GB1571447A - Substituted 2,3-alkyleneduoxybenzamides - 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

PATENT SPECIFICATION ( 11) 1571447

L' ( 21) Application No 32117/77 ( 22) Filed 1 Aug 1977 ( 31) Convention Application No7 623 835 ( 19) ( 32) Filed 4 Aug 1976 in ( 33) France (FR) ( 44) Complete Specification published 16 July 1980 ( 51) INT CL 3 C 07 D 405/12; A 61 K 31/40; (C 07 D 405/12, 207/08, 317/68, 319/18, 321/10) ( 52) Index at acceptance C 2 C 1230 1341 1344 136 X 145 X 1494 1532 1600 1626 1693 X 200 213 214 215 220 221 225 226 22 Y 246 247 250 251 252 253 255 25 Y 270 271 280 281 282 28 X 29 X 29 Y 305 30 Y 313 314 316 318 31 Y 321 323 32 Y 332 337 339 342 34 Y 351 352 355 35 X 364 366 367 368 36 Y 371 373 37 X 37 Y 385 386 387 396 39 Y 401 Y 421 42 Y 440 453 45 Y 464 470 471 490 491 510 511 51 X 536 537 538 552 553 579 57 X 57 Y 584 594 600 601 604 614 620 621 624 625 628 62 X 630 631 635 63 X 64 X 650 65 X 670 671 672 675 678 67 X 761 763 802 80 Y AA BC BE KF KJ KK KP KT KZ LL LS ML QG QS RE SJ TP UH UJ ( 72) Inventors MICHEL THOMINET, GERARD BULTEAU, JACQUES ACHER and CLAUDE COLLIGNON ( 54) SUBSTITUTED 2,3-ALKYLENEDIOXYBENZAMIDES ( 7 '1) We, SOCIETE D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-FRANCE, a French body corporate, of 46, boulevard de Latour-Maubourg, 75 Paris ( 7), France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following 5 statement:-

The present invention provides novel substituted 2,3-alkylene bis (oxy) benzamides having the general formula (I) below, their pharmaceuticallyacceptable acid-addition salts, their quaternary ammonium salts, their Noxides and their dextrorotatory and laevorotatory isomers 10 The invention also concerns processes for the preparation of such compounds, and medicaments whose active principle comprises the compounds of the invention.

The structure of the free base form of the compounds of the invention is diagrammatically shown by the following formula: 15 f R Co-Nm z o o O \ (I) yOA in which A represents a C 1 _ 3 alkylene chain optionally substituted by a C,_ 4 alkyl, C 2 _ 4 alkenyl, or C 1 _ 4 hydroxyalkyl group; R represents a hydrogen atom, a C 1 _ 4 alkyl group or a radical having the general formula (II) 20 1,571,447 (B)-N (II) R 2 in which n is 0 or 1, B represents a C 1 _ 3 alkylene chain, which may or may not be substituted by a C,_ 4 alkyl group or C 2 _ 4 alkenyl group and 5 R 1 represents a hydrogen atom, a C 1 _ 4 alkyl, C 2 _ 4 alkenyl or C 2 _ 4 alkenyl group or a substituted alkyl group in which the substituent may be, for example, a hydroxy, mercapto, acyl, thioacyl, alkoxy, alkylthio, or substituted or unsubstituted amino residue, or R 1 is joined to B to form a saturated or unsaturated nitrogenous heterocycle such as azetidine, pyrrolidine, piperidine, polyhydroazepine, a 10 pyrroline or polyhydropyridine; R 2 represents a hydrogen atom, a C 1,_ 4 alkyl, C 2 _ 4 alkenyl or C 2,4 alkynyl group; or a substituted alkyl group in which the substituent may be, for example, a hydroxy, mercapto, acyl, thioacyl, alkoxy, alkylthio or substituted or unsubstituted amino group; a substituted or unsubstituted saturated or unsaturated heterocycle 515 comprising one or more heteroatoms such as azetidine, pyrrolidine, piperidine, pyrimidine, pyrazine, furan, polyhydrofuran, pyran, polyhydropyran, quinuclidine, azabicycloalkane or diazabicycloalkane; or a phenyl, adamantyl, cycloalkyl, bicycloalkyl or cycloalkenyl group, connected to the nitrogen atom of formula (II) directly by a carbon atom of the ring or by means of a substituted or unsubstituted 20 alkylene chain; or R 2 and R 1 are connected together to form, together with the N atom of formula (II), a heterocycle, which may optionally contain other heteroatoms, e g.

an azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, morpholine or thiazolidine ring in which, when the heterocycle contains another nitrogen atom, 25 that is optionally substituted by a C 1 _ 4 alkyl, C 2 _ 4 alkenyl, C 2-4 alkynyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkanealkyl, cycloalkenealkyl, adamantyl or bicycloalkyl group, or an alkyl group substituted by a hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio group; R' represents a hydrogen atom, or a C,_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, 30 adamantyl, pyrimidinyl, pyrazinyl, diazepinyl, quinuclidinyl, azabicycloalkyl, diaza-bicycloalkyl, bicycloalkyl, substituted or unsubstituted phenyl or aralkyl group or R' and B are connected together to form a monoaza substituted or unsubstituted heterocycle such as azetidine, pyrrolidine, piperidine, polyhydroazepine or azabicycloalkane, or R' and R 1 are joined together to form a saturated or 35 unsaturated substituted or unsubstituted diaza heterocycle such as piperazine, diazepine, pyrimidine, pyrazine or diazabicycloalkane; X represents a hydrogen or halogen atom, or a hydroxy, nitro, amino, substituted amino, C 1 _ 4 alkoxy or C 1 _ 4 alkyl group, Y represents a hydrogen or halogen atom, a hydroxy, amino, substituted 40 amino, nitro, C 1 _ 4 alkoxy, C 1 _ 4 alkylsulphonyl, adamantylsulphonyl, or cycloalkyl sulphonyl group or a group of formula SO 2 NR 3 R 4 in which each of R 3 and R 4, which can be identical or different, is a hydrogen atom or a C 1 _ 4 alkyl, C 2 alkenyl, C 2 _ 4 alkylnyl, phenyl, benzyl, cycloalkyl, cycloalkanealkyl, cycloalkenealkyl, bicycloalkyl, adamantyl, pyrimidinyl or pyrazinyl group or an alkyl group having a 45 hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio substituent, or R 3 and R 4, together with the nitrogen atom to which they are attached, form a heterocycle which may optionally contain another heteroatom; Z represents a hydrogen or halogen atom or a hydroxy, amino, substituted amino, nitro, or a C 1,_ 4 alkoxy group; or 50 X and Y or Y and Z are connected together to form a substituted or unsubstituted carbon chain or through a heteroatom to form a ring such as substituted or unsubstituted triazole, imidazole, oxazole, thiadiazole, pyrazine, piperazine or diazepine ring or an oxide thereof; with the proviso that if A is -CH 2 CH 2 N-CH 2-, at least one of X, Y, Z 55 R and R' is other than a hydrogen atom.

In the definitions mentioned in the present specification, the principal values of C-_ 4 alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl; the values of C 1 _ 3 alkylene are methylene, ethylene, propylene and trimethylene; the principal values of C 2 _ 4 alkenyl are vinyl and allyl; the principal values of C 2 _ 4 60 alkynyl are ethynyl and propargyl; the principal values of C 1 _ 4 alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy; the preferred values of aralkyl are benzyl and phenethyl, unsubstituted or substituted by one or more halogen atoms or alkoxy, alkyl, halomethyl or amino groups; the preferred substituents in substituted phenyl radicals are one or more halogen atoms or 5 alkoxy, alkyl, halomethyl or amino groups; halogen means chlorine, bromine, iodine or fluorine; the principal substituted amino groups are those monosubstituted or disubstituted by alky, acyl, aralkyl, furanyl, pyranyl or alkoxycarbonyl; preferred acyl groups are formyl, acetyl and phthaloyl.

Preferred values of X are hydrogen, alkoxy, particularly methoxy, nitro, 10 halogen, particularly chlorine, amino and acylamino, particularly acetamido; preferred values of Y are hydrogen, halogen, particularly bromine or chlorine, amino, acylamino, particularly acetamido, alkylsulphonyl, particularly ethylsulphonyl, sulphamoyl, sulphamoyl N-mono-substituted by alkyl, particularly methyl, or by adamantyl, and sulphamoyl N,N-disubstituted by alkyl, particularly 15 methyl and/or ethyl; preferred values of Z are hydrogen, halogen, particularly bromine or chlorine, nitro, acylamino, particularly acetamido, and amino.

The preferred pairs of values of the substituents in the di-substituted compounds are:

(a) X is alkoxy, especially methoxy, and Y is sulphamoyl; 20 (b) X is acylamino, especially acetamido, and Y is nitro; (c) X and Y are joined together through a heteroatom to form a triazole ring; (d) X and Y are both amino; (e) X is halogen, especially chlorine, and Y is amino; (f) X is amino and Y is acylamino, especially acetamido; 25 (g) X and Y are both acylamino, especially acetamido; (h) Y and Z are both nitro; (i) Y and Z are both acylamino, especially acetamido; (j) Y and Z are both halogen, especially bromine; (k) Y and Z are both amino groups; 30 ( 1) Y and Z are joined together through a heteroatom to form a triazole ring.

