40 ml of ~ nitric acid in 40 ml of acetic acid was added. The mixture was :~
~ - 32 -. . . . ~ . . .

~ '7 ~

dgitated at 40 - 45C, then cooled. The crystals were dr;ed off, washed and dried. 34 9 of 7-nitro-1l4-benzodioxane-5-carboxylic acid were ob~ained. (M.P. - 246C; yield - 27%).
5- ~ 4-methyl-1-piperazinyl)carbony ~-7-nitro-1,4-benzodioxane, hydrochloride _ -22 ml of water, 22.5 9 of 7-nitro-1,4-benzodioxane-5-carboxylic acid, 65 ml of acetone and 10.5 9 of triethylamine were introduced into a 250 ml balloon flask provided with an agitator and a thermometer.
lD The mixture was cooled to 10C and then 14 9 of isobutyl chloroformiate was added. The mixture was agitated, the temperature being allowed to rise. The oily compound formed was cooled to 10, 11 9 of N-methyl piperazine was added, and then the mixture was agitated, allowing the temper-ature to rise.
The crystals formed were washed with water. 20.5 9 of 5- ~ 4-methyl-1-piperazinyl)carbony ~-7-nitro-1,4-benzo-dioxane was produced. (Yield: 66.7%; melting point: 218C).
The 20.5 9 o~ base produced was treated by a solution 20 of 7 ml of hydrochloric acid (specific gravity - 1.18) in 100 ml of water. The crystals formed by cooling were washed with water and then dried. 20.5 9 of 5- ~4-methyl-1-piperazinyl)-carbony ~-7-nitro-1,4-benzodioxane hydrochlor;de was ~roduced.
(Yield: 89.4%; melting point: 250C~.

5- ~ 4-methyl-1-piperazinyl)carbony ~-7- ~l-adamantyl)-sulfamoy~7-1,4-benzodioxane, hydrochloride_ 7-(1-adamantyl)sulfamoyl-1,4-benzodioxane-5-carboxylic acid 187.5 9 of adamantylamine hydrochloride, 500 ml of soda and 1000 ml of triethylamine were introduced into a balloon f1ask provided with an agitator and a thermometer. 280 g of 7-chlorosulfonyl-1,4-benzodioxane-5~carboxylic acid were ~; ~ - 33 -,v ~ '7 ~

then added at a temperature below 15C. The mixture was agi-tated at ambient temperature and treated with 1.5 1 of methyl-ene chloride. The organic phase was separated and the solvent removed. The residue was treated with 1200 ml of water and lS0 ml of hydrochloric acid, then the precipitate was dis-solved in 1200 ml of water and 120 ml of soda. The solution was filtered and treated with 150 ml of hydrochloric acid. The crystals were dried off, washed and dried. 200 9 of 7-(1-adamantyl)sulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. 205C; yield ~ 51%).
5- ~4-methyl-1-piperazinyl)carbony ~-7- ~l-adamantyl)-sulfamoy~/-1,4-benzodioxane, hydrochloride 500 ml of dioxane and 49 g of 7-(1-adamantyl)-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were introduced into a 1 litre balloon flask provided with an agitator and a thermometer. After agitation of the mixture, 12.5 9 of tri-ethylamine was addedg then, in small amounts, 17 9 of isobutyl-chloroformiate.
After agitation of the mixture at a temperature of 20C, a solution of 14 9 of N-methyl piperazine in 50 ml of dioxane was introduced. The mixture was agitated and then cooled. The triethylamine hydrochloride formed was removed by filtrationg the filtrate was concentrated under vacuum, and then dissolved in 300 ml of water. 15 ml of hydrochloric acid was added, then the solution was treated with 20 ml of ammonia.
The product formed was dissolved in 150 ml of boiling ethanol and the solution was filtered hot.
A solution of hydrochloric acid in absolute ethanol was added to the filtrate, until the pH-value was 1.
The crystals formed were dried off, washed with ethanol and dried. 37 9 of 5- ~4-methyl-1-piperazinyl)-carbony ~-7- ~l-adamantyljsulfamoy ~-1,4~benzodioxane hydro-\

7~
chloride was produced. (Yield: 58%; melting point: 260C).

N-(piperidinoethyl)-7-chloro-1,4-benzodioxane-5-carboxamide, hydrochloride _______ 7-amino-1,4-benzodioxane-5- arboxylic acid 56 9 of 7-nitro-1,4-benzodioxane-5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were introduced into an autoclave, then hydrogen under a pressure of 65 kg/cm was introduced while heating. The mixture was then agitated at 60C, and treated with a solution of 50 ml of soda lye in 450 ml of water. The solution was filtered and treated with 50 ml ; of hydrochloric acid. The precipitate was dried off, washed with water and dried. 36.5 9 of 7-amino-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. = 220C; yield - 75%).
7-chloro-1,4-benzodioxane-5-carboxylic acid 49 9 of 7-amino-1,4-benzodioxane-5-carboxylic acid, 200 ml of water and 50 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermo-meter. The mixture was cooled to 5C, then a solution of 17.5 9 of sodium nitrite in 38 ml of water was added.
The suspension was then poured into a solution of 20 g of cuprous chloride in 75 ml of hydrochloric acid. The pre-cipitate was dried off, washed and dissolved in a solution of 42 9 of sodium bicarbonate in 420 ml of water. The solution was filtered and treated with 100 ml of hydrochloric acid: 50 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid were obtained.
(M.P. = 180C; yield = 92.7%).
` 7-chloro-1,4-benzodioxane-5-carbonyl chloride 32.2 g of 7-chloro-1,4-benzodioxane-5-carboxy1ic acid 3~ and 64 ml of thiony~ chloride were introduced into a balloon flask provided with an agitator, a thermometer and a condenser.
The mixture was heated under reflux, then the thionyl chloride ~ 35 -in excess was distilled off under vacuum. 35 9 of 7-chloro~
1,4-benzodioxane-5-carbonyl chloride were obtained. (M.P. -140C; yield 100%).
N-(piperidinoethyl)-7-chloro-1,4-benzodioxane-5-carboxamide, hydrochloride 150 ml of methyl ethyl ketone and 22 9 of N-(amino-ethyl)piperidine were introduced into a 500 ml balloon flask provided with an agitator and a thermometer. The mixture was cooled, then a suspension of 35 g of 7-chloro-1,4-benzodioxane-5-carbonyl chloride in 200 ml of methyl ethyl ketone was added at a temperature of from 15 to 20C.
After agitation, the crystals formed were dried off, then washed with methyl ethyl ketone. 35 9 of N- ~iperidino ethy ~-7-chloro-1,4-benzodioxane-5-carboxamide hydrochloride was produced. (Yield: 64.5%, melting point: 192C).

N-(butyl)-7- ~l-adamantyl)sulfamoy ~-1,~-benzodioxane-5-carboxamide 500 ml of dioxane, 50 ml of water, 49 9 of 7- ~1-adamantyl)sulfamoy ~-1,4-benzodioxane-5-carboxylic acid and 12.5 9 of triethylamine were introduced into a 2 litre balloon flask provided with an agitator and a thermometer. The solution was agitated at ambient temperature, then 17 9 of isobutyl chloroformiate was added.
The mixture was agitated and then 10 9 of butylamine was introduced. After agitation of the mixture, dioxane was removed.
The residue was dissolved in 200 ml of water in a hot condition. The crystals formed by cooling were washed with water, dried and redissolved in 250 ml of acetone at boiling temperature. The solution was filtered hot. The crystals formed by cooling were dr~ed off, washed and dried. 26 g of N-(butyl)~7- ~l-adamantyl)sulfamoy ~-1,4-benzodioxane-5-carbox-amide was produced. (M.P. - 147C; yield - 46.4%)~

~ N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5--~ carboxamide oxalate '.:;
8-methoxy-1,4-benzodioxane-5-carboxylic acid 171.5 g of 2,3-dihydroxy-4-methoxybenzoic acid, 515 cm3 of alcohol, 280 cm3 of soda lye and 175 9 of ethylene bromide were introduced into a balloon flask provided with an agitator, a thermometer and an inlet pipe for nitrogen. The mixture was heated under reflux, then cooled and poured into 2.8 1 of water. The solution was filtered and treated with 85 cm of concentrated hydrochloric acid. The precipitate was dried off, washed and dried. After recrystallization in dimethylformamide, 110 9 of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. - 224 - 226C; 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 introduced into a balloon flask provided with a condenser. The mixture was heated at 50 - 55C and the thionyl chloridé in excess was distilled off under vacuum. 151 9 of 8-methoxy-1,4-benzodioxane-5-carbonyl ~` chloride were obtained ~yield 100%).
., .
N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide oxalate -- - , 87 9 of 1-ethy1-2-aminomethyl pyrrolidine and 775 ccm of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer, and then, in 30 portions, 155 9 of 8-methoxy-1~4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5 to 10C. After agitation, the mixture was dissolved :

~$~ 3'7~

with 1500 ccm of water -then the methyl ethyl ke-tone was dis-tilled. The remaining solution was filt:ered then treated with sodium hydroxide. The oil was decanted, then extracted with methylene chloride. The solution was dried on potassium carbonate and then methylene chloride was distilled under vacuum.
224.5 g of N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide was produced.
197.5 g of the base produced was dissolved in 760 ccm of absolute alcohol, then 67 g of oxalic acid in solution in 195 ccm of absolute alcohol was added. The crystals formed were dried off, washed with absolute alcohol and then dried.
208.5 g of N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide oxalate was produced. (Yield:
82%; melting point: 129 - 130C).

