CH629198A5 - PROCESS FOR THE PREPARATION OF NEW SUBSTITUTED 2,3-ALKYLENE-BIS (OXY) -BENZAMIDES. - Google Patents

Description

The present invention relates to the preparation of new substituted 2,3-alkylene-bis (oxy) -benzamides. The licensee noted that the family of compounds below had interesting characteristics: anxiolytic, psychostimulant, disinhibitor, even thymo-analeptic, resulting in properties susceptible of therapeutic applications in the psychofunctional sphere and in particular in gastroenterology, cardiology, urology, rheumatology, gynecology, etc. Their low toxicity is compatible with use in human therapy without risk of side effects.

The present invention relates to the preparation of new 2,3-alkylene-bis- (oxy) -benzamides of general formula (I), their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts, their oxides and their dextrorotatory and levorotatory isomers. The structure of the compounds prepared according to the invention can be diagrammed by the following formula:

R

CO-N „» W

R

z

Y

X

in which:

A represents an alkylene chain C] _3 substituted or not substituted by an alkyl group CM, alkenyl C2.4, hydroxyalkyl CM;

R represents a hydrogen atom, an alkyl radical or a radical of general formula (II):

Ra in which:

B represents a single bond, an alkylene chain Cj.3 substituted or not by an alkenyl group C2_4;

R 1 represents a hydrogen atom, a CM alkyl group, C2_4 alkenyl, C2_4 alkinyl, alkyl substituted for example by a hydroxy group, mercapto, acyl, thioacyl, alkoxy, alkylthio, amino substituted or not, and can be linked to B for forming a saturated or unsaturated nitrogen heterocycle, such as for example azetidine, Pyrrolidine, piperidine, polyhydroazepine, pyrroline, polyhydropyridine;

R2 represents a hydrogen atom, a C1 + alkyl group C2.4 alkenyl, C2-4 alkinyl, alkyl substituted for example by a hydroxy group, mercapto, acyl, thioacyl, alkoxy, alkythio, amino substituted or not, a heterocycle, substituted or not , saturated or unsaturated, comprising one or more heteroatoms such as, for example, azetidine, Pyrrolidine, piperidine, pyrimidine, pyrazine, furan, polyhydrofuran, pyran, polyhydropyranne, quinuclidine, azabicycloalkane, diazabicycloalkane or a phenyl group, adamantyl, bicycloalkyl, cycloalkenyl, linked to the nitrogen atom of formula (II) directly by a carbon atom of the ring or via a substituted or unsubstituted alkylene chain;

R2 and Rj can be linked together to form a heterocycle possibly containing other heteroatoms; the cycles thus formed are for example azetidine, Pyrrolidine, piperidine, imidazoli-dine, piperazine, morpholine, thiazolidine; when the heterocycle contains another nitrogen atom, this may be substituted by a CH alkyl, CM alkenyl, C2.4 alkinyl, phenyl, benzyl, cycloalkyl, cycloalkenyl group; cycloalkanealkyle, cycloalkenealkyl, adamantyl, bicycloalkyl or alkyl substituted by a hydroxy, mercapto, acyl, thioacyl, alkoxy, alkythio group;

R ′ represents a hydrogen atom, a C 1 -C 4 alkyl group, CM alkenyl, C 2 -C 4 alkinyl, adamantyl, pyrimidinyl, pyrazinyl, diazepinyl, quinuclidinyl, azabicycloalkyl, diazabicycloalkyl,

bicycloalkyl, substituted or unsubstituted phenyl, aralkyl; R 'and B can be linked together to form monoazotated heterocycles such as azetidine, Pyrrolidine, piperidine, polyhydroazepine, azabicycloalkane, etc., which may or may not be substituted;

R 'and R! can be linked together to form diazotized heterocycles, saturated or not, such as piperazine, diazepine, pyrimidine, pyrazine, diazabicycloalkane, which may or may not be substituted;

X represents a hydrogen atom, a halogen atom, a hydroxy group, an amino, amino-substituted group, CM alkoxy, C [.4 alkyl, nitro;

Y represents a hydrogen or halogen atom, a hydroxy group, an amino, amino-substituted group, nitro, a C 1-4 alkoxy group, C [.4 alkylsulfonyl, adamantylsulfonyl, cycloalkylsulfonyl, a sulfonyl group substituted by an amino group, mono- or disubstituted of formula NR3R4 in which R3 and R4, which may be identical or different, are hydrogen atoms, C 1 -C alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkanealkyl, cycloalkenealkyl, bicycloalkyl, adamantyl, pyrimidinyl, pyrazinyl or alkyl substituted by a hydroxy, mercapto, acyl, thioacyl, alkoxy, alkylthio group, or together form, with the nitrogen atom to which they are attached, a heterocycle possibly containing another heteroatom substituted or not;

Z represents a hydrogen atom, a halogen atom, a hydroxy group, an amino, amino-substituted group, nitro, an alkoxy group Cm;

X and Y or Y and Z may be linked together via a substituted or unsubstituted carbon chain, or via one or more heteroatoms to form a ring such as triazole, imidazole, oxazole, thiadiazole, pyrazine , piperazine, diazepine, substituted or not, and their oxides.

In the definitions mentioned in the present application, CM alkyl preferably comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,

alkylene C | .3 preferably comprises methylene, ethylene, propylene,

C2_4 alkenyl preferably includes vinyl, allyl,

C2-4 alkinyl preferably includes ethinyl, propargyl,

alkoxy Cj_4 preferably comprises methoxy, ethoxy, propoxy isopropoxy, butoxy, isobutoxy, t-butoxy,

aralkyl preferably comprises benzyl, phenethyl, substituted or not substituted by one or more halogen, alkoxy, alkyl, halomethyl, amino,

substituted phenyl preferably comprises a phenyl ring substituted by one or more halogen, alkoxy, alkyl, halomethyl, amino,

halogen preferably comprises chlorine, bromine, iodine, fluorine, amino-substituted preferably comprises an amino group mono-or disubstituted by alkyl, acyl, aralkyl, furannyl, pyrannyl, alkoxycarbonyl groups,

acyl preferably includes formyl, acetyl, phthaloyl. The preferred values of the substituents are:

- for X: hydrogen, alkoxy, preferably methoxy, nitro, halogen, preferably chlorine, amino, acylamino, preferably acetamino;

- for Y: hydrogen, halogen and preferably bromine and chlorine, amino, acylamino, preferably acetamino, alkylsulfonyl, preferably ethylsulfonyl, substituted sulfonyl:

- by an amino group;

- By a monosubstituted amino group in particular by an alkyl group, preferably methyl, by an adamantyl group;

- By a disubstituted amino group, in particular by alkyl groups, preferably methyl, ethyl;

- for Z: hydrogen, halogen, preferably bromine, chlorine, nitro, acylamino, preferably acetamino, amino.

The preferred values of the substituents are, in the disubstituted compounds:

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for:

f X: alkoxy, preferably methoxy 1 Y: sulfonyl substituted with an amino group f X: acylamino, preferably acetamino 1 Y: nitro

X and Y can be linked together via a heteroatom, preferably a nitrogen atom to form a triazole ring.

X = Y = amino

ÌX = halogen, preferably chlorine

Y = amino X = amino

Y = acylamino, preferably acetamino

X = Y = acylamino, preferably acetamino

Y = Z = nitro

Y = Z = acylamino, preferably acetamino

Y = Z = halogen, preferably bromine

Y = Z = amino

Y and Z can be linked together via a heteroatom, preferably a nitrogen atom, to form a triazole ring.

The preferred values of A are unsubstituted alkylene such as methylene, propylene and, preferably, ethylene.

The preferred values of R 'are:

- a hydrogen atom,

An alkyl group, preferably ethyl, butyl,

An aralkyl group, preferably benzyl, which may be substituted by a halogen atom, preferably bromine and fluorine, by a trifluoromethyl group,

- an adamantyl, pyrimidinyl group,

- A saturated diazotized heterocycle formed with Rj, preferably a piperazine which can be substituted.

The preferred values of R are:

- a hydrogen atom,

An alkyl group, preferably ethyl,

- a radical of formula (II) in which the preferred values of B are:

- a single link,

An alkylene chain, preferably ethylene, propylene,

- a nitrogen heterocycle formed with Rt as defined below. The preferred values of Rt are:

An alkyl group, preferably ethyl,

A saturated nitrogen heterocycle formed with B, preferably Pyrrolidine, piperidine,

- a nitrogen heterocycle formed with Rz

- preferably a Pyrrolidine, a piperidine,

- or comprising another heteroatom, in particular a nitrogen atom, preferably a piperazine substituted by an alkyl group, preferably methyl, ethyl,

- A saturated diazotized heterocycle formed with R ', preferably a substituted piperazine.

When simultaneously Rj is linked to R2 to form a nitrogen heterocycle, preferably Pyrrolidine, and R! is linked to R 'to form a saturated diazotized heterocycle, preferably piperazine, the whole forms a bicyclic radical, preferably a diazabicy-clononane.

The compounds are prepared according to the invention by reaction of a compound of general formula:

(III)

COD

x in which:

A, X, Y, Z have the above meanings,

D represents a hydroxy group, a halogen atom or a group capable of forming a reactive acid derivative, on an amine of general formula:

R

HN ^ (IV)

R '

in which R and R 'have the abovementioned meanings, or by reaction of their reactive derivatives.

In the starting compound, the groups capable of forming reactive acid derivatives can be lower alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl; reactive acid esters such as methoxymethyl ester, cyano-methyl ester, substituted or unsubstituted aromatic esters, N-hydroxyimide-esters; acid azides; acid hydrazides; symmetrical anhydrides; mixed anhydrides such as, for example, those formed from carbonic acid esters and haloformic esters; azolides such as triazolides, tetrazolides and especially imidazolides; substituted w-trihaloacetophenones, acid isothiocyanates; substituted α-oxobenzene acetonitriles; benzamides substituted on the nucleus, or other equivalents, or the compound of general formula:

CH -C0-NH-CoH

C00

(formed from acid and an isoxazolium salt). In this formula, A, X, Y, Z, have the above meanings. The invention is however not limited to the reactive derivatives mentioned above. According to the process of the invention, the amine can react in the form of one of its reactive derivatives. By way of example, mention may be made of the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl-, diaryl-, orthophenylenechlorophosphites, alkyl- or aryldichlorophosphites or isothiocyanate of the amine or sulfonamides symmetrical or not of the amine, the corresponding symmetric urea, the corresponding enamines or any other equivalent.

The reactive derivatives mentioned above can react with the acid in situ or after preliminary isolation. The invention however is not limited to the reactive derivatives described above.

In addition, it is also possible to carry out the reaction of the free acid and the free amine in the presence of a condensing agent such as, for example, silicon tetrachloride, phosphorous anhydride or a carbodiimide. such as dicyclohexylcarbodiimide or alkoxyacetylenes such as methoxy- or ethoxyacetylene.

In the process of the invention for preparing the compounds of formula (I), the use of an acid halide is particularly suitable

- unsubstituted compounds on the benzene ring,

- to monosubstituted compounds with a halogen atom, a nitro group, an alkylsulfonyl, adamantylsulfonyl group,

cycloalkylsulfonyl, a substituted sulfonyl radical

- by an amino group,

- By an amino group mono- or disubstituted by an alkyl, adamantyl, cycloalkyl group.

The use of alkyl esters, reactive acid esters, aromatic esters is particularly suitable:

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- to compounds containing hydroxy, amino, acylamino, alkylsulfonyl, adamantylsulfonyl, cycloalkylsulfonyl, substituted sulfonyl groups on the nucleus

- by an amino group,

- by an amino group mono- or disubstituted by an alkyl, adamantyl, cycloalkyl group,

- to compounds in which two of the radicals X and Y or Y and Z are linked, to form a ring.

The use of mixed anhydrides (formed in situ by reaction of the starting benzoic acid with haloformic esters, preferably esters of chloroformic acid) is particularly suitable for compounds substituted by nitro, acylamino, sulfonyl groups substituted

- by an amino group,

- By an amino group mono- or disubstituted by an alkyl, adamantyl, cycloalkyl group.

The use of reactive derivatives of amines preferably with phosphorus chlorides and in particular phosphorus trichloride, with alkyl- and arylchlorophosphites is particularly suitable for primary amines, especially aliphatics.

The amidation reaction of the invention can be carried out in the presence or in the absence of solvent. The systems used as solvent, inert with respect to the amidation reaction, are, for example, alcohols, polyols, benzene, toluene, dioxane, chloroform, dimethyl ether of diethylene glycol, xylene. It is also possible to use an excess of the amine used as raw material as solvent. It may be preferable to heat the reaction mixture during the amidification, for example to the boiling point of the solvents mentioned above.

The compound obtained according to the process of the invention can react if necessary with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, l oxalic acid, acetic acid, tartaric acid, citric acid, methanesulfonic acid, to give acid addition salts. It can also react, if necessary, with alkyl halides or sulfates to give quaternary ammonium salts. It can be oxidized in a manner known per se, for example by means of hydrogen peroxide and manganese dioxide to give the corresponding N-oxide.

In order to illustrate the technical characteristics of the present invention, some exemplary embodiments will be described, it being understood that these are not limiting as to their mode of implementation and to the applications that can be made of them.

Example 1:

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

7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid:

670 g of sulfuric hydrochloride were introduced into a flask fitted with an agitator, a condenser and a thermometer, then 173 g of 1,4-benzodioxane 5-carboxylic acid, in small quantities, maintaining the temperature at 5-10 ° C.

The mixture was then heated to 55 ° C, then cooled and poured into ice. The precipitate formed was drained, washed and then dried.

