SE437027B - SET TO MAKE SUBSTITUTED 2,3-ALKYLENE-BIS (OXO) BENZAMIDES - Google Patents

Abstract

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

Description

Wherein B represents a direct bond or an alkylene group having 1-3 carbon atoms, which may be optionally substituted with alkyl having 1-4 carbon atoms or alkenyl having 2-4 carbon atoms, R 1 represents hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbon atoms, alkynyl of 2-4 carbon atoms, or an alkyl group substituted, for example, by hydroxy, mercapto, acyl, thioacyl, alkoxy, alkylthio or substituted p or unsubstituted amino, and which may be attached to B to form a saturated or unsaturated, nitrogen-containing heterocyclic group, such as azetidine, pyrrolidine, piperidine, polyhydroazepine, pyrroline or polyhydropyridine, and R 2 represents hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbon atoms, alkynyl of 2-4 carbon atoms or alkyl, which is substituted, for example, by hydroxy, mercapto, asylum, thioacyl, alkoxy, alkylthio or substituted or unsubstituted amino, or a substituted or unsubstituted, saturated or unsaturated heterocyclic group, containing they have one or more heteroatoms, such as azetidine, pyrrolidine, piperidine, pyrimidine, pyrazine, furan, polyhydrofurah, pyran, polyhydropyran, quinuclidine, azabicycloalkane or diazabicycloalkane, or phenyl, adamantyl, cycloalkyl, bicycloalkylalkyl or cycloalkylalkyl or cycloalkylalkyl directly with a carbon atom in the ring or over a substituted or unsubstituted alkyl chain, or wherein B2 and B1 may be joined to form a heterocyclic group, which may optionally contain other heteroatoms. The rings formed are, for example, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, morpholine or thiazolidine, and when the heterocyclic group contains an additional nitrogen atom, it may be substituted with alkyl having 1-4 carbon atoms, alkenyl having 2-4 carbon atoms, alkynyl having 2-4 carbon atoms, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkanalkyl, cycloalkenalkyl, adamantyl, bicycloalkyl or alkyl, substituted by hydroxy, mercapto, acyl, thioaeyl, alkoxy or alkylthio. R 'represents hydrogen or alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbon atoms, alkinyl of 2-4 carbon atoms, adamantyl, pyrimidinyl, pyrazernyl, diazepinyl, quinuclidrinyl, azabicycloalkyl, diazabicycloalkyl, bicycloalkad, or substituent phenyl or araixyl. n 'and B can be. connected. : 111 am form heterocyclic groups having a nitrogen atom, such as azetidine, pyrrolidine, piperidine, polyhydroazepine, azabicycloalkane, etc., which groups may be optionally substituted. R 1 and R 1 may be joined to form a saturated or unsaturated heterocyclic group having two nitrogen atoms, such as piperazine, diazepine, pyrimidine, pyrazine or diazabicycloalkane, which may be optionally substituted.

X represents hydrogen or halogen, hydroxy, amino, substituted amino, nitro, alkoxy of 1-4 carbon atoms or alkyl of 1-4 carbon atoms.

Y represents hydrogen or halogen, or hydroxy, amino or substituted amino, nitro, alkoxy having 1-4 carbon atoms, alkylsulfonyl having 1-4 carbon atoms, adamantylsulfonyl or cycloalkylsulfonyl, or a sulfonyl group substituted with an amino group or a mono- or disubstituted NR4 amino , wherein H3 and R4 may be the same or different and represent hydrogen or alkyl of 1-4 carbon atoms, alkenyl of 2-4 carbon atoms, alkynyl of 2-4 carbon atoms, phenyl, benzyl, cycloalkyl, cycloalkanalkyl, cycloalkenalkyl, bicycloalkyl , adamantyl, pyrimidinyl, pyrazinyl or alkyl, substituted by hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio, or together with a nitrogen atom to which they are attached form a heterocyclic group, which may optionally contain a additional heteroatom.

Z represents hydrogen or halogen, hydroxy, amino or substituted amino, nitro or alkoxy of 1-4 carbon atoms, and X and Y or Y and Z may be connected by a substituted or unsubstituted carbon chain or by other heteroatoms to form of a cyclic group, such as substituted or unsubstituted triazole, imidazole, oxazole, thiadiazole, pyrazine, piperazine, diazepine or their oxides.

In the definitions given herein, by alkyl of 1-4 carbon atoms is meant mainly methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl Alkylene having 1-3 carbon atoms essentially comprises methylene, ethylene and propylene. Alkenyl of 2-4 carbon atoms mainly comprises vinyl and allyl, while alkynyl of 2-4 carbon atoms mainly comprises ethynyl and propargyl. Alkoxy having 1-4 carbon atoms mainly comprises methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy. Aralkyl essentially includes benzyl and phenethyl, optionally substituted with one or more of the groups halogen, alkoxy, alkyl, halomethyl and amino. By substituted phenyl is meant essentially to include a phenyl ring substituted with one or more of the groups halogen, alkoxy, alkyl, halomethyl and amino. Halogen essentially includes chlorine, bromine, iodine and fluorine. Substituted amino 'essentially comprises an amino group which is mono- or disubstituted by alkyl, acyl, aralkyl, furanyl, pyranyl and / or alkoxycarbonyl. Acyl essentially includes formyl, acetyl and phthaloyl.

The - for X: - for Y: - for Z: the preferred meanings for the substituents. are the following: hydrogen, alkoxy, mainly methoxy, nitro, halogen, mainly chlorine, amino and acylamino, mainly acetylamino. hydrogen, halogen, mainly bromine or chlorine, amino, acylamino, mainly acetylammo, alkylsulfonyl, mainly ethylsulfonyl, and a sulfonyl group, substituted with an amino group, an amino group which is especially monosubstituted with alkyl, mainly then. methyl, or with an adamantyl group, or an amino group, which is especially disubstituted with alkyl, especially then. methyl and ethyl. hydrogen, halogen, mainly bromine or chlorine, nitro, acylamino, mainly acetylamino, and amino.

The preferred. the meanings of the substituents. in the disubsti- compounds they are as follows: tuera.de X LY few.

XXY í Fx N W4K2I tuerated t: alkoxy, mainly methoxy sulfonyl, substituted with an amino group acylamino, mainly acetylamino nitro and Y can be connected over a heteroatom, mainly nitrogen, to form a cyclic triazole X = Y = amino halogen, mainly chloro amino ammo acylamino, mainly acetylamino Y = acylamino, mainly acetylamino ZJ = nitro Z = acylamino, mainly acetylamino Z L-. halogen, mainly bromine Z e amino and Z may be attached via a heteroatom, mainly then. nitrogen, to form a cyclic tria.zol.

The preferred. the meanings. for the substituents. in the trisubbi compounds they are the following: ll nitro Z = halogen, mainly chlorine or bromine 77088164) I-X = halogen, mainly chlorine or bromine \ = Z = ni fi P0 = nitro KÉ> <Il Z = acylamino, mainly acetylamino.

The preferred meaning for A is alkylene having 1-3 carbon atoms, such as methylene, propylene and especially ethylene.

The preferred values for R 'are hydrogen, and butyl, aralkyl, mainly benzyl, which may be substituted by halogen, suitably bromine or fluorine, or by a trifluoroethyl group, adamantyl, dyrimidinyl, or, when attached to R 1, a saturated, heterocyclic group having two nitrogen atoms, mainly a piperazine ring, which may be substituted.

The preferred meanings for R are hydrogen, or a group of formula II, wherein the preferred meanings for B are a single bond, an alkylene group, mainly ethylene or propylene, or, when attached to R 1, a heterocyclic group having a nitrogen atom as defined below. The preferred meanings for R 1 are alkyl, mainly ethyl, or, when attached to B, a saturated, nitrogen heterocyclic group, mainly pyrrolidine or piperidine, or, when attached to H 2, a nitrogen heterocyclic group, mainly pyrrolidine or piperidine, or containing another heteroatom, especially when nitrogen, mainly a piperazine, substituted with alkyl, preferably methyl or ethyl, or, when attached to R ', a saturated, heterocyclic group having two nitrogen atoms, mainly one substituted piperazine- EPUPP- When simultaneously R 1 is attached to R 2 to form a nitrogen heterocyclic group, mainly a pyrrolidine group. and R 1 is attached to R 'to form a saturated heterocyclic group having two nitrogen atoms, mainly a piperazine group, to form the whole bicyclic group, preferably a diazabicyclone group.

The compounds according to the invention can be prepared by a compound of the general formula: alkyl, mainly ethyl D alkyl, mainly ethyl, con Z 2, wherein A, X, Y and Z have the previously stated meaning and D represents hydroxy, halogen or an organic group, is reacted with (III) an amine of the general formula: (IV), wherein R and R 'are as defined above, or by reaction of their active derivatives.

In the starting compound includes the organic. the group groups that can form. reactive acid derivatives. These may be lower alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl, reactive acid esters, such as the methoxymethyl ester or cyanomethyl ester, substituted or unsubstituted aromatic. esters or N-hydroxyimide esters, acid azides, acid hydrazides, symmetrical. anhydrides, mixed anhydrides, such as those formed from carboxylic acid esters and haloformic acid esters, azolides, such as triazolides, tetrazolides and especially imidazolides, substitute the (IJ -trihaloacetophenone acid isothiocyanates, substituted oxides or oxybenzenate, other equivalent groups, or the compound of the general formula: zi Y oo -c = cH-co-NH-c2H5 x / 'I /, ° -A a so3H * (formed from the acid and an isoxazolium salt). The above formula has the meanings previously given by A, X, Y and Z. However, the invention is not limited to only the reactive derivatives given above.

According to the invention, the amine can react. in the form a.v an a.v their. reactive. derivative. Examples of these are the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl and orthophenylene chlorophosphites, alkyl or aryl dichlorophosphites or isothiocyanate of the amine, or the symmetrical ones. or the asymmetric sulfamides of the amine, the corresponding symmetrical urea, the corresponding enamines. or any other equivalent association.

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

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

Among the processes described for the preparation of the compounds of the invention, the use of an acid halide is particularly suitable for compounds which are unsubstituted in the benzene ring, and compounds which are monosubstituted by halogen, nitro, alkylsulfonyl, adamantylsulfonyl, cycloalkylsulfonyl or a sulfonyl group. , substituted with amino or amino which is mono- or di-substituted with alkyl, adamantyl or cycloalkyl. The use of alkyl esters, activated acid esters or aromatic esters is particularly suitable for compounds in which the benzene ring is substituted by hydroxy, amino, acylamino, alkylsulfonyl, adamantylsulfonyl, cycloalkylsulfonyl or a sulfonyl group substituted by amino or by amino mono- or disubstituted mono- or disubstituted with alkyl, adamantyl or cycloalkyl, and to compounds in which two groups X and Y or Y and Z are linked to a cyclic group.

Use of mixed anhydrides (prepared in situ by reaction between the starting benzoic acid and haloformic acid esters, especially chloroformic acid esters) is particularly suitable for compounds which are substituted by nitro, acylamino or by sulfonyl, substituted by amino or amino which is mono- or disubstituted by alkyl, adamantyl or cycloalkyl.

The use of reactive amine derivatives, especially prepared with phosphorus chlorides, mainly phosphorus trichloride, or with alkyl and aryl chlorophosphites, is particularly suitable for primary amines and especially aliphatic amines.

The amidation reaction according to the invention can be carried out in the presence or absence of a solvent. Useful solvent systems which are inert to the amidation reaction are, for example, alcohols, polyols, benzene, toluene, dioxane, chloroform or diethylene glycol dimethyl ether, or xylene. It is also possible to use a surplus of the amine used as starting material as solvent. It may be appropriate to heat the reaction mixture during the amidation process, for example up to the boiling point of the indicated solvents. The compound prepared by the present process can, if desired, be reacted with pharmacologically acceptable organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid or methanesulfonic acid to give acid advice. It can also, if desired, be reacted with alkyl halides or sulfates to obtain quaternary ammonium salts. Furthermore, the compound can also be oxidized in a manner known per se, e.g. with hydrogen peroxide and manganese dioxide, to obtain the corresponding N-oxide.

The invention is further illustrated by the following examples, which, however, are not intended to have any limiting meaning.

Example Gel 1- N- (1-allyl-α-pyrrolidynylethyl) -7-methyl sulfamoyl-1,1α1-benzodioxane-carboxamide 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid 670 g of chlorosulfonic acid were charged to a round bottom flask , equipped with a cooler and thermometer, after which 173 g of 1,4-benzodioxane-5-carboxylic acid were added in small portions while maintaining the temperature at 5-10 ° C.