N-(l-ethyl-2-pyrrolidylmethyl~-8-methoxy-7-sulfamoyl-1,4-` benzodioxane-5-carboxamide 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid 1045 cm3 of chlorosulfonic acid were introduced into a balloon flask provided with an agitator, a thermometer and a condenser, then, in portions, 110 g of 8-methoxy-1,4-benzo-dioxane-5-carboxylic acid were added with the temperature being maintained at from 5 to lQC. The mixture was agitated at ambient temperature then poured on ice. The precipitate was dried off, washed and dried. 159 g of 8-methoxy-7-chloro-sulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained (yield 98%).
8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 300 g of 34% ammonia were introduced into a balloon flask provided with an agitator and a thermometer, theng 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-c:arboxylic ~, :

acid were added in portions, the temperature being maintained at from 0 to 5C. The mixture was agitated~ then the precipi-tate was dissolved in water. The solution was filtered and treated with 280 cm3 of concentrated hydrochloric acid. The precipitate was dried off, washed and dried. 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. 247 - 248C; yield 82%).
Methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate 396 g of methanol were introduced ;nto a balloon flask provided with a condenser, then 51 g of sulfuric acid and 114.5 g oF 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added while cooling. The mixture was heated under -reflux then poured into 485 cm3 of water and 40 g of sodium carbonate. The precipitate was dried off, washed and dried.
110.5 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained. (M.P. - 202 - 203C; yield - 92%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide _ _ 150 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzo-dioxane-5-carboxylate and 750 ccm of ethylene glycol were introduced into a balloon flask. After dissolution, 127 9 of l-ethyl-2-aminomethyl pyrrolidine was added and the mixture was heated at 50C. The resulting solution was dissolved with 2 litres of water and acidified by means of 120 ccm of acetic acid. The precipitate formed was dried off, washed with water and then dried.
The precipitate was then redissolved in 915 ccm of hot water. The solution was filtered and then the base was pre-cipitated with ammonia. The precipitate was dried ofF, washed with water and then dried. 144 g of N-(l-ethyl-2-pyrrolidyl-methyl)-8-methoxy-7-sulFamoyl-1,4-benzodioxane-5-carboxamide was produced. (Yield: 73%; melting point: 110 115C).

-. ~ - .

4-(1,4-benzodioxane-5-carbonyl)-1,4-diazabicyclo (4-3-0) nonane 63 9 of 1,4-diazabicyclo (4-3-0) nonane and 400 ml of chloroform were introduced into a 1 litre balloon flask pro-vided with an agitator and a thermometer and then, in portions, 50 9 of 1,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at 10C.
The mixture was then agitated at ambient temperature, and then 1 litre of water was added. ;~
After the addition of acetic acid to give a pH-value of 4, the addition of carbon black and filtration, the product was precipitated with ammonia.
After extraction by methylene chloride, the solution was dried and then filtered. The solvent was removed under vacuum and the resulting product was purified by recrystalli-zation from ethanol. 50 g of 4-(1,4-benzodioxane-5-carbonyl~-,; 1,4-diazabicyclo (4-3-0) nonane was produced. (Yield: 69%;
, melting point: 128C).

N-(benzyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 200 ml of water~ 100 ml of diethylamine and 200 ml of triethylamine were introduced into a balloon flask provided with an agitator and a thermometer, then, 140 9 of 7-chloro-sulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, the temperature being maintained at from 20 to 30C.
The mixture was agitated at ambient temperature then 500 ml of water were added. The solution was filtered and treated with 300 ml of hydrochloric acid. The precipitate was dried off~
washed and dried. 117 9 of 7-diethylsulfamoyl-1,4-benzo-dioxane-5-carboxylic acid were obtained. (M.P. - 149C; yield - 74%).

.

. .
,, 't~

N- ~benzyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide 37.8 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 40 ml of water, 12.5 g of triethylamine and 120 ml of acetone were introduced into a balloon flask provided with an agitator and a thermometer.
The mixture was cooled to about 10 to 15C and then 17.2 g of isobutyl chloroformiate was added.
After the addition, at a temperature of from 15 to 20C, of 14.1 g of benzylamine and agitation of the mixture, the crystals formed were dried off9 washed with water and then purified by recrystallization from ethanol.
33 g of N-(benzyl)-7-diethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide was produced. (Yield: 68%; melting point: 125C).

N-(l-benzyl-4-piperidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 70 ml of water, 68.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 25.5 g of triethylamine and 200 ml of acetone were introduced into a balloon flask provided with an agitator and a thermometer and then 34.5 g of isobutyl chloroformiate was added, with the temperature being kept at from 15 to 20C.
After the addition, at a temperature of from 15 to ` 20C, of 52 g of 1-benzyl 4-aminopiperidine and agitation of the mixture, the crystals formed were dried o-Ff, washed with water and then dried.
The product formed was purified by treatment with a solution of hydrochloric acid then precipitation by means of sodium hydroxide. The precipitate was then dried off, washed with water and dried.
76 g of N-(l-benzyl-4-piperidyl)-7-methylsulfamoyl-~ 3'7~

1,4-benzodioxane-5~carboxamide was produced. (Yield: 68%;
melting point: 228C).
EXAMPLE ~0 N-(l-adamantyl)-l,~-benzodioxane-5-carboxamide 200 ml of chloroform and 37.5 9 of adamantamine were introduced into a balloon flask provided with an agitator and a thermometer~ and then 50 g of 1,4-ben7Odioxane-5-carbonyl chloride was added in portions, at a temperature oF From 5 to 10C. After agitation at ambient temperature, 1500 ml of water was added and then chloroform was removed under vacuum. The base which was precipitated by ammonia was extracted by means of methylene chloride. AFter removal of the solvent, the residue was dissolved in hydrochloric ethanol. The crystals formed by cooling were dried off, washed and then dried. 20 g of N-(l-adamantyl)-1,4-benzodioxane-5-carboxamide was produced.
(Yield: 25%; melting point: 137C).

N-(l-benzyl-2-pyrrolidylmethyl)-7-diethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide phosphate ~0 ml of water, 37.8 9 of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 12.5 g of triethylamine and 120 ml of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer, and then 17.2 g of isobutyl chloroformiate was added at a temperature of From 15 to 20 C.
After agitation of the mixture 25 g of 1-benzyl-2-aminomethyl pyrrolidine was added, with the temperature being maintained at from 15 to 2~C.
The mixture was agitated at ambient temperature and then the solvents were removed. The residue was dissolved in 200 ml of methylene chloride and 300 ml oF water. After agi-tation, the solvent was decanted and then dried on magnesium ., . . ~ .

3\7~

sulfate. The solution was filtered and then the solvent removed. The resulting compound was dissolved in ethanol at boiling temperature and 18 g of 85% phosphoric acid was added.
The crystals formed by cooling were dried off, washed with ice-cold ethanol and then dried. 56 g of N~ benzyl-2-pyrrolidyl-methyl)-7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide phosphate was produced. (Yield: 79.6%; melting point 180C).

N-~l-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide, hydrochloride 200 ml of chloroform and 50 9 of 1-benzyl-4-amino-piperidine were introduced into a balloon flask provided with an agitator and a thermometer, and then 50 g of 1,4-benzo-dioxane-5-carbonyl chloride was added in portions, at a temper-ature of from 5 to 10C.
After agitation of the mixture at ambient tempera-ture, the solvent was removed under vacuum and the residue was dissolved in 300 ml of water. After precipitation of the base by addition of ammonia, the water was removed and the resulting product was treated with a solution of hydrochloric acid. 75 g of N-(l-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide hydrochloride was produced. (Yield: 77%; meltiny point:
205C).

N-(l-ethyl-2-pyrrolidylmethyl)-8 ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide, hydrochloride 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid A solution of 106 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 273 ml of acetic acid and 159.5 g of tin were introduced into a balloon flask provided with an agitator and a thermometerO The mixture was agitated under heatin~ at 40 - 45C, then 705 ml of concen-3'7~ ::
trated hydrochloric acid were added. After hea ~iIng at 55 -60C, the solution was cooled. The precipitate was dried off, washed and dried. 65 9 of 8-mercapto-2H-3,4-dil~dro-1,5-benzo-dioxepine-6-carboxylic acid were obtained. (M.IP.. = 99 5 -100C; yield - 80%).
8-ethylthio-2H-3,4-dih~dro-1,5-benzodioxepine-6-- rboxylic acid 8~ 9 of 8-mercapto-2H-3,4-dihydro-1,5- ~nzodioxepine-

6-carboxylic acid, 152 ml of water, 76 ml of sod~a and 58.5 9 of ethylsulfate were introduced into a balloon flas;k provided with a condenser. The mixture was heated under refl~x then cooled.
150 ml of water were added, then the solution wal~ filtered and treated with 60 ml of hydrochloric acid. The pre~ipitate was dried off, washed and dried. 88 9 of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid wert~ obtained.
(M.P. - 66 - 670; yield = 91%~.
8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepin~e-6-carboxyl;c ; acid - 88 9 of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine- ~-6-carboxylic acid in 528 ml of acetic acid were hntroduced into a balloon flask provided with a condenser, then ~10 ml of hydrogen peroxide were added in portions. The s~lution was ~ ;
heated and the a~etic acid removed under vacuum. The residue was dissolved in 180 ml of water and cooled. Th~ precipitate was dried off, washed and dried. 90 9 of 8-ethylsulfony7-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were obta-ined.
(M.P. = 142 - 1430; yield = gl%).
~ 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl -~ chloride - -75 9 of thionyl chloride and 90 9 of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were intro-duced into a balloon flask provided with a condenser. The mixture was heated at 45 - 50C and ~he thionyl chloride in .