The preferred values X, Y and Z in trisubstituted compounds are:

(a) X is nitro and Y and Z are both halogen, especially chlorine and/or bromine; (b) X is halogen, especially chlorine and bromine, and Y and Z are both nitro; 35 (c) X is nitro group and Y and Z are both acylamino, especially acetamido.

The preferred values of A are C_ 3 alkylene, such as methylene and propylene, but especially ethylene.

The preferred values of R' are hydrogen, alkyl, especially ethyl or butyl, aralkyl group, especially benzyl, either unsubstituted or substituted with a halogen 40 atom, preferably bromine or fluorine, or with a trifluoromethyl group, adamantyl, pyrimidinyl, or, when linked to R, a saturated di-nitrogen heterocycle, especially a substituted or unsubstituted piperazine ring.

The preferred values of R are hydrogen, G_ 4 alkyl, particularly ethyl, or a radical of formula 45 R, / -N R 2 or R, / -B-N R 2 in which B is a C,_ 3 alkylene group, particularly ethylene or propylene, and R, is C,4 alkyl, especially ethyl, or R, and B are linked to form, together with the N 50 atom, a saturated nitrogen heterocycle, especially a pyrrolidine or piperidine ring; or R, and R 2 are linked to form, together with the N atom, a heterocyclic ring, especially a pyrrolidine or piperidine ring or a ring containing another nitrogen 1,571,447 atom, especially a piperazine substituted with an N-alkyl (preferably methyl or ethyl) group, or R, and R' are linked to form, together with the two intervening nitrogen atoms, a saturated di-nitrogen heterocyclic ring, particularly a substituted piperazine ring; or R, is linked to R 2 and to R' to form a bicyclic nitrogen heterocycle, especially a diazabicyclonane group 5 The compounds of the invention can be prepared by the reaction of a compound having the following general formula:

(III) X in which A, X, Y and Z are as defined above and D represents an organic residue capable of forming a reactive derivative, a hydroxy group or a halogen atom, with 10 an amine having the general formula:

R / HN (IV) R' in which R and R' are as defined above, or by the reaction of their reactive derivatives Those compounds of Formula III in which D is hydroxy and A is ethylene or propylene are claimed in this specification of our pending application 1 s

No 44877/78 (Series No 1571278).

In the starting compound, the organic residue comprises groups that are capable of forming reactive acid derivatives These can be C 1 _ 5 alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, or isopentyl; reactive acid esters such as methoxymethyl and cyanomethyl esters, substituted or 20 unsubstituted aromatic esters, or N-hydroxyimide esters; acid azides; acid hydrazides; symmetrical anhydrides; mixed anhydrides such as those formed from carboxylic acid esters and haloformic esters; azolides such as triazolides, tetrazolides, and especially imidazolides; substituted cotrihaloacetophenones; acid isothiocyanates; substituted a-oxo benzeneacetoritriles; ring-substituted 25 benzamides, or other equivalents, or a compound having the following general formula:

Z Yo>,,C O CC-CH-CO VM-Cez H 0-A 50 (formed from the acid and an isoxazolium salt) in which A, X, Y and Z are as defined above However, the invention is not limited to the use of the reactive 30 derivatives mentioned above.

According to the process of this invention, the amine can react in the form of one of its reactive derivatives By way of example, mention can be made of the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl, and orthophenylene chlorophosphites, alkyl or aryl 35 dichlorophosphites or isothiocyanate of the amine or the symmetrical or asymmetrical sulphamides of the amine, the corresponding symmetrical urea, or the corresponding enamines.

The above-mentioned reactive derivatives can react with the acid in situ or 1,571,447 after preliminary isolation However, the invention is not limited to the use of the reactive derivatives described above.

In addition, it is also possible to perform the reaction of the free acid and the free amine in the presence of a condensing agent, for example silicon tetrachloride, phosphoric anhydride, a carbodiimide such as dicyclohexyl carbodi S imide, or alkoxyacetylenes such as methoxyacetylene or ethoxyacetylene.

Among the synthesis processes described for the preparation of the compounds according to the invention, the use of an acid halide is particularly suitable for compounds unsubstituted on the benzene ring and compounds that are monosubstituted with a halogen atom, a nitro group, an alkylsulphonyl group, an 10 adamantyl sulphonyl group, a cycloalkylsulphonyl group, or a sulphamoyl group, either unsubstituted or monosubstituted or disubstituted with alkyl, adamantyl or cycloalkyl; the use of alkyl esters, activated acid esters or aromatic esters is particularly suitable for compounds having the benzene ring substituted with a s 15 hydroxy group, an amino group, an acylamino group, an alkylsulphonyl group, an S 15 adamantyl sulphonyl group, a cycloalkylsulphonyl group, or a sulphamoyl group, either unsubstituted or monosubstituted or disubstituted with alkyl, adamantyl or cycloalkyl; and for compounds having two of the X, Y and Z linked together so as to form a ring; the use of mixed anhydrides (formed in situ by reaction of the starting benzoic acid with haloformic esters, preferably chloroformic acid esters) is 20 particularly suitable for compounds substituted with a nitro group, an acylamino group, or a sulphamoyl group monosubstituted or disubstituted with alkyl, adamantyl or cycloalkyl; and the use of reactive derivatives of amines, preferably formed with phosphorus chlorides, particularly phosphorus trichloride, or with alkyl and aryl chlorophosphites, is particularly suitable for primary amines and 25 especially aliphatic amines.

The amidification reaction of the invention can be carried out in the presence or in the absence of a solvent The systems used as a solvent, which are inert with respect to the amidification reaction, include, for example, alcohols, polyols, benzene, toluene, dioxane, chloroform, diethylene glycol dimethyl ether, or xylene 30 It is also possible to use, as the solvent, an excess of the amine used as the starting material It may be preferable to heat the reaction mixture during the amidification operation, for example, up to the boiling temperature of the abovementioned solvents.

The compound produced by the process of the invention can react if necessary 35 with pharmaceutically acceptable organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid or methane sulphonic acid, to give acidaddition salts It can also react if desired, e g with alkyl halides or sulphates, to give quaternary ammonium salts It can also be oxidized in a manner known per se, for instance by 40 means of hydrogen peroxide and manganese dioxide, to obtain the corresponding N-oxide.

In order to illustrate the present invention, some illustrative embodiments will now be described.

EXAMPLE 1 45

N-( 1 -allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4-benzodioxane-5carboxamide.

7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid 670 g of chlorosulphonic acid was introduced into a balloon flask provided with a condenser and a thermometer 173 g of 1,4-benzodioxan-5-carboxylic acid was 50 added in portions, with the temperature being maintained at 5-10 C The mixture was heated at 55 C then cooled and poured into ice The precipitate was dried off, washed and dried 250 g of 7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid was obtained (M P = 210-215 C; yield = 93 5 %).

7-methylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 55 139 5 g of a 40 % methylene aqueous solution and 139 5 cc of water were introduced into a balloon flask provided with an agitator and a thermometer, then in portions, 250 g of 7-chlorosulphonyl-l,4-benzodioxane-5-carboxylic acid and a solution of 180 cc of 30 % soda lye in 180 cc of water were added The mixture was agitated and then poured into 2200 cc of water The solution was filtered, then 60 treated with 139 cc of concentrated hydrochloric acid The precipitate was dried off, washed and dried 190 5 g of 7-methylsulphamoyl-l,4-benzodioxane-5carboxylic acid was obtained (M P = 208-209 C; yield = 80 %).

u S 1,571,447 7-methvlsulphamoyl- 11,4-benzodioxane-S-carbonyl chloride 176 5 g of thionyl chloride was introduced into a balloon flask provided with a condenser; then, in portions, 135 g of 7-methylsulphamoyl-1,4benzodioxane-5-carboxylic acid was added under heating at 40-45 C.

The mixture was heated under reflux then treated by 250 cc of chloroform The 5 precipitate was dried off and washed with chloroform.

N-( 1-allyvl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane-5carboxamide 69 g of 1-allyl-2-aminomethyl-pyrrolidine and 432 ml of chloroform were introduced into a l-litre balloon flask provided with a thermometer and an agitator.

144 g of 7-methylsulphamoyl-l,4-benzodioxane-5-carbonyl chloride were added in 10 portions, with the temperature being maintained at from 5 to 10 C Agitation of the mixture was continued for one hour, and then the mixture was treated with 1750 ml of water After distillation of the chloroform, the mixture was acidified to a p H of 4, by 4 ml of 20 % sulphuric acid, and then filtered on carbon black; the solution of the sulphate formed was rendered alkaline by 60 ml of 20 % ammonia 15 After crystallization, the base was dried off, washed with water and dried at 40 C.

After recrystallization from acetonitrile, 134 g of N-( 11-allyl-2pyrrolidinylmethyl)-7methyl-sulphamoyl-1,4-benzodioxane-5-carboxamide was produced (Yield: 68 7 %; Melting point: 142-143 C).

The Nuclear Magnetic Resonance spectra are compatible with the proposed 20 structure.

EXAMPLE 2.

N-( 1-ethyl-2-pyrrolidinylmethyl)-7-sulphamoyl 1,4-benzodioxane-5carboxamide.

7-sulphamoyl-1,4-benzodioxane-5-carboxylic acid 209 g of 34 % ammonia and 97 g of 7-chlorosulphonyl-l,4-benzodioxane-5car 25 boxylic acid were introduced into a balloon flask provided with an agitator and a thermometer, at a temperature of 5-10 C The mixture was agitated at ambient temperature, then the precipitate was dissolved in 415 cc of water The solution was filtered and treated with 140 cc of concentrated hydrochloric acid The crystals were dried off, washed with water and dried 78 g of 7-sulphamoyl- 11,4benzo 30 dioxane-5-carboxylic acid was obtained (M P = 272-274 C; Yield = 87 %).