The mixture was heated to 5500, after which it was cooled and precipitated on ice. The precipitate formed was collected, washed and dried to give 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid in a yield of 93.5% and with a melting point of 210-21500. 7-Methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 139.5 g of a 40% aqueous solution of methylamine and 139.5 ml of water were charged to a round bottom flask equipped with a stirrer and thermometer, after which 250 g of 7-chlorosulfonyl were added portionwise. 1,4-benzodioxane-5-carboxylic acid and a solution of 180 ml of 30% sodium hydroxide solution in 180 ml of water. The mixture was stirred and then poured into 2200 ml of water. The solution was filtered and then treated with 139 ml of concentrated hydrochloric acid, after which the precipitate formed was filtered off, washed and dried. 190.5 g were obtained of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid in a yield of 80% and with a melting point of 20 DEG-28 DEG-29 DEG. 7-Methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride 176.5 g of thionyl chloride were charged to a round bottom flask equipped with a condenser, after which 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonic acid were added portionwise under heating at 40 DEG-40 DEG. 45 ° C. The mixture was heated under reflux and then treated with 250 ml of chloroform.

The precipitate was collected and washed with chloroform. N- (1-allyl-Zygyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 69 g of 1-allyl-2-aminomethylpyrrolidine and 432 ml of chloroform were charged to a 1 liter round bottom flask, equipped with a thermometer and stirrer. 144 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added portionwise, keeping the temperature at 5-10 ° C. Stirring of the mixture was continued for one hour, after which it 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 filtered with carbon, and the solution of the resulting sulfate was basified with 60 ml of 20% ammonia. After crystallization, the base was separated, washed with water and dried at 4000. After recrystallization from acetonitrile, 134 g of N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide were obtained in yield 68 .7% and with a melting point of 142-143 ° C. NMR spectra are consistent with the assumed structure.

Example 2 N- (1-ethyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 209 g of 34% ammonia and 97 g of Z-chlorosulfonyl 1,4-Benzodioxane-5-carboxylic acid is charged to a round bottom flask equipped with a stirrer and thermometer at a temperature of 5 DEG-10 DEG C. The mixture is stirred at room temperature, after which the precipitate formed is dissolved in 415 ml of water. The solution is filtered and treated with 140 ml of concentrated hydrochloric acid. The crystals are separated, washed with water and dried to give 78 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid in 87% yield, m.p. 272-27190.

Methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate 429 g of methanol are charged to a round bottom flask equipped with a condenser, after which 54 g of 93% sulfuric acid and 11 g of 7-sulphamoyl-1,4 -benzodioxane-5-carboxylic acid is added. The mixture is heated under reflux and then cooled. The crystals formed are separated, washed with methanol and then heated with 500 ml of water and 5 g of sodium carbonate. The precipitate formed is separated, washed with water and dried to give 95 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate in a yield of 81% and with a melting point of 225-22600.

N- (1-ethyl-Zipyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-carboxamide '- 145 g of methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 81 g 5 g of 1-ethyl-2-aminomethylpyrrolidine are charged to a round bottom flask equipped with a reflux condenser and stirrer. The resulting suspension is heated on a water bath until a sample taken is soluble in dilute acid. The reaction mixture is then treated with one liter of water and acidified with 70 ml of acetic acid. The resulting acetate solution is filtered with carbon, and the base is precipitated with 20% ammonia. The crystals are separated, washed with water and dried, and the benzamide is purified by transferring to hydrochloride (m.p. 238-24000), after which the base is reprecipitated by adding 20% ammonia. 120 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide are obtained in a yield of 61.5% and with a melting point of 160-166 ° C.

NM spectra correspond to the assumed structure.

Example 3 _ __.

N- (1-methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 7-mercapto-1,4-benzodioxane-5-carboxylic acid 243 g 7-chlorosulfonyl-1,1-benzodioxane- 5-Carboxylic acid and 654 ml of acetic acid were charged to a round bottom flask equipped with a stirrer and condenser.

The mixture was heated to 9000 and then cooled to 45 ° C, after which 389 g of tin and 1744 ml of hydrochloric acid were added. The mixture was heated at 55-60 ° C, and cooled and boiled in 1 water. The resulting precipitate was separated, washed and dried to give 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid in 90% yield, m.p. 191-192 ° C. 7-Ethylthio-1,4-benzodioxane-5-carboxylic acid 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 ml of water, 216 ml of sodium hydroxide solution and 181 g of ethyl sulphate were charged to a round-bottomed flask equipped with a condenser. . The mixture was heated under reflux and then cooled. The solution was poured into 1.3 liters of water, filtered and treated with 10 ml of hydrochloric acid. The precipitate was separated, washed with water and dried to give 152 g of 7-ethylthio-1,1-benzodioxane-5-carboxylic acid in a yield of 81% and with a melting point of 135-15400. 7-Ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid and 958 ml of acetic acid were charged to a round bottom flask equipped with a condenser. 398 ml of hydrogen peroxide were then added, and the mixture was heated. The crystals formed on cooling were separated, washed and dried to give 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid in a yield of 81% and with a melting point of 217-218 ° C. 7-Ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride 243 g of thionyl chloride, a few drops of dimethylformamide and 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid were charged to a round bottom flask equipped with a condenser. The mixture was heated, after which the excess thionyl chloride was distilled off under vacuum. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were obtained in 100% yield and with a melting point of 146-147 ° 0.

N- (1-methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 59 g of 1-methyl-2-aminomethylpyrrolidine and 450 ml of chloroform were charged to a round bottom flask equipped with a stirrer and thermometer, each after 150 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride in small portions were added at a temperature of 5-110 ° C. The mixture was then stirred for one hour at room temperature, and 1850 ml of water was added. After distilling off the chloroform, the solution was filtered over carbon black, and benzamide precipitated by adding 65 ml of sodium hydroxide solution. The solid product was separated, washed with water and dried at 4000. After recrystallization from absolute alcohol, 151 g of N- (1-methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxanes-s-carboxamia were obtained in the yield 80,596 and with melting point 140 ° -141 ° C. The structure of the compound was confirmed by NMR.

Example 4 1- (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 57 g of triethylamine were charged in a 1-liter three-necked flask, equipped with a stirrer, thermometer and dropping funnel. The mixture was heated at 40-5000, and 80 ml of water was added, after which the solution was cooled to -1000 and 61.5 g of ethyl chloroformate were added. Stirring of the mixture was continued for one hour at 10 ° C, and 93 g of 1- (2-pyrimidinyl) -piperazine were added without allowing the temperature to rise above 15 ° C.

Mixing was continued for one hour at room temperature, and after adding 1500 ml of water, the mixture was made alkaline to pH 10 with ammonia. The crystals formed after vacuum distillation of the solvents and cooling were separated, washed with water, dried in a drying oven at 5000, and then purified by treatment with 120 ml of chloroform. After filtration and drying, 92 g of 1- (2,3-ethylenedioxy-5-sulfamoylbenzoyl) -4- (2-pyrimidinyl) -piperazine were obtained in a yield of 40.2% and with a melting point of 23900. The structure was confirmed by NMB- analysis. Example 7 N- (1-methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide. 7-Dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 500 ml of acetone and a solution of 99 g of dimethylamine in 250 ml of acetone were charged to a round-bottomed flask equipped with a stirrer and thermometer.

The mixture was cooled to 0 ° C, after which 139 g of 7-chlorosulfonyl-1,1-benzodioxane-5-carboxylic acid were added. The whole was stirred at room temperature, after which the acetone was distilled off and the residue was dissolved in 1 liter of water. The solution was made alkaline, filtered and treated with 70 ml of hydrochloric acid, and the precipitate formed was separated, washed and dried. 128 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid. was obtained in 89% yield and with a melting point of 22 ° -221 ° C. 7-Dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride 190 g of thionyl chloride and 153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonic acid were charged to a round bottom flask equipped with a condenser. The mixture was heated, after which the excess thionyl chloride was distilled off. 163 g were obtained of T-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride in cold yield and with a melting point of 160 DEG-162 DEG.

N- (1-methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide 5 a 61 g of 1-methyl-2-aminomethylpyrrolidine and 560 ml of chloroform were charged to a round bottom flask equipped with a stirrer and thermometer , after which, while maintaining the temperature at 0 DEG-5 DEG C., 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added. The mixture was stirred for one hour, during which time the temperature was allowed to rise, after which 1 liter of water was added. After distilling off the chloroform, the solution was filtered, and the carboxamide was precipitated by adding% sodium hydroxide solution. The crystals formed were filtered, washed with water and dried. After recrystallization from absolute alcohol, 157 g of N- (1-methyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-kerboxamide were obtained in 76.9% yield, m.p. 165-166 ° C.

NMB spectra confirm the assumed structure.

Example 6 7 N- (1-Benzyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide phosphate 440 ml of chloroform and 110 g of 1-benzyl-2-aminomethylpyrrolidine were charged to a round bottom flask equipped with a stirrer and thermometer. after at 5-1000 110 μl of 4-benzodioxane-5-carbonyl chloride was added.

After stirring the mixture and adding 3 liters of water, the chloroform was removed. The solution was treated with ammonia, after which the precipitate formed was extracted with methylene chloride. The organic solution was dried, after which the solvent was evaporated and the resulting compound, dissolved in absolute ethanol, was treated with 30 ml of 85% phosphoric acid. The precipitate formed was separated, washed with ethanol and dried to give 153 g of N- (1-benzyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide phosphate in 61% yield and melting point 165 ° C.

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 was charged to a round bottom flask equipped with a condenser; the mixture was heated on a water bath until a sample taken was soluble in dilute acids, after which 1 liter of water was added. The precipitated carboxamide was redissolved by formation of acetate. The resulting solution was filtered with carbon black, after which the base precipitated by the addition of 20% ammonia. The crystals formed were removed, washed with water, dried and purified by transferring to hydrochloride (m.p. 228-23000), followed by conversion to base by treatment with 20% ammonia. 131 g of N- (1-allyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamia were obtained in 64.8% yield, with an emission point of 143-144 ° C. the structure was confirmed by NMR analysis.

Example 8 'N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide Methyl 7-methylsulphemyl-1,4-benealxene-5-kerbexyate 750 ml of methanol was charged to a round bottom flask , equipped with a condenser, after which 273 g of concentrated sulfuric acid and 150 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added during cooling. The mixture was heated under reflux, and cooled and precipitated in water and sodium carbonate. The precipitate was separated, washed and dried to give 143 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate in 85% yield with an emit point of 159-160 ° C.

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-aminoethylpyrrolidine was charged to a round bottom flask equipped with a stirrer and reflux condenser. The mixture was heated on a water bath until a sample taken was completely soluble in dilute acids. The carboxamide formed by cooling was purified by transfer to acetate and subsequent treatment with 100 ml of acetic acid in 950 ml of water. After filtering the resulting solution with carbon black, the base was precipitated by adding 20% ammonia. The resulting crystals were separated, washed with water, dried and purified by recrystallization from boiling isopropanol. 12 g of N- (1-ethyl-2-pyrrolidylmethyl) -β-methylsulfamoyl-1,4-benzodioxane-5-carboxamide were obtained in 66.2% yield and with a melting point of 139-140 ° C. The structure was confirmed by NMR analysis. The corresponding hydrochloride was prepared by treating the carboxamide with hydrochloric acid (density 1,18), and melting at 186-188 ° C.

Example 9 - N- (1-ethyl-2-pyrrolidylmethyl) -2,3-methylenedioxybenzamide Similarly, 34.9 g of ethyl 2,3-methylenedioxybenzoate was reacted with 24.2 g of 1-ethyl-2- aminomethylpyrrolide, whereby after treatment and purification, 28.3 g of N- (1-ethyl-2-pyrrolidylmethyl) -2,3-methylenedioxybenzamide were obtained. NMR spectra.consistent with the expected structure.

Example 10 Left-handed N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide 65 g of left-handed 1-ethyl-2-aminomethylpyrrolidine were dissolved in 430 ml of round-bottomed chloroform, equipped with stirrer and thermometer.

The resulting solution was cooled to 5 ° C, after which 148 g of finely powdered 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added while maintaining the temperature at 5-10 ° C. After complete addition of this compound, the mixture was stirred for one hour and then treated with 1 liter of water. After distilling off the chloroform, the solution was filtered over carbon black, and the base precipitated through an excess of 30% soda. The obtained crystals were separated, washed with water, dried and recrystallized from isopropanol. 151.5 g of left-handed N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide were obtained in 77.7% yield and with a melting point of 111-112 ° C. (ago = -54.2 ° (in 5% solution 1 aimecyiformamia).