250 g of 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 210-215 ° C; Yield: 93.5%).

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

139.5 g of a 40% aqueous methylamine solution and 139.5 cm3 of water were introduced into a flask fitted with an agitator and a thermometer, then 250 g of d acid obtained in the previous stage, each introduction of acid being followed by the addition of 18 cm3 of a solution of 180 cm3 of 30% sodium hydroxide solution in 180 cm3 of water.

After stirring, the mixture was poured into 2200 cm3 of water. The solution was filtered and then treated with 139 cm 3 of concentrated hydrochloric acid. The precipitate formed was drained, washed and then dried.

190.5 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 208-209 ° C; Yield: 80%).

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

176.5 g of thionyl chloride were introduced into a flask fitted with a condenser and then, in portions, while heating to 40-45 ° C, 135 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carboxylic acid. After heating at reflux, the mixture was taken up in 250 cm3 of chloroform. The precipitate formed was drained and washed with chloroform.

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

69 g of 1-allyl 2-aminomethylpyrrolidine and 432 ml of chloroform were introduced into a 11-liter flask fitted with a thermometer and an agitator. 144 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride were added in portions while maintaining the temperature between 5 and 10 ° C. The mixture was allowed to stir for 1 h, then was treated with 1750 ml of water. After distilling off the chloroform, the mixture was acidified to pH 4 with 4 ml of 20% sulfuric acid and then filtered through carbon black; the sulfate solution formed was basified with 60 ml of 20% ammonia. After crystallization, the base was drained, washed with water, dried at 40 ° C. After recrystallization from acetonitrile, 134 g of N- (1-allyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 68.7%; M .: 142-143 ° C ).

The nuclear magnetic resonance spectra are compatible with the proposed structure.

Example 2:

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

7-sulfamoyl 1,4-benzodioxane 5-carboxylic acid:

In a flask fitted with a stirrer and a thermometer were introduced 209 g of 34% ammonia and 97 g of 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid while maintaining the temperature between 0 and 5 ° vs. After stirring the mixture at room temperature, the precipitate formed was dissolved in 415 cm3 of water, then the solution filtered and treated with 140 cm3 of concentrated hydrochloric acid. The precipitate formed was drained, washed with water, then dried.

78 g of 7-sulfamoyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 272-274 ° C; yield: 87%).

7-Sulfamoyl 1,4-benzodioxane 5-methyl carboxylate:

429 g of methyl alcohol were introduced into a flask fitted with a condenser, then, while cooling, 54 g of 93% sulfuric acid and finally 111 g of 7-sulfamoyl 1,4-benzodioxane 5-carboxylic acid. The mixture was heated to reflux, then cooled. The crystals formed were drained, washed with methyl alcohol, then treated with 500 cm3 of water and 5 g of sodium carbonate. The precipitate was drained, washed with water, then dried.

95 g of methyl 7-sulfamoyl 1,4-benzodioxane 5-carboxylate were obtained (m.p .: 225-226 ° C; yield: 81%).

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

145 g of methyl 7-sulfamoyl 1,4-benzodioxane 5-carboxylate, 48 g of water, 81.5 g of 1-ethyl 2 were introduced into a flask fitted with a reflux condenser and a stirrer -aminomethylpyrrolidine. The suspension obtained was heated in a water bath until a test portion was soluble in dilute acids. The reaction mixture was then treated with 11 ml of water and acidified with 70 ml of acetic acid. The acetate solution formed was filtered through carbon black and the base was precipitated with 20% ammonia. The crystals were wrung, washed with water and dried. The benzamide was purified by passage through the hydrochloride (mp: 238-240 ° C). The base was reprecipitated by addition of 20% ammonia.

120 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-sulfamoyl 1,4-benzo-dioxane 5-carboxamide were obtained (Yield: 61.5%; M .: 160-161 ° C).

The NMR spectra are compatible with the proposed structure.

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Example 3:

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

7-mercapto 1,4-benzodioxane 5-carboxylic acid:

243 g of 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid and 654 cm3 of acetic acid were introduced into a flask fitted with an agitator and a condenser. The mixture was heated to 90 ° C, then cooled to 45 ° C. 389 g of tin were added and then, drop by drop, 1744 cm3 of hydrochloric acid. The mixture was heated to 55-60 ° C, then cooled and poured into water. The precipitate formed was drained, washed and then dried. 166 g of 7-mercapto 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 191-192 ° C; 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 sodium hydroxide solution and 181 g of ethyl sulphate were introduced into a flask fitted with a condenser. The mixture was heated to reflux, then cooled and the solution was poured into 1.31 of water, filtered, then treated with 110 cm 3 of hydrochloric acid. The precipitate formed was drained, washed with water, then dried.

152 g of 7-ethylthio 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 153-154 ° C; yield: 81%).

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

152 g of 7-ethylthio 1,4-benzodioxane 5-carboxylic acid and 958 cm3 of acetic acid were introduced into a flask fitted with a condenser. After dissolution, 398 cm3 of hydrogen peroxide was added, then the mixture was heated.

After cooling, the crystals formed were drained, washed and then dried.

139 g of 7-ethylsulfonyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 217-218 ° C; yield: 81%).

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

243 g of thionyl chloride, a few drops of dimethylformamide and then 139 g of 7-ethylsulfonyl 1,4-benzodioxane 5-carboxylic acid were introduced into a flask fitted with a condenser. The mixture was heated and then the excess thionyl chloride was distilled in vacuo.

148 g of 7-ethylsulfonyl 1,4-benzodioxane 5-carbonyl chloride were obtained (m.p .: 146-147 ° C; Yield: 100%).

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

59 g of 1-methyl 2-aminomethylpyrrolidine, 450 ml of chloroform and then, in portions, 150 g of 7-ethylsulfonyl 1,4-benzodioxane chloride 5- were placed in a flask fitted with a stirrer and a thermometer carbonyl at a temperature between 5 and 10 ° C. The mixture was then kept stirring for 1 h at room temperature, then 1850 ml of water were added. After distilling off the chloroform, the solution was filtered through carbon black and the benzamide was precipitated by adding 65 ml of sodium hydroxide solution. The solid was drained, washed with water, dried at 40 ° C. After recrystallization from absolute alcohol, 151 g of N- (1-methyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 80.5%; MP: 140-141 ° C ). The structure was confirmed by NMR.

Example 4:

l- (2,3-Ethylenedioxy 5-sulfamoylbenzoyl) 4- (2-pyrimidinyl) -piperazine

146 g of 7-sulfamoyl 1,4-benzodioxane 5-carboxylic acid, 300 ml of dioxane, and then into a three-necked flask of 11 fitted with a stirrer, a thermometer and an introduction bulb. 57 g of triethylamine. The mixture was heated to 40-45 ° C and 80 ml of water was added. The solution was cooled to a temperature between 5 and 10 ° C and 61.5 g of ethyl chloroformate were added. The mixture was stirred for 1 hour at 10 ° C and 93 g of 1- (2-pyrimidinyl) piperazine were added without the temperature exceeding 15 ° C. The mixture was stirred for 1 h at room temperature and then, after the addition of 1500 ml of water, was basified to pH 10 with ammonia. The crystals, obtained after vacuum distillation of the solvents and cooling, were drained, washed with water, dried in an oven at 50 ° C., then purified by treatment with 120 ml of chloroform. After filtration, drying, 92 g of 1- (2,3-ethylenedioxy 5-sulfamoylbenzoyl) 4- (2-pyrimidinyl) -piperazine were obtained. (YId: 40.2%; M: 239 ° C).

The structure was confirmed by NMR analysis.

Example 5:

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

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

500 cm3 of acetone were introduced into a flask fitted with an agitator and a thermometer, then a solution of 99 g of dimethylamine in 250 cm3 of acetone. The mixture was cooled to 0 ° C, then 139 g of 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid were added.

After stirring the mixture at room temperature, the acetone was distilled, then the residue taken up in 11 of water. The solution was basified, filtered, then treated with 70 cm3 of hydrochloric acid. The precipitate formed was drained, washed and dried.

128 g of 7-dimethylsulfamoyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 220-221 ° C; Yield: 89%).

7-Dimethylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride:

190 g of thionyl chloride and 153 g of 7-dimethylsulfamoyl 1,4-benzodioxane 5-carboxylic acid were introduced into a flask fitted with a condenser. The mixture was heated, then the excess thionyl chloride was distilled. 163 g of 7-dimethylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride were obtained (m.p .: 160-162 ° C; Yield: 100%).

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

61 g of 1-methyl 2-aminomethylpyrrolidine, 560 ml of chloroform and then, maintaining the temperature between 0 and 5 ° C., 163 g of 7- chloride were introduced into a flask fitted with an agitator and a thermometer. dimethylsulfamoyl 1,4-benzodioxane 5-carbonyl. The mixture was kept stirring for 1 h while allowing the temperature to rise, then 11 of water was added. After distilling off the chloroform, the solution was filtered and the carboxamide was precipitated by adding 30% sodium hydroxide solution. The crystals obtained were filtered, washed with water, dried.

After recrystallization from absolute alcohol, 157 g of N- (1-methyl 2-pyrrolidylmethyl) 7-dimethylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 76.9%; M .: 165-166 ° VS).

The NMR spectra are compatible with the proposed structure.

Example 6:

N- (1-benzyl2-pyrrolidylmethyl) 1,4-benzodioxane 5-carboxamide phosphate

440 ml of chloroform and 110 g of 1-benzyl 2-aminomethylpyrrolidine were introduced into a flask fitted with an agitator and a thermometer and then, at 5-10 ° C., 110 g of 1,4-benzodioxane chloride 5 -carbonyl. After stirring the mixture and adding 31 of water, the chloroform was removed. The solution was treated with ammonia, then the precipitate extracted with methylene chloride. The organic solution was dried, then the solvent removed. The compound obtained, dissolved in absolute ethanol, was treated with 30 ml of 85% phosphoric acid. The precipitate formed was drained, washed with ethanol and dried. 153 g of N- (1-benzyl 2-pyrrolidylmethyl) 1,4-benzodioxane 5-carboxamide phosphate were obtained (m.p .: 165 ° C; Yield: 61%).

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Example 7:

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

145 g of methyl 7-sulfamoyl 1,4-benzodioxane 5-carboxylate, 48 g of water and 89 g of 1-allyl 2-aminomethylpyrrolidine were introduced into a flask fitted with a condenser. The mixture was heated in a water bath until a test sample was soluble in dilute acids, then 11 of water was added. The precipitated carboxamide was redissolved by formation of acetate. The solution formed was filtered through carbon black, then the base was precipitated by addition of 20% ammonia. The crystals obtained were drained, washed with water, dried and purified by passage through the hydrochloride (mp: 228-230 ° C), then transformation into base by treatment with 20% ammonia.

131 g of N- (1-allyl 2-pyrrolidylmethyl) 7-sulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 64.8%; mp: 143-144 ° C).

The structure was confirmed by NMR analysis.

Example 8:

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

7-Methylsulfamoyl 1,4-benzodioxane 5-methyl carboxylate:

750 g of methyl alcohol were introduced into a flask fitted with a condenser, then, while cooling, 273 g of concentrated sulfuric acid and finally 160 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carboxylic acid. The mixture was heated to reflux, then cooled and poured into water and sodium carbonate. The precipitate obtained was drained, washed and dried.

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

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

137 g of methyl 7-methylsulfamoyl 1,4-benzodioxane 5-carboxylate, 43 g of water and 73 g of 1-ethyl 2-amino were introduced into a flask fitted with a stirrer and a reflux condenser -methylpyrrolidine. The mixture was heated in a water bath until a test portion was completely soluble in dilute acids. The carboxamide obtained by cooling was purified by passage through acetate, by treatment with 100 ml of acetic acid in 950 ml of water. After filtration on carbon black of the solution obtained, the base was precipitated by adding 20% ammonia. The crystals obtained were drained, washed with water, dried and purified by recrystallization from boiling isopropyl alcohol.

121 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 66.2%; M: 139-140 ° C).

The structure was confirmed by NMR analysis.

The corresponding hydrochloride was obtained by treatment of the carboxamide with hydrochloric acid (d: 1.18) (mp 186-188 ° C).

Example 9:

N- (1-ethyl 2-pyrrolidylmethyl) 2,3-methylenedioxybenzamide

Similarly, 34.9 g of ethyl 2,3-methylenedioxybenzoate reacted with 24.2 g of 1-ethyl 2-aminomethylpyrrolidine to give, after treatment and purification, 28.3 g of N- (1 -ethyl 2-pyrrolidylmethyl) 2,3-methylenedioxybenzamide.

The NMR spectra are compatible with the expected structure.

Example 10:

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

In a flask fitted with an agitator and a thermometer, 65 g of levorotatory 1-ethyl 2-aminomethylpyrrolidine were dissolved in 430 ml of chloroform. The solution obtained was cooled to 5 ° C,

then 148 g of 7-ethylsulfonyl 1,4-benzodioxane chloride

Finely pulverized 5-carbonyl was added while maintaining the temperature between 5 and 10 ° C. At the end of the introduction, the mixture was kept stirring for 1 h, then was treated with 11 of water. After distilling off the chloroform, the solution was filtered through carbon black and the base was precipitated by an excess of 30% sodium hydroxide. The crystals obtained were drained, washed with water, dried and recrystallized from isopropyl alcohol.

151.5 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzodioxane 5-carboxyl levorotatory were obtained (Yield: 77.7%; mp: 111-112 ° C); (a) 2 ^ = —54.2 ° (in 5% solution in dimethylformamide).