Methyl-7-sulphamoyl-1,4-benzodioxane-5-carboxylate 429 g of methanol was introduced into a balloon flask provided with a condenser, then, under cooling, 54 g of 93 % sulphuric acid and 11 lg of 7-sulphamoyl- 11,4-benzodioxane-5-carboxylic acid was added The mixture was heated 35 under reflux, then cooled The crystals were dried off, washed with methanol, then treated with 500 cc of water and 5 g of sodium carbonate The precipitate was dried off, washed with water and dried 95 g of methyl 7-sulphaffhoyl-1,4benzodioxane-5carboxylate was obtained (M P = 225-226 C; Yield = 81 %).

N-(l-ethyl-2-pyrrolidinylmethyl)-7-sulphamoyl-1,4-benzodioxane-Scarboxamide g of methyl 7-sulphamoyl-l,4-benzodioxane-5-carboxylate, 48 g of water and 81 5 g of l-ethyl-2-aminoethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser and an agitator The resulting suspension was heated on a water bath until a test sample was soluble in dilute acids The reaction mixture was then treated with 1 litre of water and acidified by 70 ml of acetic acid 45 The acetate solution formed was filtered on carbon black and the base was precipitated by 20 % ammonia The crystals were dried off, washed with water and dried The benzamide was purified by conversion to its hydrochloride (melting point: 238-240 C) The base was precipitated by the addition of 20 % ammonia.

120 g of N-( 1-ethyl-2-pyrrolidinylmethyl)-7-sulphamoyl-1,4-benzodioxane5-car 50, boxamide was produced (Yield: 61 5 %; melting point 160-161 C).

EXAMPLE 3.

N (I methyl 2 pyrrolidinylmethyl)7 ethylsulphonyl 1,4 benzodioxane 5 carboxamide.

7-mercapto-1,4-benzodioxane-5-carboxylic acid 55 243 g of 7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid and 654 cc of acetic acid were introduced into a balloon flask provided with an agitator and a condenser The mixture was heated at 90 C and then cooled at 45 C 389 g of tin and 1744 cc of hydrochloric acid were then added The mixture was heated at 1,571,447 55-60 C, cooled and poured into water The precipitate was dried off, washed and dried 166 g of 7-mercapto-l,4-benzodioxane-5-carboxylic acid was obtained (M P.

= 191-192 C; Yield = 90 %).

7-ethylthio-1,4-benzodioxane-5-carboxylic acid 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 cc of water, 215 cc 5 of soda lye and 181 g of ethylsulphate were introduced into a balloon flask provided with a condenser The mixture was heated under reflux, then cooled The solution was poured into 1 3 1 of water, filtered and treated with 110 cc of hydrochloric acid.

The precipitate was dried off, washed with water and dried 152 g of 7ethylthio-1,4benzodioxane-5-carboxylic acid was obtained (M P = 153-154 C; Yield = 81 %) 10 7-ethylsulphonyl-1,4-benzodioxane-5-carboxylic acid 152 g of 7-ethylthio-l,4-benzodioxane-5-carboxylic acid and 958 cc of acetic acid were introduced into a balloon flask provided with a condenser 398 cc of hydrogen peroxide was then added and the mixture was heated The crystals formed by cooling were dried off, washed and dried 139 g of 7ethylsulphonyl-l,4 15 benzodioxane-5-carboxylic acid was obtained (M P = 217-218 C; Yield = 81 %).

7-ethylsulphonyl-1,4-benzodioxane-5-carbonyl chloride 243 g of thionyl chloride, a few drops of dimethyl-formamide and 139 g of 7ethylsulphonyl-l,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser The mixture was heated, then the excess of thionyl 20 chloride was distilled off under vacuum 148 g of 7-ethylsulphonyl-l,4benzodioxane-5-carbonyl chloride was obtained (M P = 146-147 C Yield = 100 %).

N (I methyl 2 pyrrolidinylmethyl)7 ethylsulphonyl 1,4 benzodioxane 5 carboxamide 59 g of 1-methyl-2-aminomethylpyrrolidine, 450 ml of chloroform and then, in 25 portions, 150 g of 7-ethylsulphonyl-l,4-benzodioxane-5-carbonyl chloride, were introduced, at a temperature of from 5 to 10 C, into a balloon flask provided with an agitator and a thermometer The mixture was then agitated for one hour at ambient temperature, and then 1850 ml of water was added After distillation of the chloroform, the solution was filtered over carbon black and benzamide was 30 precipitated by the addition of 65 ml of soda lye The solid was dried off, washed with water and dried at 40 C After recrystallisation from absolute alcohol, 151 g of N-( l -methyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide was obtained (Yield: 80 5 %; melting point: 140-141 C).

The structure was confirmed by NMR 35 EXAMPLE 4.

I -( 2,3-Ethylenedioxy-5-sulphamoylbenzoyl)-4-( 2-pyrimidinyl)-piperazine 146 g of 7-sulphamoyl-1,4-benzodioxane-5-carboxylic acid, 300 ml of dioxane and then 57 g of triethylamine were introduced into a 1-litre 3-neck flask provided with an agitator, a thermometer and an introduction funnel The mixture was 40 heated at 40 to 50 C and 80 ml of water was added The solution was cooled to a temperature of from 5 to 10 C and 61 5 g of ethyl chloroformate was added.

Agitation of the mixture was maintained for 1 hour at 10 C and 93 g of 1( 2pyrimidinyl)piperazine was added, without the temperature rising above 15 C.

Agitation of the mixture was continued for a further 1 hour at ambient temperature 45 and then, after the addition of 1500 ml of water, the mixture was rendered alkaline to a p H of 10, by ammonia After distillation under vacuum of the solvents and cooling, the resulting crystals were dried off, washed with water, dried in a drying oven at 50 C and then purified by treatment with 120 ml of chloroform After filtration and drying, 92 g of 1-( 2,3-ethylenedioxy-5-sulphamoylbenzoyl)4-( 2-pyrim 50 idinyl)-piperazine was produced (Yield: 40 2 %; melting point: 239 C) The structure was confirmed by NMR analysis.

EXAMPLE 5.

N-( 1 -methyl-2-pyrrolidinylmethyl)-7-dimethylsulphamoyl 1,4-benzodioxane5carboxamide 55 7-Dimethylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 500 cc of acetone and a solution of 99 g of dimethylamine in 250 cc of acetone were introduced into a balloon flask provided with an agitator and a thermometer.

The mixture was cooled at O C and then 139 g of 7-chlorosulphonyl-l,4benzodiox1,571,447 ane-5-carboxylic acid was added The mixture was agitated at ambient temperature, the acetone distilled off and the residue dissolved in 11 of water The solution was rendered alkaline, filtered and treated with 70 cc of hydrochloric acid.

The precipitate was dried off, washed and dried 128 g of 7dimethylsulphamoyl 1,4benzodioxane-5-carboxylic acid was obtained (M P = 220-221 C; Yield = 89 %) 5 7-Dimethylsulphamoyl-1,4-benzodioxane-5-carbonyl chloride g of thionyl chloride and 153 g of 7-dimethylsulphamoyl-l,4-benzodioxane5-carboxylic acid were introduced into a balloon flask provided with a condenser.

The mixture was heated, then the excess of thionyl chloride was distilled off 163 g of 7-dimethylsulphamoyl-l,4-benzodioxane-5-carbonyl chloride was obtained 10 (M.P = 160-162 C; Yield = 100 %).

N-( 1-methyl-2-pyrrolidinylmethyl)-7-dimethylsulphamoyl 1,4-benzodioxane5-carboxamide 61 g of 1-methyl-2-aminomethyl-pyrrolidine and 560 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, and S 15 then, with the temperature being kept at from 0 to 5 C, 163 g of 7dimethylsulphamoyl-l,4-benzodioxane-5-carbonyl chloride was introduced The mixture was agitated for 1 hour, allowing the temperature to rise, and then 1 litre of water was added After distillation of the chloroform the solution was filtered and the carboxamide was precipitated by the addition of 30 % of soda lye The crystals 20 produced were filtered, washed with water and dried.

After recrystallisation from absolute alcohol, 157 g of N-(l-methyl-2pyrrolidinylmethyl)-7-dimethylsulphamoyl 1,4-benzodioxane-5-carboxamide was obtained (Yield: 76 9 %; melting point: 165-166 C) The NMR spectra are compatible with the proposed structure 25 EXAMPLE 6.

N-( 1-benzyl-2-pyrrolidinylmethyl) 1,4-benzodioxane-5-carboxamide phosphate 440 ml of chloroform and 110 g of 1-benzyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with an agitator and a thermometer, and then, at a temperature of from 5 to 10 C, 110 g of 1,4-benzodioxane-5carbonyl 30 chloride was added After agitation of the mixture and addition of 3 litres of water, chloroform was removed.

The solution was treated with ammonia and then the precipitate was extracted by means of methylene chloride The organic solution was dried and then the solvent was removed The resulting compound, dissolved in absolute ethanol, was 35 treated with 30 ml of 85 % phosphoric acid The precipitate formed was dried off, washed with ethanol and dried 153 g of N-(l-benzyl-2-pyrrolidinylmethyl)l,4benzodioxane-5-carboxamide phosphate was produced (Yield: 61 %; melting point:

C).