Example Gel 11 'Right-turn N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide Similarly, 64.5 g of right-turn 1-ethyl-2-aminomethylpyrrolidine was reacted with 146 g of 7-ethylsulfonyl-1,4-benzodioxane-carbonyl chloride, whereby after treatment and purification 133.5 g of right-turning N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4- benzodioxane-5-carboxamide in 69.8% yield and melting point III-11200. (a) š ° = 55.5 ° (1 5% solution 1 dimethylformamide).

Example 12 N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide Similarly, 58 g of 1-ethyl-2-aminomethylpyrrolidine was reacted with 131 g of 7-ethylsulfonyl-1-carboxamide. 4-Benzodioxane-5-carbonyl chloride, whereby after treatment and purification, 103.5 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide were obtained in 60.2 g % yield and with melting point 118-119 ° C. 100 g of the base prepared were dissolved in 220 ml of acetone, after which the solution was filtered over carbon black and a solution of 9.5 g of hydrochloric acid in acetone was added. The hydrochloride crystals formed were separated, washed with acetone and dried to give 96 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxanes-carboxamide hydrochloride in 88.2% yield and melting point 148 DEG-158 DEG. ° c.

Example gel 13 N- (1-methyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide 131 g methyl 7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 43 g water and 66 g of 1-methyl-2-aminomethylpyrrolidine were charged to a round bottom flask equipped with a reflux condenser. The mixture was heated on a water bath until a sample taken was completely soluble in dilute acids. The carboxamide formed on cooling was purified by treatment with a solution of 50 ml of acetic acid in 1250 ml of water. After filtering the resulting carbon black solution, the base precipitated by adding% ammonia. The obtained crystals were separated, washed with water, dried and purified by recrystallization from boiling methanol. 119.5 g of N- (1-methyl-2-pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide were obtained in 70.1% yield and with a melting point of 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 charged to a round bottom flask equipped with a stirrer and thermometer, after which 120 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were added, keeping the temperature at 5-10 ° C. After mixing and adding 40 liters of water, the chloroform was distilled off. The resulting solution was filtered with carbon black, after which the base precipitated by adding 40 ml of 30% sodium hydroxide solution. The crystals formed were separated, washed with water and dried to give 152 g of N- (1-allyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide in 93.4% yield and m.p. 78-8000. 146 g of the base obtained were dissolved in heat in 290 ml of absolute alcohol, after which the solution was filtered with carbon black and acidified by adding a solution of 13.5 g of hydrogen chloride in 100 ml of absolute alcohol. After cooling, the crystals formed were removed, washed with absolute alcohol and dried, after which they were purified by recrystallization from absolute alcohol. 119.5 g were obtained of N- (1-allyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride in 75% yield and with a melting point of 138-140 ° C.

Example 15 N- (1-ethyl-z-pyrrolidylmethyl) -2H-3,5-hydrohydrolo-1,5-benzodioxepine-6-carboxamide Methyl-2H-3,4-dihydro-1,5-benzodioxepine 6-Carboxylate 11 g of methyl 2,3-dihydroxybenzoate, 660 ml of methyl ethyl ketone, 167 g / l, 3-dibromopropane and 10 g of sodium iodide were charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was heated at 4000, after which § 182; potassium carbonate was added. The whole was heated under reflux, and 2 liters of water were added. The oil phase was decanted off and extracted with ether, and the solution was washed with 10% soda, and dried. The ether was evaporated by vacuum distillation to give 86.5 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate in 63% yield and with xoxpunxt 166-176 ° C for 1.0 ml. 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 160 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate and 388 ml of soda were charged to a round bottom flask equipped with a condenser . The mixture was heated under reflux, then poured into 1 liter of water, and treated with 5 g of sodium metabisulfite. The solution was filtered and treated with 77 ml of concentrated hydrochloric acid, and the precipitate formed was filtered off, washed with water and dried, 120 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were obtained in 80.5% yield and with melting point 65-6700. 2H-3,4-Dihydro-1,5-benzodioxepine-6-carbonyl chloride 246 g of thionyl chloride and 13 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were charged to a round bottom flask equipped with a condenser. The mixture was heated under reflux, after which the excess thionyl chloride was distilled off under vacuum. 147 g were obtained of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride in 100% yield and with a melting point of -37 ° C.

N- (1-ethyl-2-pyrrolidylmethyl) -2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide 92 g of 1-ethyl-2-aminomethylpyrrolidine and 458 ml of chloroform were charged to a round bottom flask equipped with with stirrer and thermometer, after which 152 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were added, keeping the temperature at 5-10 ° C. After stirring for one hour, allowing the temperature to rise, 1450 ml of water were added, after which ä; the chloroform was distilled off. The solution was filtered under carbon black, mw and the base was precipitated by the addition of 75 ml of 20% ammonia.

The obtained crystals were collected, washed with water and dried, yielding 191 g of N- (1-ethyl-2-pyrrolidylmethyl) -2H-3,4- [1- [1] dinydrole-1,5-benzoicoxepin-6-carboxamide mononyarate 1 82,476 yield and with a melting point 51-52 ° C. 73.5 g of the compound formed are dissolved in 750 ml of absolute alcohol. The solution was filtered over carbon black, after which a solution of 62 g of 85% phosphoric acid in 100 ml of absolute alcohol was added. The crystals formed were collected, washed with absolute alcohol and dried, after which they were recrystallized from alcohol. 198 g were obtained of N- (1-ethyl-2-pyrrolidylmethyl) -2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide phosphate in 92% yield and with melting point 189 DEG-190 DEG.

Example gel 16 N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 169 g of methyl 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine was charged to a round bottom flask equipped with a reflux condenser. The mixture was heated in a water bath until a sample taken was completely soluble in dilute acids. The obtained crystals were dissolved in a mixture of 50 ml of acetic acid and 1250 ml of water, after which the solution was filtered over carbon black and the base was reprecipitated by adding 100 ml of 20% ammonia.

The crystals were collected, washed with water and dried to give 182 g of the N- (1-methyl-E-pyrrolidylmethyl) f-methylsulfasnyl-L11f-benzo-aioxane-s-carboxes in 83.5 ß yield and meaosnaitpunk 1sa-190 ° c .

Example 17 N- (Diethylaminoethyl) -1,4-benzodioxane-5-carboxamide hydrochloride 21 g of diethylaminoethylamine and 85 ml of acetone were charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 100 DEG C., after which 36 g of 1,1-benzodioxane-5-carbonyl chloride were added. The crystals formed at room temperature were collected, washed with acetone, dried and purified by recrystallization from isopropanol. 36.5 g were obtained of N- (diethylaminoethyl) -1,4-benzodioxane-5-carboxamide-nehydrochioria in 64% yield and with melting point 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 carbonyldiimidazole was charged to a round bottom flask equipped with a stirrer, thermometer and condenser. The mixture was stirred at room temperature, after which 9.5 g of 1-ethyl-2-aminomethylpyrrolidine were added. Stirring was continued at room temperature, after which the solvent was evaporated off under vacuum. The formed crystals were washed with water and dried to give 14 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide in 73.8% yield and with melting point 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 charged to a round bottom flask equipped with a stirrer, thermometer and condenser, after which, while stirring and maintaining the temperature at 0 DEG-5 DEG C., a solution of 3.5 g of phosphorus trichloride in 20 ml of pyridine was added dropwise. Stirring was continued at 0-5 ° C, and then at room temperature. Then, 14.5 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid was added, and the mixture was heated with stirring.

After the mixture was cooled and the solvent was evaporated, the residue was dissolved in chloroform, after which the solution was washed with an aqueous solution of 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 in 64.5% yield and with a melting point of 165-166 ° C.

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 was charged to a round bottom flask equipped with a stirrer and thermometer. After stirring the mixture, the base was extracted with methylene chloride, after which the solvent was evaporated. The crystals formed were dissolved in boiling absolute alcohol, and the resulting solution was filtered over carbon black. The crystals formed after cooling were dissolved in an acetic acid solution in water, after which the solution was filtered with carbon and the base was reprecipitated by adding 20% ammonia. 129.5 g were obtained of N- (1-cyclohexyl-3-pyrrolidyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamia 1 61.22; yield and with melting point 16o-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 charged to a round bottom flask equipped with a stirrer and thermometer, after which 153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added, while maintaining the temperature at 0-5 ° C. The mixture was stirred for one hour, during which time the temperature was allowed to rise, after which 1 liter of water was added. After distilling off the chloroform, the solution was filtered, and the carboxamide precipitated by the addition of 30% sodium hydroxide solution. The formed crystals were filtered, washed with water and dried, and after recrystallization from absolute alcohol, 144.5 g of N- (1-ethyl-2-pyrrolidylmethyl) -7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxamide were obtained in 72.8% yield and m.p. 146-148 ° C.

Example Gel 22 Right-turning N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide 82 g Right-turning 1-ethyl-2-aminomethylpyrrolidine, 600 ml chloroform and 200 g small portions at 5-10 ° C of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride was charged to a round bottom flask equipped with a stirrer and thermometer. After adding 1 liter of water, the chloroform was distilled off, and the remaining solution was filtered. The base was precipitated by adding 60 ml of 20% ammonia, and the resulting crystals were collected, washed with water and dried. 162 g were obtained of right-turn N- (1-ethyl-z-pyrrolidylmethyl) -7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide in 66% yield and with a melting point of 136-137 ° C.

Example Gel 23 Left-handed N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide In a similar manner to the previous example, 82 g of left-handed 1-ethyl-2-aminomethylpyrrolidine were reacted with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 151 g of left-handed N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5- carboxamide in 62% yield and m.p. 136-137 ° C.

Example Gel 24 Left-handed N- (1-allyl-2-pyrrolidylmethyl) -7-methyl-sulfamoyl-1,4-benzodioxane-5-carboxamide 85 g of left-handed 1-allyl-2-aminomethylpyrrolidine and 610 ml of chloroform were charged to a round bottom flask equipped with with stirrer and thermometer, after which 178 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added portionwise at 5-10 ° C. After stirring the mixture, 1.2 liters of water were added, after which the chloroform was distilled off. The remaining solution was filtered, after which the base was precipitated with 70 ml of 20% ammonia. The crystals formed were separated and washed with water. After recrystallization from ethyl acetate, 117 g of left-handed N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide were obtained in 49% yield and melting point 100-110 ° C. Right-turn N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide In a similar manner to the previous example, 84 g of right-turn 1-allyl-2-aminomethylpyrrolidine was reacted with 175 g 7 g of methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, 125 g of purifying N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide being obtained after purification. 6% yield and with melting point 1o4-1o5 ° c.

Example 26 1 Right-turning N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,1-benzodioxane-5-carboxamide W 61 g of right-turning 1-methyl-2-aminomethylpyrrolidine and 465 ml of chloroform were charged to a round bottom flask. , equipped with a stirrer and thermometer, after which 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were added in small portions while maintaining the temperature at 5-1 ° C. After stirring the mixture and adding 1850 ml of water, the chloroform was distilled off and the remaining solution was filtered. The base was precipitated by the addition of 65 ml of 20% ammonia, and the crystals formed were separated, washed and dried. 154 g were obtained of right-turn N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane -5-carboxamide in 78.5% yield ooh with melting point 187-188 ° c. Example 7 27 Left-handed N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide In a similar manner to the previous example, 71 g of left-handed 1-methyl-2- aminomethylpyrrolidine to react with 180.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 175 g of left-handed N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5 -carboxamide in 77% yield and with melting point 187-187, 5 ° c.

Example 28 N- (1-Ethyl-bipyrrolidylmethyl) -8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine 6-Carboxylic acid 1092 ml of chlorosulfonic acid were charged to a round bottom flask equipped with a stirrer, condenser and thermometer, after which 106 g of 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were added in small portions, keeping the temperature at 5- 10 ° C. The mixture was stirred at room temperature and then poured onto ice, and the crystals formed were separated, washed with water and dried. 146 g were obtained of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 91% yield and with a melting point of 114-115 ° C. 8-Methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonic acid 233 g of aqueous solution of methylamine were charged to a round bottom flask equipped with a stirrer and thermometer followed by 146 g of 8-chlorosulfonyl-2H-3 4-Dihydro-1,5-benzodioxepine-6-carboxylic acid was added, keeping the temperature at 5-1000. The mixture was stirred, and the precipitate formed was then dissolved in water. The solution was filtered and treated with 150 ml of concentrated hydrochloric acid, and the crystals formed were separated, washed and dried. 112 g were obtained of 8-methylsulphamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 78% yield. Melting point 145-146 ° C. 8-Methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride 220 g of thionyl chloride and 177 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were charged 1 round piston, equipped with radiator. The mixture was heated, after which the excess thionyl chloride was distilled off under vacuum. 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were obtained in 100% yield and with a melting point of 93-94 ° C. 7708M94) 22 N- (1-ethyl-2-pyrrolidylmethyl) -8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide 79 g of 1-ethyl-2-aminomethylpyrrolidine and 750 ml of methyl ethyl ketone A round bottom flask equipped with a stirrer and thermometer was charged, after which 188 g of 8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were added portionwise, keeping the temperature at 5-10 ° C. The precipitated hydrochloride was separated, washed with methyl ethyl ketone and dried. After recrystallization from methanol, the hydrochloride was dissolved in 1,850 ml of water, after which the solution was filtered and the base was then precipitated by adding 60 ml of 20% ammonia. The formed crystals were separated, washed with water and dried to give 180 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-methylsulfamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide in 618 % yield and with forging puncture 144-145 ° c.