, ,. : : .

3~7~

excess was removed under vacuum. The residue was treated with petrolic ether, then dried off, washed and dried. 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were obtained. (M.P. - 10~ - 110C; yield - 98%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine 6-carboxamide, hydrochloride 39.5 g of 1-ethyl-2-aminomethyl pyrrolidine in 282 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, then, 94 g of 8 ethyl-10 sulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were added in portions, the temperature being maintained at from 5 to 10C. The mixture was heated then poured into water.
The aqueous phase was cooled, filtered and treated with 30 ml of soda. The precipitate was extracted by methylene chloride and the organic phase was dried on potassium carbonate. The solvent was distilled off, the residue dissolved in isopropyl alcohol and treated with a solution of hydrochloric acid in isopropyl alcohol. The precipitate was dried off, washed with alcohol and dried. 98 g of N-(l-ethyl-2-pyrrolidylmethyl)-8-20 ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide were obtained. (M.P. - 141 - 142C; yield = 73~

5- ~4-methyl-1-piperazinyl)carbony ~-6~7-dibromo-8-nitro-1,4-benzodioxane 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 introduced into a balloon flask provided with an agitator, an introduction funnel and a condenser. The mixture was heated to 55C, then a solution of 700 y of bromine in 360 ml o~ acetic acid was added in portions. The mixture was heated to 120C, then cooled to 15C. The precipitate was dried off, washed with acetic acid and dried. 332 g of 6,7-: . .

dibromo-1,4-benzodioxane-5-carboxylic acid were obtained.
(M.P. ~ 212C). The structure was confirmed by NMR analysis.
6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid 166 9 of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid and 500 ml of acetic acid were introduced into a balloon flask. The mixture was heated to 37C then a solutior of 60 ml of nitric acid (d - 1.49) in 60 ml of acetic acid and sulfuric acid, as catalyst, were added. After heating at 50C, the mixture was poured in cold water, under agitation. The pre-cipitate was dried off, washed with water and dried. 107 9 oF6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. - 237C). The acid was purified by treatment with a solution oF 50 9 of sodium bicarbonate in 500 ml of water and precipitation by hydrochloric acid. The precipitate was dried off, washed and dried. Crystals were obtained.
. . .
(M.P. - 238C; yield = 61%). The structure was confirmed by NMR analysis.
6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride 96 9 of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid and 2Q0 ml of thionyl chloride were introduced into a balloon Flask provided with an agitator and a thermo-meter. The mixture was heated under reflux, then the thionyl chloride in excess was removed under vacuum. The residue was dissolved in 100 ml of isopropyl ether, then the solvent removed and the product air-dried. 91 9 of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were obtalned.
(M.P~ ~ 215C; yield - 91%).
5- ~4 methyl-1-piperazinyl)carbony ~-6,7-dibromo-8-nitro-1,4-benzodioxane 400 ml of methyl ethyl ketone and 11 9 of methyl-piperazine were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was coolecl to 10C, then, ~1 9 of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were added in portions with the temperature being maintained below 20C. After agitation of the mixture, the crystals were dried o~f~ washed with methyl ethyl ketone and dried, then dissolved in water and reprecipitated by addition of 50 ml of 20% ammonia. The crystals were dried off~ washed with water and dried. 33 9 of 5- ~4-methyl-1-piperazinyl)-carbony ~-6,7-dibromo-8-nitro-1,4-benzodioxane were obtained.
(M.P. 1&4C; yield 69.6%). The structure was con~irmed by I.R. and NMR analysis.

N-(l ethyl-2-pyrrolidylmethyl)-6,7-dibromo-8-nitro-1,4-benzo-dioxane-5-carboxamide .
In a similar manner, by substituting l-ethyl-2-amino-methyl pyrrolidine for methylpiperazine, N-(l-ethyl-2-pyrrol-idylmethyl)-6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide was obtained. (M.P. - 213C; yield 65%). The structure was confirmed by NMR analysis.

20 N-(l-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide _ 8-amino-1,4-benzodioxane-5-carboxylic acid 400 ml of water, 98.5 g of 6,7-dibromo-8-nitro-194-benzodioxane-5-carboxylic acid, 100 ml of soda and 10 9 of Pd/C
were introduced into an autoclave, then hydrogen under a pressure of 40 kg/cm2 was introduced while heating at 50C.
The mixture was ~iltered then treated with 95 ml of hydro-chloric acid. The precipitate was dried off, washed and dried.
42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were . .
30 obtained. (M.P. 186C, yield 83.7%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-amino-1,4~benzodioxane-5-carboxamide __ According to the method described in Example 2, 42 g -3'~

of 8-amino-1,4-benzodioxane-5-carboxylic acid were treated with methanol and the resulting compound treated with 33 9 of 1-ethyl-2-aminomethyl pyrrolidine and then with a solution of 13 g of hydroch1Oric acid in absolute alcnhol. 49 9 of N-(l-ethyl-2-pyrrolidylmethyl)-8-amino-1,4~benzodioxane-S-carbox- ~
- amide dihydrochloride were obtained. (M.P. - 173C; yield - -60%).

5- ~4-methyl-1-piperazinyl)carbony ~-8-chloro-1,4-benzodioxane 8-chloro-1,4-benzodioxane-5-carboxylic acid 29.3 9 of 8-amino-1~4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml oF hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermo-meter. The mixture was heated to 40C, then cooled to 5C and a solution of 10.5 9 of sodium nitrite in 20 ml of water was added in portions, with the temperature being maintained at from 5 to 10C. The mixture was agitated then poured into a solution of 12 9 of cuprous chloride in 45 ml of hydrochloric acid (d 1.18), with the temperature being maintained below 30C. The precipitate was dried off, washed with hydrochloric acid and water, then dissolved in 300 ml of water and 25 9 of sod;um bicarbonate. The solution was filtered and treated with hydrochloric acid. The precipitate was dried off, washed with water and dried. 20 g of 8-chloro-1,4-benzodioxane-5-carbox-ylic acid were obtained. (M.P. - 195C, yield - 62~).
5- ~4-methyl-1-piperazinyl)carbony ~-8-chloro-1,4-benzodioxane According to the method described in Example 33, 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were treated with thionyl chloride and the resulting 8-chloro-1,4-benzo-dioxane-5-carbonyl chloride. (M.P. - 830) was treated with 10.5 g of methylpiperazine. 14 g of 5- ~4-methyl-1-pipera-. :

zinyl)carbony ~-8-chloro-1,4-benzodioxane were obtained. (M.P.
= 260C with decomposition, yield 50.5%).

N-(l-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-carboxamide 8-acetamino-1,4-benzodioxane-5-carboxylic acid 43 9 of 8-amino-1,4-benzodioxane-5-carboxylic acid and 72 ml of acetic acid were introduced into a balloon flask, then 24.5 ml of acetic anhydride were added in portions. The mixture was heated at 60 - 70C, then cooled. The precipitate was dried off, washed with acetic acid and water and dried. 44 g of ~-acetamino-1,4-benzodioxane-5-carboxylic acid were ob-tained. (M.P. = 233C; yield - 84%).
N-(l-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide _ `
According to the method described in Example 31, the 8-acetamino-1,4-benzodioxane-5-carboxylic acid was treated with isobutyl chloroformate and l-ethyl-2-aminomethyl pyrrolidine.
N-(l-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide was obtained. The structure was confirmed by NMRanalysis.

N-(diethylaminoethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-carboxamide 42 g of 8-acetamino-1,4-benzodioxane-5-carboxylic acid, 75 ml of acetic acid and 74 ml oF acetic anhydride were introduced into a balloon flask, then a solution of 17.5 ml of nitric acid (d - 1.49) in 17 ml of acetic acid was added, with the temperature being left rising. After dissolution and ; 30 crystallization, 50 ml of acetic acid were added. The mixture was agitated at 40 - 45C then cooled to 20C. The precipitate was dried off, washed with acetic acid and water and dried.
13.5 g of a 50% mixture of 7-nitro-8-acetamino-1,4-benzo-~h~

dioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-benzo-dioxane-5-carboxylic acid were obtained. The 7-nitro-8-acet-amino-1,4-benzodioxane-5-carboxylic acid was separated and then treated according to the process of Example 31, with isobutyl chloroformate and diethylaminoethylamine. N-(diethylamino-ethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-carboxamide was obtained. The structure was confirmed by NMR analysis.
EX~MPLE 50 N-(l-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzodioxane-5-carboxamide

7,8-azimido-1,4-benzodioxane-5-carboxylic acid 13 g of a 50% mixture of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid, 90 ml of water, 4.5 ml of sodium hydroxide, some Raney nickel and hydrogen under a 50 kg/cm2 press~re were introduced into an autoclave. At the end of the hydrogen absorption, the nickel was filtered off and the solution was treated with 12 ml of hydrochloric acid then with a solution of 3.5 g of sodium nitrite in 10 ml of water, at a temperature of from 20 to 25C. The obtained precipitate was dried off, washed then treated with an aqueous sodium hydroxide solution. The mixture was acidified, then the precipitate was dried off, washed and dried. 3 g of 7,8-azimido-1,4-benzo-dioxane-5-carboxylic acid were obtained. (M.P. : 260C with decomposition - yield 59%).
N-(l-allyl-2-pyrrolidylmethyl)-7,8-azimido-1~4-benzodioxane-5-carboxamide The 7,8-azimido-1,4-benzodioxane-5-carboxylic acid was treated with the N-hydroxyphthalimide together with the dicyclohexylcarbodiimide. The obtained phthalimide carboxylate was treated with the l-allyl-2-aminomethyl pyrrolidine. The N-(l-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzod-ioxane-5-~ 37~

carboxamide was obtained~ the structure oF which was confirmed by NMR.