EXAMPLE 7 40

N-( l -allyl-2-pyrrolidinylmethyl)-7-sulphamoyl 1,4-benzodioxane-5carboxamideg of methyl 7-sulphamoyl-l,4-benzodioxane-5-carboxylate, 48 g of water and 89 g of 1-allyl-2-aminomethyl-pyrrolidine were introduced into a balloon flask provided with a condenser The mixture was heated on a water bath until a test sample was soluble in dilute acids, and then 1 litre of water was added The 45 precipitate carboxamide was redissolved, by acetate formation The solution formed was filtered over carbon black and then the base was precipitated by the addition of 20 % ammonia The resulting crystals were dried off, washed with water, dried and purified by conversion to the hydrochloride (melting point: 228230 C), followed by transformation into a base by treatment with 20 % ammonia 131 g of 50 N( I -allyl-2-pyrrolidinylmethyl-7-sulphamoyl 1,4-benzodioxane-5carboxamide was produced (Yield: 64 8 %; melting point: 143-144 C) The structure was confirmed by NMR analysis.

EXAMPLE 8.

N-( 1-ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane-5carbox 55 amide Methyl 7-methylsulphamoyl-1,4-benzodioxane-5-carboxylate 750 ml of methanol was introduced into a balloon flask provided with a condenser Then, under cooling, 273 g of concentrated sulphuric acid and 150 g of 7methylsulphamoyl-1,4-benzodioxane-5-carboxylic acid were added The mixture 60 1,571,447 was heated under reflux, cooled and poured into water and sodium carbonate The precipitate was dried off, washed and dried.

143 g of methyl 7-methylsulphamoyl-1,4-benzodioxane-5-carboxylate was obtained (M P = 159-160 C; Yield = 85 %).

N-( 1-ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane-5carboxamide 5 137 g of methyl 7-methylsulphamoyl-l,4-benzodioxane-5-carboxylate, 43 g of water and 73 g of 1-ethyl-2-aminomethyl-pyrrolidine were introduced into a balloon flask provided with an agitator and a reflux condenser The mixture was heated on a water bath until a test sample was totally soluble in dilute acids The carboxamide produced by cooling was purified by conversion to the acetate, and then treatment 10 with 100 ml of acetic acid in 950 ml of water After the resulting solution had been filtered on carbon black, the base was precipitated by the addition of 20 % ammonia The resulting crystals were dried off, washed with water, dried and purified by recrystallisation from boiling isopropyl alcohol 121 g of N(l-ethyl-2pyrrolidinylmethyl)-7-methylsulphamoyl 1,4-benzodioxane-5-carboxamide was 15 produced (Yield: 66 2 %; melting point: 139-140 C) The structure was confirmed by NMR analysis The corresponding hydrochloride (melting point: 186-188 C) was produced by treatment of the carboxamide with hydrochloride acid of specific gravity 1 18.

EXAMPLE 9 20

N-( 1 -ethyl-2-pyrrolidinylmethyl)-2,3-methylenedioxybenzamide In a similar manner, 34 9 g of ethyl 2,3-methylenedioxybenzoate was reacted with 24 2 g of l-ethyl-2-aminomethyl-pyrrolidine, to give, after treatment and purification, 28 3 g of N-( 1-ethyl-2-pyrrolidinylmethyl)2,3methylenedioxybenzamide The NMR spectra are compatible with the expected structure 25 EXAMPLE 10.

Laevorotatory N-( 1-ethyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4benzodioxane-5-carboxamide g of laevorotatory 1 l-ethyl-2-aminomethyl-pyrrolidine was dissolved in 430 ml of chloroform in a balloon flask provided with an agitator and a thermometer The 30 resulting solution was cooled to 5 C and then 148 g of finely pulverised 7-ethylsulphonyl-l,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5 to 10 C After this addition had been completed, the mixture was agitated for 1 hour and then treated with 1 litre of water After distillation of the chloroform, the solution was filtered on carbon black and the 35 base was precipitated by an excess of 30 % caustic soda The resulting crystals were dried off, washed with water, dried and recrystallised from isopropyl alcohol.

151 5 g of laevorotatory N-(l-ethyl-2-pyrrolidinylmethyl)-7ethylsulphonyl-1,4benzodioxane-5-carboxamide was produced (Yield: 77 7 %; melting point:

111-112 C); lal 21 =-54 2 (in 5 % solution in dimethylformamide) 40 EXAMPLE 11.

Dextrorotatory N-( 1 -ethyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4benzodioxane-5-carboxamide In a similar manner, 64 5 g of dextrorotary 1-ethyl-2-aminomethylpyrrolidine was reacted with 146 g of 7-ethylsulphonyl-1,4-benzodioxane-5-carbonyl chloride to 45 give, after treatment and purification, 133 5 g of dextrorotatory N-(lethyl-2pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5-carboxamide (Yield:

69.8 %; melting point: 111-112 C); la Crl 20 = 55 5 (in 5 % solution in dimethylformamide).

EXAMPLE 12 50

N-( l -ethyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide In a similar manner, 58 g of 1-ethyl-2-aminomethyl-pyrrolidine was reacted with 131 g of 7-ethylsulphonyl-l,4-benzodioxane-5-carbonyl chloride to give, after treatment and purification, 103 5 g of N-(l-ethyl-2-pyrrolidinylmethyl)-7ethyl 55 sulphonyl I,4-benzodioxane-5-carboxamide (Yield: 60 2 %; melting point:

118-119 C) 100 Og of the base produced was dissolved in 220 ml of acetone, the resulting solution was filtered on carbon black and a solution of 9 5 g of hydrochloric acid in acetone was added The resulting hydrochloride crystals were dried off, washed with acetone and then dried 96 g of N-( 1-ethyl-2pyrrolidinyl 60 1,571,447 methyl)-7-ethylsulphonyl 1,4-benzodioxane-5-carboxamide hydrochloride was produced (Yield: 88 2 %; melting point: 148-150 C).

EXAMPLE 13.

N-( 1 -methyl-2-pyrrolidinylmethyl)-7-sulphamoyl 1,4-benzodioxane-5carboxamide 5 131 g of methyl 7-sulphamoyl- 11,4-benzodioxane-5-carboxylate, 43 g of water and 66 g of l-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser The mixture was heated on a water bath until a test sample was totally soluble in dilute acids The carboxamide produced by cooling was purified by treatment with a solution of 50 ml of acetic acid in 1250 ml of 10 water After the resulting solution had been filtered on carbon black, the base was precipitated by the addition of 20 % ammonia The resulting crystals were dried off, washed with water, dried and purified by recrystallisation from boiling methyl alcohol 119 5 g of N-( 1-methyl-2-pyrrolidinylmethyl)-7-sulphamoyl-1,4benzodioxane-5-carboxamide was produced (Yield: 70 1 %; melting point: 187-188 C) 15 EXAMPLE 14.

N-( l -allyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide 58 g of l-allyl-2-aminomethyl-pyrrolidine and 360 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer and 20 then, with the temperature being maintained at 5 to 10 C, 120 g of 7ethylsulphonyl- 11,4-benzodioxane-5-carbonyl chloride was added After agitation of the mixture and the addition of a litre of water, chloroform was distilled off The resulting solution was filtered on carbon black and then the base was precipitated by the addition of 40 ml of 30 % caustic soda The resulting crystals were dried off, 25 washed with water and then dried 152 g of N-( 1-allyl-2pyrrolidinylmethyl)-7-ethylsulphonyl-l,4-benzodioxane-5-carboxamide was produced (Yield: 93 4 %; melting point: 78-80 C) 146 g of the resulting base was dissolved hot in 290 ml of absolute alcohol and then the solution was filtered on carbon black and acidified by the addition of a solution of 13 5 g of hydrochloric acid in 10 Oml of absolute alcohol 30 After cooling, the crystals formed were dried off, washed with absolute alcohol and dried, and then purified by recrystallisation from absolute alcohol 119 5 g of N-(lallyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide hydrochloride was produced (Yield: 75 %; melting point: 138-140 C).

EXAMPLE 15 35

N-( 1-ethyl-2-pyrrolidinylmethyl)-2 H-3,4-dihydro-1,5-benzodioxepin-6carboxamide Methyl 2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylate 11 lg of methyl 2,3-dihydroxybenzoate, 660 cc of methyl ethyl ketone, 167 g of 1,3-dibromopropane and l Og of sodium iodide were introduced into a balloon flask 40 provided with an agitator and a thermometer The mixture was heated at 40 C and 182 g of potassium carbonate was added The mixture was heated under reflux and 2 1 of water-was added The oily phase was decanted and extracted y ether and the solution was washed with 10 % caustic soda and dried The ether was removed by distillation under vacuum 86 5 g of methyl 2 H-3,4-dihydro-l,5benzodioxepin-5 45 carboxylate was obtained (Boiling point = 166-176 C under 8 mm/Hg; Yield = 63 %.