Example 11:

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

Similarly, 64.5 g of dextrorotatory 1-ethyl 2-aminomethylpyrrolidine reacted on 146 g of 7-ethylsulfonyl 1,4-benzodioxane 5-carbonyl chloride to give, after treatment and purification, 133.5 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzodioxane 5-carboxamide dextrorotatory (yield: 69.8%; mp: 111-112 ° C); (oOd = 55.5 ° (in 5% solution in dimethylformamide).

Example 12:

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

Similarly, 58 g of 1-ethyl 2-aminomethylpyrrolidine reacted on 131 g of 7-ethylsulfonyl 1,4-benzodioxane 5-carbonyl chloride to give, after treatment and purification, 103.5 g of N- ( l-ethyl 2-pyrrolidylmethyl)

7-ethylsulfonyl 1,4-benzodioxane 5-carboxamide (yield: 60.2%; mp: 118-119 ° C). 100 g of the base obtained were dissolved in 220 ml of acetone, the solution was filtered through carbon black, then a solution of 9.5 g of hydrochloric acid in acetone was added. The hydrochloride crystals obtained were drained, washed with acetone, then dried.

96 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzodioxane 5-carboxamide hydrochloride were obtained (Yield: 88.2%; M: 148-150 ° C).

Example 13:

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

131 g of methyl 7-sulfamoyl 1,4-benzodioxane 5-carboxylate, 43 g of water and 66 g of 1-methyl 2-aminomethylpyrrolidine were introduced into a flask fitted with a reflux condenser. The mixture was heated in a water bath until a test portion was completely soluble in dilute acids. The carboxamide obtained by cooling was purified by treatment with a solution of 50 ml of acetic acid in 1250 ml of water. After filtration on carbon black of the solution obtained, the base was precipitated by adding 20% ammonia. The crystals obtained were drained, washed with water, dried and purified by recrystallization from boiling methyl alcohol. 119.5 g of N- (1-methyl 2-pyrrolidylmethyl) 7-sulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 70.1%; mp 187-188 ° C).

Example 14:

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

58 g of 1-allyl 2-aminomethylpyrrolidine and 360 ml of chloroform were introduced into a flask fitted with an agitator and a thermometer and 120 g of chloride of 7-, maintaining the temperature between 5 and 10 ° C. ethylsulfonyl 1,4-benzodioxane 5-carbonyl. After stirring the mixture and adding 11 of water, the chloroform was distilled. The solution obtained was filtered through carbon black, then the

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base was precipitated by addition of 40 ml of 30% probe detergent. The crystals obtained were drained, washed with water, then dried.

152 g of N- (1-allyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzo-dioxane 5-carboxamide were obtained (Yield: 93.4%; M: 78-80 ° C). 146 g of the base obtained were dissolved hot in 290 ml of absolute alcohol, then the solution was filtered through carbon black and acidified by addition of a solution of 13.5 g of hydrochloric acid in 100 ml of 'absolute alcohol. After cooling, the crystals formed were drained, washed with absolute alcohol and dried, then purified by recrystallization from absolute alcohol. 119.5 g of N- (1-allyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzodioxane hydrochloride

5-carboxamide were obtained (yield: 75%; m .: 138-140 ° C).

Example 15:

N- (1-ethyl 2-pyrrolidylmethyl) 2H-3,4-dihydro 1,5-benzodioxêpine

6-carboxamide

2H-3,4-Dihydro 1,5-benzodioxepine 6-methyl carboxylate:

111 g of methyl 2,3-dihydroxybenzoate, 660 cm3 of methyl ethyl ketone, 167 g of 1,3-dibromopropane and 10 g of sodium iodide were placed in a flask fitted with an agitator and a thermometer. The mixture was heated to 40 ° C, then 182 g of potassium carbonate was added. The mixture was heated to reflux, then the residue taken up in 21 of water. The oily layer is decanted, extracted with ether, then the solution washed with 10% sodium hydroxide and dried. After elimination of the ether and distillation under vacuum, 86.5 g of 2H-3,4-di-hydro 1,5-benzodioxepine 6-methyl carboxylate were obtained (m .: 166-176 ° C under 8 mm Hg; Yield: 63%).

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

160 g of 2H-3,4-dihydro 1,5-benzodioxepine 6-methyl carboxylate and 388 cm3 of sodium hydroxide were introduced into a flask fitted with a condenser. The mixture was heated to reflux, then the solution diluted in 11 of water was treated with 5 g of sodium metabisulfite. The solution was filtered and then treated with 77 cm 3 of concentrated hydrochloric acid.

The precipitate formed was drained, washed with water and dried. 120 g of 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were obtained (m.p .: 65-6TC; Yield: 80.5%).

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

246 g of thionyl chloride and 134 g of 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were introduced into a flask fitted with a condenser. The mixture was heated to reflux. The excess thionyl chloride was then distilled in vacuo.

147 g of 2H-3,4-dihydro 1,5-benzodioxepine 6-carbonyl chloride were obtained (m.p .: 35-37 ° C; Yield: 100%).

N- (1-ethyl 2-pyrrotidylmethyl) 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxamide:

92 g of 1-ethyl 2-aminomethylpyrrolidine and 458 ml of chloroform were introduced into a flask fitted with an agitator and a thermometer, then 152 g of 2H-3 chloride, while maintaining the temperature between 5 and 10 ° C. , 4-dihydro 1,5-benzodioxepine 6-carbonyl. After stirring for 1 h while allowing the temperature to rise, 1460 ml of water were added, then the chloroform was distilled. The solution was filtered through carbon black and the base precipitated by the addition of 75 ml of 20% ammonia. The crystals formed were wrung, washed with water and dried.

191 g of N- (1-ethyl 2-pyrrolidylmethyl) 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxamide monohydrate were obtained (Yield: 82.4%; M: 51-52 ° C) . 173.5 g of the compound obtained were dissolved in 750 ml of absolute alcohol. The solution was filtered through carbon black, then a solution of 62 g of 85% phosphoric acid in 100 ml of absolute alcohol was added. The crystals formed were drained, washed with absolute alcohol and dried, then recrystallized from alcohol. 198 g of N- (1-ethyl 2-pyrrolidylmethyl) 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxamide phosphate were obtained (Yield: 92%; M: 189-190 ° C).

Example 16:

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

Into a flask fitted with a reflux condenser were introduced 169 g of methyl 7-methylsulfamoyl 1,4-benzodioxane 5-carboxylate, 53 ml of water and 81 g of 1-methyl 2-aminomethylpyrrolidine. The mixture was heated in a water bath until a test portion was completely soluble in dilute acids. The crystals obtained were dissolved in a solution of 50 ml of acetic acid in 1250 ml of water, then the solution was filtered through carbon black and the base was reprecipitated by addition of 100 ml of 20% ammonia . The crystals were wrung, washed with water and dried.

182 g of N- (1-methyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 83.6%; M: 189-190 ° C).

Example 17:

N- (diethylaminoethyl) 1,4-benzodioxane 5-carboxamide hydrochloride

21 g of diethylaminoethylamine and 85 ml of acetone were introduced into a flask fitted with a stirrer and a thermometer, and the mixture was cooled to 0 ° C. 36 g of 1-4-benzodioxane 5-carbonyl chloride were then added while maintaining the temperature at 0 ° C. After standing at room temperature, the crystals formed were drained, washed with acetone, dried and purified by recrystallization from isopropyl alcohol.

36.5 g of N- (diethylaminoethyl) 1-4-benzodioxane 5-carboxamide hydrochloride were obtained (yield: 64%; mp: 120 ° C).

Example 18:

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

13 g of 7-ethylsulfonyl 1,4-benzodioxane 5-carboxylic acid, 300 ml of tetrahydrofuran and 13 g of carbonyldiimidazole were introduced into a flask fitted with an agitator, a thermometer and a condenser. The mixture was stirred at room temperature, then 9.5 g of 1-ethyl 2-aminomethylpyrrolidine was added. Stirring was continued at room temperature, then the solvent was evaporated in vacuo. The crystals obtained were washed with water and then dried.

14 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-ethylsulfonyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 73.8%; mp 118-119 ° C).

Example 19:

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

A solution of 6 g of 1-methyl 2-aminomethylpyrrolidine in pyridine was introduced into a flask fitted with a stirrer, a thermometer and a condenser, then drop by drop,

with stirring and maintaining the temperature between 0 and 5 ° C, a solution of 3.5 g of phosphorus trichloride in 20 ml of pyridine. Stirring was maintained between 0 and 5 ° C, then at room temperature. 14.5 g of 7-dimethylsulfamoyl 1,4-benzodioxane 5-carboxylic acid were then added. The mixture was heated with stirring. After cooling the mixture and removing the solvent, the residue was dissolved in chloroform, then the solution was washed with aqueous sodium carbonate and dried over anhydrous magnesium sulfate.

After concentration under reduced pressure, 12.5 g of N- (1-methyl 2-pyrrolidylmethyl) 7-dimethylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 64.5%; m .: 165-166 ° VS).

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Example 20:

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

84 g of 1-cyclohexyl 3-aminopyrrolidine, 430 ml of chloroform and 146 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride were introduced into a flask fitted with a stirrer and a thermometer. After stirring the mixture, the base was extracted with methylene chloride, then the solvent was evaporated. The crystals formed were dissolved in boiling absolute alcohol and the solution obtained was filtered through carbon black. The crystals obtained after cooling were dissolved in a solution of acetic acid in water, then the solution was filtered through carbon black and the base reprecipitated by the addition of 20% ammonia.

129.5 g of N- (1-cyclohexyl 3-pyrrolidyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 61.2%; M: 160-161 ° C).

Example 21:

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

64 g of 1-ethyl 2-aminomethylpyrrolidine and 530 ml of chloroform were introduced into a flask fitted with an agitator and a thermometer, and then 153 g of 7- chloride, maintaining the temperature between 0 and 5 ° C. dimethylsulfamoyl 1,4-benzodioxane 5-carbonyl. The mixture was kept stirring for 1 h while allowing the temperature to rise, then 11 of water was added. After distilling off the chloroform, the solution was filtered and the carboxamide was precipitated by adding 30% sodium hydroxide solution. The crystals obtained were filtered, washed with water and dried.

After recrystallization from absolute alcohol, 144.5 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-dimethylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 72.8%; F .: 146- 148 ° C).

Example 22:

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

82 g of 1-ethyl 2-aminomethylpyrrolidine dextrorotatory, 600 cm 3 of chloroform and, little by little, at a temperature of 5-10 ° C., 200 g of chloride were introduced into a flask fitted with an agitator and a thermometer. of 7-methylsulfamoyl 1,4-benzodioxane 5-carbonyl. After adding 11 of water, the chloroform was distilled, then the remaining solution was filtered. The base was precipitated by adding 60 cm3 of 20% ammonia. The crystals formed were drained, washed with water, then dried.

162 g of N- (1-ethyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide dextrorotatory were obtained (m.p .: 136-137 ° C; yield: 66%).

Example 23:

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

In a similar manner to that of the previous example, 82 g of levorotatory 1-ethyl 2-aminomethylpyrrolidine reacted with 195 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride to give 151 g of N- ( 1-ethyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-levorotatory carboxamide (mp: 136-137 ° C; yield: 62%).

Example 24:

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

85 g of levorotatory 1-allyl 2-aminomethylpyrrolidine are placed in a flask fitted with an agitator and a thermometer,

610 cm3 of chloroform and, gradually, 178 g of 7-methyl chloride

sulfamoyl 1,4-benzodioxane 5-carbonyl, at a temperature of 5-10 ° C. After stirring the mixture, 1.21 of water was added, then the chloroform was distilled. The remaining solution was filtered, then the base precipitated with 70 cm3 of 20% ammonia. The crystals formed were drained and washed with water.

After recrystallization from ethyl acetate, 117 g of N- (1-allyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide levorotatory were obtained (mp: 101-102 ° C; Yield: 49 %).

Example 25:

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

5-carboxamide dextrorotatory

In a similar manner to that of the previous example, 84 g of 1-allyl 2-aminomethylpyrrolidine dextrorotatory reacted with 175 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride to give, after purification, 125 g N- (1-allyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide dextrorotatory (mp: 104-105 ° C; yield: 52.6%).

Example 26:

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

61 g of 1-methyl 2-aminomethylpyrrolidine dextrorotatory, 465 cm3 of chloroform and, in portions, 155 g of 7-methylsulfamoyl 1,4-benzodioxane chloride 5 were introduced into a flask fitted with a stirrer and a thermometer -carbonyl, maintaining the temperature at 5-10 ° C. After stirring the mixture and adding 1850 cm3 of water, the chloroform was distilled, then the remaining solution was filtered. The base was precipitated by adding 65 cm3 of 20% ammonia. The crystals formed were wrung, washed and dried.

154 g N- (1-methyl 2-pyrrolidylmethyl) 7-methylsulfamoyl

1.4-Benzodioxane 5-carboxamide dextrorotatory were obtained (m.p .: 187-188 ° C; Yield: 78.5%).

Example 27:

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

In a similar manner to that of the previous example, 71 g of levorotatory 1-methyl 2-aminomethylpyrrolidine reacted with 180.5 g of 7-methylsulfamoyl 1,4-benzodioxane 5-carbonyl chloride to give 175 g of N - (1-methyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-levorotatory carboxamide (mp: 187-187.5 ° C; yield: 77%).