N-(2-pyrimidyl)-6-chloro-1,4-benzodioxane-5-carboxamide 6-nitro-1,4-benzodioxane-5-carboxylic ac _ 1600 ml of acetic acid~ 1600 ml of acetic anhydride, 100~ 9 of 1,4-benzodioxane-S-carboxylic acid were introduced in a 6 liter bal100n flask provided with an agitator and a thermo-meter. The mixture was heated to 40C and a solution of 400 ml o~ nitric acid in 400 ml of acetic acid was added. AFter the introduction, the mixture was stirred at 40 - 45C for 2 hours, then cooled to 5C. The precipitate was dried off, washed with 600 ml of acetic acid, then with water and dried at 40C. 700 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were collected~
the structure of which was confirmed by NMR (M.P. : 246C).
The mother-liquors were diluted with 25 liters of water~ and ;~
the obtained precipi~ate w~s dried o~f, washed with water and dried. The S-ni~ro-194-ben70dioxane-5-carboxylic acid was obtained. (M.P. : 188C).
6-amino-1,4-benz dioxane-5-carboxylic acid, hydrochloride 195 9 of 6-nitro-1,4-benzodioxane-5-carboxylic acid, ~ 1950 ml of ethanol, some Raney nickel were introduced into an -~ ~utoclave. The mixture was hydrogenated under a hydrogen -~ pressure o~ 35 kg/cm~ at 60C for one hour, then cooled. -The nickel was filtered and the solution was acidi~ied with 160 ml of an ethanolic solution of hydrochloric acid ~23 9/lOO ml~.
The precipitate was filtered, dried. 115 9 of 6-am;no-1,4-benzodioxane-5-carboxylic aoid hydrochloride were obtainedO
(M.P. : 160C - yield 57.5X).
6-chloro-1,4-benzodioxane-5-carboxylic acid 58 9 of 6-amino-1~4-benzodioxane-5-carboxylic aeid ~ '7 hydrochloride, 116 ml of water were introduced in a 500 ml balloon flask provided with a stirrer, a thermometer and a dropping funnel. 28 ml of hydrochloric acid (d _ 1.18) were added and the mixture was cooled to a temperature of from 0 to 5C.
A solution of 17.5 g of sodium nitrite in 38 ml of water was added at a temperature within the 0 - 5C range. The mixture was stirred for one hour. 20 g of cuprous chloride and 75 ~1 of hydrochloric acid were added. The mixture wa~
allowed to stand overnight, ~hen filtered.
The solid was washed with water, dried at 50C and purified by treatment with carbon black in alkaline solution (200 ml of water and 25 ml of 36 Bé caust;c soda lye), then addition of 25 ml of hydrochloric acid. 40 9 of 6-chloro-1,4-; benzodioxane-5-carboxylic asid were obtained. (M.P. : 162C -yield 74%).
; 6-chloro-1,4-benzodioxane-5-carbonyl chloride - 56 ml of thionyl chlorideg 28 9 of 6-chloro-1,4-benzodioxane-5-carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer7 a condenser and a thermometer . The mixture was heated at the reflux temperature for 30 minutes. The excess of thionyl chloride was removed by distillation under reduced pressure. 28.5 9 of 6-chloro-1,4-.. . .
benzodioxane-5-carbonyl chloride were obtained; (M.P. : 50C - `
yield 93X~.
N-(2-pyrimidyl~-6-chloro-1,4-benzodioxane-5-carboxamide 280 ml o~ methyl ethyl ketone,13 9 of 2-aminopyrimi-dine were put into a 500 ml balloon flask provided with a stirrer :.
and a thermometer. The mixture was cooled to 10C and 28 9 of ground 6-chloro-1,4-benzod;Qxane-5-carbonyl chloride was added and stirred for 2 hours, the temperature being allowed to rise .

-to 20C. The obtained solid was filtered off, washed with 30 ml of methyl ethyl ketone~ then dissolved in 250 ml of boiling water. The solution was treated wi~h 10 ml of 35 Be caustic soda lye. After filtra~ion 12 9 of product were obtained and crystallized again from 150 ml o~ ethanoll. 9.5 9 of N-(2-pyrimidyl)-6-chloro-1,4-benzodioxane-5-carboxamide were obtained.
(M.P. = 223C with decomposition). The structure was confirmed by NMR analysis.

5- ~ 4-methyl~l-piperazinyl )carbony~-6-nitro-1 ,4-benzodioxane hYdrochloride .
360 m~ of methyl ethyl ketone and 16 9 of N-methyl piperazine were introduced into a 500 ml balloon flask provided with a stirrer and a thermometer. The mixture was cooled to 10C then~ 36.5 9 of 6-nitro-1,4-benzodioxane-5-carbonyl ~; chloride were added in portions. The mixture was maintained under stirring at ambient temperature for one hour. The pre~
eipitate was dried oFf, washed with 150 ml of methyl ethyl ketone, dried and then dissolved in 210 ml of cold water. The solu~ion was acidified ~o pH-l by addition of hydrochloric acid, treated with carbon black and filtered. The base was precipitated by addition of lS ml of soda lye. The precipitate was washed with water and dried. 24 9 were obtained. (M.P. -221C).
The base was then treated with 168 ml of ethanoi containing ~ ml of water and 8 ml of hydrochloric acid (d _ 1.18). After crystalliza~ion~ the solid was filtered off, washed, dried. 19.5 g of 5- ~ 4-me~hyl-1-piperazinyl)carbony ~-6-nitro-1,4-benzodioxane hydrochloride was obtained. (M.P. :
205C with decomposition~ The structure was confirmecl by NMR
analysis.

~ 53 ~

~ 3'~

N-diethyl-7-cyclohe~ moyl-1,4-benzodioxane-5-carboxamide .
7-cyclohexylsulfamcyl-1_,4-benzodioxane-5-carbo~ylic acid 250 ml of water and 300 m1 of cyclohexylamine were put into a 1 liter balloon flask. 13g 9 of moist 7-chloro-sulfonyl-1,4-benzodioxane-~-carboxylic acid were added by -~
fractions, the temperature being maintained at from 20 to 30C.
- The mixture was stirred at room temperature for 3 hours then the solution was treated with 30 9 of carbon black 35. After filtratio~, 300 ml of hydrDchloric acid (d = 1.18) were added.
The precipitate was recrystalli~ed, washed with water, dried.
92 9 of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained. (M.P. ; 150C).
N-diethyl-7-cyclohexylsulfamoyl-194-benzodioxane-5-carboxam;de 34.1 9 of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 35 ml of water and 10.5 9 of triethylamine were introduced into a 250 ml balloon ~lask provided with a stirrer and a thermometer. 100 ml of acetone were added and the mixture was cooled to 10C. 14 g of isobutyl chloro-formiate were added and the mixture was maintained under stirring for 30 m~nutes at room temperature. 8 9 of diethyl-amine were introduced at a temperature of from 15 to 20C.
After stirring during 3 hours, the solvent was removed under vacuum. The residue was washed with water, dr~ied, dissolYed in:
180 ml of absolute ethanol and treated with 3 g of black`
carbQn. After filtration3 crystallizationp 23 9 of N-diethyl-7-cyclohexylsulfamoyl-1~4-benzodioxane-5-carboxamide were obtained. (M.P. : 201C). The structure was con~irmed by IR
and NMR analyses.
~ 30 EXAMPLE 54 - N-(4-methyl-1-piperazinyl)~7-nitro 1,4-benzodioxane-5-carboxamide, hydrochloride __ :

~ 3'~

7-nitro-1,4-benzodioxane-5-carbonyl chlori~e 112 ml of thionyl chloride, 56 9 of J-nitro-l 94-ben~odioxane-5-carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a thermometer and a reflux condenser. The mixture was stirred and 1 ml of dimethylformamide was added with heating. After stirring for 1 hour at ~he reflux temperature, the excess o~ thionyl chloride was removed by distillation under vacuum. 61 9 of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were obtained.
(M.P. : 108C, yield near 100%).
N-(4-methyl-l~piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide 33 9 of 1-amino-4-methylpiperazine were dissolved in 630 ml of methyl ethyl ketone. The mixture was cooled to 10C
and 61 g of 7-nitro-1~4-benzodioxane-5-carbonyl chloride were introduced by portions. The mix~ure was stirred for 2 hours then the solid was filtered off, washed wi~h 150 ml of methyl ethyl ketone~ The obtained product was purified by transfor-mation in~o the base (M.P. : 212C) and crystallization by ~- 20 treatment with hydrochloric ethanol.
45 9 of N-(4-methy~ piperazinyl)-7-nitro-~,4-benzo-dioxane-5-carboxamide were obtained. ~M.P~ = 210~ with one mole of water~. The structure was confirmed by NMR and IR
analyses.
EXA~PLE 55 N-(l-allyl-2-pyrrolidylmethyl) 6,7-az;mido-1,4-benzodioxane-5-carboxamide, h~drochloride 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid 165 ml of nitric acid ~d - 1.49) were put into a 500 ml b~lloon flask provided with a mechanical stirrer and a thermometer. 90 g of 1,4-benzodioxane-5-carboxylic acid ~ere added a~ -10C. The mixture was maintained for 2 hours at room ~ t_......
` .