2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid g of methyl 2 H-3,4-dihydro-l,5-benzodioxepin-6-carboxylate and 388 cc of caustic soda were introduced into a balloon flask provided with a condenser The 50 mixture was heated under reflux and then poured into 1 1 of water and treated with g of sodium metabisulphite The solution was filtered and treated with 77 cc of concentrated hydrochloric acid The precipitate was drained off, washed with water and dried 120 g of 2 H-3,4-dihydro-l,5-benzodioxepin-6-carboxylic acid was obtained (M P = 65-67 C; Yield = 80 5 %) 55 2 H-3,4-dihydro-1,5-benzodioxepin-6-carbonyl chloride 246 g of thionyl chloride and 134 g of 2 H-3,4-dihydro-l,5-benzodioxepin6carboxylic acid were introduced into a balloon flask provided with a condenser.

The mixture was heated under reflux, then the excess of thionyl chloride was 1,571,447 distilled off under vacuum 147 g of 2 H-3,4-dihydro-l,5-benzodioxepin-6carbonyl chloride was obtained (M P = 35-37 C; Yield = 100 %).

N-( I-ethyl-2-pyrrolidinylmethyl)-2 H-3,4-dihydro-1,5-benzodioxepin-6carboxamide 92 g of l-ethyl-2-aminomethylpyrrolidine and 458 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, and 5 then, with the temperature being kept at from 5 to 10 C, 152 g of 2 H-3, 4-dihydro1,5-benzodioxepin-6-carbonyl chloride was added After agitation for 1 hour, with the temperature being allowed to rise, 1450 ml of water was added, then chloroform was distilled The solution was filtered over carbon black and the base was precipitated by the addition of 75 mi of 20 % ammonia The crystals formed were 10 dried off, washed with water and dried 191 g of N-(l-ethyl-2pyrrolidinylmethyl)2 H-3,4-dihydro-l,5-benzodioxepin-6-carboxyamide monohydrate was produced (Yield: 82 4 %; melting point: 51 to 52 C) 173 5 g of the compound produced was dissolved in 750 ml of absolute alcohol The solution was filtered over carbon black and then a solution of 62 g of 85 % phosphoric acid in 10 Oml of absolute alcohol was 15 added The crystals formed were dried off, washed with absolute alcohol and dried, and then recrystallised from alcohol 198 g of N-( 1-ethyl-2pyrrolidinylmethyl)-2 H3,4-dihydro- 11,5-benzodioxepin-6-carboxamide phosphate was produced (Yield:

92 %; melting point: 189-190 C).

EXAMPLE 16 20

N-( -methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4-benzodioxane-5carboxamide 169 g of methyl 7-methylsulphamoyl-l,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser 25 The mixture was heated on a water bath until a test sample was totally soluble in dilute acids The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1250 ml of water, then the solution was filtered over carbon black and the base was reprecipitated by the addition of 10 Oml of 20 % ammonia The crystals were dried off, washed witlr water and dried 182 g of N-( 1-methyl-2pyrrolidinyl 30 methyl)-l,4-benzodioxane-5-carboxamide was produced (Yield: 83 6 %; melting point 189-190 C).

EXAMPLE 17.

N-(Diethylaminoethyl) 1,4-benzodioxane-5-carboxamide hydrochloride 21 g of diethylaminoethylamine and 85 mi of acetone were introduced into a 35 balloon flask provided with an agitator and a thermometer The mixture was cooled to O C, then 36 g of 1,4-benzodioxane-5-carbonyl chloride was added The crystals formed at ambient temperature were dried off, washed with acetone, dried and prupurified by recrystallisation from isopropyl alcohol 36 5 g of N(diethylaminoethyl) 1,4-benzodioxane-5-carboxamide hydrochloride was obtained (M P = 40 C; Yield = 64 %).

EXAMPLE 18.

N-( 1 -ethyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide f 13 g of 7-ethylsulphonyl-l,4-benzodioxane-5-carboxylic acid, 300 ml of tetra 45 hydrofuran and 13 g of carbonyldiimidazole were introduced into a balloon flask provided with an agitator, a thermometer and a condenser The mixture was agitated at ambient temperature and then 9 5 g of 1-ethyl-2-aminomethylpyrrolidine was added Agitation was maintained at ambient temperature and then the solvent was evaporated under vacuum The crystals produced were washed 50 with water and then dried 14 g of N-(l-ethyl-2-pyrrolidinylmethyl)-7ethylsulphonyl-l,4-benzodioxane-5-carboxamide was produced (Yield: 73 8 %; melting point: 118-119 C).

EXAMPLE 19.

N-( 1 -methyl-2-pyrrolidinylmethyl)-7-dimethylsulphamoyl 1,4-benzodioxane5 55 carboxamide A solution of 6 g of l-methyl-2-aminomethylpyrrolidine in pyridine was introduced into a balloon flask provided with an agitator, a thermometer and a condenser A solution of 3 5 g of phosphorus trichloride in 20 ml of pyridine was then added, dropwise with agitation, with the temperature being kept at from 0 to 60 1 1 1,571,447 I 1 C Agitation was maintained at a temperature of from 0 to 5 C and then at ambient temperature 14 5 g of 7-dimethylsulphamoyl-1,4-benzodioxane-5carboxylic acid was then added The mixture was heated with agitation After the mixture had been cooled and the solvent removed, the residue was dissolved in chloroform, then the solution was washed with aqueous sodium carbonate and 5 dried over anhydrous magnesium sulphate After concentration under reduced pressure, 12 5 g of N-( 1-methyl-2-pyrrolidinylmethyl)-7dimethylsulphamoyl-1,4benzodioxane-5-carboxamide was produced (Yield: 64 5 % melting point:

165-166 C).

EXAMPLE 20 10

N-( 1 -cyclohexyl-3-pyrrolidinyl)-7-methylsulphamoyl 1,4-benzodioxane-5carboxamide 84 g of 1-cyclohexyl-3-aminopyrrolidine, 430 ml of chloroform and 146 g of 7methylsulphamoyl-l,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer After agitation of the 15 mixture, the base was extracted with methylene chloride and then the solvent was evaporated The crystals formed were dissolved in boiling absolute alcohol and the resulting solution was filtered on carbon black The crystals produced after cooling were dissolved in a solution of acetic acid in water, then the solution was filtered over carbon black and the base was reprecipitated by the addition of 20 % 20 ammonia 129 5 g of N-(l-cyclohexyl-3-pyrrolidinyl)-7-methylsulphamoyl-1,4benzodioxane-5-carboxamide was produced (Yield: 61 2 %; melting point:

160-161 C).

EXAMPLE 21.

N-( 1-ethyl-2-pyrrolidinylmethyl)-7-dimethylsulphamoyl- 11,4-benzodioxane5 25 carboxamide 64 g of l-ethyl-2-aminomethyl-pyrrolidine and 530 mi of chloroform were introduced into a balloon flask provided with an agitator and a thermometer, and then, with the temperature being maintained at from 0 to 5 C, 153 g of 7dimethylsulphamoyl-1,4-benzodioxane-5-carbonyl chloride was added The mixture was 30 agitated for an hour, allowing the temperature to rise, and then 1 litre of water was added After distillation of the chloroform, the solution was filtered and the carboxamide was precipitated by the addition of 30 % caustic soda The crystals produced were filtered, washed with water and dried After recrystallisation from absolute alcohol, 144 5 g of N-(l-ethyl-2-pyrrolidinylmethyl)-7dimethylsul 35 phamoyl-l,4-benzodioxane-5-carboxamide was obtained (Yield: 72 8 %; melting point: 146-148 C).

EXAMPLE 22.

Dextrorotatory N-( 1-ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4benzodioxane-5-carboxamide 40 82 g of dextrorotatory 1-ethyl-2-aminomethyl-pyrrolidine, 600 cc of chloroform and, gradually, at a temperature of from 5 to 10 C, 200 g of 7methylsulphamoyl1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask with an agitator and a thermometer.

After the addition of a litre of water, chloroform was distilled off, then the 45 remaining solution was filtered The base was precipitated by the addition of 60 cc of 20 % ammonia The crystals formed were dried off, washed with water and then dried 162 g of dextrorotatory N-( 1 -ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-l,4-benzodioxane-5-carboxamide was produced (Yield: 66 %; melting point: 136-137 C) o 50 EXAMPLE 23.

Laevorotatory N-( 1-ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4benzodioxane-5-carboxamide In a similar manner to that of the above example, 82 g of laevorotatory 1ethyl2-aminomethyl-pyrrolidine was reacted with 195 g of 7-methylsulphamoyl-l, 4-ben 55 zodioxane-5-carbonyl chloride, to give 151 g of laevorotatory N-(l-ethyl2pyrrolidinylmethyl)-7-methylsulphamoyl 1,4-benzodioxane-5-carboxamide (Yield:

62 %; melting point: 136-137 C).

1,571,447 EXAMPLE 24.

Laevorotatory N-( 1-allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4benzodioxane-5-carboxamide g of laevorotatory 1-allyl-2-aminomethyl-pyrrolidine, 610 cc of chloroform, and gradually at a temperature of from 5-10 C, 178 g of 7methylsulphamoyl-l,4 5 benzodioxane-5-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer.

After agitation of the mixture, 1 2 litres of water was added, then chloroform was distilled off.

The remaining solution was filtered and then the base was precipitated by 70 cc 10 of 20 % ammonia The crystals formed were dried off and washed with water.

After recrystallisation from ethyl acetate, 117 g of laevorotatory N-(lallyl-2pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane-5-carboxamide was produced (Yield: 49 %; melting point: 101-102 C).