Example 29 N- (1-ethyl-2-pyrrolidylmethyl) -2,3-methylenedioxybenzamide hydrochloride 134 g of 1-ethyl-2-aminomethylpyrrolidine and 950 ml of chloroform were charged to a round bottom flask equipped with a stirrer and thermometer, after which 183 g 2,3-Methylenedioxybenzoyl chloride was added portionwise while maintaining the temperature at 5-10 ° C. After adding 1 liter of water, the chloroform was distilled off and the remaining solution was filtered. After adding 120 ml of 20% ammonia and extracting with ether, the ether solution was dried over potassium carbonate and then evaporated. The resulting base was dissolved in 300 ml of acetone, after which a solution of 34 g of hydrogen chloride in 1,330 ml of acetone was added.

The hydrochloride precipitate was collected, washed with acetone and dried. After recrystallization from isopropanol, 154 g of N- (1-ethyl-2-pyrrolidylmethyl) -2,3-methylenedioxybenzamide hydrochloride were obtained in H9.7% yield, m.p. 127.5-128.5 ° C.

Example 30 4- (1,4-Benzodioxane-7-ethylsulfonyl-5-carbonyl) -1,4-diazabicyclo [4-3-olnonane 41.5 g 1,4-diazabicyclo [4-3-O] nonane and 300 ml of chloroform was charged to a 1 liter round bottom flask. The mixture was cooled to 5 ° C, after which 87 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were added in small portions. After stirring the mixture at room temperature, 5 g of activated carbon were added. After filtration and removal of the chloroform, the oily residue was dissolved in 200 ml of water, after which 30 ml of 20% ammonia were added. The resulting precipitate was collected and then recrystallized from acetone to give 40 g of 4- (1,4-benzodioxane-7-ethylsulfonyl-5-carbonyl) -1,4-diazabicycloin-3-olene nane. 35% yield one with emäitpunkt 147%.

Example 31 is [(4-methyl-lepiperazinyl) -carbonyl] -7-nitro-1,4-benzodioxane-Sihydrochloride p 7-nitro-1,4-benzodioxane-5-carboxylic acid 160 ml acetic acid, 160 ml acetane anhydride and 100 g .4-Benzodioxane-5-carboxylic acid was charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was heated, and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added, after which the whole was stirred at 40-Å5 ° C and then cooled. The obtained crystals were separated, washed and dried to give 34 g of 7-nitro-1,4-benzodioxane-s-kerbeneyrene in 27% yield with an emission point of 246%. - [(4-methyl-1-piperazinyl) -carbonyl] -7-nitro-1,4-benzodioxane-Sahydrochloride '. 22 ml of water, 22.5 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid , 65 ml of acetone and 10.5 g of triethylamine were charged to a 250 ml round bottom flask equipped with a condenser and thermometer. The mixture was cooled to 10 ° C, after which 14 g of isobutyl chloroformate were added, and the whole was stirred, during which the temperature was allowed to rise. The oily compound formed was cooled to 100 ° C, after which 11 g of N-methylpiperezm was added and the mixture was then stirred while allowing the temperature to rise.

The crystals formed were washed with water to give 20.5 g of - [(4-methyl-1-piperazinyl) carbonyl] -7-nitro-1,4-benzodioxane in 66.7% yield and m.p. The obtained 20.5 g of base were treated with a solution of hydrochloric acid (density 1.18) in 100 ml of water, and the crystals formed on cooling were washed with water and dried. 5 g were obtained of 5 - {(4-methyl-1-piperazinyl) carbonyl] -7-nitro-1,4-benzodioxane hydrochloride in 89.4% yield and with a melting point of 25,000.

Example 32 - [(4-Methyl-1-piperazinyl) -carbonyl] -7 - [(1-adamantyl) -sulfamoyl-1,4-benzodioxane hydrochloride 7- (1-adamantyl) -sulfamoyl-1,4-benzodioxane-5 Carboxylic acid 187.5 g of adamantylamine hydrochloride, 500 ml of soda and 1000 ml of triethylamine were charged to a round bottom flask equipped with a stirrer and thermometer, after which 280 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added at a temperature below 1500 The mixture was stirred at room temperature and treated with 1.5 liters of methylene chloride, after which the organic phase was separated and the solvent was evaporated. The residue was treated with 1200 ml of water and 150 ml of hydrochloric acid, after which the precipitate formed was dissolved in 1200 ml of water and 120 ml of soda.

The solution was filtered and treated with 150 ml of hydrochloric acid, and the crystals formed were separated, washed and dried. 200 g were obtained of 7- (1-adamantyl) sulfamoyl-1,4-benzodioxane-5-carboxylic acid in 51% yield and with a melting point of 20500. ~ [(4-methyl-1-piperazinyl) -carbonyl] -7 - [( 1-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 charged into a 1-liter round flask equipped with stirrer and thermometer. After stirring the mixture, 12.5 g of triethylamine were added and then in small portions 17 g of isobutyl chloroformate. After mixing the whole at 2000, a solution of 14 g of N-methylpiperazine in 50 ml of dioxane was added, after which the mixture was stirred and then cooled. The resulting triethylamine hydrochloride was filtered off, and the filtrate was concentrated in vacuo, then dissolved in 300 ml of water, 15 ml of hydrochloric acid was added, after which 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.

To the filtrate was added a solution of hydrogen chloride in absolute ethanol, until the pH was 1, and the crystals formed were separated, washed with ethanol and dried. 37 g were obtained of 5 - [(4-methyl-1-piperazmyl) -carbonyl] -7 - [(1-ammonium) -sulifamoyl] -1, le-benzo-oxane hydrochloride in 58% yield and with a melting point of 260 ° C.

Example 33 N- (piperidinoethyl) -7-chloro-1,4-benzodioxane-5-carboxamide hydrochloride 7-amino-1,4-benzodioxane-5-carboxylic acid 56 g 7-nitro-1,4-benzodioxane-5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were charged to an autoclave, after which hydrogen gas under a pressure of 6.4 MPa was started under heating. The mixture was then stirred at 60 ° C, and treated with a solution of 50 ml of sodium hydroxide solution in 450 ml of water. The solution was filtered and treated with 50 ml of hydrochloric acid, and the precipitate formed was separated, washed with water and dried. 36.5 g were obtained of 7-amino-1,4-benzodioxane-5-carboxylic acid in 75% yield and with a melting point of 220 ° C. 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 charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 500, after which a solution of 770-8849-0 17.5 g of sodium nitrite in 38 ml of water was added. The suspension was then poured into a solution of 20 g of copper (I) chloride in 75 ml of hydrochloric acid. The precipitate formed was separated, washed and dissolved in a solution of 42 g of sodium bicarbonate in 420 ml of water. The solution was filtered and treated with 100 ml of hydrochloric acid to give 50 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid in 92.7% yield and with a melting point of 180 ° C. 7-Chloro-1,4-benzodioxane-5-carbonyl chloride 32.2 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid and 64 ml of thionyl chloride were charged to a round bottom flask equipped with a stirrer, thermometer and condenser. The mixture was heated under reflux, after which the excess thionyl chloride was distilled off under vacuum. 35 g of 7-chloro-1,4-benzodioxane-5-carbonyl chloride were obtained in 100% yield and with a melting point of 140 ° C. i - N- (piperiamoecyl) -7-1 <1or-1,4-benzodioxane-5-carboxamide hydrochloride 150 ml of methyl ethyl ketone and 22 g of N- (aminoethyl) -piperidine were charged to a 500 ml round bottom flask equipped with a stirrer and thermometer .

The mixture was cooled, after which a suspension of 35 g of 7-chloro-1,4-benzodioxane-5-carbonyl chloride in 200 ml of methyl ethyl ketone was added at a temperature of 15-2000. After stirring, the crystals formed were separated and washed with methyl ethyl ketone to give 35 g of N-pipiperidinoethyl-7-chloro-1,4-benzodioxane-5-carboxamide hydrochloride in 64.5% yield, m.p.

Example gel 34 N- (butyl) -7 - [(1-adamantyl) sulfamoyl] -1,4-benzodioxane-5-carboxamide 5co ml of auxane, 50 ml of water, 49 g of 7 - [(1-aamantyl) -sulfonamyl] -1 , 4-Benzodioxane-5-carboxylic acid and 12.5 g of triethylamine were charged to a 2 liter round bottom flask equipped with a stirrer and thermometer. The solution was mixed at room temperature, after which 17 g of isobutyl chloroformate were added. The whole was stirred, after which 10 g of butylamine were added, and after stirring this mixture, the dioxane was evaporated off. The residue is dissolved in 200 ml of water in heat, and the crystals formed on cooling are washed with water, dried and redissolved in 250 ml of acetone at boiling temperature, after which the solution is filtered hot. The crystals formed on cooling were separated, washed and dried to give 26 g of N- (butyl) -7 - [(1-adamantyl) -sulfamoyl] -1,4-benzodioxane-5-carboxamide in 46.4% yield and with melting point 147%. Example 7 N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-carboxamide oxalate '8-methoxy-1,4-benzodioxane-5-carboxylic acid 171.5 g 2, 3-Dihydroxy-4-methoxybenzoic acid, 515 ml of alcohol, 280 ml of sodium hydroxide solution and 175 g of ethylene bromide were charged to a round bottom flask equipped with a stirrer, thermometer and nitrogen inlet tube. The mixture was heated under reflux, after which it was cooled and poured into 2.8 liters of water. The solution was filtered and treated with 85 ml of concentrated hydrochloric acid, and the precipitate formed was separated, washed and dried. After recrystallization from dimethylformamide, 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were obtained in 57% yield and with a melting point of 224-226 ° C. 8-Methoxy-1,4-benzodioxane-5-carbonyl chloride 391 g of thionyl chloride and 138 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were charged to a round bottom flask equipped with a condenser. The mixture was heated at 50-55 ° C, and the excess thionyl chloride was distilled off under vacuum. 151 g were obtained from 8-methoxy-1,4-benzodioxane-5-carbonyl chloride in 100% yield.

N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide oxalate 87 g of 1-ethyl-2-aminomethylpyrrolidine and 775 ml of methyl ethyl ketone were charged to a round bottom flask equipped with a stirrer and thermometer. , after which 155 g of small 8-methoxy-1,4-benzodioxane-5-carbonyl chloride were added in small portions, while maintaining the temperature at 5-10 ° C. After stirring, the mixture was dissolved with 1500 ml of water, after which the methyl ethyl ketone was distilled off. The remaining solution was filtered and then treated with sodium hydroxide. The resulting oil was decanted and then extracted with methylene chloride, and the solution was dried over potassium carbonate, after which the methylene chloride was evaporated in vacuo. 224.5 g were obtained of N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide. 197.5 g of the base prepared were dissolved in 760 ml of absolute alcohol, after which 67 g of oxalic acid, dissolved in 195 ml of absolute alcohol, were added. The imaged crystals were separated, washed with absolute alcohol and then dried. 208.5 g were obtained of N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-1,4-benzodioxane-5-carboxamide oxalate in 82% yield and with a melting point of 129-130 ° C.

Example Gel 36 N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide 7-8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5 Carboxylic acid 1045 ml of chlorosulfonic acid were charged to a round bottom flask equipped with a stirrer, thermometer and condenser, after which 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were added portionwise while maintaining the temperature at 5-10 °. C. The mixture was stirred at room temperature and then poured onto ice. The precipitate formed was separated, washed and dried to give 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid in 98% yield. 8-Methoxy-7-sulfamoyl-1,4-benzodioxane-5-carbonic acid 300 g of 34% ammonia were charged to a round bottom flask equipped with a stirrer and thermometer, then 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane -5-Carboxylic acid was added portionwise, keeping the temperature at 0-5 ° C. The mixture was stirred, after which the precipitate formed was dissolved in water, and the solution was filtered and treated with 280 ml of concentrated hydrochloric acid. The precipitate formed was separated, washed and dried to give 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carbonic acid in 82% yield and with a melting point of 247-248 ° C.

Methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate 396 g of methanol were charged to a round bottom flask equipped with a condenser, followed by 51 g of sulfuric acid and 114.5 g of 8-methoxy-7-sulfamoyl. 1,4-Benzodioxane-5-carboxylic acid was added under cooling. The mixture was heated under reflux and then poured into 485 ml of water and 40 g of sodium carbonate. The precipitate formed was separated, washed and dried to give 110.5 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate in 92% yield, m.p. 202-203 ° C, N- ( 1-ethyl-2-pyrrolidylmethyl) -8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide 150 g of methyl 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate and 750 ml ethylene glycol was charged to a round bottom flask, and after dissolution, 127 g of 1-ethyl-2-aminomethylpyrrolidine was added and the mixture was heated to 50 ° C. The resulting solution was added with 2 liters of water and acidified with 120 ml of acetic acid. The precipitate formed was separated, washed with water and dried. The precipitate was then redissolved in 915 ml of hot water, and the solution was filtered, after which the base was precipitated with ammonia. The precipitate was removed, washed with water and then dried to give 144 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide in 73% yield and m.p. 110-115 ° C. Example 37 4- (1,4-Benzodioxane-5-carbonyl) -1,4-diazabicyclo [4-3-O] nonane W 63 g 1,4-Diazabicyclo [4-3-O] Nonane and 400 ml of chloroform were charged to a 1 liter round bottom flask equipped with a stirrer and thermometer, after which 50 g of 1,4-benzodioxane-5-carbonyl chloride were added portionwise while maintaining the temperature at 10 ° C. The mixture was then stirred at room temperature, after which 1 liter of water was added. After adding acetic acid to pH 4, as well as adding carbon and filtration, the product precipitated with ammonia. After extraction with methylene chloride, the solution was dried and then filtered, after which the solvent was evaporated in vacuo and the product obtained was purified by recrystallization from ethanol. 50 g were obtained of 4- (1,4-benzodioxane-5-carbonyl) -1,4-diazabicyclo [4-3-O] nonane in 69% yield and with melting point 128%.

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 charged in a round bottom flask equipped with a stirrer and thermometer, after which 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, keeping the temperature at 20-30 ° C. The mixture was stirred at room temperature, after which 500 ml of water were added, and the solution was filtered and heated with 300 ml of hydrochloric acid. The precipitate formed was separated, washed and dried to give 117 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid in 74% yield and melting point 149%.

N-(Benzyl) -7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide 37.8 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 40 ml of water, 12.5 g of triethylamine and 120 ml of acetone were charged in a round-bottomed flask, equipped with a stirrer and thermometer. The mixture was cooled to about -15 ° C, after which 17.2 g of isobutyl formate were added. After adding 14.1 g of benzylamine at a temperature of 15-2000 and stirring the mixture, the crystals formed were separated, washed with water and then purified by recrystallization from ethanol. 33 g of N- (benzyl) -7-diethylsulfamoyl-1,4-benzodioxane-5-carboxamide were obtained in 68% yield and with a melting point of 25 ° C.

Example 39 N-fl-benzyl2-4-piperidyl2-1-methylsulfamoyl-1,1'-benzodioxane-1-carboxamide 40 ml of water, 68.5 g of 7-methylsulfamoyl-1,4-benzodioxane-5 Carboxylic acid, 25.5 g of triethylamine and 200 ml of acetone were charged to a round bottom flask equipped with a stirrer and thermometer, after which 34.5 g of isobutyl chloroformate were added while maintaining the temperature at 15-20 ° C.

After adding 52 g of 1-benzyl-4-aminopiperidine at a temperature of 15-2000 and stirring the mixture, the crystals formed were separated, washed with water and dried. The resulting product was purified by treatment with a hydrochloric acid solution, and subsequent precipitation with sodium hydroxide. The precipitate was then filtered off, washed with water and dried to give 76 g of N- (benzyl-4-piperidyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide in 68% yield and with a melting point of 22800.

Example 40 N- (1-adamantyl) -1,4-benzodioxane-5-carboxamide 200 ml of chloroform and 37.5 g of adamantanamine were charged to a round bottom flask equipped with a stirrer and thermometer, then 50 μl, 4- Benzodioxane-5-carbonyl chloride was added in small portions at a temperature of from 5 to 10 ° C. After stirring at room temperature, 1500 ml of water were added, after which the chloroform was evaporated in vacuo. The base precipitated with ammonia was extracted with methylene chloride, and after evaporation of the solvent, the residue was dissolved in ethanolic hydrochloric acid.

The crystals formed on cooling were separated, washed and dried to give 20 g of N- (1-adamantyl) -1,4-benzodioxane-5-kerbexamine in 25% yield, m.p. 137 ° C.

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 of methyl ethyl ketone were charged to a round bottom flask equipped with a stirrer and thermometer, after which 17.2 g of a butyl clay clay were added at a temperature of from 15 to 20 ° C.

After stirring the mixture, 25 g of 1-benzyl-2-aminomethylpyrrolidine were added, keeping the temperature at 15-20 ° C. The mixture was stirred at room temperature, after which the solvents were evaporated and the residue was dissolved in 200 ml of methylene chloride and 300 ml of water.

After mixing, the solvent was decanted off and dried over magnesium sulfate, after which the solution was filtered and the solvent was evaporated. The resulting compound was dissolved in boiling ethanol, and 18 g of 85% phosphoric acid was added. The crystals formed on cooling were separated, washed with ice-cold ethanol and then dried to give 56 g of N- (1-benzyl-2-pyrrolidylmethyl) -7-diethylsulfamoyl-1,4- benzodioxane-5-carboxamide phosphate in 79.6% yield and with melting point 180 ° C.

Example 42 N- (1-benzyl-4-piperidyl) -1,4-benzodioxane-5-carboxamide hydrochloride 200 ml of chloroform and 50 g of 1-benzyl-4-aminopiperidine were charged to a round bottom flask equipped with a stirrer and thermometer, then 50 g 1,4-Benzodioxane-5-carbonyl chloride was added in portions at a temperature of 5-110 ° C. After stirring the mixture at room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in 300 ml of water. After precipitating the base by adding ammonia, the water was removed, and the remaining product was treated with a hydrochloric acid solution. 75 g of N- (1; benzyl-4-piperidyl) -1,4-benzodioxane-5-carboxamide hydrochloride were obtained in 77% yield and with a melting point of 20500.

Example gel 43 N- (1-ethyl-2-pyrrolidylmethyl) -8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-coreboxamide hydrochloride 8-mercapto-2H-3,4-dihydro-1,5 -benzodioxepine-6-carboxylic acid A solution of 105 g of 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 273 ml of acetic acid and 159.5 g of tin was charged to a round bottom flask, provided with stirrer and thermometer. The mixture was stirred while heating at 40-45 ° C, after which 705 ml of concentrated hydrochloric acid were added. After heating at 55-60 ° C, the solution was cooled, and the precipitate was separated, washed and dried. 65 g were obtained of 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 80% yield and with a melting point of 99.5-100 ° C. 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 86 g 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid, 152 ml water, 76 ml of soda and 58.5 g of ethyl sulphate were charged to a round-bottomed flask equipped with a condenser. The mixture was heated under reflux and then cooled, after which 150 ml of water were added and the solution was filtered and treated with 50 ml of hydrochloric acid. The resulting precipitate was separated, washed and dried to give 88 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 91% yield and melting point 66-67 ° C. In 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 88 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 528 ml of acetic acid were charged in a round-bottomed flask equipped with a condenser, after which 210 ml of hydrogen peroxide were added in portions. The solution was heated, and the acetic acid was evaporated in vacuo, after which the residue was dissolved in 180 ml of water and cooled. The precipitate formed was separated, washed and dried to give 90 g of 8-ethylsulfonyl-2H-3,4- dihydro-1,5-benzodioxepine-6-carbonic acid in 91% yield and with a melting point of 142-143 ° C. ¶ 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride 75 g thionyl chloride and 90 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid were charged to a round-bottomed flask equipped with a cooler, the mixture was heated at 45-50 ° C and the excess thionyl chloride was evaporated in vacuo The residue was treated with petroleum ether and then filtered, washed and dried, 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride in 98% yield and with a melting point of 80 DEG-110 DEG. c.

N- (1-ethyl-2-pyrrolidylmethyl) -8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxamide hydrochloride 39.5 g of 1-ethyl-2-aminomethylpyrrolidine 1,282 ml of chloroform charge In a round bottom flask equipped with a stirrer and thermometer, 94 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carbonyl chloride were added in 1 portion, keeping the temperature at 5-110 ° C. .

The mixture was heated and then poured into water, and the aqueous phase was cooled, filtered and treated with 30 ml of soda. The precipitate was extracted with methylene chloride, and the organic phase was dried over potassium carbonate, after which the solvent was evaporated and the residue was dissolved in isopropanol and treated with a solution of hydrogen chloride 1 in isopropanol. The precipitate formed was separated, washed with alcohol and dried to give 98 g of N- (1-ethyl-2-pyrrolidylmethyl) -1-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepline-6-carboxamide hydro chloride 1 73% yield and m.p. 141-142 ° C.

Example 44 44 - [(4-methyl-1-piperazinyl) carbonyl] -6,7-dibromo-8-nitro-1,4-benzodioxane 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid 1440 ml acetic acid and 360 g of 1,4-benzodioxane-5-carboxylic acid were charged to a round flask equipped with a stirrer, inlet funnel and condenser.

The mixture was heated to 55 ° C, after which a solution of 700 g of bromine in 360 ml of acetic acid was added in portions. The whole was heated to 12,000 and then cooled to 155 ° C, after which the precipitate formed was separated, washed with acetic acid and dried. 332 g were obtained of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid, m.p. 212 ° C. The structure was confirmed by NMB analysis. 7,788-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid 166 g of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid and 500 ml of acetic acid were charged to a round bottom flask. and the mixture was heated to 37 ° C, after which a solution of 60 ml of nitric acid (d = 1.49) in 60 ml of acetic acid and sulfuric acid as catalyst was added; After heating at 50 ° C, the mixture was poured into cold water with stirring, and the precipitate formed was separated, washed with water and dried. 107 g were obtained of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, m.p. 23,700. The acid was purified by treatment with a solution of 50 g of sodium bicarbonate in 500 ml of water and precipitating with hydrochloric acid. The precipitate was separated, washed and dried to give crystals in 61% yield and melting point 238 ° C.

The structure was confirmed by NMR analysis. 6,7-Dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride 96 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid and 200 ml of thionyl chloride were charged to a round bottom flask equipped with with stirrer and thermometer. The mixture was heated under reflux, after which the excess thionyl chloride was evaporated off under vacuum. The residue was dissolved in 100 ml of isopropyl ether, after which the solvent was removed and the product was air-dried. 91 g were obtained of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride in 91% yield and with a melting point of 25 ° C. - [(4-methyl-1-piperazinyl) carbonyl] -6,7-dibromo-8-nitro-1,4-benzodioxane 400 ml of methyl ethyl ketone and 11 g of methyl piperazine were charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 10 ° C, after which 41 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were added in portions, keeping the temperature below 20 ° C. After stirring the mixture, the crystals formed were separated, washed with methyl ethyl ketone and dried, after which they were dissolved in water and reprecipitated by adding 50 ml of 20% ammonia. The crystals were separated, washed with water and dried to give 33 g of 5 - [(4-methyl-1-piperazinyl) carbonyl] -6,7-dibromo-8-nitro-1, H-benzodioxane in 69.6% yield and with melting point l64 ° C. The structure was confirmed by IR and NMRe analysis.

Example Ä5 N- (1-ethyl-2-pyrrolidylmethyl) -6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide In a similar manner, but using 1-ethyl-2-aminomethylpyrrolidine instead of methylpiperazine, N- (1-ethyl-2-pyrrolidylmethyl) -6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxamide was prepared in 65% yield and melting point 21300. The structure was confirmed by NMR analysis.

Example gel 46 N- (1-ethyl-2-pyrrolidylmethyl) -8-amino-1,4-benzodioxane-5-carboxamide 8-amino-1,4-benzodioxane-5-carboxylic acid 400 ml water, 98.5 g 6, 7-Dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml of soda and 10 g of palladium-on-carbon were charged into an autoclave, after which hydrogen gas with a high pressure of 3.9 MPa was started and the whole was heated at 5000. The mixture was filtered and then treated with 95 ml of hydrochloric acid, and the precipitate formed was separated, washed and dried. 42 g were obtained of 8-amino-1,4-benzodioxane-carboxylic acid in 83.7% yield and with a melting point of 186 ° C.