Example 28:

N- (1-ethyl 2-pyrrolidylmethyl) 8-methylsulfamoyl 2H-3,4-dihydro

1.5-benzodioxepine 6-carboxamide

8-chlorosulfonyl acid 2H-3,4-dihydro 1,5-benzodioxêpine

6-carboxylic:

1.092 cm3 of sulfuric hydrochlorine were introduced into a flask fitted with an agitator, a condenser and a thermometer, then 106 g of 2H- acid, in portions, keeping the temperature between 5 and 10 ° C 3,4-dihydro 1,5-benzodioxepine 6-carboxylic. After stirring at room temperature, the mixture was poured onto ice. The crystals formed were drained, washed with water, then dried.

146 g of 8-chlorosulfonyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were obtained (m.p .: 114-115 ° C; Yield: 91%).

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

233 g of an aqueous methylamine solution and, little by little, 146 g of 8-chlorosulfonyl 2H-3,4-dihydro 1,5- acid were introduced into a flask fitted with a stirrer and a thermometer. benzo-

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6-carboxylic dioxepin, keeping the temperature between 0 and 5 ° C. After stirring the mixture, the precipitate formed was dissolved in water, the solution filtered, then treated with 150 cm3 of concentrated hydrochloric acid. The crystals formed were drained, washed and then dried.

112 g of 8-methylsulfamoyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were obtained (m.p .: 145-146 ° C; yield: 78%).

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

220 g of thionyl chloride and then 177 g of 8-methylsulfamoyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were introduced into a flask fitted with a condenser. The mixture was heated, then the excess of thionyl chloride distilled in vacuo.

188 g of 8-methylsulfamoyl chloride 2H-3,4-dihydro 1,5-benzodioxepine 6-carbonyl were obtained (m.p .: 93-94 ° C; Yield: 100%).

N-f 1-ethyl 2-pyrrolidylmethyl) 8-methylsulfamoyl 2H-3,4-dihydro 1,5-benzodioxêpine 6-carboxamide:

79 g of 1-ethyl 2-aminomethylpyrrolidine, 750 cm3 of methyl ethyl ketone and, little by little, 188 g of 8-methylsulfamoyl chloride 2H-3,4- were introduced into a flask fitted with a stirrer and a thermometer. dihydro 1,5-benzodioxepine 6-carbonyl, keeping the temperature between 5 and 10 ° C. The hydrochloride precipitate was drained, washed with methyl ethyl ketone, then dried. After recrystallization from methyl alcohol, the hydrochloride was dissolved in 850 cm3 of water. The solution was filtered, then the base precipitated by adding 60 cm3 of 20% ammonia. The crystals formed were drained, washed with water, then dried.

180 g of N- (1-ethyl 2-pyrrolidylmethyl) 8-methylsulfamoyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxamide were obtained (MFP: 144-145aC; Yield: 63.8%).

Example 29:

N- (1-ethyl 2-pyrrolidylmethyl) 2,3-methylenedioxybenzamide hydrochloride

134 g of 1-ethyl 2-aminomethylpyrrolidine, 950 cm3 of chloroform and, little by little, 183 g of 2,3-methylene-dioxybenzoyl chloride were introduced into a flask fitted with a stirrer and a thermometer. now the temperature between 5 and 10 ° C. After adding 11 of water, the chloroform was distilled, then the remaining solution was filtered. After addition of 120 cm3 of 20% ammonia and extraction with ether, the ethereal solution was dried over potassium carbonate, then the ether was distilled.

The base obtained was dissolved in 300 cm3 of acetone, then a solution of 34 g of hydrochloric acid in 330 cm3 of acetone was added. The hydrochloride precipitate was drained, washed with acetone, then dried.

After recrystallization from isopropyl alcohol, 154 g of N- (1-ethyl 2-pyrrolidylmethyl) 2,3-methylenedioxybenzamide hydrochloride were obtained (mp: 127.5-128.5 ° C; yield: 49.7% ).

Example 30:

4- (1,4-Benzodioxane 7-ethylsulfonyl 5-carbonyl) 1,4-diazabicyclo (4-3-0) -nonane

41.5 g of 1,4-diazabicyclo (4-3-0) -nonane and 300 ml of chloroform were introduced into an 11-flask. The mixture was cooled to 5 ", then 87 g of 7-ethylsulfonyl 1,4-benzodioxane chloride

5-carbonyl were added in small amounts. After stirring the mixture at room temperature, 5 g of actarbone was added. After filtration and elimination of the chloroform, the oily residue was dissolved in 200 ml of water, then 30 ml of 20% ammonia were added. The residue obtained was dried and then recrystallized from acetone.

40 g of 4- (1,4-benzodioxane 7-ethyl sulfonyl 5-carbonyl) 1,4-diazabicyclo (4-3-0) -nonane were obtained (m.p .: 147 ° C; yield: 35%).

Example 31:

5-f (4-methyl l-piperazinyl) carbonyl] 7-nitro 1,4-benzodioxane hydrochloride

7-nitro 1,4-benzodioxane 5-carboxylic acid:

160 ml of acetic acid, 160 ml of acetic anhydride and 100 g of 1,4-benzodioxane 5-carboxylic acid were placed in a flask fitted with a stirrer and a thermometer. The mixture was heated, then a solution of 40 ml of nitric acid in 40 ml of acetic acid was added. After stirring at 40-45 ° C, the mixture was cooled. The crystals formed were drained, washed and then dried. After purification by recrystallization from ethanol, 34 g of 7-nitro 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 246 ° C; Yield: 27%).

5- [(4-methyl 1-piperazinyl) carbonyl] 7-nitro 1,4-benzodioxane hydrochloride:

22 ml of water, 22.5 g of 7-nitro acid, 1,4-benzodioxane 5-carboxylic acid, 65 ml of acetone and 10 were introduced into a flask fitted with a stirrer and a thermometer. 5 g of triethylamine. The mixture was cooled to 10 ° C, then 14 g of isobutyl chloroformate was added. The mixture was stirred allowing the temperature to rise. The oily compound formed was cooled to 10 ° C, 11 g of N-methylpiperazine were added, then the mixture was stirred allowing the temperature to rise. The crystals formed were washed with water. 20.5 g of 5 - [(4-methyl 1-piperazinyl) carbonyl] 7-nitro 1,4-benzodioxane were obtained (m.p .: 218 ° C; Yield: 66.7%).

The 20.5 g of base obtained were treated with a solution of 7 ml of hydrochloric acid (d = 1.18) in 100 ml of water. The crystals formed by cooling were washed with water and then dried. 20.5 g of 5 - [(4-methyl 1-piperazinyl) carbonyl] 7-nitro 1,4-benzodioxane hydrochloride were obtained (m.p .: 250 ° C; yield: 89.4%).

Example 32:

5- [(4-methyl 1-piperazinyl) carbonyl] 7- (1-adamantyl) sulfamoyl 1,4-benzodioxane hydrochloride

7- (l-adamantyl) sulfamoyl 1,4-benzodioxane 5-carboxylic acid:

187.5 g of adamantylamine hydrochloride, 500 ml of sodium hydroxide and 1000 ml of triethylamine were introduced into a flask fitted with an agitator and a thermometer. 280 g of 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid were then added, at a temperature below 15 ° C. The mixture was stirred at room temperature and then treated with 1.51 methylene chloride. The organic phase was separated, then the solvent removed. The residue was treated with 1200 ml of water and 150 ml of hydrochloric acid, then the precipitate was redissolved in 1200 ml of water and 120 ml of sodium hydroxide. The solution was filtered and then treated with 150 ml of hydrochloric acid. The crystals formed were drained, washed and then dried.

200 g of 7- (1-adamantyl) sulfamoyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 205 ° C; Yield: 51%).

5 - [(4-methyl l-pipêrazinyl) carbonyl] 7- (l-adamantyl) sulfamoyl 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 11-liter flask fitted with a stirrer and a thermometer. After stirring the mixture, 12.5 g of triethylamine were added and then, in small quantities, 17 g of isobutyl chloroformate. After stirring the mixture at 20 ° C, a solution of 14 g of N-methylpiperazine in 50 ml of dioxane was introduced. The mixture was stirred and then cooled. The triethylamine hydrochloride formed was removed by filtration, the filtrate concentrated in vacuo, then taken up in 300 ml of water. 15 ml of hydrochloric acid were 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 pH = 1.

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The crystals formed were drained, washed with ethanol and dried.

37 g of 5 - [(4-methyl 1-piperazinyl) carbonyl] hydrochloride 7 - [(1-adamantyl) sulfamoyl] 1,4-benzodioxane were obtained (m.p .: 260 ° C; yield: 58%).

Example 33:

N- (piperidinoethyl) hydrochloride 7-chloro 1,4-benzodioxane 5-carboxamide

7-amino 1,4-benzodioxane 5-carboxylic acid:

56 g of 7-nitro 1,4-benzodioxane 5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were introduced into an autoclave, followed by hydrogen under a pressure of 65 kg / cm 2, while heating . At the end of the absorption of hydrogen, the mixture was stirred at 60 ° C, then treated with a solution of 50 ml of sodium hydroxide solution in 450 ml of water. The solution was filtered and then treated with 50 ml of hydrochloric acid. The precipitate was drained, washed with water and dried.

36.5 g of 7-amino 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 220 ° C; Yield: 75%).

7-chloro 1,4-benzodioxane 5-carboxylic acid:

49 g of 7-amino 1,4-benzodioxane 5-carboxylic acid, 200 ml of water and 50 ml of hydrochloric acid were introduced into a flask fitted with an agitator and a thermometer. The mixture was cooled to 5 ° C, then a solution of 17.5 g of sodium nitrite in 38 ml of water was added. The suspension formed was then poured into a solution of 20 g of cuprous chloride in 75 ml of hydrochloric acid. The precipitate obtained was drained and washed, then dissolved in a solution of 42 g of sodium bicarbonate in 420 ml of water. The solution was filtered and then treated with 100 ml of hydrochloric acid.

50 g of 7-chloro 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 180 ° C; Yield: 92.7%).

7-chloro 1,4-benzodioxane 5-carbonyl acid chloride:

32.2 g of 7-chloro 1,4-benzo-dioxane 5-carboxylic acid and 64 ml of thionyl chloride were introduced into a flask fitted with an agitator, a thermometer and a condenser. The mixture was heated to reflux, then the excess thionyl chloride was removed in vacuo.

35 g of 7-chloro 1,4-benzodioxane 5-carbonyl chloride were obtained (m.p .: 140 ° C; Yield: 100%).

N- (piperidinoethyl) 7-chloro, 1,4-benzodioxane 5-carboxamide hydrochloride:

150 ml of methyl ethyl ketone and 22 g of N- (aminoethyl) piperidine were introduced into a flask fitted 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 between 15 and 20 ° C. After stirring, the crystals formed were drained, then washed with methyl ethyl ketone.

35 g of N- (piperidinoethyl) 7-chloro 1,4-benzodioxane 5-carboxamide hydrochloride were obtained (m.p .: 192 ° C; Yield: 64.5%).

Example 34:

N- (butyl) 7- (adamantyljsulfamoyl 1,4-benzodioxane 5-carboxamide

500 ml of dioxane, 50 ml of water and 49 g of acid 7 - [(l-adamantyl) sulfamoyl] 1,4-benzodioxane 5 were introduced into a 21 flask fitted with a stirrer and a thermometer. -carboxylic and 12.5 g of triethylamine. The solution was stirred at room temperature, then 17 g of isobutyl chloroformate was added. The mixture was stirred, then 10 g of butylamine were introduced. After stirring the mixture, the dioxane was removed. The residue was dissolved in 200 ml of hot water. The crystals formed by cooling were washed with water, dried and redissolved in 250 ml of boiling acetone. The solution was filtered hot. The crystals formed by cooling were drained, washed and dried.

26 g of 5- (butylaminocarbonyl) 7 - [(l-adamantyl) sulfamoyl] 1,4-benzodioxane were obtained (m.p .: 147 ° C; yield: 46.4%).

Example 35:

N- (1-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 were introduced into a flask fitted with an agitator, a condenser, a thermometer and a nitrogen inlet tube. cm3 of alcohol, 280 cm3 of sodium hydroxide solution, then 175 g of ethylene bromide. The mixture is heated to reflux, then cooled and then taken up in 2.81 of water. The solution is filtered and then treated with 85 cm3 of concentrated hydrochloric acid. The precipitate formed is drained, washed and dried.

After recrystallization from dimethylformamide, 110 g of 8-methoxy 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 224-226 ° C; Yield: 57%).

8-methoxy 1,4-benzodioxane 5-carbonyl chloride:

In a flask equipped with a condenser were introduced 391 g of thionyl chloride and 138 g of 8-methoxy 1,4-benzodioxane 5-carboxylic acid. The mixture was heated to 50-55 ° C. The excess thionyl chloride was then distilled in vacuo. 151 g of 8-methoxy 1,4-benzodioxane 5-carbonyl chloride were obtained (Yield: 100%).

N- (1-ethyl 2-pyrrolidylmethyl) 8-methoxy 1,4-benzodioxane 5-carboxamide oxalate:

87 g of 1-ethyl 2-aminomethylpyrrolidine and 775 cm3 of methyl ethyl ketone were introduced into a flask fitted with an agitator and a thermometer, then 155 g of 8-methoxy 1,4-benzodioxane chloride 5- carbonyl keeping the temperature between 5 and 10 ° C. After stirring, the mixture was taken up in 1500 cm3 of water, then the methyl ethyl ketone was distilled. The remaining solution was filtered and then treated with sodium hydroxide. The oil was decanted, then extracted with methylene chloride. The solution was dried over potassium carbonate, then the methylene chloride was distilled in vacuo.

224.5 g of N- (1-ethyl 2-pyrrolidylmethyl) 8-methoxy 1,4-benzodioxane 5-carboxamide were obtained.