EXAMPLE 25 15

Dextrorotatory N-( 1-allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4benzodioxane-5-carboxamide In a similar manner to the above example, 84 g of dextrorotatory 1-allyl2aminomethyl-pyrrolidine was reacted with 175 g of 7-methylsulphamoyl-l,4benzodioxane-5-carbonyl chloride, to give, after purification, 125 g of dextrorotatory N 20 ( 1-allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-l,4-benzodioxane 5 carboxamide (Yield: 52 6 %; melting point: 104-105 C).

EXAMPLE 26.

Dextrorotatory N-( l -methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4benzodioxane-5-carboxamide 25 61 g of dextrorotatory 1-methyl-2-aminomethyl-pyrrolidine, 465 cc of chloroform, and, in portions with the temperature being maintained at 5 to 10 C, 155 g of 7-methylsulphamoyl-l,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer After agitation of the mixture and the addition of 1850 cc of water, chloroform was distilled off and the 30 remaining solution was filtered The base was precipitated by the addition of 65 cc of 20 % ammonia The crystals formed were dried off, washed and dried 154 g of dextrorotatory N-( 1-methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4benzodioxane-5-carboxamide was produced (Yield: 78 5 %; melting point: 187-188 C).

EXAMPLE 27 35

Laevorotatory N-( 1-methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4benzodioxane-5-carboxamide In a similar manner to that of the above example, 71 g of laevorotatory 1methyl-2-aminomethylpyrrolidine was reacted with 180 5 g of 7methylsulphamoyl1,4-benzodioxane-5-carbonyl chloride to give 175 g of laevorotatory N-(lmethyl-2 40 pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane-5-carboxamide (Yield:

77 %; melting point: 187-187 5 C).

EXAMPLE 28.

N-( 1 l-ethyl-2-pyrrolidinylmethyl)-8-methylsulphamoyl-2 H-3,4-dihydro 1, 5-benzodioxepin-6-carboxamide 45 8-chlorosulphonyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 1092 cc of chlorosulphonic acid was introduced into a balloon flask provided with an agitator, a condenser and a thermometer Then, in portions, 106 g of 2 H3,4-dihydro-l,5-benzodioxepin-6-carboxylic acid was added, with the temperature being maintained at from 5 to 10 C The mixture was agitated at ambient 50 temperature and then poured onto ice The crystals were dried off, washed with water and dried 146 g of 8-chlorosulphonyl-2 H-3,4-dihydro-l,5benzodioxepin-6carboxylic acid were obtained (M P = 114-115 C; Yield = 91 %).

8-Methylsulphamoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 233 g of an aqueous solution of methylamine was introduced into a balloon 55 flask provided with an agitator and a thermometer; then, in portions, 146 g of 8chlorosulphonyl-2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxylic acid was added, with the temperature being maintained at from 5 to 10 C The mixture was agitated and the precipitate was then dissolved in water The solution was filtered and treated with 150 cc of concentrated hydrochloric acid The crystals were dried off, washed 60 1,571,447 and dried 112 g of 8-methylsulphamoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6carboxylic acid was obtained (M P = 145-146 C; Yield = 78 %).

8-Methylsulphamoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carbonyl chloride 220 g of thionyl chloride and 177 g of 8-methylsulphamoyl-2 H-3,4-dihydro11,5benzodioxepin-6-carboxylic acid were introduced into a balloon flask provided S with a condenser The mixture was heated, then the excess of thionyl chloride was distilled off under vacuum 188 g of 8-methylsulphamoyl-2 H-3,4-dihydro-1, 5-benzodioxepin-6-carbonyl chloride was obtained (M P = 93-94 C; Yield = 100 %).

N-( 1-ethyl-2-pyrrolidinylmethyl)-8-methylsulphamoyl-2 H-3,4-dihydro-1,Sbenzodioxepin-6-carboxamide 10 79 g of 1-ethyl-2-aminomethyl-pyrrolidine, 750 cc of methyl ethyl ketone and, gradually with the temperature being maintained at from 5 to 10 C, 188 g of 8methylsulphamoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carbonyl chloride were introduced into a balloon flask provided with an agitator and a thermometer.

The hydrochloride precipitate was dried off, washed with methyl ethyl ketone 15 and then dried.

After recrystallisation from methyl alcohol, the hydrochloride was dissolved in 850 cc of water The solution was filtered and then the base was precipitated by the addition of 60 cc of 20 % ammonia The crystals formed were dried off, washed with water and then dried 180 g of N-( 1-ethyl-2-pyrrolidinylmethyl)-8methylsulph 20 amoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxamide was produced (Yield:

63.8 %; melting point: 144-145 C).

EXAMPLE 29.

N-( 1-ethyl-2-pyrrolidinylmethyl)-2,3-methylenedioxybenzamide hydrochloride 134 g of l-ethyl-2-aminomethyl-pyrrolidine, 950 cc of chloroform and, 25 gradually with the temperature being maintained at from 5 to 10 C, 183 g of 2,3methylenedioxy benzoyl chloride were introduced into a balloon flask provided with an agitator and a thermometer.

After the addition of 1 litre of water, chloroform was distilled off and then the remaining solution was filtered 30 After the addition of 120 cc of 20 % ammonia and extraction with ether, the ethereal solution was dried on potassium carbonate and then the ether was distilled off.

The base produced was dissolved in 300 cc of acetone and then a solution of 34 g of hydrochloride acid in 330 cc of acetone was added The hydrochloride 35 precipitate was dried, washed with acetone and then dried.

After recrystallisation from isopropyl alcohol, 154 g of N-(l-ethyl-2pyrrolidinylmethyl)-2,3-methylenedioxybenzamide hydrochloride was produced (Yield: 49 7 %; melting point: 127 5-128 5 C).

EXAMPLE 30 40

4-( 1,4-benzodioxane-7-ethylsulphonyl-5-carbonyl)-l,4-diazabicyclol 4 3 0 lnonane 41.5 g of 1,4-diazabicyclol 4 3 10 lnonane and 300 ml of chloroform were introduced into a l-litre balloon flask.

The mixture was cooled to 5 , then 87 g of 7-ethylsulphonyl-1,4-benzodioxane-5-carbonyl chloride was added in small amounts After agitation of the 45 mixture at ambient temperature, 5 g of active carbon was added.

After filtration and removal of the chloroform, the oily residue was dissolved in 200 ml of water and then 30 ml of 20 % ammonia was added 40 g of 4-( 1, 4-benzodioxane-7-ethylsulphonyl-5-carbonyl)-1,4-diazabicyclol 4 3 O lnonane was produced (Yield: 35 %; melting point: 147 C) 50 EXAMPLE 31.

5-l( 4-Methyl l-piperazinyl)carbonylll-7-nitro 1,4-benzodioxane hydrochloride 7-nitro-1,4-benzodioxane-5-carboxylic acid ml of acetic acid, 160 ml of acetic anhydride and l O Og of 1,4benzodioxane5-carboxylic acid were introduced into a balloon flask provided with an agitator 55 and a thermometer.

The mixture was heated and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added The mixture was agitated at 40-45 C, then cooled The crystals were dried off, washed and dried 34 g of 7-nitro-1,4-benzodioxane-5carboxylic acid was obtained (M P = 246 C; Yield = 27 %) 60 1,571,447 5-l( 4-methyl-l-piperazinyl)carbonyll-7-nitro-1,4-benzodioxane hydrochloride 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 introduced into a 250-mi balloon flask provided with an agitator and a thermometer.

The mixture was cooled to 10 C and then 14 g of isobutyl chloroformate was 5 added The mixture was agitated, the temperature being allowed to rise The oily compound formed was cooled to 10 %, 1 lg of N-methylpiperazine was added, and then the mixture was agitated, allowing the temperature to rise.

The crystals formed were washed with water 20 5 g of 5-l( 4-methyl-lpiperazinyl)carbonyll-7-nitro-l,4-benzodioxane was produced (Yield: 66 7 %; 10 melting point: 218 C) This was treated by a solution of 7 ml of hydrochloric acid (specific gravity = 1 18) in 10 Oml of water The crystals formed by cooling were washed with water and then dried 20 5 g of 5-l( 4-methyl-1-piperazinyl) carbonyll-7nitro-l,4-benzodioxane hydrochloride was produced (Yield: 89 4 %; melting point:

250 C) 15 EXAMPLE 32.

5-l( 4-methyl-l -piperazinyl)carbonylll-7-l( 1 -adamantyl)sulphamoyll-l,4benzodioxane hydrochloride 7-( 1-adamantyl)sulphamoyl-1,4-benzodioxane-5-carboxylic acid 187 5 g of adamantylamine hydrochloride, 500 ml of caustic soda and 100 l ml of 20 triethylamine were introduced into a balloon flask provided with an agitator and a thermometer 280 g of 7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid was then added at a temperature below 15 C The mixture was agitated at ambient temperature and treated with 1 51 of methylene chloride The organic phase was separate and the solvent removed The residue was treated with 1200 ml of water 25 and 150 ml of hydrochloric acid, then the precipitate was dissolved in 1200 ml of water and 120 ml of soda The solution was filtered and treated with 150 ml of hydrochloric acid The crystals were dried off, washed and dried 200 g of 7-( 1adamantyl)sulphamoyl-1,4-benzodioxane-5-carboxylic acid was obtained (M P = 205 C; Yield = 51 %) 30 l( 4-methyl-1-piperazinyl)carbonyll-7-l( 1 -adamantyl)sulphamoyll,4benzodioxane hydrochloride 500 ml of dioxane and 49 g of 7-(l-adamantyl)sulphamoyl-1,4-benzodioxane5carboxylic acid were introduced into a l-litre balloon flask provided with an agitator and a thermometer After agitation of the mixture, 12 5 g of triethylamine 35 was added, then, in small amounts, 17 g of isobutyl chloroformate.