N- (1-ethyl-C] pyrrolidylmethyl) -8-amino-1,4-benzodioxane-β-carboxamide In the same manner as in Example 2, 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were heated with methanol. and the compound formed was treated with 33 g of 1-ethyl-2-aminomethylpyrrolidine and then with a solution of 13 g of hydrogen chloride in absolute alcohol. 49 g of N- (1-ethyl-2-pyrrolidylmethyl) -8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride were obtained in 60% yield and with a melting point of 73 ° C.

Example gel 47 - [(4-methyl-1-piperazinyl) carbonyl] -8-chloro-1,4-benzodioxane-8-chloro-1,4-benzodioxane-5-carbonic acid 29.3 g 8-amino-1,4 -benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were charged to a round-bottomed flask equipped with a stirrer and thermometer. The mixture was heated to 4000 and then cooled to 5 ° C, and a solution of 10.5 g of natriwmitric 1 eo ml of water was added portionwise while maintaining the temperature at 5-10 ° C.

The mixture was stirred and then poured into a solution of 12 g of copper (I) chloride in 45 ml of hydrochloric acid (d = 1.18), keeping the temperature below 30 ° C. The precipitate formed was separated, washed with hydrochloric acid and water, and then dissolved in 300 ml of water and 25 g of sodium bicarbonate. The solution was filtered and treated with hydrochloric acid, and the precipitate formed was washed, washed with water and dried to give 20 g of 8-chloro-1,4-benzodioxane-carboxylic acid in 62% yield and with a melting point of 195 ° C. 7 - 08849-β 34 - [(4-methyl-piperazinyl) carbonyl] -8-chloro-1,4-benzodioxane In the same manner as in Example 33, 20 g of 8-chloro-1,4-benzodioxane was heated. -5-Carboxylic acid with thionyl chloride, after which the obtained B-xloro-1,4-benzodioxane-5-carbonyl chloride (melting point 83 ° C) was treated with 10.5 g of methylpiperazine. 14 g were obtained of 5 - [(4-methyl-1-piperazinyl) carbonyl] -8-chloro-1,4-benzodioxane in 50.5% yield and with a melting point of 260 ° C 'with decomposition.

Example 48 N- (1-Ethyl-2-pyrrolidylmethyl) -eracetamino-1,4-benzodioxane-5-carboxamide 8-acetamino-1,4-benzodioxane-5-carboxylic acid 43 g 5-Carboxylic acid and 72 ml of acetic acid were charged to a round bottom flask, after which 24.5 ml of acetane anhydride were added in portions. The mixture was heated at 60-70 ° C and then cooled, and the precipitate was separated, washed with acetic acid and water and dried. 44 g were obtained of 8-acetamino-1,4-benzodioxane-5-carboxylic acid in 84% yield and with a melting point of 233%.

N- (1-ethyl-2-pyrrolidylmethyl) -8-acetamino-1,4-benzodioxane-5-carboxamide In the same manner as in Example 31, 8-acetamino-1,4-benzodioxane-5-carboxylic acid was treated with isobutyl chloroformate and 1-ethyl-2-aminomethylpyrrolidine to give N- (1-ethyl-2-pyrrolidylmethyl) -8-acetamino-1,4-benzodioxane-5-carboxamide. The structure was confirmed by NMB analysis.

Example 42 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 acetane anhydride were charged to a round bottom flask, after which a solution of 17.5 ml of nitric acid (d = 1.49) in 17 ml of acetic acid was added, leaving the temperature to rise. After dissolution and crystallization, 50 ml of acetic acid were added, and the mixture was stirred at 40-4500, and then cooled to 20 ° C. The precipitate formed was separated, washed with acetic acid and water and dried to give 13.5 g of a mixture 50/50 of β-nitro-β-acetamino-1-benzenodiocan-5-carboxylic acid and 6-nitro-8-acetaminophen. 1,4-benzodioxane-5-carboxylic acid. 7-Nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid was separated and then treated in the same manner as in Example 3l with isobutyl chloroformate and diethylaminoethylamine to give N- (diethylaminoethyl) -7- nitro-8-acetamino-1,44benzodioxane-5-carboxamide. The structure was confirmed by NMR analysis. Example 7 N- (1-allyl-2-byrrolidylmethyl) -7,8-azimido: 1,4-benzodioxane-5-carboxamide 7,8-azimido-1,4-benzodioxane-5-carboxylic acid 13 g «of a 50/50 mixture of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and 6-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid, 90 ml of water, 4.5 ml of sodium hydroxide, some Raney nickel and hydrogen at a pressure of 4.9 MPa were charged to an autoclave. After complete uptake of hydrogen, nickel was filtered off, and the solution was treated with 12 ml of hydrochloric acid and then with a solution of 3.5 g of sodium nitrite in 10 ml of water at a temperature of 20-25 ° C. The precipitate formed was separated, washed and then treated with an aqueous solution of sodium hydroxide. The mixture was acidified, after which the formed compound was separated, washed and dried. 3 g were obtained of 7,8-azimido-1,4-benzodioxane-5-carboxylic acid in 59% yield and with a melting point of 26,000 with decomposition.

N- (1-allyl-C] pyrrolidylmethyl) -7,8-azimido-1,4-benzodioxane-5-carboxamide 7,8-azimido-1,4-benzodioxane-5-carboxylic acid were treated with N-hydroxyphthalimide together with dicyclohexylcarbodiimide, and the obtained phthalimide carboxylate was treated with 1-allyl-2-aminomethylpyrrolidine to give N- (1-allyl-2-pyrrolidylmethyl) -7,8-azimido-1,4-benzodioxane-5-carboxamide, the structure of which was confirmed by NMR.

Example gel N- (2-pyrimidyl) -6-chloro-1,4-benzodioxane-5-carboxamide 6-nitro-1,4-benzodioxane-5-carboxylic acid 1600 ml acetic acid, 1600 ml acetane anhydride and 1000 μl, 4-benzodioxane -5-Carboxylic acid was charged to a 6 liter round bottom flask equipped with a stirrer and thermometer. The mixture was heated to 40 ° C, and a solution of 400 ml of nitric acid in 400 ml of acetic acid was added. After the addition, the mixture was stirred at 40-45 ° C for 2 hours, after which it was cooled to 5 ° C. The precipitate formed was separated, washed with 600 ml of acetic acid and then with water, and dried at 40 ° C. 700 g were obtained of 7-nitro-1,4-benzodioxane-5-carboxylic acid (melting point 246 ° C), the structure of which was confirmed by NMR. The mother liquors were diluted with 25 liters of water, and the resulting precipitate was separated, washed with water and dried to give 6-nitro-1,4-benzodioxane-5-carboxylic acid with a melting point of 188 ° C. 6-Amino-1,4-benzodioxane-5-carboxylic acid hydrochloride 195 g of 6-nitro-1,4-benzodioxane-5-carboxylic acid, 1950 ml of ethanol and some Raney nickel were charged to an autoclave, and the mixture was hydrogenated at a hydrogen pressure of 3.4 MPa and 6000 for 1 hour, after which it was cooled. Nickel was filtered off, and the solution was acidified with 150 ml of ethanolic hydrochloric acid (23 g / 100 ml). The precipitate formed was filtered off and dried, yielding 115 g of 6-amino-1,4-benzodioxane-5-carbonic acid hydrochloride in 57.5% yield, m.p. 6-Chloro-1,4-benzodioxane-5-carboxylic acid 58 g of 6-amino-1,4-benzodioxane-5-carboxylic acid hydrochloride and 116 ml of water were charged to a 500 ml round bottom flask equipped with a stirrer, thermometer and dropping funnel. 28 ml of hydrochloric acid (d = 1.18) were added and the mixture was cooled to a temperature of 0-5 ° C. A solution of 17.5 g of sodium nitrite in 38 ml of water was added at a temperature in the range 0-5 ° C, and the mixture was stirred for 1 hour. 20 g of copper (I) chloride and 75 ml of hydrochloric acid were then added, and the mixture was allowed to stand overnight, after which it was filtered. The solid product was washed with water, dried at 50 ° C and purified by treatment with carbon black in alkaline solution (200 ml of water and 25 ml of 30% sodium hydroxide solution), after which 25 ml of hydrochloric acid were added. 40 g were obtained of 6-chloro-1,4-benzodioxane-5-carboxylic acid in 74% yield and with a melting point of 162 ° C. 6-Chloro-1,4-benzodioxane-5-carbonyl chloride 56 ml of thionyl chloride and 28 g of 6-chloro-1,4-benzodioxane-5-carboxylic acid were charged to a 250 ml round bottom flask equipped with a stirrer, condenser and thermometer. The mixture was heated at reflux for minutes, after which the excess thionyl chloride was removed by distillation under reduced pressure. 28.5 g were obtained of 6-chloro-1,4-benzodioxane-5-carbonyl chloride in 93% yield and with a melting point of 50 ° C.

N- (2-pyrimidyl) -6-chloro-1,4-benzodioxane-5-carboxamide 280 ml of methyl ethyl ketone and 13 g of 2-aminopyrimidine were charged to a 500 ml round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 100 ° C, added with 28 g of ground 6-chloro-1,4-benzodioxane-carbonyl chloride, and stirred for 2 hours, allowing the temperature to rise to 20 ° C. The resulting solid product was filtered off, washed with 30 ml of methyl ethyl ketone, and dissolved in 250 ml of boiling water, after which the solution was treated with 10 ml of 30% sodium hydroxide solution.

After filtration, 12 g of product were obtained, which was recrystallized from 150 ml of ethanol to give 9.5 g of N- (2-pyrimidyl) -6-chloro-1,4-benzodioxane-5-camboxamide with the melt. 223 ° C during decomposition. The structure was confirmed by NMR analysis. 40 7703849-0. Example 52 - [(4-Methyl-1-piperazinyl) carbonyl] -6-nitro-1,4-benzodioxane hydrochloride 360 ml of methyl ethyl ketone and 16 g of N-methylpiperazine were charged to a 500 ml round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 1000 and 36.5 g of 6-nitro-1,4-benzodioxane-5-carbonyl chloride were added portionwise. The whole was stirred at room temperature for 1 hour, after which the precipitate formed was separated, washed with 150 ml of methyl ethyl ketone, dried and then dissolved in 210 ml of cold water. The solution was acidified to pH 1 by the addition of hydrochloric acid, treated with carbon and filtered. The base was precipitated by adding 15 ml of sodium hydroxide solution, and the precipitate was washed with water and dried to give 24 g, m.p. 221 ° C.

The base was then treated with 168 ml of ethanol, containing 8 ml of water and 8 ml of hydrochloric acid (d = 1.18). After crystallization, the solid product was filtered off, washed and dried to give 19.5 g of 5 - [(4-methyl-1-piperazinyl) carbonyl] -6-nitro-1,4-benzodioxane hydrochloride, m.p. during decomposition. The structure was confirmed by NMB analysis.

Example 53 N-Diethyl-7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxamide 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 250 ml of water and 300 ml of cyclohexylamine were charged to a 1 liter round bottom flask, and 139 g Moist 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was added in small portions, keeping the temperature at 20-30 ° C.

The mixture was stirred at room temperature for 3 hours, after which the solution was treated with 30 g of carbon black 3 S. After filtration, 300 ml of hydrochloric acid (d = 1.18) were added, and the precipitate formed was recrystallized, washed with water and dried. 92 g were obtained of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, m.p. 15 ° C.

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 were charged to a 250 ml round flask, equipped with a stirrer and thermometer, after which 100 ml of acetone were added and the whole was cooled to 10 ° C. 14 g of isobutyl chloroformate were added, and the mixture was kept under stirring for 30 minutes at room temperature, after which 8 g of diethylamine were added at a temperature of 15-2000.

After stirring for 3 hours, the solvent was removed in vacuo, and the residue was washed with water, dried, dissolved in 180 ml of absolute ethanol and treated with 3 g of carbon black. After filtration and crystallization, 23 g of N-diethyl-7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxamide, m.p. 20100, were obtained. The structure was confirmed by IR and NMR analyzes. Example 54 - N- (4-methyl-1-piperazinyl) -7-nitro-1,1-benzodioxane-5-carboxamide hydrochloride 7-nitro-1,4-benzodioxane-5-carbonyl chloride 112 ml thionyl chloride and 55 g 7- Nitro-1,4-benzodioxane-5-carboxylic acid was charged to a 250 ml round bottom flask equipped with a stirrer, thermometer and reflux condenser. The mixture was stirred, and 1 ml of dimethylformamide was added with heating. After stirring for 1 hour at boiling temperature, excess thionyl chloride was removed by distillation under vacuum. 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were obtained in close to 100% yield and with a melting point of 108 ° C.