197.5 g of the base obtained were dissolved in 760 cm3 of absolute alcohol, then 67 g of oxalic acid in solution in 195 cm3 of absolute alcohol were added. The crystals formed were drained, washed with absolute alcohol, then dried.

208.5 g of N- (1-ethyl 2-pyrrolidylmethyl) 8-methoxy 1,4-benzodioxane 5-carboxamide oxalate were obtained (Yield: 82%; m.p .: 129-130 ° C).

Example 36:

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

8-methoxy 7-chlorosulfamoyl 1,4-benzodioxane 5-carboxylic acid:

1045 cm3 of sulfuric hydrochloride were introduced into a flask fitted with an agitator, a thermometer and a condenser, then 110 g of 8-methoxy 1,4-benzodioxane 5-carboxylic acid, in portions. the temperature between 5 and 10 ° C. The mixture was stirred at room temperature and then poured onto ice. The precipitate formed is drained, washed and dried. 159 g of 8-methoxy 7-chlorosulfonyl 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 was introduced into a flask fitted with a stirrer and a thermometer, then little by little 159 g of 8-methoxy 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid, keeping the temperature between 0 and 5 ° C. After stirring the mixture, the precipitate was taken up in 21 of water. The solution was filtered and then treated with 280 cm3 of concentrated hydrochloric acid. The precipitate formed was drained, washed and dried.

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118 g of 8-methoxy 7-sulfamoyl 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 247-248 ° C; Yield: 82%).

8-Methoxy 7-sulfamoyl 1,4-benzodioxane 5-methyl carboxylate:

396 g of methyl alcohol were introduced into a flask fitted with a condenser, then gradually, while cooling, 51 g of sulfuric acid and 114.5 g of 8-methoxy 7-sulfamoyl 1,4-benzo acid -5-carboxylic dioxane. The mixture was heated to reflux, then poured into 485 cm3 of water and 40 g of sodium carbonate. The precipitate formed is drained, washed and dried.

110.5 g of 8-methoxy 7-sulfamoyl 1,4-benzodioxane 5-methyl carboxylate were obtained (m.p .: 202-203 ° C; Yield: 92%).

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

150 g of 8-methoxy 7-sulfamoyl 1,4-benzodioxane 5-methyl carboxylate and 750 cm3 of ethylene glycol were introduced into a flask. After dissolution, 127 g of 1-ethyl 2-aminomethylpyrrolidine were added and the mixture was heated to 50 ° C. The solution obtained was taken up in 21 of water and acidified with 120 cm 3 of acetic acid. The precipitate formed was drained, washed with water, then dried. The precipitate was then redissolved in 915 cm3 of hot water. The solution was filtered, then the base was precipitated with ammonia. The precipitate was drained, washed with water, then dried.

144 g of N- (1-ethyl 2-pyrrolidylmethyl) 8-methoxy 7-sulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (Yield: 73%; m.p .: 110-115 ° C).

Example 37:

4- (1,4-Benzodioxane 5-carbonyl) 1,4-diazabicyclo (4-3-0) -nonane.

63 g of 1,4-diazabicyclo (4-3-0) -nonane and 400 ml of chloroform were then introduced into a 11-liter flask fitted with an agitator and a thermometer and then, in portions, 50 g of 1,4-Benzodioxane 5-carbonyl while maintaining the temperature at 10 ° C. The mixture was then stirred at room temperature, then 11 of water was added. After addition of acetic acid to pH = 4, addition of carbon black and filtration, the product was precipitated with ammonia. After extraction with methylene chloride, the solution was dried and then filtered. The solvent was removed in vacuo and the product obtained purified by recrystallization from ethanol.

50 g of 4- (1,4-benzodioxane 5-carbonyl) 1,4-diazabicyclo (4-3-0) -nonane were obtained (mp: 128 ° C; yield: 69%).

Example 38:

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 flask fitted with an agitator and a thermometer, then 140 g of 7-chlorosulfonyl 1,4-benzodioxane 5 acid -carboxylic, keeping the temperature between 20 and 30 ° C. After stirring at room temperature, 500 ml of water was added. The solution was filtered and then treated with 300 ml of hydrochloric acid. The precipitate formed was drained, washed and dried. 117 g 7-diethylsulfamoyl 1,4-benzodioxane acid

5-carboxylic were obtained (m.p .: 149 ° C; Yield: 74%).

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 were introduced into a flask fitted with a stirrer and a thermometer acetone. The mixture was cooled to 10-15 ° C, then 17.2 g of isobutyl chloroformate was added. After addition, at 15-20 ° C, of 14.1 g of benzylamine and stirring of the mixture, the crystals formed were drained, washed with water, then purified by recrystallization from ethanol.

33 g of N- (benzyl) 7-diethylsulfamoyl 1,4-benzodioxane 5-carboxamide were obtained (mp: 125 ° C; yield: 68%).

Example 39:

5 N-f 1-benzyl 4-piperidyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide

70 ml of water, 68.5 g of 7-methylsulfamoyl 1,4-benzo-10-dioxane 5-carboxylic acid, 25.5 g of triethylamine were introduced into a flask fitted with a stirrer and a thermometer. and 200 ml of acetone then, maintaining the temperature between 15 and 20 ° C, 34.5 g of isobutyl chloroformate were added. After addition, at 15-20 ° C, of 52 g of 1-benzyl 4-aminopiperidine and stirring of the mixture, the crystals formed were drained, washed with water, then dried. The product formed was purified by treatment with a hydrochloric acid solution, then precipitation with sodium hydroxide. The precipitate was then drained, washed with water and dried.

76 g of N- (1-benzyl 4-piperidyl) 7-methylsulfamoyl 1,4-benzo-dioxane 5-carboxamide were obtained (m.p .: 228 ° C; yield: 68%).

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Example 40:

N- (1-adamantyl) 1,4-benzodioxane 5-carboxamide

200 ml of chloroform and 37.5 g of adamantamine were introduced into a flask fitted with a stirrer and a thermometer and then, at 5-10 ° C., 50 g of 1,4-benzodioxane 5 chloride. carbonyl were added in fractions. After stirring at room temperature, 1500 ml of water was added, then the chloroform was removed in vacuo. The base, precipitated with ammonia, was extracted with methylene chloride. After removing the solvent, the residue was dissolved in hydrochloric ethanol. The crystals formed by cooling were drained, washed and then dried.

20 g of N- (l-adamantyl) 1,4-benzodioxane 5-carboxamide were obtained (mp: 137 ° C; yield: 25%).

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Example 41:

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

40 ml of water, 37.8 g of 7-diethylsulfamoyl 1,4-benzodioxane 5-carboxylic acid, 12.5 g of triethylamine and 120 ml were introduced into a flask fitted with a stirrer and a thermometer. methyl ethyl ketone and then, at 15-20 ° C, 17.2 g of isobutyl chloroformate were added. After stirring the mixture, 25 g of 1-benzyl 45 2-aminomethylpyrrolidine were added while maintaining the temperature at 15-20 ° C. The mixture was stirred at room temperature, then the solvents were removed. The residue was taken up in 200 ml of methylene chloride and 300 ml of water. After stirring, the solvent was decanted, then dried over magnesia sulfate. The solution was filtered and the solvent removed. The compound obtained was dissolved in ethanol at the boil, then 18 g of 85% phosphoric acid were added. The crystals formed by cooling were drained, washed with ice-cold ethanol, then dried.

56 g of N- (1-benzyl 2-pyrrolidylmethyl) 7-diethyl-55 sulfamoyl 1,4-benzodioxane 5-carboxamide phosphate were obtained (mp: 180 ° C; yield: 79.6%).

Example 42:

N- (1-benzyl 4-piperidyl) 1,4-benzodioxane 5-carboxamide hydrochloride

OR

200 ml of chloroform and 50 g of 1-benzyl 4-aminopiperidine were introduced into a flask fitted with a stirrer and a thermometer and then, at 5-10 ° C., 50 g of 1,4-benzodioxane chloride 5 -carbonyl were added in fractions. After stirring the mixture 65 at room temperature, the solvent was removed in vacuo, then the residue was dissolved in 300 ml of water. After precipitation of the base by addition of ammonia, the water was removed, then the product was treated with a hydrochloric acid solution.

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75 g of N- (1-benzyl 4-piperidyl) 1,4-benzodioxane 5-carboxamide hydrochloride were obtained (m.p .: 205 ° C; yield: 77%).

Example 43:

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

8-mercapto 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid: A solution of 106 g of 8-chlorosulfonyl 2H-3 acid was introduced into a flask fitted with a stirrer and a thermometer , 4-dihydro 1,5-benzodioxepine 6-carboxylic in 273 ml of acetic acid and 159.5 g of tin. The mixture was stirred and heated to 40-45 ° C, then 705 ml of concentrated hydrochloric acid was added dropwise. After heating to 55-60 ° C, the solution was cooled. The precipitate formed was drained, washed and dried.

65 g of 8-mercapto 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were obtained (m.p .: 99.5-100 ° C; yield: 80%).

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

86 g of 8-mercapto 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid, 152 ml of water and 76 ml of sodium hydroxide were introduced into a flask fitted with a condenser. , 5 g of ethyl sulphate. The mixture was heated to reflux, then cooled. After adding 150 ml of water, the solution was filtered and then treated with 60 ml of hydrochloric acid. The precipitate formed was drained, washed and dried.

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

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

A solution of 88 g of 8-ethylthio 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid in 528 ml of acetic acid was then introduced into a flask equipped with a condenser. Gradually, 210 ml of hydrogen peroxide at 110 volumes. The solution was heated, then the acetic acid removed in vacuo. The residue was taken up in 180 ml of water, then cooled. The precipitate formed was drained, washed and then dried.

90 g of 8-ethylsulfonyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were obtained (m.p .: 142-143 ° C; yield: 91%).

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

75 g of thionyl chloride and 90 g of 8-ethylsulfonyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxylic acid were introduced into a flask fitted with a condenser. The mixture was heated to 45-50 ° C, then the excess thionyl chloride was removed in vacuo. The residue was taken up in petroleum ether, then drained, washed and dried. 94 g of 8-ethylsulfonyl chloride 2H-3,4-dihydro 1,5-benzodioxepine 6-carbonyl were obtained (m.p .: 108-110 ° C; Yield: 98%).

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

39.5 g of 1-ethyl 2-aminomethylpyrrolidine dissolved in 282 ml of chloroform and then, in portions, 94 g of 8-ethylsulfonyl 2H-3 chloride are placed in a flask fitted with a stirrer and a thermometer , 4-dihydro 1,5-benzodioxepine 6-carbonyl, keeping the temperature between 5 and 10 ° C. The mixture was then heated, then poured into water. The aqueous phase was cooled,

filtered, then treated with 30 ml of sodium hydroxide. The precipitate was extracted with methylene chloride, then the organic phase was dried over potassium carbonate. After distilling off the solvent, the residue was dissolved in isopropanol, then treated with a solution of hydrochloric acid in isopropanol. The precipitate was drained, washed with alcohol and dried.

98 g of N- (1-ethyl 2-pyrrolidylmethyl) 8-ethyl-sulfonyl 2H-3,4-dihydro 1,5-benzodioxepine 6-carboxamide hydrochloride were obtained (mp: 141-142 ° C; yield: 73 %).

Example 44:

5 - [(- Methyl 1-pipêrazinyl) carbonyl] 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 are introduced into a flask of 31 fitted with a sealed stirrer, an introduction bulb and an ascending condenser. The mixture is heated to 55 ° C. and a solution of 700 g of bromine in 360 ml of acetic acid is gradually introduced into the bulb. The temperature rises to 67 ° C. Hydrobromic acid develops and is slowly heated to 120 ° C. After 6 h (from the start of the introduction), the mixture is allowed to cool to 15 ° C., the precipitate formed is drained, washed with acetic acid and dried at 50 ° C. 332 g are obtained 6,7-dibromo 1,4-benzodioxane 5-carboxy-acid, melting at 212 ° C.

The NMR spectrum conforms to the expected structure.

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

In a 21 flask, 166 g of the 6,7-dibromic acid obtained in the preceding stage are mixed with 500 ml of acetic acid. The mixture is heated to 37 ° C. and a solution of 35 ml of nitric acid (d = 1.49) in 60 ml of acetic acid is added in the presence of a small amount of sulfuric acid as catalyst. The mixture is heated at 50 ° C for 3 h. Then the reaction mixture is poured into ice-cold water, with stirring. The solid product is drained, washed with water, and dried at 40 ° C. 107 g of 6,7-dibromo 8-nitro 1,4-benzodioxane 5-carboxylic acid are obtained, melting at 237 ° C. .

The acid obtained is purified by treatment with a solution of 50 g of sodium bicarbonate in 500 ml of water and reprecipitation with hydrochloric acid (d = 1.18). It is wrung, washed with water and dried. A pale yellow solid is obtained which melts at 238 ° C, and whose NMR spectrum conforms to the expected structure (Yield 61%).

6,7-dibromo 8-nitro 1,4-benzodioxane 5-carboxyl chloride:

96 g of 6,7-dibromo 8-nitro 1,4-benzodioxane 5-carboxylic acid and 200 ml of thionyl chloride are introduced into a 500 ml flask fitted with a mechanical stirrer and a thermometer. A gas evolution occurs, and the temperature drops to around 0 ° C. It is gradually heated to reflux for 40 min, then the thionyl chloride is removed in vacuo. The residue is taken up in 100 ml of isopropyl ether, then the solvent is evaporated. The product is air dried. 91 g (yield 91%) of the expected chloride are obtained, melting at 215 ° C.