After agitation of the mixture at a temperature of 20 C, a solution of 14 g of Nmethylpiperazine in 50 ml of dioxane was introduced The mixture was agitated and then cooled The triethylamine hydrochloride formed was removed by filtration, the filtrate was concentrated under vacuum, and the resulting residue was dissolved 40 in 300 ml of water 15 ml of hydrochloric acid was added, then the solution was treated with 20 ml of ammonia The product was dissolved in 150 ml of boiling ethanol and the solution was filtered hot.

A solution of hydrochloric acid in absolute ethanol was added to the filtrate, until the p H was 1 45 The crystals formed were dried off, washed with ethanol and dried 37 g of 5l( 4-methyl-l-piperazinyl)carbonyll-7-l( 1 adamantyl)sulphamoyll 1,4 benzo-dioxane hydrochloride was produced (Yield: 58 %; melting point: 260 C).

EXAMPLE 33.

N-(Piperidinoethyl)-7-chloro 1,4-benzodioxane-5-carboxamide hydrochloride 7 50 amino 1,4-benzodioxane-5-carboxylic acid 56 g of 7-nitro-l,4-benzodioxane-5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were introduced into an autoclave, then hydrogen under a pressure of 65 kg/cm 2 was introduced while heating The mixture was then agitated at 60 C and treated with a solution of 50 ml of caustic soda in 450 ml of water The 55 solution was filtered and treated with 50 ml of hydrochloric acid The precipitate was dried off, washed with water and dried 36 5 g of 7-amino-l,4benzodioxane-5carboxylic acid was obtained (M P = 220 C; Yield = 75 %).

7-Chloro-1,4-benzodioxane-5-carboxylic acid 49 g of 7-amino-l,4-benzodioxane-5-carboxylic acid, 200 ml of water and 50 ml 60 of hydrochloric acid were introduced into a balloon flask provided with an agitator 1,571,447 and a thermometer The mixture was cooled to 5 C, then a solution of 17 5 g of sodium nitrite in 38 ml of water was added.

The suspension was then poured into a solution of 20 g of cuprous chloride in ml of hydrochloric acid The precipitate was dried off, washed and dissolved in a solution of 42 g of sodium bicarbonate in 420 ml of water The solution was filtered 5 and treated with 10 Oml of hydrochloric acid 50 g of 7-chloro-l,4benzodioxane-5carboxylic acid was obtained (M P = 180 C; Yield = 92 7 %).

7-chloro-1,4-benzodioxane-S-carbonyl chloride 32.2 g of 7-chloro-l,4-benzodioxane-5-carboxylic acid and 64 ml of thionyl chloride were introduced into a balloon flask provided with an agitator, a 10 thermometer and a condenser The mixture was heated under reflux, then the excess of thionyl chloride was distilled off under vacuum 35 g of 7chloro-l,4benzodioxane-5-carbonyl chloride was obtained (M P = 140 C; Yield = 100 %).

N-(Piperidinoethyl)-7-chloro-1,4-benzodioxane-5-carboxamide hydrochloride 150 ml of methyl ethyl ketone and 22 g of N-(aminoethyl)piperidine were 15 introduced into a 500-ml balloon flask provided with an agitator and a thermometer.

The mixture was cooled, then a suspension of 35 g of 7-chloro-l,4benzodioxane-5carbonyl chloride in 200 ml of methyl ethyl ketone was added at a temperature of from 15 to 20 C.

After agitation, the crystals formed were dried off, then washed with methyl 20 ethyl ketone 35 g of N-piperidinoethyl-7-chloro-1,4-benzodioxane-5carboxamide hydrochloride was produced (Yield: 64 5 %; melting point: 192 C).

EXAMPLE 34.

N-butyl-7-l( 1-adamantyl)sulphamoyll 1,4-benzodioxane-5-carboxamide 500 ml of dioxane, 50 ml of water, 49 g of 7-l( 1-adamantyl)sulphamoyll-l, 4 25 benzodioxane-5-carboxylic acid and 12 5 g of triethylamine were introduced into a 2-litre balloon flask provided with an agitator and a thermometer The solution was agitated at ambient temperature, then 17 g of isobutyl chloroformate was added.

The mixture was agitated and then l Og of butylamine was introduced After agitation of the mixture, dioxane was removed 30 The residue was dissolved in 200 ml of water in a hot condition The crystals formed by cooling were washed with water, dried and re-dissolved in 250 ml of acetone at boiling temperature The solution was filtered hot The crystals formed by cooling were dried off, washed and dried 26 g of N-butyl-7-l( 1adamantyl)sulphamoyll-l,4-benzodioxane-5-carboxamide was produced (M P = 747 C; Yield 35 = 46 4 %).

EXAMPLE 35.

N-( 1 -Ethyl-2-pyrrolidinylmethyl)-8-methoxy 1,4-benzodioxane-5carboxamide oxalate 8-Methoxy-1,4-benzodioxane-5-carboxylic acid 40 171 5 g of 2,3-dihydroxy-4-methoxybenzoic acid, 515 cc of ethanol, 280 cc of caustic soda and 175 g of ethylene bromide were introduced into a balloon flask provided with an agitator, a thermometer and an inlet pipe for nitrogen The mixture was heated under reflux, then cooled and poured into 2 8 1 of water The solution was filtered and treated with 85 cc of concentrated hydrochloric acid The 45 precipitate was dried off, washed and dried After recrystalisation in dimethylformamide, 110 g of 8-methoxy-l,4-benzodioxane-5-carboxylic acid was obtained (M.P = 224-226 C; Yield = 57 %).

8-Methoxy-1,4-benzodioxane-5-carbonyl chloride 391 g of thionyl chloride and 138 g of 8-methoxy-l,4-benzodioxane-5carboxylic 50 acid were introduced into a balloon flask provided with a condenser The mixture was heated at 50-55 C and the excess of thionyl chloride was distilled off under vacuum.

151 g of 8-methoxy-l,4-benzodioxane-5-carbonyl chloride was obtained (Yield = 100 %) 55 N-( 1-ethyl-2-pyrrolidinylmethyl)-8-methoxy-1,4-benzodioxane-Scarboxamide oxalate 87 g of l-ethyl-2-aminomethyl-pyrrolidine and 775 cc of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer, and then, in portions, 155 g of 8-methoxy-l,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5 to 10 C After 60 1,571,447 agitation, the mixture was dissolved in 1500 cc of water and the methyl ethyl ketone was distilled off The remaining solution was filtered then treated with sodium hydroxide The resulting oil was decanted, then extracted with methylene chloride.

The solution was dried over potassium carbonate and the methylene chloride was distilled off under vacuum 5 224 5 g of N-( l -ethyl-2-pyrrolidinylmethyl)-8-methoxy 1,4-benzodioxane5carboxamide was produced.

197 5 g of the base produced was dissolved in 760 cc of absolute alcohol, then 67 g of oxalic acid in solution in 195 cc of absolute alcohol was added The crystals formed were dried off, washed with absolute alcohol and then dried 10 208 5 g of N-( 1 l-ethyl-2-pyrrolidinylmethyl)-8-methoxy-l,4-benzodioxane5carboxamide oxalate was produced (Yield: 82 %; melting point: 129-130 C).

EXAMPLE 36.

N-( 1 -ethyl-2-pyrrolidinylmethyl)-8-methoxy-7-sulphamoyl 1,4benzodioxane-5carboxamide 15 8-Methoxy-7-chlorosulphonyl-1,4-benzodioxane-S-carboxylic acid 1045 cc of chlorosulphonic acid was introduced into a balloon flask provided with an agitator, a thermometer and a condenser, then, in portions, 1 l Og of 8methoxy-l,4-benzodioxane-5-carboxylic acid was added with the temperature being maintained at from 5 to 10 C The mixture was agitated at ambient 20 temperature and then poured onto ice The precipitate was dried off, washed and dried 159 g of 8-methoxy-7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid was obtained (Yield = 98 %).

8-Methoxv-7-sulphamoyl-1,4-benzodioxane-S-carboxylic acid 300 g of 34 % ammonia was introduced into a balloon flask provided with an 25 agitator and a thermometer and 159 g of 8-methoxy-7-chlorosulphonyl-l,4benzodioxane-5-carboxylic acid was added in portions, the temperature being maintained at from 0 to 5 C The mixture was agitated; then the precipitate was dissolved in water The solution was filtered and treated with 280 cc of concentrated hydrochloric acid The precipitate was dried off, washed and dried 118 g of 8-meth 30 oxy-7-sulphamoyl-l,4-benzodioxane-5-carboxylic acid was obtained (M P = 247-248 C; Yield = 82 %).