N- (4-methyl-1; piperazinyl) -7-nitro-1,4-benzodioxane-5-carboxamide 33 g of 1-amino-4-methylpiperazine were dissolved in 630 ml of methyl ethyl ketone, after which the solution was cooled to 10 ° C and 61 g g 7-nitro-1,4-benzodioxane-carbonyl chloride was added in 1 portions. The mixture was stirred for 2 hours, after which the solid product was filtered off and washed with 150 ml of methyl ethyl ketone. The resulting product was purified by transfer to the base (mp 212 ° C) and crystallization by treatment with ethanolic hydrochloric acid. 45 g were obtained of N- (4-methyl-1-piperazinyl) -7-nitro-1,4-benzodioxane-5-carboxamide hydrochloride, m.p. 20 ° C with one mole of water. The structure was confirmed by NMB and IR analyzes. Example 55 N- (1-allyl-2-pyrrolidylmethyl) -6,7-azimido-1,1-benzodioxane-5-carboxamide hydrochloride 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid 165 ml nitric acid (d = 1.49) was charged to a 500 ml round bottom flask equipped with a mechanical stirrer and thermometer, after which 90 g of 1,4-benzodioxane-5-carboxylic acid were added at -1000. The mixture was kept for 2 hours at room temperature, after which 1 liter of ice water was added. The precipitate was filtered off; was washed with water and dried at 150 ° C, after which it was purified by recrystallization from acetic acid. 87 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid with a melting point of 211% were obtained. 4,4-Benzodioxane-6,7-diamino-5-carboxylic acid 77088149-0 39 135 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid, 500 ml of water and 50 ml of sodium hydroxide solution were charged to a 1-liter autoclave and hydrogenated at a hydrogen pressure of 7.85 MPa in the presence of Raney nickel.

The mixture was heated at 100 ° C for 2 hours, then cooled and filtered. Filtered off nickel was washed on the filters with 200 ml of water, and all the filtrates were combined. A sample was acidified with hydrochloric acid to give 1,4-benzodioxane-6,7-diamino-5-carboxylic acid dihydrochloride, which was filtered, washed and dried (m.p. 15300). 1,4-Benzodioxane-6,7-azimido-5-carboxylic acid The filtrate obtained in the previous step was charged to a 2 liter round bottom flask equipped with a mechanical stirrer and thermometer, and a solution of 35 g of sodium nitrite in 70 ml of water was added dropwise. at a temperature from 20 to 2500. The crystallized product was filtered off, washed with water and dried at 50 ° C to give 96 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid in 87% yield .

The structure was confirmed by NMR analysis. 1,4-Benzodioxane-6,7-azimido-5-N-phthalimide carboxylate 74 g / l, 4-Benzodioxane-6,7-azimido-5-carboxylic acid, 1 liter of dimethylformamide, 57 g of N-hydroxyphthalimide and 74.5 g dicyclohexylcarbodiimide was heated at 9000 for 30 minutes. After cooling to 20 ° C, the crystals were filtered off and washed with 150 ml of dimethylformamide.

The combined filtrates were evaporated in vacuo and the residue was treated with 400 ml of methanol. The solid product was filtered, washed and dried to give 80 g of 1,4-benzodioxane-6,7-azimido-N-phthalimide carboxylate in 65.5% yield and with a melting point above 25,000.

N- (1-allyl-2-pyrrolidylmethyl) -6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride 92 g, 4-benzodioxane-6,7-azimido-5-N-phthalimide carboxylate and 500 ml of dimethylformamide were charged in a 1-liter round-bottomed flask, equipped with a mechanical stirrer and thermometer. 45 g of 1-allyl-2-aminomethylpyrrolidine were added with stirring, which was maintained at room temperature for 2 hours. After evaporation of the solvent, the residue was treated with 500 ml of hot acetone, and after filtration, 50 ml of ethanolic hydrochloric acid was added to the filtrate. The product was filtered off, washed and recrystallized to give 50 g of N- (1-allyl-z-pyrrolidylmethyl) -6,7-azimido-1,4-benzodioxane-5-carboxamide hydrochloride, m.p. 25,500. The structure was confirmed by IR and NMR- In analyzes. Exemgel 56 - [(4-methyl-1-piperazinyl) carbonyl] -6,7-dinitro-1,4-benzodioxane 1,4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate 54 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid and 400 ml of dimethylformamide were charged to a 1 liter round bottom flask equipped with a mechanical stirrer and thermometer, and with stirring 34.2 g of N-hydroxyphthalimide and 44 , 4 g of dicyclohexylcarbodiimide. The mixture was heated at 90 ° C for 30 minutes, after which it was cooled to 10 ° C.

After filtration, the filtrate was evaporated in vacuo and the residue was recrystallized from methanol to give 67.5 g of 1,4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate in 81 l, 3% yield and melting point 225%.

- [1 H-Mecyl-1-pigerazinyl] carbonyl] -6,4-f-nitro-1,4-benzodioxane 67 μl, 4-benzodioxane-6,7-dinitro-5-N-phthalimide carboxylate was dissolved in 400 ml of dimethylformamide and 20 g N-methylpiperazine was added, after which the mixture was stirred for 2 hours After evaporation of the solvent in vacuo, 1 liter of water was added to the residue, the solid product was filtered and recrystallized from dimethylformamide to give 40 g of 5 - [(4- methyl-1-piperazinyl) carbonyl] -6,7-dinitro-1,4-benzodioxane, m.p. 254 DEG C. The structure was confirmed by NMR analysis.

Example 57 57 N- (1-piperidinopropyl) -6,7-diacetamino-1,4-benzodioxane-5-carboxamide In the same manner as in Example 53, 6,7-diacetamino-1,4-benzodioxane-5 carboxylic acid (prepared by acetylation of 6,7-diamino-1,4-benzodioxane-5-carboxylic acid) with 1-piperidinopropylamine in the presence of isobutyl chloroformate to give N- (1-piperidinopropyl) -6,7-diacetamino-1 , 4-Benzodioxane-5-carboxamide, m.p. 25,000 DEG C. during decomposition. The structure was confirmed by NM analysis.

Example Gel 58 - [(4-methyl-1-piperazinyl) carbonyl] -7-amino-1,4-benzodioxane I In the same manner as in Example 2, 7-amino-1,4-benzodioxane-5-carboxylic acid was treated with methanol , after which the obtained carboxylic acid ester was reacted with N-methylpiperazine. 5 - [(4-methyl-1-piperazinyl) carbonyl] -7-amino-1,4-benzodioxane was obtained, m.p. 170 ° C. Example 9 N- (1-ethyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamide hydrochloride In the same manner as in Example 17, by reaction between 1,11-benzodioxane-S- carbonyl chloride and 1-ethyl-α-aminomethylpyrrolidine N- (1-ethyl-2-pyrrolidylmethyl) -1,4-benzodioxane-5-carboxamianyl hydrochloride, m.p. 149 DEG-150 DEG.

The compound monkeys prepared according to the foregoing synthesis examples are summarized in Table I. 7708849-0 '42 n 1 z - [zoo f _! mä »mz xwïmë- nššmom m m» wmonmnwwmo _ _ | mä- mz -N fi mmovl mmzmow m N. w _ _ © mmu- _ _ | mä- az -ßwäï m m w ~ m 2 / m .. n m _ mo nu _ mz -m ^ mmovu_ N75? om m m 1 F \ / _ w m w m u- .. z .. - A moT É om m à ß 2 \\ f,. fi _ mmu _ z_ mmm. mz -ßmmuï mzwomow m n _ z m = mmwu _ _ ä mz -wßwmoï Nwzwow m w _ z N - - mmwmmuhmo _ mo mz l fl wmvv .. mmuwäuow m, H m = få m. . w \ L .å <..... x Ä .z 7708849-0 43 m N N H mmmo _ \ Qx mao, mz | m ^ mmov | m o om w m m .. S mmmo mmmoå -mm fl ïmmul mz - ^ m8 m \ _ m _ ... m. wa z / .l mä. ä -ß me- nä? å 3 _ \ Z N | , UmNU i J | m0 m2 ... MANSUY- ä m. "» u _ Z 1 x | m .NN _ mmmumnïmmo å _ »mmm .m2 -mAmmQY wo om i _ nä _ z _ mä - š -m ^ mmuV- mmzmow ß 23 mm _ m NN f 4 m ..mm .. mo om E. T mmmo à 2% .ä - E ^ m8 Sv 3 _ m = mo _ ju mmm-: z Lñmmov- mmm: .fi zz mm am .z, 4 .zz «. 44 7708819-0 _ mm 2 w. Mo 7 Q»: uf m2 hä- m mm mm _ N. Mozm I nw 1: uo az 1 A mål mšë fi wow ww,. L - Mmo. 2 NmU I m2 N m.. * _ - A .äv-. N Sv ä .mëä ow Sv mm _ _ mo ä ä _ _ .ä .. E -ßmm8 | näšåwow m .w 7.7 ._ mo | »wwg 8 _ _ mo mz A m8- nämzmøw A5 mm 1 n E z _ OA m2 | w ^ mmov | ._, nmomv fi mow om _ ¶ fö z / lmmo ..

N w í Q mz 1 Å m8 .. fl nmovzmom 2 m: få mv wa .ä <w å .z w- 7708849-0 45 @ z, V "| -fl wmuï mm R _ mwmu TL. Mmm 1 mz -m fi wmov- wczwow fi šo wm mw mmwo _ J. ä - š sßmms- _. m _ mao R m .nmunhwmoïz -ßwmoï wš fl mom m å.

A z 1 .wuhmnw mz -fl mmoï B m nn xf / - nmo .. z z | -ßmmoï wmzaom m mn. w nä 7, \ z -w fi mmuï oz m R m z | . _ \ J: -ßmmoï mmwomøm m om W ... må n \ IW Q .WX NW 02 '46 77088-16-0 mmm ". G \ .ä 1 _ _ mz fßmmuv .. å .Nm moz 9 .. n. \ | I ../ .hßwmvvf .Nm .Hm moz 3 få: z / Iaxz; mama. Émmu .. mz n fl mmoï ¶ m _ .mmwomom m Q _ @. ~ ä | 0 š fß fl ë- _ mwm ä. ,,. @, wä BW; m5 - mz RAwmOV- mí mïmwovzmow m 3 m Awz -ßwšï mmm 3 OÛ-mmo ..z \ / | I. | V. mz: ßmmoï m nmomzmom m mn m ®mš I z. ußmmov .. m ßmmmovzwom m mn m? .nwäz mf Ez <N wx ä. .z 77088119-0 47 à mmwo mmwoå -ßmmoï m ozzwøm. m R man .. z \ ||, w -w ^ mmov .. moz mm Nm / || \ \ zwwm., zl - A m8- 3 mm G ¶ z u. m É »fl m5 - N m. wælv * _ i \ ~ mmmu mmwuå .mm9mmo- m2« m ^ mmov- m moz nmooumä 3 ß / Iw mmmo _ m0 1 E. -ßwmoï mm nmoooš 3 \ |||| / ßö | zz | w ^ mm8- mm S 5 _. mmwu * z / wl mo .. E. - ~ ^ N_§- mz NE. 3 m H. .zs f ..: _ k ... ä «N wx å a. .few w 7708849-0 z, m -. mzmv z ._ .. zu zz Äwmß- mm mm ßö 1 z \ / z .. _ .mzmzoï m wzz mm _ _ \ _ n _ _ m A z = -Äwzoï mz vmzmmuv .. | z8omz _ _ .moooäz »m m8 fz / .lxz 1 fßwzov- moz moz wm _ wzo fl zuhzo zf »mä .. zz lmzmmov- Ä mm P_ _ z \ n al) _ _: o I z z! : z -Nñwzov- z møz ä. w: ... zz mzx .zz <N w ä az 7708 849 - 0 49 Compounds of the invention are used in various forms, such as capsules, tablets, pills, granules or injectable solvents. whose production is known per se. Substances which do not react with the compounds can be used, such as lactose, magnesium stearate, starch, talc, cellulose varieties, levilite, alkali metal lanryl sulfates, sucrose and other carriers used for medicinal preparations. Compounds of the invention may be administered in doses of 50 to 900 mg per day. It is convenient to use 50 to 300 mg per day and preferably then about 100 to 150 mg per day.

The following examples show pharmacological compositions prepared by methods known per se, containing the compounds of the invention.