temperature, then 1 liter iced water was added. The precipi-tate was filtered ofF, washed with water, dried at 50C, ~hen " purified by recrystallization in the acetic acid. 87 g oF 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid were collected.
(M.P. : 211C).
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 o~ soda lye were introduced into a 1 liter autoclave and hydrogenated under a 80 kg pressure in presence of Raney nickel. The mixture was heated to 100C for 2 hours then cooled, filtered; the nickel was washed on the filter with 200 ml of water and the filtrates were kept all together. A sample was acidified with the hydrochloric acid to form the 1,4-benzodioxane-6,7-diamino-5-carboxylic acid di-hydrochloride which was filtered, washed and dried. (M.P. -153C).
1,4-benzodioxane-6,7-azimido-5-carboxylic acid The above obtained filtrate was introduced in a 2 liter balloon flask provided with a mechanical stirrer and a thermometer. A solution of 35 g of sndium nitrite in 70 ml of water was added dropwise at a temperature from 20 to 25C. The crystallized product was filtered off, washed with water, dried at 50C. 96 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid was obtained (yield 87%). The structure was confirmed by NMR analysis.
1,4-benzodioxane-6,7-azimido-5-N-phthalimide carboxylate 74 g of the 1,4-benzodioxane-6,7-azimido-5-carboxylic acid, 1 liter of dimethylformamide, 57 g of N-hydroxyphthal-imide, 74.5 g of dicyclohexylcarbodiimide were heated at a temperature of 9~C for 30 minutes. After cooling to 20C, the crystals were filtered off, washed with 150 ml of dimethyl-; - 56 -t ~ 3'7~

formamide. The filtrates were evaporated under vacuum and the residue was treated with 400 ml of methanol. The solid was filtered, washed and dried. 80 g oF 1,4-benzodioxane-6,7-azimido-5-N-phthalimide carboxylate were obtained. (M.P. :
above 250C - yield 65.6%).
N-(l-allyl-2-pyrrolidylmethyl)-6,7 azimido-1,4-benzodioxane-5-carboxamide, hydrochloride 92 9 of 1,4-benzodioxane-6,7-azimido-5-N-phthalimide carboxylate, 500 ml of dimethylformamide were introduced into a 1 liter balloon flask provided wi~ha mechanical stirrer and a thermometer. 45 9 of 1-allyl-2-aminomethyl pyrrolidine were added under stirring which was maintained at room temperature for 2 hours. After evaporating of the solvent, the residue was treated with 500 ml of hot acetone. After filtration, 50 ml of an ethanolic solution of hydrochloric acid were added to the ;
filtrate. The product was filtered, washed, recrystallized.
50 9 of N-(l-allyl-2-pyrrolidylmethyl-6,7-azimido-1,4-benzo-dioxane-5-carboxamide hydrochloride were obtained. (M.P. :
255C). The structure was confirmed by IR and NMR analyses.
EXAMPL~ 56 5- ~4-methyl-1-piperazinyl)carbony ~-6,7-dinitro-1,4-benzo-dioxane 1,4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate 54 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid, 400 ml of dimethylformamide were introduced in a 1 liter balloon flask provided wit;h a mechanical stirrer, a thermo-meter. 34.2 9 of N-hydroxyphthalimide, 44.4 9 of dicyclohexyl-carbodiimide were added under stirring. The mixture was heated to 90C for 30 minutes, then cooled to 10C. After filtration, the filtrate was reduced under vacuum and the residue re-crystallized in the methanol. 67.5 9 of 1,4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate were obtained. (M.P.
; 225C - yield : 81.3%).

~ 3~ ~

5- ~4-methyl-1-piperazinyl)carbony ~-6,7-dinitro-1,4-benzo-dioxane -67 9 of 1,4-benzodioxane-6,7 dinitro-5-N-phthalimide carboxylate were dissolved in 400 ml of dimethylformamide. 20 9 of N-methylpiperazine were added and the mixture was stirred for 2 hours. After evaporating of the solvent under vacuum, 1 liter of water was added to the residue. The solid was filtered, recrystallized in the dimethylformamide. 40 g of 5~
~4-methyl-1-piperazinyl)carbony ~-6,7-dinitro-1,4-benzodioxane were obtained. (M.P. 254C). The structure was confirmed by NMR analysis.

N-(l-piperidinopropyl)-6,7-diacetamino-1,4-benzodioxane-5-carboxamide In a same manner as described in the Example 53, the 6,7-diacetamino-1,4-benzodioxane-5-carboxylic acid ~prepared by acetylation of the 6,7-diamino-1,4-benzodioxane-5-carboxylic acid) was condensated with the l-piperidinopropylamine in the presence of the isobutyl chloroformiate. The N-(l-piperidino-propyl)-6,7-diacetamino-1,4-benzodioxane-5-carboxamide was obtained. (M.P. - above 260C with decomposition). The structure was confirmed by NMR analysis.

5- ~4-methyl-1-piperazinyl)carbony ~-7-amino-1,4-benzodioxane - - .
In a same manner as described in the Example 2, the 7-amino-1,4-benzodioxane-5-carboxylic acid was treated with the methanol, then the obtained carboxylic ester had reacted with ;~ the N-methylpiperazine. The 5- ~4-methyl-1-piperazinyl)-carbony ~-7-amino-1,4-benzodioxane was obtained. (M.P. :
170C).

N-(l-ethyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide, hvdrochloride ~ 3~

In a same manner as described in the Example 17, by reaction of the l,4-benzodioxane-5-carbonyl chloride with the l-ethyl-2-aminomethyl pyrrolidine, the N~ ethyl-2-pyrrolidyl-methyl)-1,4-benzodioxane-5-carboxamide hydrochloride was obtained. (M.P. : 149 - 150C).
The structure of the compounds prepared according to Examples 1-59 is illustrated in Table I.

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Compounds according to the invention are used under various forms such as capsules, tablets, pills, granules, injectable solutions, the preparation of which are known per se. Substances that do not react with ~he compounds may be used, e.g. lactose, magnesium stearate, starch, talc, cellu-loses, levilite, alkali metal lauryl su-l~ates, saccharose and other vehicles used in medicinal preparations.
Compounds according to the in~/ention may be adminis-tered at dosages of 50 to 900 mg per day. It is advantageous to use 50 to 300 mg per day and preferably about lO0 to 150 mg per day.
The following examples concern pharmaceutical compo-sitions prepared by a method known per se ~ wi th the compounds . .. .
of the invention.

Tablets of the following composition are prepared:
form l form 2 form 3 N-(l-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide...........................50 mg 50 mg 50 mg Dried starch............................ 30 mg 30 mg 20 mg Lactose................................. 80 mg 80 mg 120 mg Methylcellulose 1500 cps...............1,3 mgl,2 mg li2 mg Magnesium stearate..................... 3 mg 2,5 mg 3 mg Levilite................................................. 8 mg 6,3 mg 5,8 mg ; Tablets ~f the following composition are prepared:
N-(l-methyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide............................. 50 mg Dried starch......................................................... 2G mg Lactose.............................................................. 80 mg Methylcellulose 1500 cps............................................ 1,3 mg Levilite.............................................................. 6 mg ; Magnesium stearate.................................................... 3 mg - - ~
~L~ 3'7 ~

Tablets of the following composition are prepared:
Form 1 form 2 N~ allyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide.... 50 mg S0 mg Dried starch........ ~............................ 15 mg 10 mg Lactose.......................................... 50 mg 62 mg Methylcellulose 1500 cps.................... .1 mg 1 mg Levilite.................................... .5 mg 5 mg 10 Magnesium stearate............................ .2 mg 2 mg Tablets of the following composition are prepared:
N-(l-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide................... 50 mg Dried starch............................................... 10 mg Lactose.................................................... 50 mg Methylcellulose.......................................... 0,94 mg Levilite.................................................... 6 mg ~agnesium stearate.......................................... 2 mg Tablets of the following composition are prepared:
N-(l-methyl-2-pyrrolidylmethyl)-7-ethyl-sulfonyl-1,4-benzodioxane-5-carboxamide.................... 50 mg Dried starch............................................... 10 mg Lactose Codex.............................................. 50 mg Methylcellulose 1500 cps................................. 0,55 mg Levilite.................................................... 4 mg Magnesium stearate.......................................... 2 mg Capsules of the following composition are prepared:
N-(l-ethyl-2-pyrrolidylmethyl)-7-ethyl-sulfonyl-1~4-benzodioxane-5-carboxamide...~................ 50 mg Dried starch............................................. .. 15 mg Lactose.................................................. .. 50 mg - 6~ -' ' , 3'~L