5-f (4-Methyl 1-piperazinyl) carbonyl] 6,7-dibromo 8-nitro 1,4-benzodioxane:

400 ml of methyl ethyl ketone and 11 g of methylpiperazine are mixed in a flask of 11 fitted with mechanical stirring and a thermometer. The mixture is cooled to 10 ° C. and 41 g of 6,7-dibromo 8-nitro 1,4-benzodioxane 5-carbonyl chloride are added in portions, without exceeding a temperature of 20 ° C. The mixture is left stirring for another 1 h and the crystals formed are wrung out. They are washed with methyl ethyl ketone (50 ml) and dried at 40 ° C. The product is recrystallized in solution in 500 ml of water after treatment with carbon black and precipitation with 50 ml of 20% ammonia. It is drained, washed with water and dried. 33 g (yield 69.6%) of 5 - [(4-methyl 1-piperazinyl) carbonyl] 6-7-dibromo 8-nitro 1,4-benzodioxane are obtained, melting at 164 ° C. The IR and NMR spectra conform to the expected structure.

Example 45:

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

Proceeding exactly as in Example 44, but replacing methylpiperazine with 1-ethyl 2-aminomethylpyrrolidine, N- (1-ethyl 2-pyrrolidylmethyl) 6,7-dibromo 8-nitro 5-carboxamide is obtained. at 213 ° C, and whose NMR spectrum confirms the structure (yield after purification: 65%).

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Example 46:

N- (1-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 1,4-benzodioxane 5-carboxylic acid, 100 ml of sodium hydroxide and 10 g of Pd / C were introduced into an autoclave. hydrogen under a pressure of 40kg / cm2, heating to 50 ° C. At the end of the absorption of hydrogen, the mixture was filtered, then the solution treated with 95 ml of hydrochloric acid. The precipitate was drained, washed and dried.

42 g of 8-amino 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 186 ° C; Yield: 83.7%).

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

According to the method described in Example 2, the 42 g of 8-amino 1,4-benzodioxane 5-carboxylic acid were treated with methyl alcohol, then the compound obtained was treated with 33 g of 1-ethyl 2-aminomethylpyrrolidine, then with a solution of 13 g of hydrochloric acid in absolute alcohol.

49 g of N- (1-ethyl 2-pyrrolidylmethyl) 8-amino 1,4-benzodioxane 5-carboxamide dihydrochloride were obtained (m.p .: 173 ° C; yield: 60%).

Example 47:

5-f (4-Methyl 1-piperazinyl) carbonyl] 8-chloro 1,4-benzodioxane

8-chloro 1,4-benzodioxane 5-carboxylic acid:

29.3 g of 8-amino 1,4-benzodioxane 5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were introduced into a flask fitted with an agitator and a thermometer. The mixture was heated to 40 ° C, then cooled to 5 ° C, and a solution of 10.5 g of sodium nitrite in 20 ml of water was added little by little, keeping the temperature between 5 and 10 ° C. The mixture was stirred, then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (d = 1.18) while maintaining the temperature below 30 ° C. The precipitate formed was drained, washed with hydrochloric acid and with water, then taken up in 300 ml of water and 25 g of baking soda. The solution was filtered and then treated with hydrochloric acid. The precipitate was drained, washed with water and dried.

20 g of 8-chloro 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 195 ° C; Yield: 62%).

5- [(4-Methyl 1-pipêrazinyl) carbonyl] 8-chloro 1,4-benzodioxane:

According to the method described in Example 33, the 20 g of 8-chloro 1,4-benzodioxane 5-carboxylic acid were treated with thionyl chloride to give 8-chloro 1,4-benzodioxane 5 chloride. carbonyl (mp: 83 ° C) which has been treated with 10.5 g of N-methylpiperazine to give 14 g of 5 - [(4-methyl 1-piperazinyl) -carbonyl] 8-chloro 1,4-benzodioxane (mp : 260 ° C with decomposition; Yield: 50.5%) .;

Example 48:

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

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

43 g of 8-amino 1,4-benzodioxane 5-carboxylic acid and 72 ml of acetic acid were introduced into a flask and then, in small quantities, 24.5 ml of acetic anhydride. The mixture was heated to 60-70 ° C, then cooled. The precipitate formed was drained, washed with acetic acid and with water, then dried.

44 g of 8-acetamino 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 233 ° C; Yield: 84%).

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

The 8-acetamino 1,4-benzodioxane 5-carboxylic acid was treated according to the method of Example 31, with isobutyl chloroformate and 1-ethyl 2-aminomethylpyrrolidine. N- (1-ethyl 2-pyrrolidylmethyl) 8-acetamino 1,4-benzodioxane 5-carboxamide was obtained. Its structure has been confirmed by NMR.

Example 49:

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 75 ml of acetic anhydride were introduced into a flask, followed by a solution of 17.5 ml of nitric acid ( d = 1.49) in 17 ml of acetic acid was added little by little, allowing the temperature to rise. After dissolution, then crystallization, 50 ml of acetic acid were added. The mixture was stirred at 40-45 ° C, then cooled to 20 ° C. The precipitate formed was drained, washed with acetic acid and water, then dried. 13.5 g of a 50% mixture of 7-nitro 8-acetamino 1,4-benzodioxane 5-carboxylic acids and

6-nitro 8-acetamino 1,4-benzodioxane 5-carboxylic were obtained. After separation of the 7-nitro acid, this compound was treated, according to the method of Example 31, with isobutyl chloroformate and diethylaminoethylamine. N- (diethylaminoethyl) 7-nitro 8-acetamino 1,4-benzodioxane 5-carboxamide was obtained. Its structure has been confirmed by NMR.

Example 50:

N- (1-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 acids were introduced into an autoclave and

6-nitro 8-acetamino 1,4-benzodioxane 5-carboxylic, 90 ml of water, 4.5 ml of soda and Raney nickel, then hydrogen under a pressure of 50 kg / cm2. At the end of the absorption of hydrogen, the nickel was filtered and the solution treated with 12 ml of hydrochloric acid, then with a solution of 3.5 g of sodium nitrite in 10 ml of water, maintaining the temperature between 20 and 25 ° C. The precipitate formed was drained, washed, then treated with an aqueous sodium hydroxide solution. The mixture was then acidified, then the precipitate was drained, washed and dried.

3 g of 7,8-azimido 1,4-benzodioxane 5-carboxylic acid were obtained (m.p .: 260 ° C with decomposition; Yield: 59%).

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

The 7,8-azimido 1,4-benzodioxane 5-carboxylic acid was treated with N-hydroxyphthalimide in the presence of dicyclohexyl-carbodiimide, then the phthalimide carboxylate obtained was treated with 1-allyl 2-aminomethylpyrrolidine. N- (1-allyl 2-pyrroIidyl-methyl) 7,8-azimido 1,4-benzodioxane 5-carboxamide was obtained. Its structure has been confirmed by NMR.

Example 51:

N- (2-pyrimidyl) 6-chloro 1,4-benzodioxane 5-carboxamide

6-nitro 1,4-benzodioxane 5-carboxylic acid:

1600 ml of a glacial acetic acid, 1600 ml of acetic anhydride and 1000 g of acid 1.4 are placed in a 61-ml flask fitted with a mechanical stirrer, a thermometer and an introduction bulb. -benzodioxane-5-carboxylic. The mixture is heated to 40 ° C. and a solution of 400 ml of nitric acid in 400 ml of acetic acid is introduced through the bulb. When the introduction is complete, the mixture is kept at 40-45 ° C. for another 2 h, with stirring. Then cooled to 5 ° C and the crystallized product is wrung. It is washed with 600 ml of acetic acid, then with water, and dried at 40 ° C. 700 g of crystals are obtained, the NMR spectrum of which reveals that they are acid

7-nitro 1,4-benzodioxane 5-carboxylic. It melts at 246 ° C. The mother liquors are diluted with 251 of water, and the precipitate obtained is drained,

washed with water and dried.

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6-nitro 1,4-benzodioxane 5-carboxylic acid is obtained, melting at 188 ° C.

6-amino 1,4-benzodioxane 5-carboxylic acid hydrochloride: In an autoclave of 51 we put 195 g of 6-nitro 1,4-benzo-dioxane 5-carboxylic acid, 1950 ml of ethanol, and a spoonful of Raney nickel. Hydrogenation is carried out under a pressure of 35 kg, at 60 ° C., for 1 h, before cooling and filtering the nickel. The solution obtained is acidified with 150 ml of hydrochloric acid in ethanol (23 g / 100 ml). The hydrochloride crystallizes. It is wrung, dried, and 115 g (yield: 57.5%) of 6-amino 1,4-benzodioxane 5-carboxylic acid hydrochloride, melting at 160 ° C., are obtained.

6-chloro 1,4-benzodioxane 5-carboxylic acid:

In a 500 ml flask fitted with mechanical stirring, a thermometer and an introduction funnel, 58 g of the hydrochloride of the acid obtained in the preceding stage are dissolved in 116 ml of water. 28 ml of hydrochloric acid (d = 1.18) are added and the mixture is cooled to 0-5 ° C. A solution of 17.5 g of sodium nitrite in 38 ml of water is added, keeping the temperature between 0 and 5 ° C. The mixture is left stirring for 1 h, then a mixture of 20 g of cuprous chloride and 75 ml of hydrochloric acid is introduced. After standing overnight, it is drained, washed with 20 ml of hydrochloric acid, then with water, and dried at 50 ° C. The product obtained is purified by treatment with vegetable black in alkaline solution (200 ml d water and 25 ml of sodium hydroxide solution at 36 ° B), and the acid is again isolated by addition of 25 ml of hydrochloric acid. 40 g of 6-chloro 1,4-benzodioxane 5-carboxylic acid are obtained, melting at 162 ° C. (yield: 74%).

6-chloro 1,4-benzodioxane 5-carbonyl chloride:

56 ml of thionyl chloride and 28 g of acid obtained in the preceding stage are introduced into a 250 ml flask fitted with a sealed mechanical agitation, an ascending condenser and a thermometer. The mixture is heated to reflux, with stirring, for 30 min. The excess thionyl chloride is removed by vacuum distillation. 28.5 g (93% yield) of 6-chloro 1,4-benzo-dioxane 5-carbonyl chloride, melting at 50 ° C., are obtained.

N- (2-pyrimidyl) 6-chloro 1,4-benzodioxane 5-carboxamide:

280 ml of methyl ethyl ketone and 13 g of 2-aminopyrimidine are placed in a 500 ml flask fitted with a mechanical stirrer and a thermometer. The mixture is cooled to 10 ° C. and 28 g of ground 6-chloro 1,4-benzodioxane 5-carbonyl chloride are introduced over 15 min. The temperature is allowed to rise to 20 ° C, while maintaining stirring for 2 h. The solid obtained is drained, washed with 30 ml of methyl ethyl ketone, dissolved in 250 ml of boiling water, and the solution is treated with 10 ml of sodium hydroxide solution at 36 "B.

12 g of crystals are obtained by wringing, which are recrystallized from 150 ml of ethanol. 9.5 g of N- (2-pyrimidyl) -6 chloro 1,4-benzodioxane 5-carboxamide are then obtained, melting at 223 ° C (with decomposition).

NMR analysis confirms the structure of the product.

Example 52:

5 [(4-methyl 1-piperazinyl) carbonyl] 6-nitro 1,4-benzodioxane hydrochloride

360 ml of methyl ethyl ketone and 16 g of N-methylpiperazine are introduced into a 500 ml flask fitted with mechanical stirring and a thermometer. The mixture is cooled to 10 ° C. and 36.5 g of 6-nitro-1,4-benzodioxane 5-carbonyl chloride as obtained in Example 51 are introduced over 20 min. The mixture is left to stir for another hour at room temperature and the solid obtained is drained. It is washed with 150 ml of methyl ethyl ketone. We dry. This product is dissolved in 210 ml of cold water and brought to pH 1 by the addition of a few drops of hydrochloric acid. After treatment with carbon black and filtration, the base is precipitated with 15 ml of sodium hydroxide solution, washed with water and dried (mp: 221 ° C; weight: 24 g).

This base is dissolved in 168 ml of ethanol containing 8 ml of water and 8 ml of hydrochloric acid (d = 1.18); the hydrochloride which crystallizes is drained, washed and dried.

19.5 g of 5 [(4-methyl 1-piperazinyl) -carbonyl] 6-nitro 1,4-benzodioxane hydrochloride are obtained, melting at 205 ° C (with decomposition).

NMR analysis confirms the expected structure.

Example 53:

N-diethyl 7-cyclohexylsulfamoyl 1,4-benzodioxane 5-carboxamide

7-cyclohexylsulfamoyl, 4-benzodioxane 5-carboxylic acid:

250 ml of water and 300 ml of cyclohexylamine are introduced into a 11-liter flask fitted with mechanical stirring and a thermometer. 139 g of wet 7-chlorosulfonyl 1,4-benzodioxane 5-carboxylic acid are added in portions, maintaining the temperature at 20-30 ° C. The mixture is left to stir for 3 h at room temperature. The solution obtained is treated with 30 g of Acticarbone 3S black, and filtered. 300 ml of hydrochloric acid (d = 1.18) are added and the 7-cyclohexylsulfamoyl 1,4-benzodioxane 5-carboxylic acid precipitates.

After crystallization, washing with water and drying, 92 g of acid melting at 150 ° C. are obtained.