Example 60 Tablets of the following composition are prepared: Form 1 Form 2 Form 3 N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide ...... 50 mg 50 mg 50 mg Dry starch .............................. 30 mg 30 mg 20 mg Lactose ........ ............................. 80 mg 80 mg 120 mg Methylcellulose 1500 eps .....; ...... ......... 1.3 mg 1.2 mg 1.2 mg Magnesium stearate .....; ...................... 3 mg 2.5 mg 3 mg Levilit ......................., .., .......... 8 mg 6, 3 mg 5.8 mg Example 61 Tablets of the following composition are prepared: N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide ........... ......... 50 mg Dry starch .................................. 20 mg Lactose ......................................... 80 mg Methylcellulosa 1500 eps .... ..................... 1.3 mg Levilit ........................ ................. 6 mg Magnesium Stearate .............................. .. 3 mg Example 62 Tablets with the following composition prepared: 77088164) 50 N- (1-allyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-2929-L1,4-benzodioxane-5-carboxamide ................... 50 mg Dry starch ................................ 15 mg Lactose ............ ............................ 50 mg Methylcellulose 1500 eps ................. ...... l mg Levilit ....................................... 5 mg Magnesium stearate .............................. 2 mg Example 63 Tablets with the following composition are prepared: N- (1-methyl-2- pyrrolidylmethyl) -7-sulfamoyl-1,4-benzodioxane-5-carboxamide .................... 50 mg Dry starch .......... ........................ l0 mg Lactose .................:. 2: .. ................... 50 mg Methylcellulose ............................ ..... 0.94 mg Levilit ........................................ 6 mg 0Magnesium stearate ............, ................... 2 mg Exemgel 64 Tablets with the following composition are prepared: N- (l -methyl-2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide ................... 50 mg Dry starch .................................. 10 mg Lactose ......... ................................ 50 mg Methylcellulose 1500 eps ............. ........ 0.55 mg Levilit ...........; ......................... 4 mg Magnesium stearate .............................. 2 mg Exemgel 65 Capsules with the following composition are prepared: N- (1-ethyl -2-pyrrolidylmethyl) -7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide Dry starch .................... 50 mg ....... ........................... 15 mg lactose .................... ....., ................ 50 mg Methylcellulosa 1500 eps ....................... .. 1 mg Levilit ......................................... 5 mg Magnesium stearate. .............................. 2.5 mg Tablets are prepared by mixing the selected compound form 2 50 ms mg 62 mg 1 mg mg 2 mg with starch and lactose by the successive dilution method.

Granules are prepared from the mixture and methylcellulose, and levity, magnesium stearate and talc are added to the granules before the tablets are beaten. Methylcellulose can be replaced by any other suitable granulating agent, such as ethylcellulose, polyvinylpyrrolidone, starch paste or gum arabic. The starch can also be replaced by another dispersant, such as corn starch, carboxymethyl starches, alginates or microcrystalline cellulose.

Injectable solutions may be prepared by dissolving a compound of the invention in any of the acids hydrochloric acid, levelic acid, gluconic acid or glucoheptonic acid. The same solution can be prepared without preservatives, filling ampoules under a nitrogen atmosphere and then sterilizing for half an hour at 100 ° C.

The compounds according to the invention have interesting anxiolytic, psychostimulatory, disinhibiting and also thymoanaleptic effects, which provide the properties which are suitable for therapeutic use in the psychofunctional field, and especially in gastroenterology, cardiology, urology, rheumatology and gynecology. Their low toxicity makes them useful in human therapy without any risk of side effects.

The acute toxicity of the compounds of the invention was determined in Swiss mice by parenteral (intravenous, intraperitoneal and subcutaneous) and oral administration. The 50% lethal doses are shown in Table II. The numbering of the compounds in the following tables corresponds to the numbers in the examples. 770884941 52 TABLE II - TOXICITY IV 01958. - mšékg (bag. ._ PO 1 111,5-112 522-500 1300-1000 2 00-03,0 312-320 530- 020 0% 'v¿¿3000 mg / kg 3 120-120.0 _220.0-225.0 7 30.0-100 0 00.0-30 322-320 _ 1050-1000 30% v1d2000 mg / kg 5 150-151.5 350-303 '1200 -1300 11 100-100 002-050 - _ 12 107-150 000__ 1225-1230 1000-1070 13 00-07,5 230-200 030- 032 0% v100000 mg / kg 100-157 325-330 0020-002 2300 -3031 73.7-00.2 220-227 '"512-013 150 00-90 300-330 325-1010 Ü2700-2300 17 03.1 201 515 -500-073 72.5-70 100-100.5 070-033.5 1130-1200 21 130-200 22 03.0-00 23 115.5-120 210-232 100-100 0 20 105-110 21 00-03.0 101-150 307.5-010. 1020-1050 2100-2000 33 100-115 5 030-351 300 1500-1000 '770-8849-0 53 Furthermore, the compounds of the invention are substantially free of cataleptic activity, were administered subcutaneously to rats, and the criterion of cataleptic state was immobility. in the animal for 30 seconds, keeping the animal's front feet apart and carefully applied to wooden blocks 4 cm high, so that thereby the animal came into an unusual and uncomfortable position.

The ka.ta.leptic. activity was measured at the maximum. the effect.

The results are shown in Table III.

TABLE III - CATALEPTIC ACTIVITY Förening Enso sc '- Råneå. - ng / xg l 40% effect at 200 mg / kg 2 Inactive. .. at 200 mg / kg 3 325 30 56 effect at 200 mg / kg 7 Inactive. .. at 200 mg / kg 8 10 3% effect at 200 mg / kg Inactive at 200 mg / kg ll Inactive. .. at 200 mg / kg 12 Inactive ... At 200 Ing / kg 13 i Inactive at 200 mg / kg 14 10 76 effect at 200 mg / kg Inactive at zoo mg / xg 16 Inactive. .. at 200 mg / kg 17 'S89 Inactive. . . at 200 mg / kg 21 'Inactive at zoo »ng / kg 24 30 96 effect at 200 mg / kg Inactive ... at 200 mg / kg 28 Inactive. . . at 200 mg / kg 39 f Inactive. .. at 200 mg / kg Of these. The results show that the compounds of the invention are substantially free of cataleptic activity in rats.

This property enables clinical use of the compounds. according to the invention with a high tolerance in question. about the extra pyramidal. the system. The compounds according to the invention also prove to be particularly active. in dogs with respect to central emetic. agents such as apomorphine. As an experimental procedure, it followed according to CHEN AND ENSOR. The associations. according to the invention, 10+ was administered subcutaneously 30 minutes before the apomorphine (100 pgrams per kg SC), and the animal was observed for half an hour after the injection of the alkaloid. The results are shown in Table IV.

TABLE IV 2 ANTIEMETIC ACTIVITY Compound ED5O pg / kg / SC - Dog 1 3 2 81 fi š effect at 5 pg / kg / SC 3 5.5 lO 8 1.5 lO 2 ll 11-0 12 3.5 13 9 14 3 , 9 30 16 2,3 3,5 21 ll- The interest aroused by the tests carried out on laboratory animals has been shown to a very large extent to be motivated by carrying out human clinical tests with the compounds according to the invention. Examples include the following: A 38-year-old patient suffered from Hodgkin's disease and was subjected to repeated chemotherapy in outpatient care once a week. Each occasion was accompanied by dizzy spells and thereafter very significant. vomiting, which persisted for 21+ hours despite normal. treatments. Treatment 24 hours before the start of perfusion and 4 hours after with 50 mgN- (1-ethyl-Z-pyrrolidylmethyl) -T-methylsulfamoyl-1,1α1-benzodioxane-carboxamide completely suppressed bouts of dizziness and tingling. The product was excellently tolerated, and no side effects were observed.

A 28-year-old computer operator suffered from a character neurosis with anxiety attacks, which culminated in three suicide attempts. Analytical treatment for 18 months enabled a social readjustment, but had little effect on anxiety. Administration of 50 mg of N- (1-methyl-Q-pyrrolidylmethyl) -T-methylsulfarnoyl-β-benzodioxane-S-carboxamide three times daily resulted in complete disappearance of any anxiety within a few days without no bothersome sedative effect. The product was excellently tolerated, and no side effects were observed. A 78-year-old patient had for 8 months suffered from a severe reaction depression (loss of a close relative). The presence of a prostate adenoma contraindicated the use of picyclic compounds. The patient was treated three times a day with 50 mg of N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide, and after three weeks the patient was able to leave the hospital as the condition improved significantly. The treatment, which continued at home for 3 months, made it possible to maintain an excellent mental balance with a resumption of the normal activities of a pensioner of this age. The product was excellently tolerated, and no side effects were observed.

A 42-year-old patient had undergone a hysterectomy for a fibroid 5 months earlier. A few days after the operation, bouts of heat and redness (10 to 20 per day) occurred together with bouts of sweating, which woke the patient during the night and caused problems during work. The patient was treated with N- (1-ethyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-carboxamide in a single dose of 100 mg per day. the symptoms disappeared within 4 days. Only one bout of heat and redness remained during the day, occurring every two or three days.

The product was excellently tolerated, and no side effects were observed.

A 47-year-old patient suffered after the menopause from repeated attacks of cystitis with such a frequency and severity that no social life was possible. The patient had consulted general practitioners and specialists, all tests were negative, and all treatment was without effect 1 such a classic case of cystitis. The patient was treated for a few days with N- (1-methyl-2-pyrrolidylmethyl) -7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide at a dose of 150 mg per day, the symptoms completely disappeared and the psychological state returned to normal. .

Claims (6)

7708849-0 56 Patent claims A process for the preparation of substituted 2,3-alkylene-bís (oxo) -benzamides, and their pharmacologically acceptable acid addition salts, their quaternary ammonium salts, their oxides and their right-hand and left-hand isomers, having the general formula: CONRR 'AI \\ () 0 / x wherein A represents an alkylene chain having 1 to 3 carbon atoms, mainly when methylene, ethylene or propylene, R represents hydrogen, alkyl having 1 to 4 carbon atoms, mainly when methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t -butyl, or a group of the general formula R1 NX ¶R (II) B______ 2 wherein B represents a single bond or an alkylene chain having 1-3 carbon atoms, especially when methylene, ethylene or propylene, R1 represents alkyl having 1-Ä carbon atoms , mainly when methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, or are linked by B to form a pyrrolidinyl or piperidinyl group. H2 represents, alkyl having 1-U carbon atoms, mainly methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, alkenyl having 2-U carbon atoms, mainly vinyl or allyl, alkynyl having 2-H carbon atoms, mainly when ethynyl or propargyl, or pyrimidinyl, benzyl or cycloalkyl, and R 2 and R 1 may be connected to form a piperidinyl- or U-alkyl-piperazinyl group, R 'represents hydrogen, alkyl having 1-U carbon atoms, mainly when methyl , ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, adamantyl, pyrimidinyl, or benzyl, and K 'R' may be attached with R 1 to form a piperazinyl group, or with R 1 and R 2 to form a diazabicycloalkyl ÅPUPP, 'X represents hydrogen, halogen, hydroxy, alkoxy having 1-4 carbon atoms, vvoseus-o 57 mainly methoxyethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy, alkyl having 1-U carbon atoms, mainly methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, nitro or acetamino, Y represents hydrogen, halogen, nitro, amino or acetamino, or Y represents alkylsulfonyl having 1-N carbon atoms, especially when methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl or t-butylsulfonyl, or sulphamoyl, C or is attached to X to form an azimido group, Z represents hydrogen, halogen, nitro or acetamino, or is attached to Y to form an azimido group, characterized in that a compound of the general formula: COD Ä ( in) v O / X wherein A, X, Y and Z are as previously defined, and D represents a hydroxy group, a halogen atom or an alkoxy or phthalimidoxy group, are reacted with an amine of the general formula: R / HN (Iv) \ R. wherein R and R 'are as previously defined, or with any of its reactive derivatives. 2. A process according to claim 1, characterized in that a compound of formula III, wherein D represents a halogen atom, is treated with an amine of formula IV. 3. A process according to claim 1, characterized in that a compound of formula III, wherein D represents an alkoxy group, is treated with an amine of formula IV. 4. A process according to claim 1, characterized in that a compound of formula III, wherein D represents a hydroxy group, in the presence of an alkyl haloformate, is treated with an amine of formula IV. 770881194) 58 5. A process according to claim 1, characterized in that a compound of formula III, wherein D represents a hydroxy group, in the presence of an imidazolid is treated with an amine of formula IV. 6. A process according to claim 1, characterized in that a compound of formula III, wherein D represents a hydroxy group, in the presence of a phosphorus halide is treated with an amine of formula IV.