Methylcellulose 1500 cps................................... 1 mg Levilite................................................... 5 mg Magnesium stearate....................................... 2,5 mg Tablets are prepared by mixing the elected compound with starch and lactose by successive dilutions method.
Granules are prepared from the mixture and methylcellulose.
; Levilite, magnesium stearate and talc are added to granules before compressing. Methylcellulose may be replaced by any suitable granulating agent such as ethylcellulose, polyvinyl-pyrrolidone,starch paste, gum-arabic...
Starch may also be replaced by another partition agent such as maize-starch, carboxymethylic amyloids, algi- i nates, microcrystalline cellulose Injectable solutions may be prepared by dissolving a compound according to the invention in the following acids:
hydrochloric, levulinic, gluconic or glucoheptonic acids.
The solution pr~pared under sterile conditions is made isotonic by an alkali metal chloride such as sodium chloride, then preservatives are added.
The same solution may be prepared without preserva-tives: the ampulla is filled under nitrogen atmosphere, then sterilized half an hour at 100C.
The compounds of the invention have attractive anxio-lytic, psychostimulant, disinhibiting and indeed thymoanaleptic effects giving rise to properties suitable for therapeutic uses in the psychofunctional sphere and in particular in gastro-enterology, cardiology, urology, rheumatology and gynecology Their low level of toxicity is compatible with use in human therapy, without the danger of secondary effects.
Ihe acute toxicity of the compounds of the invention was determined in Swiss mice by parenteral (intravenous, intra-3'7~

peritoneal and subcutaneous) and by oral administration.
.: Lethal doses 50 are shown in Table II.
The numbering of the compounds in the following tables corresponds to the numbers of the examples.
.' :
:~ TABLE II - TOXICITY
. _ pound IV LD 50 - MI( SC ~
1 171,5-172 522-540 1344-1440 _ 2 48-49,6 312-320 594-624 0% at 3000 mg/kg 3 120-120,4 5220,8-225,6 ~:~
7 96,6-100 _ _ : 8 84,6-90 322-328 1450-1485 35% at 2Q00 mg/kg 10 150-157,5 350-363 1260-1360 :
.
-.~ 11 168-184 442-450 13 64-67,5 234-240 430-437 0% at 3000 mg/kg . :

.:
. 15 79,7-86,2 224-227 572-613 756 17 49,1 241 575 544-679 72,5-76 180-184,5 476-499,5 1190-~2Q0 21 196-208 .
_ ~: 22 83,6-86 . ,~, _ . 23_ 115,5-126 _ .~ 24 216-232 . 25 160-168 26 lQ5-116 27 80-83,6 _ _ 28 141-154 387,5-418 ~620-~850 2~00-2400 29 ~64-~75 896-957 960 ~560-1600 ~ 3''~
The compounds of the invention are moreover virtually devoid of cataleptic activity. They were administered subcu- ;
taneously to rats. The criterion in respect of the cataleptic state was immobility of the animal for 30 seconds, the front limbs of ~he animal being spread apart an~ arranged carefully on wood cubes which were 4 cm in height, thus putting the animal into an unusual and uncomfortable position. Cataleptic activity was measured at the maximum of the effect. The -~
results are given in table III.

TABLE III - CATALEPTIC ACTIVITY
. . .
; Compound ED 50 SC - Rat - mg/kg .
1 Effect of 40% at 200 mg/kg 2 Inactive...... at 200 mg/kg Effect of 30% at 200 mg/kg ; 7 Inactive...... at 200 mg/kg

8 Effect of 10% at 200 mg/kg Inactive...... at 200 mg/kg 11 Inactive...... at 200 mg/kg 12 Inactive...... at 200 mg/kg ; 13 Inactive...... at 200 mg/kg 14 Effect of 10% at 200 mg/kg Inactive...... at 200 mg/kg 1~ Inactive...... at 200 mg/kg 17 38g Inactive...... at 200 mg/kg 21 Inactive...... at 200 mg/kg 24 Effect of 30% at 200 mg/kg Inactive...... at 200 mg/kg 28 Inactive...... at 200 mg/kg 39 Inactive...... at 200 mg/kg , 3'7~

From these results it will be seen that the compounds of the invention are virtually devoid o~ ca~eleptic activity in a rat. This property permits clinical usage of the compounds of the inventionS with a high degree of tolerance in respect of the extrapyramidal system. The compounds of the invention are also found to be particularly ac~ive in a dog in respect of the central emetic agents such as apomorphine. The experimental procedure followed was that of CHEN and ENSOR. The compounds , of the invention were administered subcutaneously 30 minutes before apomorphine (100 ~n/kg/SCJ, the animal was observed half an hour after the injection of the alkaloid. The results are given in table IY. ;;
',, . .:
TABLE IY - ANTIEMETIC ACTIYITY
_ _ ~.:
Compound ED 50 ~g/kg/SC - Dog ,, i:"

1 Effect of 81%at 5 ~g/kg/SC
3 5,~

~: ~ 12 3,5 14 3,9 ``
3~
16 2,3 ~0 3,5 21 4 .

~ .? - 72 -:' ' ,' ~' '~ ,, . ' ~ '7~
The interest aroused by the experiments carried out on laboratory animals has been found to be very largely justi-fied when carrying out human clinical tests of ~he compounds of the invention.
The following can be quoted by way of example:
- the case of a 38 year old pat;ient suffering from Hodgkins disease; subjected to repeated chemotherapy as an out-pa~ient, once a week; each session was accompanied by fits of nausea and then very substantia1 vomiting, persisting for 24 hours in spite of the usual treatments.
Treatment, 24 hours before the beginning of the per~usion and 4 hours afterwards9 with 50 mg of N~ ethyl-Z-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carbox-amide totally suppressed the nausea and vomiting att~cks.
The product was perfectly well tolerated, and no secondary ef~ect was observed.
- a 28 year old da~a proce~sing engineer suffered from a charac~erial neurosis with bouts of anxiety culminating in three attempts at suicide. Analytical treatment for 18 months made it possible to achieve social reintegration but had little effect on the anxiety aspect.
The administration of 50 mg of N-(1-methyl-2-pyrrolidylmethyl~-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide three times per day~ caused in a few days the complete disappearance of any anxiety, without any troublesome sedative action.
The product was perfec~ly well ~olerated~ and no secondary effect was observed.
a 7~ year old subject had been su~fering for 8 mon~hs from seYere reactional depression ~close bereavement).
The existen~e Df a prostatic adenoma contraindicated the use of yc7ics.

, ~ 3~
He was treated three times a day with 50 mg of N~ methyl-2-pyrrolidylmethy1)-7-methylsulfamoyl-1,4-benzo-dioxane-5-carboxamide, and in three weeksl as his condition had substantially improved, he was able to leave hospital. The treatment, which has been continued at home ~or 3 months, makes it possible to maintain an excellen~ psychic balance, with the resumption of normal act;vity ;n a retired person of this age. ~
The product was perfectly well tolerated, and no ~ ~ ;
secondary effect was observed.
- a 42 year old subject underwent a hysterectomy for a fibroma 6 months ago. Some days after the operation, hot flushes (10 to 20 a day) appeared with attacks o~ sweating which awoke the patient during the night and caused her to be embarrassed during her work.
She was treated with the N~(l-ethyl-2-pyrrolidyl-methyl)-7-methylsulfamoyl-1,4-benzodioxane-~-carboxamide at a single dose of 100 mg a day, the symptoms disappeared within 4 - days. Only one hot flush still persisted during the day occurring every 2 or 3 days.
The product was perfectly well tolerated, and no side-effects were observed.
- a 47 year old patient suffered, after the meno-pause, from repeated attacks of cystitis with frequency and severe urgency such that no social life was possible. Thë
patien~ consulted general practitioners and specialists~ All the tests were negative and all treatments were without effect în this classical case of cystitls.
She was treated for some days wi~h the N-(l-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1~4-benzodioxane-5-carbox-amide at a dose of 150 mg a day and the symptoms completely disappeared and her psychological st~te became normal~

.;.. .. .

Claims (116)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. Process for preparing 2,3- alkylene bis(oxy)-benzamides of the formula:
(I) in which:
A represents a C1-3 alkylene chain;
R represents hydrogen, a C1-4 alkyl group, or a radical having the following general formula:
(II) in which:
B represents a single bond or a C1-3 alkylene chain;
R1 represents a C1-4 alkyl group or can be connected to B so as to form a pyrrolidinyl or piperidinyl group hetero-cycle;
R2 represents a C1-4 alkyl group, a C2-4 alkenyl group, benzyl, cycloalkyl, pyrimidyl, or is linked to R1 to form a piperidinyl or 4-alkylpiperazinyl;
R' represents hydrogen, a C1-4 alkyl group, benzyl, adamantyl, pyrimidinyl, or is linked to R1 to form a piper-azinyl group, or is linked to R1 and R2 to form a diaza-bicycloalkyl group;
X represents hydrogen, a halogen atom, a C1-4 alkoxy group, nitro, amino or acetamino;

Y represents hydrogen, a halogen atom, nitro, amino, acetamino, sulfamoyl, C1-4 alkylsulfamoyl, C1-4 alkyl-sulfonyl, adamantylsulfamoyl, C3-8 cycloalkylsulfamoyl, C1-4 dialkylsulfamoyl, or is linked to X to form an azimido group;
Z represents hydrogen, a halogen atom, nitro, amino or acetamino, or is linked to Y to form an azimido group;
and their oxides, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts and their dextrorotatory and levorotatory isomers, which comprises reacting a compound of the formula:
wherein A, X, Y and Z are as previously defined, and D represents hydroxy, a halogen atom or an organic residue with an amine of the formula:
wherein R and R' are as defined above, or one of its reactive derivatives.

2. The process of Claim 1, wherein 1-allyl-2-amino-methyl pyrrolidine is reacted with 7- methylsulfamoyl -1,4-benzo-dioxane-5-carbonyl chloride to form the N-(1-allyl-2-pyrrol-idylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

3. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate to form the N-(1-ethyl-2-pyrrolidyl-methyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide.

4. The process of Claim 1, wherein 1-methyl-2-amino-methyl pyrrolidine is reacted with 7-ethylsulfonyl-1,4-benzo-dioxane-5-carbonyl chloride to form the N-(1-methyl-2-pyrrol-idylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide.

5. The process of Claim 1, wherein 1-methyl-2-amino-methyl pyrrolidine is reacted with 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to form the N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide.

6. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with 2H-3,4-dihydro-1,5-benzo-dioxepine-6-carbonyl chloride to form the N-(1-ethyl-2-pyrrol-idylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide.

7. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with 8-methylsulfamoy1-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride to form the N-(1-ethy1-2-pyrrolidylmethyl)-8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-5-carboxamide.

8. The process of Claim 1, wherein N-methylpiper -azine is reacted with 7-nitro-1,4-benzodioxane-5-carboxylic acid to form the 5-[(4-methyl-1-piperazinyl)carbonyl]-7-nitro-1,4-benzodioxane.

9. The process of Claim 1, wherein N-methylpiper-azine is reacted with 7-(1-adamantyl)sulfamoyl-1,4-benzo-dioxane-5-carboxylic acid to form the 5-[(4-methyl-1-piper-azinyl)carbonyl]-7-[(1-adamantyl)sulfamoyl]-1,4-benzodioxane.

10. The process of Claim 1, wherein N-(aminoethyl)-piperidine is reacted with 7-chloro-1,4-benzodioxane-7-carbonyl chloride to form the N-(piperidinoethyl)-7-chloro-1,4-benzo-dioxane-5-carboxamide.

11. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with 8-methoxy-1,4-benzodioxane-5-carbonyl chloride to form the N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide.

12. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate to form the N-(1-ethyl-2-pyrrol-idylmethyl)-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carbox-amide.

13. The process of Claim 1, wherein benzylamine is reacted with 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid to form the N-(benzyl)-7-diethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide.

14. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride to form the N-(1-ethyl-2-pyrrolidylmethyl)-8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide.

15. The process of Claim 1, wherein methylpiperazine is reacted with 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride to form the 5-[(4-methyl-1-piperazinyl)carbonyl]-6,7-dibromo-8-nitro-1,4-benzodioxane.

16. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with 8-amino-1,4-benzodioxane-5-carboxylic acid to form the N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide.

17. The process of Claim 1, wherein methylpiperazine is reacted with 8-chloro-1,4-benzodioxane-5-carboxylic acid to form the 5-[(4-methyl-1-piperazinyl)carbonyl]-8-chloro-1,4-benzodioxane.

18. The process of Claim 1, wherein 1-ethyl-2-amino-methyl pyrrolidine is reacted with 8-acetamino-1,4-benzodioxane-5-carboxylic acid to form the N-(1-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide.

19. The process of Claim 1, wherein diethylamino-ethylamine is reacted with 7-nitro-8-acetamino-1,4-benzo-dioxane-5-carboxylic acid to form the N-(diethylaminoethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-carboxamide.

20. The process of Claim is wherein 1-allyl-2-amino-methyl pyrrolidine is reacted with 7,8-azimido-1,4-benzo-dioxane-5-carboxylic acid to form the N-(1-allyl-2-pyrrolidyl-methyl)-7,8-azimido-1,4-benzodioxane-5-carboxamide.

21. The process of Claim 1, wherein 2-aminopyrimidine is reacted with 6-chloro-1,4-benzodioxane-5-carbonyl chloride to form the N-(2-pyrimidyl)-6-chloro-1,4-benzodioxane-5-carbox-amide.

22. The process of Claim 1, wherein diethylamine is reacted with 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carbox-ylic acid to form the N-diethyl-7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxamide.

23. The process of Claim 1, wherein 1-allyl-2-amino-methyl pyrrolidine is reacted with 6,7-azimido-5-N-phthalimide carboxylate to form the N-(1-allyl-2-pyrrolidylmethyl)-6,7-azimido-1,4-benzodioxane-5-carboxamide.

24. The process of Claim 1, wherein 1-piperidino-propylamine is reacted with 6,7-diacetamino-1,4-benzodioxane-5-carboxylic acid to form the N-(1-piperidinopropyl)-6,7-diacet-amino-1,4-benzodioxane-5-carboxamide.

25. The process wherein 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid is reacted with 1-(2-pyrimidyl)piperazine and there is recovered the 1-(2,3-ethylenedioxy-5-sulfamoylbenzoyl)-4-(2-pyrimidinyl)piperazine.

26. The process wherein 1-benzyl-2-aminomethyl pyrrolidine is reacted with 1,4-benzodioxane-5-carbonyl chloride and there is recovered the N-(1-benzyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide.

27. The process wherein methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate is reacted with 1-allyl-2-amino-methyl pyrrolidine and there is recovered the N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide.

28. The process wherein methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate is reacted with 1-ethyl-2-aminomethyl pyrrolidine and there is recovered the N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

29. The process wherein ethyl 2,3-methylenedioxy benzoate is reacted with 1-ethyl-2-aminomethyl pyrrolidine and there is recovered the N-(1-ethyl-2-pyrrolidylmethyl)-2,3-methylenedioxy benzamide.

30. The process wherein levorotatory 1-ethyl-2-aminomethyl pyrrolidine is reacted with 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the levorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide.

31. The process wherein dextrorotatory 1-ethyl-2-aminomethyl pyrrolidine is reacted with 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide.

32. The process wherein methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate is reacted with 1-methyl-2-amino-methyl pyrrolidine and there is recovered the N-(1-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide.

33. The process wherein 1-allyl-2-aminomethyl pyrrolidine is reacted with 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the N-(1-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide.

34. The process wherein methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate is reacted with 1-methyl-2-aminomethyl pyrrolidine and there is recovered the N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

35. The process wherein diethylaminoethylamine is reacted with 1,4-benzodioxane-5-carbonyl chloride and re-covering the N-(diethylaminoethyl)-1,4-benzodioxane-5-carboxamide.

36. The process wherein 7-ethylsulfonyl-1,4-benzo-dioxane-5-carboxylic acid is reacted with 1-ethyl-2-amino-methyl pyrrolidine and recovering the N-(1-ethyl-2-pyrrolidyl methyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide.

37. The process wherein 1-cyclohexyl-3-aminopyrrol-idine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and recovering the N-(1-cyclohexyl-3-pyrrolidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

38. The process wherein 1-ethyl-2-aminomethyl pyrrolidine is reacted with 7-dimethylsulfamoyl-1,4-benzo-dioxane-5-carbonyl chloride and recovering the N-(1-ethyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide.

39. The process wherein dextrorotatory 1-ethyl-2-aminomethyl pyrrolidine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and recovering the dextro-rotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

40. The process wherein levorotatory 1-ethyl-2-aminomethyl pyrrolidine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the levorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

41. The process wherein levorotatory 1-allyl-2-aminomethyl pyrrolidine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the levorotatory N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

42. The process wherein dextrorotatory 1-allyl-2-aminomethyl pyrrolidine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the dextrorotatory N-(1-allyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide.

43. The process wherein dextrorotatory 1-methyl-2-aminomethyl pyrrolidine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the dextrorotatory N-(1-methyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide.

44. The process wherein levorotatory 1-methyl-2-aminomethyl pyrrolidine is reacted with 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the levorotatory N-(1-methyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide.

45. The process wherein 1,4-diazabicyclo (4-3-0) nonane is reacted with 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride and there is recovered the 4-(1,4-benzo-dioxane-7-ethylsulfonyl-5-carbonyl)-1,4-diazabicyclo (4-3-0) nonane.

46. The process wherein the 7-[(1-adamantyl)-sulfamoyl]-1,4-benzodioxane-5-carboxylic acid is reacted with butylamine and there is recovered the N-(butyl)-7-1-adamantyl)sulfamoyl]-1,4-benzodioxane-5-carboxamide.

47. The process wherein 1,4-diazabicyclo (4-3-0) nonane is reacted with 1,4-benzodiocane-5-carbonyl chloride and there is recovered the 4-(1,4-benzodioxane-5-carbonyl)-1,4-diazabicyclo (4-3-0) nonane.

48. The process wherein 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid is reacted with 1-benzyl-4-aminopiperidine and there is recovered the N-(1-benzyl-4-piperidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide.

49. The process wherein adamantamine is reacted with 1,4-benzodioxane-5-carbonyl chloride and there is recovered the N-(1-adamantyl)-1,4-benzodioxane-5-carboxamide.

50. The process wherein 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid is reacted with 1-benzyl-2-aminomethyl pyrrolidine and there is recovered the N-(1-benzyl-2-pyrrolidylmethyl)-7-diethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide.

51. The process wherein 1-benzyl-4-aminopiperidine is reacted with 1,4-benzodioxane-5-carbonyl chloride and there is recovered the N-(1-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide.

52. The process wherein 1-ethyl-2-aminomethyl pyrrolidine is reacted with 6,7-dibromo-8-nitro-1,4-benzo-dioxane-5-carbonyl chloride and there is recovered the N-(1-ethyl-2-pyrrolidylmethyl)-6,7-dibromo-8-nitro-1,4-benzo-dioxane-5-carboxamide.

53. The process wherein N-methylpiperazine is reacted with 6-nitro-1,4-benzodioxane-5-carbonyl chloride and there is recovered the 5-[(4-methyl-1-piperazinyl)carbonyl]-6-nitro-1,4-benzodioxane.

54. The process wherein 1-amino-4-methylpiperazine is reacted 7-nitro-1,4-benzodioxane-5-carbonyl chloride and there is recovered the N-(4-methyl-1-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide.

55. The process wherein 1,4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate is reacted with N-methyl-piperazine and there is recovered the 5-[(4-methyl-1-piperazinyl)carbonyl]-6,7-dinitro-1,4-benzodioxane.

56. The process wherein 7-amino-1,4-benzodioxane-5-carboxylic acid is reacted with N-methylpiperazine and there is recovered the 5-[(4-methyl-1-piperazinyl)carbonyl]-7-amino-1,4-benzodioxane.