N-diethyl 7-cyclohexylsulfamoyl 1,4-benzodioxane 5-carboxamide:

34.1 g of 7-cyclohexylsulfamoyl 1,4-benzodioxane 5-carboxylic acid, 35 ml of water and 10.5 g of triethylamine. 100 ml of acetone are added to dissolve the whole. Cool to 10 ° C and gradually add 14 g of isobutyl chloroformate. The mixture is left stirring for 30 min at room temperature and 8 g of diethylamine are introduced, while maintaining at 15-20 ° C. The mixture is left to stir for 3 h before removing the solvent under vacuum. The residue is washed with water, dried and taken up in 180 ml of absolute ethanol. It is treated with 3 g of vegetable black, filtered and allowed to crystallize. 23 g (yield: 58%) of N-diethyl 7-cyclo-hexylsulfamoyl 1,4-benzodioxane 5-carboxamide are obtained, melting at 201 ° C.

The NMR and IR spectra are compatible with the expected structure.

Example 54:

N- (4-methyl l'-pipérazinyl) 7-nitro 1,4-benzodioxane 5-carboxamide

7-nitro 1,4-benzodioxane 5-carbonyl chloride:

112 ml of thionyl chloride and 56 g of 7-nitro 1,4-benzodioxane 5-carboxylic acid are introduced into a 250 ml flask fitted with a mechanical stirrer, a thermometer and an ascending condenser. Stir and add 1 ml of dimethylformamide while heating. Maintained for 1 hour at reflux, then the excess thionyl chloride is removed in vacuo. 61 g (yield of almost 100%) of 7-nitro-1,4-benzodioxane 5-carbonyl chloride, melting at 108 ° C., are obtained.

N- (4-methyl 1-piperazinylj 7-nitro 1,4-benzodioxane 5-carboxamide:

In a flask fitted with an agitator and a thermometer, 33 g of 1-amino 4-methylpiperazine are dissolved in 630 ml of methyl ethyl ketone. The mixture is cooled to 10 ° C., then 61 g of 7-nitro-1,4-benzodioxane 5-carbonyl chloride are added in portions. The mixture is stirred for 2 h, then the solid is filtered and washed with 150 ml of methyl ethyl ketone. The product obtained is purified by passage through the base (m.p .: 212 ° C) and crystallization from hydrochloric ethanol.

45 g of N- (4-methyl 1-piperazinyl) 7-nitro 1,4-benzodioxane are obtained (m.p .: 210 ° C, with 1 mol of water).

The structure was confirmed by NMR and IR spectra.

Example 55:

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

1,4-Benzodioxane 6,7-dinitro 5-carboxylic acid:

In a 500 ml flask fitted with mechanical agitation and

10

15

20

25

30

35

40

45

50

55

60

65

629198

16

165 ml of fuming nitric acid (d = 1.49) are introduced from a thermometer, and, while cooling to -10 ° C., 90 g of 1,4-benzodioxane 5-carboxylic acid are added. Stirring is continued for 2 h at room temperature, then 11 liters of ice water are added. It is filtered, washed with water, dried at 50 ° C the precipitate obtained and recrystallized from acetic acid.

87 g of 1,4-benzodioxane 6,7-dinitro 5-carboxylic acid are obtained, melting at 211 "C.

1,4-Benzodioxane 6,7-diamino 5-carboxylic acid:

135 g of 1,4-benzodioxane 6,7-dinitrocarboxylic acid, 500 ml of water and 50 ml of sodium hydroxide solution at 30 ° B are placed in an 11-liter autoclave. 2 spoonfuls of Raney nickel are added and hydrogen is introduced (pressure: 80 kg). After 2 hours of absorption at 100 °, it is cooled, filtered and washed with 200 ml of water which is joined to the filtrate. An assay of this filtrate is acidified with hydrochloric acid (d = 1.18) to obtain the dihydrochloride which is isolated, washed with water, and dried (melting point: 153 ° C.) .

1,4-Benzodioxane 6,7-azimido 5-carboxylic acid:

The filtrate obtained in the previous stage is placed in a 21 flask fitted with mechanical stirring and a thermometer. A solution of 35 g of sodium nitrite in 70 ml of water is added dropwise, maintaining the temperature between 20 and 25 ° C. The crystallized product is drained, washed with water and dried at 50 ° C.

96 g (yield: 87%) of 1,4-benzodioxane 6,7-azimido 5-carboxylic acid are obtained.

The NMR spectrum conforms to the expected structure.

1,4-Benzodioxane 6,7-azimido 5-N-phthalimide carboxylate:

In a 21 flask fitted with a mechanical stirrer and a thermometer, 74 g of acid obtained in stage 3.11 of dimethylformamide, 57 g of N-hydroxyphthalimide and 74.5 g of dicyclohexylcarbodiimide are heated to 90 ° C. for 30 min. Cool to 20 ° C. and drain the crystals formed. It is washed with 150 ml of dimethylformamide which is joined to the filtrate.

The filtrate is concentrated under vacuum and its residue is taken up in 400 ml of methanol. It is drained, washed with methanol and dried.

80 g (yield: 65.6%) of 1,4-benzodioxane 6,7-azimido 5-N-phthalimide carboxylate are obtained, which melts above 250 ° C.

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

92 g of the phthalimide ester prepared in the preceding stage and 500 ml of dimethylformamide are introduced into a flask of 11 fitted with mechanical stirring and a thermometer. With stirring, 45 g of 1-allyl 2-aminomethylpyrrolidine are added. The temperature rises to 30 ° C. The mixture is further stirred for 2 h at room temperature and the solvent is removed. The residue is taken up in 500 ml of acetone, hot. After filtration, 50 ml of a solution of hydrochloric acid in ethanol (22 g / 100 ml) are added to the filtrate. The crystals which form are drained, washed with 200 ml of acetone, then 100 ml of alcohol.

After two recrystallizations from a water / methanol mixture, 50 g of hydrochloride, melting at 255 ° C., are obtained.

NMR and IR spectra are compatible with the expected structure.

Example 56:

5 - [(4-Methyl 1-pipèrazinyljcarbonyl] 6,7-dinitro 1,4-benzodioxane 1,4-Benzodioxane 6,7-phthalimide dinitrocarboxylate:

54 g of 1,4-benzodioxane 6,7-dinitro 5-carboxylic acid and 400 ml of dimethylformamide are introduced into a 11 flask fitted with a mechanical stirrer and a thermometer. With stirring, 34.2 g of N-hydroxyphthalimide and 44.4 g of dicyclohexylcarbodiimide are added. The mixture is heated to 90 ° C for 30 min, cooled to 10 C and filtered. The filtrate is distilled under vacuum to remove the solvent and its residue recrystallized from methanol.

67.5 g are obtained (yield: 81.3%) of phthalimide 1,4-benzodioxane 6,7-dinitrocarboxylate, melting at 225 ° C.

5- [(4-Methyl 1-pipêrazinyl) carbonyl] 6,7-dinitro 1,4-benzodioxane:

In a 500 ml flask provided with mechanical stirring and a thermometer, 63 g of 1,7-benzodioxane 6,7-dinitro 5-N-phthalimide carboxylate are dissolved in 400 ml of dimethylformamide. 20 g of N-methylpiperazine are added and the mixture is left to stir for 2 h. Almost all of the solvent is removed in vacuo and 11 ml of water is added to the residue. The 5 - [(4-methyl 1-piperazinyl) carbonyl] 6,7-dinitro 1,4-benzo-dioxane precipitates. It is drained and recrystallized from dimethylformamide.

40 g of crystals are obtained, melting at 254 ° C. The NMR spectrum confirms the expected structure.

Example 57:

N- (l'-piperidinopropyl) 6,7-diacetamino 1,4-benzodioxane 5-carboxamide

By proceeding as in Example 53, the 6,7-diacetamino 1,4-benzodioxane 5-carboxylic acid is condensed (prepared by acetylation of 6,7-diamino 1,4-benzodioxane 5-carboxylic acid ) with l-piperidinopropylamine in the presence of isobutyl chloroformate.

N- (l'-piperidinopropyl) 6,7-diacetamino 1,4-benzodioxane 5-carboxamide is obtained, melting above 260 ° C.,

with decomposition.

The structure of the compound is confirmed by its NMR spectrum.

Example 58:

5- (4-Methyl 1-piperazinyl) carbonyl 7-amino 1,4-benzodioxane

According to the method described in Example 2, the 7-amino 1,4-benzodioxane 5-carboxylic acid was treated with methyl alcohol, then the methyl carboxylate obtained was treated with N-methylpiperazine. 5 - [(4-methyl 1-piperazinyl) carbonyl] 7-amino 1,4-benzodioxane was obtained (m.p. 170 ° C).

Example 59:

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

In a similar manner to that described in Example 17, by reaction of 1,4-benzodioxane 5-carbonyl chloride and

1-ethyl 2-aminomethylpyrrolidine, N- (1-ethyl hydrochloride

2-pyrrolidylmethyl) 1,4-benzodioxane 5-carboxamide was obtained (m.p .: 149-150 ° C).

The compounds whose synthetic examples are mentioned above are collated in Table I.

The products according to the invention are used in the form of capsules, tablets, pills, granules, solution for injection, the preparation of which is known per se. It is possible to use substances which are inert with respect to the invention, such as lactose, magnesium stearate, starch, talc, celluloses, levilite, alkali metal lauryl sulphates, sucrose and vehicles usual in medicinal preparations.

The compounds of the invention can be administered in doses of 50 to 900 mg / d, more particularly from 50 to 300 mg / d, the preferred daily dosage being approximately 100 to 150 mg.

Table I on pages 17-22

To prepare tablets, the selected compound is mixed with starch and lactose, by the method of successive dilutions; the mixture is granulated with methylcellulose. Levilite, magnesium stearate and talc are added to the granules before compression.

It is possible to replace the methylcellulose by any other suitable granulating agent, such as for example ethyl cellulose, polyvinylpyrrolidone, starch paste, gum arabic, etc. Starch can also be replaced by a different disintegrating agent, such as cornstarch, carboxymethyl starches, alginates, microcrystalline cellulose, etc.

5

10

15

20

25

30

35

40

45

50

55

60

65

Table I

Example no

X

Y

Z

AT

nr '

r b nr! r2

1

-h so2nhch3

h

- (ch2) 2-

nh i

ch2 - ch = ch2

2

h so2nh2

h

- (ch2) 2-

nh

-ch2-

1

c2h5

3

h so2c2h5

h

- (ch2) 2-

nh

-ch2-

U /

t

-

ch3

4

h so2nh2

h

- (ch2) 2-

-1 / y -

5

h so2N (CH3) 2

h

- (ch2) 2-

nh

-ch2-

not

\NOT '

1

ch3

6

h h

h

- (ch2) 2-

nh

-ch2-

N / 1

-ch- <o>

7

h so2nh2

h

- (ch2) 2-

nh

-ch2-

\NOT '

f ch2 - ch = ch2

8

h so2nhch3

h

- (ch2) 2-

nh

-ch2- [~ 1

NOT

c2h5

9

h h

h

- (ch2) -

nh

-ch2-

NN /

1

c2h5

Table I (continued) PJ

Example No

X

Y

z

AT

nr '

r b nrj r2

10 (l)

11 (d)

12 (r)

h s02c2h5

h

- (ch2) 2-

nh

-CH2-Ç

c2h5

13

h so2nh2

h

- (ch2) 2-

nh

-ch2-

\not/

1

ch3

14

h

S02C2H5

h

- (ch2) 2-

nh

-ch2-

1

ch2 - ch = ch2

15

h h

h

- (ch2) 3-

nh

-ch2-

not

^ N 1

c2h5

16

h so2nhch3

h

- (ch2) 2-

nh

-ch2-

□ 1

ch3

17

h h

h

- (ch2) 2-

nh

-ch2 -ch2-

n - c2h5

c2h5

18

h

SO2C2H5

h

- (ch2) 2-

nh

-ch2-

7)

NOT

1

c2h5

19

h s02n (ch3) 2

h

- (ch2) 2-

nh t

ch3

20

h so2nhch3

h

- (ch2) 2-

nh

S

((

-0

Table I (continued)

Example No x

y z

a nr '

r b nr! r2

21

h s02n (ch3) 2

h

- (ch2) 2-

nh

-D

1

c2h5

22 (d)

23 (l)

h so2nhch3

h

- (ch2) 2-

nh

-ch2- ^,

1

c2h5

24 (l)

25 (d)

h so2nhch3

h

- (ch2) 2-

nh

-ch2-

\

1

ch2 - ch = ch2

26 (d)

27 (l)

h so2nhch3

h

- (ch2) 2-

nh

-ch2-

not

1

ch3

28

h so2nhch3

h

- (ch2) 3-

nh

-ch2-

\NOT'

1

c2h5

29

h h

h

-ch2-

nh

-ch2-

1

c2h5

30

h s02c2h5

h

- (ch2) 2-

/ —V /

31

h no2

h

- (ch2) 2-

- / JN -

ch3

32

h so2nh ^)

h

- (ch2) 2-

- / \ -

ch3

v ©

we

N> V ©

H *

g

Table I (continued) OJ

Example No

X

y

Z

AT

nr '

r b nrj r2

33

h

Cl h

- (ch2) 2-

nh

-ch2 - ch2-

-o

34

h so2nh - <^ >>

h

- (ch2) 2-

n - (ch2) 3ch3

h

35

och3

h h

- (ch2) 2-

nh

c2h5

36

och3

so2nh2

h

- (ch2) 2-

nh

-ch2-

\ k)

t

c2h5

37

h h

h

- (ch2) 2-

-not

- N N

38

h

S02n (c2hs) 2

h

~ (ch2) 2-

h

39

h so2nhch3

h

- (ch2) 2-

nh o

C ".- <Ô>

40

h h

h

- (ch2) 2-

h

41

h s02n (c2hs) 2

h

- (ch2) 2-

nh

-ch2-

not

\ N S 1

CH, <0>

42

h h

h

- (ch2) 2-

nh o

<* <Q>

Table I (continued)

Example No

X

Y

Z

AT

nr '

r b nr „r2

43

h so2c2h5

h

- (ch2)

nh

- ch2 — J

1

c2H5

44

no2

Br

Br

- (ch2) 2-

ch3

45

no2

Br

Br

- (ch2) 2-

nh

-ch2-

No 1

c2h5

46

nh2

h h

- (ch2) 2-

nh

-ch2-

\ N>

c2h5

47

THIS

h h

- (ch2) 2-

1

Ü

1

ch3

48

NHCOCH3

h h

- (ch2) 2-

nh

-ch2-

\NOT /

1

c2h5

49

NHCOCH3

no2

h

- (ch2) 2-

nh

-ch2 - ch2- n - c2h5

c2h5

50

iGi

NZ.NH

h

- (ch2) 2-

nh

-ch2-

kddd / 1

ch2 - ch = ch2

51

h

H

Cl

- (ch2) 2-

~ o h

52

h h

no2

- (ch2) 2-

/ \ - Nv_ / N ~

ch3

(o

Ov ve £

Table I (continued)

Example n »

x y

z a

nr '

r b nrj r2

53

h so2nh - <^

h

- (ch2) 2-

n - c2h5

c2h5

54

h no2

h

- (ch2) 2-

nh

- N - CH3

55

h

K i

NVNH

- (ch2) 2-

nh

-ch2-

N t ch2 - ch = ch2

56

h no2

no2

- (ch2) 2-

_ not/ -

ch3

57

h nhcoch3

NHCOCH3

- (ch2) 2-

nh

- (ch2) 3-

-0

58

h nh2

h

- (ch2) 2-

"O"

ch3

59

h h

h

- (ch2) 2

nh

-ch2-

not

NOT

c2h5

23

629198

To prepare injectable solutions, it is possible to dissolve the compound of the invention in the following acids: hydrochloric acid, levulinic acid, gluconic acid or glucohep-tonic acid.