57. The process wherein 1-ethyl-2-aminomethyl pyrrolidine is reacted with 1,4-benzodioxane-5-carbonyl chloride and there is recovered the N-(1-ethyl-2-pyrrolidyl-methyl)-1,4-benzodioxane-5-carboxamide.

58. The process wherein 1-methyl-2-aminomethyl pyrrolidine is reacted with 7-dimethylsulfamoyl-1,4-benzo-dioxane-5-carboxylic acid in the presence of phosphorous trichloride and there is recovered the N-(1-methyl-2-pyrrolidylmethyl)-7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide.

59. The 2,3-alkylene bis(oxy)benzamides of the formula:

(I) in which:
A represents a C1-3 alkylene chain;
R represents hydrogen, a C1-4 alkyl group, or a radical having the following general formula.

(II) in which:
B represents a single bond or a C1-3 alkylene chain;
R1 represents a C1-4 alkyl group or can be connected to B so as to form a pyrrolidinyl or piperidinyl group hetero-cycle;

R2 represents a C1-4 alkyl group, a C2-4 alkenyl group, benzyl, cycloalkyl, pyrimidyl, or is linked to R1 to form a piperidinyl or 4-alkylpiperazinyl;
R' represents hydrogen, a C1-4 alkyl group, benzyl, adamantyl, pyrimidinyl, or is linked to R1 to form a piper-azinyl group, or is linked to R1 and R2 to form a diaza-bicycloalkyl group;
X represents hydrogen, a halogen atom, a C1-4 alkoxy group, nitro, amino or acetamino;
Y represents hydrogen, a halogen atom, nitro, amino, acetamino, sulfamoyl, C1-4 alkylsulfamoyl, C1-4 alkyl-sulfonyl, adamantylsulfamoyl, C3-8 cycloalkylsulfamoyl, C1-4-dialkylsulfamoyl, or is linked to X to form an azimido group;
Z represents hydrogen, a halogen atom, nitro, amino or acetamino, or is linked to Y to form an azimido group;
and their oxides, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts and their dextrorotatory and levorotatory isomers, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

60. The N-(1-allyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 2 or by an obvious chemical equiva-lent.

61. The N-(1-ethyl-2-pyrrolidylme-thyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

62. The N-(1-methyl-2-pyrrolidylmethyl)-7-ethyl-sulfonyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 4 or by an obvious chemical equiva-lent.

63. The N-(1-methyl-2-pyrrolidylmethyl)-7-dimethyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 5 or by an obvious chemical equiva-lent.

64. The N-(1-ethyl-2-pyrrolidylmethyl)-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide, when prepared by the process defined in Claim 6 or by an obvious chemical equiva-lent.

65. The N-(1-ethyl-2-pyrrolidylmethyl)-8-methyl-sulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-5-carboxamide, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.

66. The 5-[(4-methyl-1-piperazinyl)carbonyl]-7-nitro-1,4-benzodioxane, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.

67. The 5-[(4-methyl-1-piperazinyl)carbonyl]-7-[(1-adamantyl)sulfamoyl]-1,4-benzodioxane, when prepared by the process defined in Claim 9 or by an obvious chemical equiva-lent.

68. The N-(piperidinoethyl)-7-chloro-1,4-benzo-dioxane-5-carboxamide, when prepared by the process defined in Claim 10 or by an obvious chemical equivalent.

69. The N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 11 or by an obvious chemical equivalent.

70. The N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-7 sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 12 or by an obvious chemical equiva-lent.

71. The N-(benzyl)-7-diethylsulfamoyl-1,4-benzo-dioxane-5-carboxamide, when prepared by the process defined in Claim 13 or by an obvious chemical equivalent.

72. The N-(1-ethyl-2-pyrrolidylmethyl)-8-ethyl-sulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide, when prepared by the process defined in Claim 14 or by an obvious chemical equivalent.

73. The 5-[(4-methyl-1-piperazinyl)carbonyl]-6,7-dibromo-8-nitro-1,4-benzodioxane, when prepared by the process defined in Claim 15 or by an obvious chemical equivalent.

74. The N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 16 or by an obvious chemical equivalent.

75. The 5-[(4-methyl-1-piperazinyl)carbonyl]-8-chloro-1,4-benzodioxane, when prepared by the process defined in Claim 17 or by an obvious chemical equivalent.

76. The N-(1-ethyl-2-pyrrolidylmethyl)-8-acetamino-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 18 or by an obvious chemical equivalent.

77. The N-(diethylaminoethyl)-7-nitro-8-acetamino-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 19 or by an obvious chemical equivalent.

78. The N-(1-allyl-2-pyrrolidylmethyl)-7,8-azimido-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 20 or by an obvious chemical equivalent.

79. The N-(2-pyrimidyl)-6-chloro-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 21 or by an obvious chemical equivalent.

80. The N-diethyl-7-cyclohexylsulfamoyl-1,4-benzo-dioxane-5-carboxamide, when prepared by the process defined in Claim 22 or by an obvious chemical equivalent.

81. The N-(1-allyl-2-pyrrolidylmethyl)-6,7-azimido-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 23 or by an obvious chemical equivalent.

82. The N-(1-piperidinopropyl)-6,7-diacetamino-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 24 or by an obvious chemical equivalent.

83. The 1-(2,3-ethylenedioxy-5-sulfamoylbenzoyl)-4-(2-pyrimidinyl)piperazine, when prepared by the process defined in Claim 25 or by an obvious chemical equivalent.

84. The N-(1-benzyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 26 or by an obvious chemical equivalent.

85. The N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 27 or by an obvious chemical equivalent.

86. The N-(1-ethyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 28 or by an obvious chemical equiva-lent.

87. The N-(1-ethyl-2-pyrrolidylmethyl)-2,3-methylene-dioxy benzamide, when prepared by the process defined in Claim 29 or by an obvious chemical equivalent.

88. The levorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 30 or by an obvious chemical equivalent.

89. The dextrorotatory N-(1-ethyl-2-pyrrolidyl-methyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 31 or by an obvious chemical equivalent.

90. The N-(1-methyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 32 or by an obvious chemical equivalent.

91. The N-(1-allyl-2-pyrrolidylmethyl)-7-ethyl-sulfonyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 33 or by an obvious chemical equiva-lent.

92. The N-(1-methyl-2-pyrrolidylmethyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 34 or by an obvious chemical equiva-lent.

93. The N-(diethylaminoethyl)-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 35 or by an obvious chemical equivalent.

94. The N-(1-ethyl-2-pyrrolidylmethyl)-7-ethyl-sulfonyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 36 or by an obvious chemical equiva-lent.

95. The N-(1-cyclohexyl-3-pyrrolidyl)-7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 37 or by an obvious chemical equiva-lent.

96. The N-(1-ethyl-2-pyrrolidylmethyl)-7-dimethyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 38 or by an obvious chemical equiva-lent.

97. The dextrorotatory N-(1-ethyl-2-pyrrolidyl-methyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 39 or by an obvious chemical equivalent.

98. The levorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 40 or by an obvious chemical equivalent.

99. The levorotatory N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 41 or by an obvious chemical equivalent.

100. The dextrorotatory N-(1-allyl-2-pyrrolidyl-methyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 42 or by an obvious chemical equivalent.

101. The dextrorotatory N-(1-methyl-2-pyrrolidyl-methyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 43 or by an obvious chemical equivalent.

102. The levorotatory N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 44 or by an obvious chemical equivalent.

103. The 4-(1,4-benzodioxane-7-ethylsulfonyl-5-carbonyl)-1,4-diazablcyclo (4-3-0) nonane, when prepared by the process defined in Claim 45 or by an obvious chemical equivalent.

104. The N-(butyl)-7-[(1-adamantyl)sulfamoyl]-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 46 or by an obvious chemical equivalent.

105. The 4-(1,4-benzodioxane-5-carbonyl)-1,4-diaza-bicyclo (4-3-0) nonane, when prepared by the process defined in Claim 47 or by an obvious chemical equivalent.

106. The N-(1-benzyl-4-piperidyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 48 or by an obvious chemical equivalent.

107. The N-(1-adamantyl)-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 49 or by an obvious chemical equivalent.

108. The N-(1-benzyl-2-pyrrolidylmethyl)-7-diethyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 50 or by an obvious chemical equiva-lent.

109. The N-(1-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 51 or by an obvious chemical equivalent.

110. The N-(1-ethyl-2-pyrrolidylmethyl)-6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 52 or by an obvious chemical equiva-lent.

111. The 5-[(4-methyl-1-piperazinyl)carbonyl]-6-nitro-1,4-benzodioxane, when prepared by the process defined in Claim 53 or by an obvious chemical equivalent.

112. The N-(4-methyl-1-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 54 or by an obvious chemical equivalent.

113. The 5-[(4-methyl-1-piperazinyl)carbonyl]-6,7-dinitro-1,4-benzodioxane, when prepared by the process defined in Claim 55 or by an obvious chemical equivalent.

114. The 5-[(4-methyl-1-piperazinyl)carbonyl]-7-amino-1,4-benzodioxane, when prepared by the process defined in Claim 56 or by an obvious chemical equivalent.

115. The N-(1-ethyl-2-pyrrolidylmethyl)-1,4-benzo-dioxane-5-carboxamide, when prepared by the process defined in Claim 57 or by an obvious chemical equivalent.

116. The N-(1-methyl-2-pyrrolidylmethyl)-7-dimethyl-sulfamoyl-1,4-benzodioxane-5-carboxamide, when prepared by the process defined in Claim 58 or by an obvious chemical equiva-lent.