The sterile solution is made isotonic with an alkali metal chloride such as sodium chloride, then preservatives are added. It is also possible to prepare the same solution without adding preservatives: the ampoule is filled under nitrogen and sterilized Zi h at 100 ° C.

The compounds of the invention have interesting anxiolytic, psychostimulating, disinhibiting, or even thymoanaleptic effects.

that, resulting in properties susceptible of therapeutic applications in the psychofunctional sphere and in particular in gastroenterology, cardiology, urology, rheumatology, gynecology, etc. Their low toxicity is compatible with use in human therapy without risk of side effects.

The acute toxicity of the compounds of the invention was determined in Swiss mice by the parenteral route (intravenous, intraperitoneal, subcutaneous) and by the oral route. The lethal doses 50 are collated in Table II, it being understood that, in the following tables, the numbers of the compounds correspond to the numbers of the examples.

TABLE II - TOXICITY

Compound

LD 50 - mouse - mg / kg (base)

i.v.

i.p.

s.-c.

p.o.

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

5

220.8-225.6

7

96.6-100

8

84.6-90

322-328

1450-1485

35% at 2000 mg / kg

10

150-157.5

350-363

1260-1360

11

168-184

442-450

12

147-154

480

1225-1230

1400-1470

13

64-67.5

234-240

430-437

0% at 3000 mg / kg

14

146-157

325-338

420-442

2900-3491

15

79.7-86.2

224-227

572-613

756

16

88-96

380-396

925-1014

2760-2900

17

49.1

241

575

544-679

20

72.5-76

180-184.5

476-499.5

1190-1200

21

196-208

22

83.6-86

23

115.5-126

24

216-232

25

160-168

26

105-116

27

80-83.6

28

141-154

387.5-418

1620-1850

2100-2400

39

164-175

896-957

960

1560-1600

629198

24

The compounds of the invention are moreover practically devoid of cataleptic activity. They were administered subcutaneously to rats. The criterion of the cataleptic state was the immobility for 30 s of the animal whose forelimbs are spread and carefully placed on wooden cubes 4 cm high, thus putting the animal in an unusual attitude and uncomfortable. The cataleptic activity was measured at the maximum of the effect. The results are collated in Table III.

TABLE III - CATALEPTIC ACTIVITY

Compound

from 50 s.-c.

- rat - mg / kg

1

40% effect. . . .

at 200 mg / kg

2

Inactive

at 200 mg / kg

3

325

5

30% effect. . . .

at 200 mg / kg

7

Inactive

at 200 mg / kg

8

10% effect. . . .

10

Inactive

at 200 mg / kg

11

Inactive

12

Inactive

at 200 mg / kg

13

Inactive

14

10% effect. . . .

at 200 mg / kg

15

Inactive

16

Inactive

at 200 mg / kg

17

389

20

Inactive

21

Inactive

24

30% effect. . . .

at 200 mg / kg

25

Inactive

at 200 mg / kg

28

Inactive

at 200 mg / kg

39

Inactive

From these results, it can be seen that the compounds of the invention are practically devoid of cataleptic activity in the rat. This property allows the clinical use of the compounds of the invention with good tolerance vis-à-vis the extrapyramidal system. The compounds of the invention have been found to be particularly active in dogs with respect to central emetic agents such as apomorphine. The experimental protocol followed was that of Chen and Ensor. The compounds of the invention were administered subcutaneously 30 min before apomorphine (100 fxg / kg / s.-c.); the animal was observed 4 hours after the injection of the alkaloid.

The results are collated in Table IV.

TABLE IV - ANTIEMETIC ACTIVITY

Compound

50 (ig / kg / s.-c. - dog

1

3

2

Effect of 81% at 5 [ig / kg / s.-c.

3

5.5

5

10

8

1.5

10

2

11

40

12

3.5

13

9

14

3.9

15

30

16

2.3

20

3.5

21

4

The interest aroused by the experiments carried out in laboratory animals was very largely justified during the human clinical trials of the compounds of the invention.

By way of example, we can cite:

- The case of a 38-year-old patient with Hodgkin's disease; undergoing iterative multidrug therapy in a day hospital, once a week; each session is accompanied by nausea, then very significant vomiting, persisting 24 hours despite the usual treatments.

The treatment, 20 min before the start of the infusion and 4 h thereafter, with 50 mg of N- (1-ethyl 2-aminomethylpyrroidine) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide, made it possible to completely suppress nausea and vomiting.

Tolerance was perfect. No side effects were observed.

- A 28-year-old computer engineer presented a character neurosis with anxious paroxysm, leading to three suicide attempts. Analytical processing undertaken since

18 months allowed for social reintegration, but had little effect on anxiety.

The administration three times a day of 50 mg of N- (1-methyl 2-aminomethylpyrrolidine) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide made it possible in a few days to obtain the total disappearance of any anxious note without any action annoying sedative. Tolerance was perfect; no side effects were observed.

• - A 78-year-old patient had suffered from severe reaction depression for eight months (near mourning). The existence of a prostatic adenoma made the use of tricyclics contraindicated.

He was treated three times a day with 50 mg of N- (1-methyl 2-aminomethylpyrrolidine) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide and, in three weeks, his condition having improved markedly get out of the hospital. The treatment continued at home for three months makes it possible to maintain an excellent mental balance with resumption of normal activity in a pensioner of this age.

Tolerance was perfect; no side effects were observed.

- A 42-year-old patient had undergone a hysterectomy for fibroma six months ago.

A few days after the intervention, very numerous hot flushes appeared (10 to 20 in 24 hours), accompanied by sweating, waking the patient at night and considerably hampering this trader in her professional activity.

Taking 100 mg per day, once, for 20 d, of N- (1-ethyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide caused, in 3 to 4 d, the total disappearance night puffs.

There was little persistence except a single daytime puff of very moderate intensity, every 2 or 3 d.

The patient felt transformed.

Tolerance was perfect. No side effects were observed.

- A 47-year-old patient complained, shortly after menopause, of repeated cystists causing intense pollakiuria: compelling urination of such frequency that all social life was suppressed. The many generalists and specialists consulted have multiplied the examinations: everything has been negative, no treatment has changed the picture consisting of a classic crystal urine.

In a few days of treatment with N- (1-methyl 2-pyrrolidylmethyl) 7-methylsulfamoyl 1,4-benzodioxane 5-carboxamide, at a rate of 150 mg / d, the patient saw the disorders disappear completely while the psychological context has normalized.

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Claims (8)

629,198 2 1. Process for the preparation of new substituted 2,3-alkylene-bis- (oxy) -benzamides, their pharmaceutically acceptable acid addition salts, their dextrorotatory and levorotatory isomers, of general formula: CONRR1 (I) in which: A represents an alkylene chain C] _3, substituted or not substituted by an alkyl group CM, by an alkenyl group C2_4, by a hydroxyalkyl group Cj.4; R represents a hydrogen atom, an alkyl radical CM, or a radical of general formula: disubstituted, of formula NR3R4, in which R3 and R4, which may be the same or different, are: hydrogen atoms, C ^ alkyl, C ^ alkenyl, C2_4 alkinyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, s cycloalkanealkyl, cycloalkenealkyl, bicycloalkyl, adamantyl, py-rimidinyl, pyrazinyl, hydroxy-substituted alkyl, mercapto , acyl, thioacyl, alkoxy, alkylthio, or are linked together to form, with the nitrogen atom to which they are attached, a heterocycle possibly containing another heteroatom, whether or not killed; Z represents a hydrogen or halogen atom, a hydroxy group, a Cj ^ alkoxy, nitro, amino, amino mono- or disubstituted by CH, acyl, aralkyl, furanyl, pyrannyl, alkoxycarbonyl groups; X and Y or Y and Z may be linked together via a substituted or unsubstituted carbon chain or via one or more substituted or unsubstituted heteroatoms, to form a ring, characterized in that a composed of general formula: COD -B - N / \ Ri (he) R, in which: B represents a single bond, an alkylene chain C ^, substituted or not substituted by an alkyl group C ^, or by an alkenyl group C2.4; R, represents a hydrogen atom, a CH alkyl group, C2-4 alkenyl, C2-4 alkinyl, substituted alkyl and can be linked to B to form a saturated or unsaturated nitrogen heterocycle; R2 represents a hydrogen atom, an alkyl group CM, an alkenyl group C2_4, an alkinyl group C2_4, a substituted alkyl group or a heterocycle, substituted or not, saturated or unsaturated, comprising one or more heteroatoms or a phenyl, adamantyl group , cycloalkyl, bicycloalkyl, cycloalkenyl linked to the nitrogen atom of formula (II) directly by a carbon atom of the ring or via a substituted or unsubstituted alkylene chain; R2 and Rj may be linked together to form a heterocycle optionally comprising other heteroatoms and, in the case of a heterocycle comprising a second nitrogen atom, this may be substituted by an alkyl group CM, an alkenyl group CM , a CM alkinyl group, a phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkanealkyl, cycloalkenealkyl, adamantyl, bicycloalkyl or alkyl substituted by hydroxy, mercapto, acyl, thioacyl, alkoxy, alkylthio group; R 'represents a hydrogen atom, a CM alkyl group, a CM alkenyl group, a C2.4 alkinyl group, an adamantyl, pyrimidinyl, pyrazinyl, diazepinyl, quinuclidinyl, azabicycloalkyl, diazabicycloalkyl, bicycloalkyl, substituted or unsubstituted phenyl group , substituted or unsubstituted aralkyl; R 'and B may be linked together to form a mono-nitrogen heterocycle which may or may not be substituted; R 'and Rj can be linked together to form a diazotized heterocycle, saturated or not, which can be substituted or not; X represents a hydrogen or halogen atom, a hydroxy group, C [_4 alkoxy, Cj_4 alkyl, a nitro group, an amino group, an amino group mono- or disubstituted by CM, acyl, aralkyl, furannyl alkyl groups , pyrannyl, alkoxycarbonyl; Y represents a hydrogen or halogen atom, a hydroxy group, alkoxy CM, a nitro group, an amino group, an amino group mono- or disubstituted by alkyl, acyl, aralkyl, furanyl, pyrannyl, alkoxycarbonyl groups, alkylsulfonyl group CM, an adamantylsulfonyl or cycloalkylsulfonyl group, a sulfonyl group substituted by an unsubstituted or mono- or mono- or (III) 25 in which: 30 A, X, Y, Z have the above meanings, D represents a hydroxy group, a halogen atom, or a group capable of forming a reactive acid derivative, reacts on an amine of general formula: 35 HN / \ R (IV) R ' 50 in which R and R 'have the abovementioned meanings, or one of its 40 reactive derivatives. 2. Method according to claim 1, characterized in that an acid halide reacts on an amine. 3. Method according to claim 1, characterized in that an ester 45 of carboxylic acid reacts on an amine. 4. Method according to claim 1, characterized in that a carboxylic acid reacts on an amine in the presence of an alkyl haloformate. 5. Method according to claim 1, characterized in that a carboxylic acid reacts on an amine in the presence of an imidazolide. 6. Method according to claim 1, characterized in that a carboxylic acid reacts on an amine in the presence of a phosphorus halide. 7. The process as claimed in claim 1 for the preparation of a dextrorotatory or levorotatory compound of formula I, characterized in that dextrorotatory or levorotatory starting compounds are used. 8. A process for obtaining a quaternary ammonium salt 60 of a compound of formula I, characterized in that a compound of formula I, obtained according to claim 1, is subjected to a quaternization. 9. Process for obtaining an N-oxide of said compound 65 formula I, characterized in that a compound of formula I, obtained according to claim 1, is subjected to oxidation. 3 629,198