Methyl-8-methoxy-7-sulphamoyl-1,4-benzodioxane-S-carboxylate 396 g of methanol was introduced into a balloon flask provided with a condenser Then 51 g of sulphuric acid and 114 5 g of 8-methoxy-7sulphamoyl-l,4 35 benzodioxane-5-carboxylic acid were added while cooling The mixture was heated under reflux and then poured into a solution of 40 g of sodium carbonate in 485 cc of water The precipitate was dried off, washed and dried 110 5 g of methyl 8methoxy-7-sulphamoyl-1,4-benzodioxane-5-carboxylate was obtained (M P = 202-203 C; Yield = 92 %) 40 N-(I -Ethyl-2-pyrrolidinylmethyl)-8-methoxy-7-sulphamoyl-1,4-benzodioxane5-carboxamide g of methyl 8-methoxy-7-sulphamoyl- 11,4-benzodioxane-5-carboxylate and 750 cc of ethylene glycol were introduced into a balloon flask After dissolution, 127 g of 1-ethyl-2-aminomethyl-pyrrolidine was added and the mixture was heated 45 at 50 C The resulting solution was dissolved with 2 litres of water and acidified by means of 120 cc of acetic acid The precipitate formed was dried off, washed with water and then dried.

The precipitate was then redissolved in 915 cc of hot water The solution was filtered and then the base was precipitated with ammonia The precipitate was 50 dried off, washed with water and then dried 144 g of N-(l-ethyl-2pyrrolidinylmethyl)-8-methoxy-7-sulphamoyl-1,4-benzodioxane-5-carboxamide was produced (Yield: 73 %; melting point: 110-115 C).

EXAMPLE 37.

4-( 1,4-benzodioxane-5-carbonyl)1,4-diazabicyclol 4 3 O lnonane 55 63 g of 1,4-diaza-bicyclol 4 3 10 lnonane and 400 ml of chloroform were introduced into a l-litre balloon flask provided with an agitator and a thermometer and then, in portions, 50 g of 1,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at 10 C The mixture was then agitated at ambient temperature, and then 1 litre of water was added 60 1,571,447 After the addition of acetic acid to give a p H of 4, the addition of carbon black and filtration, the product was precipitated with ammonia.

After extraction by methylene chloride, the solution was dried and then filtered The solvent was removed under vacuum and the resulting product was S purified by recrystallisation from ethanol 50 g of 4-( 1,4-benzodioxane5-carbonyl) 5 1,4-diazabicyclol 4 3 O lnonane was produced (Yield: 69 %; melting point: 128 C).

EXAMPLE 38.

N-Benzyl-7-diethylsulphamoyl 1,4-benzodioxane-5-carboxamide 7-Diethylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 10 200 ml of water, 100 ml of diethylamine and 200 ml of triethylamine were introduced into a balloon flask provided with an agitator and a thermometer Then g of 7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid was added in portions, the temperature being maintained at from 20 to 30 C.

The mixture was agitated at ambient temperature and 500 ml of water was 15 added The solution was filtered and treated with 300 ml of hydrochloric acid The precipitate was dried off, washed and dried 117 g of 7-diethylsulphamoyl1,4benzodioxane-5-carboxylic acid was obtained (M P = 149 C; Yield = 74 %).

N-Benzyl-7-diethylsulphamoyl-1,4-benzodioxane-5-carboxamide 37.8 g of 7-diethylsulphamoyl-l,4-benzodioxane-5-carboxylic acid, 40 ml of 20 water, 12 5 g of triethylamine and 120 ml of acetone were introduced into a balloon flask provided with an agitator and a thermometer The mixture was cooled to about 10 to 15 C and then 17 2 g of isobutyl chloroformate was added After the addition of 14 lg of benzylamine at a temperature of from 15 to 20 C and agitation of the mixture, the crystals formed were dried off, washed with water and then 25 purified by recrystallisation from ethanol.

33 g of N-benzyl-7-diethylsulphamoyl-1,4-benzodioxane-5-carboxamide was produced (Yield: 68 %; melting point: 125 C).

EXAMPLE 39.

N-( 1 -benzyl-4-piperidinyl)-7-methylsulphamoyl 1,4-benzodioxane-5carboxamide 30 70 ml of water, 68 5 g of 7-methylsulphamoyl-1,4-benzodioxane-5carboxylic acid, 25 5 g of triethylamine and 200 ml of acetone were introduced into a balloon flask provided with an agitator and a thermometer and then 34 5 g of isobutyl chloroformate was added, with the temperature being kept at from 15 to 20 C.

After the addition of 52 g of 1-benzyl-4-aminopiperidine at a temperature of 35 from 15 to 20 C and agitation of the mixture, the crystals formed were dried off, washed with water and then dried.

The product formed was purified by treatment with a solution of hydrochloric acid, then precipitation by means of sodium hydroxide The precipitate was then dried off, washed with water and dried 40 76 g of N-( 1-benzyl-4-piperidinyl)-7-methylsulphamoyl-1,4-benzodioxane-5carboxamide was produced (Yield: 68 %; melting point: 228 C).

EXAMPLE 40.

N-( 1 -adamantyl) 1,4-benzodioxane-5-carboxamide ml of chloroform and 37 5 g of adamantamine were introduced into a 45 balloon flask provided with an agitator and a thermometer, and then 50 g of 1,4benzodioxane-5-carbonyl chloride was added in portions, at a temperature of from to 10 C After agitation at ambient temperature, 1500 ml of water was added and the chloroform was removed under vacuum The base, which was precipitated by ammonia, was extracted by means of methylene chloride After the removal of the 50 solvent, the residue was dissolved in ethanolic hydrogen chloride The crystals formed by cooling were dried off, washed and then dried 20 g of N-(ladamantyl)1,4-benzodioxane-5-carboxamide was produced (Yield: 25 %; melting point:

137 C).

EXAMPLE 41 55

N-( l -benzyl-2-pyrrolidinylmethyl)-7-diethylsulphamoyl 1,4-benzodioxane5carboxamide phosphate ml of water, 37 8 g of 7-diethylsulphamoyl-1,4-benzodioxane-5-carboxylic acid, 12 5 g of triethylamine and 120 ml of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer, and then 17 2 g of 60 isobutyl chloroformate was added at a temperature of from 15 to 20 C After is 1,571,447 agitation of the mixture, 25 g of 1-benzyl-2-aminomethylpyrrolidine was added, with the temperature being maintained at from 15 to 20 C.

The mixture was agitated at ambient temperature and then the solvents were removed The residue was dissolved in 200 ml of methylene chloride and 300 ml of water After agitation, the solvent was decanted and then dried over magnesium 5 sulphate The solution was filtered and then the solvent removed The resulting compound was dissolved in ethanol at boiling temperature and 18 g of 85 % phosphoric acid was added The crystals formed by cooling were dried off, washed with ice-cold ethanol and then dried 56 g of N-(l-benzyl-2pyrrolidinylmethyl)-7diethylsulphamoyl-l,4-benzodioxane-5-carboxamide phosphate was produced 10 (Yield: 79 6 %; melting point 180 C).

EXAMPLE 42.

N-( 1 -benzyl-4-piperidinyl) 1,4-benzodioxane-5-carboxamide hydrochloride ml of chloroform and 50 g of 1-benzyl-4-aminopiperidine were introduced into a balloon flask provided with an agitator and a thermometer, and then 50 g of 15 1,4-benzodioxane-5-carbonyl chloride was added in portions, at a temperature of from 5 to 10 C.

After agitation of the mixture at ambient temperature, the solvent was removed under vacuum and the residue was dissolved in 300 ml of water After precipitation of the base by addition of ammonia, the water was removed and the 20 resulting product was treated with a solution of hydrochloric acid 75 g of N-(lbenzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide hydrochloride was produced (Yield: 77 %; melting point: 205 C).

EXAMPLE 43.

N-( 1-ethyl-2-pyrrolidinylmethyl)-8-ethylsulphonyl-2 H-3,4-dihydro-1,5benzo 25 dioxepin-6-carboxamide hydrochloride 8-Mercapto-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid A solution of 106 g of 8-chlorosulphonyl-2 H-3,4-dihydro-l,5benzodioxepin-6carboxylic acid in 273 mil of acetic acid, together with 159 5 g of tin, was introduced into a balloon flask provided& with an agitator and a thermometer The mixture was 30 agitated with heating at 40-45 C, then 705 ml of concentrated hydrochloric acid was added After heating at 55-60 C, the solution was cooled The precipitate was dried off, washed and dried 65 g of 8-mercapto-2 H-3,4-dihydro-l,5-benzodioxepin-6-carboxylic acid was nbtained (M P = 99 5-100 C; Yield = 80 %).

8-Ethylthio-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 35 86 g of 8-mercapto-2 H-3,4-dihydro- 11,5-benzodioxepin-6-carboxylic acid, 152 ml of water, 76 mi of caustic soda and 58 5 g of ethylsulphate were introduced into a balloon flask provided with a condenser The mixture was heated under reflux then cooled 150 ml of water was added and the solution was filtered and treated with 60 ml of hydrochloric acid The precipitate was dried off, washed and 40 dried 88 g of 8-ethylthio-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid was obtained (M P = 66-67 C; Yield = 91 %).

8-Ethylsulphonyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 88 g of 8-ethylthio-2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxylic acid in 528 ml of acetic acid was introduced into a balloon flask provided with a condenser, 45 then 210 ml of hydrogen peroxide was added in portions The solution was heated and the acetic acid removed under vacuum The residue was dissolved in 180 ml of water and cooled The precipitate was dried off, washed and dried 90 g of 8-ethylsulphonyl-2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxylic acid was obtained (M P.

= 142-143 C; Yield = 91 %) 50 8-Ethylsulphonyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carbonyl chloride g of thionyl chloride and 90 g of 8-ethylsulphonyl-2 H-3,4-dihydro-1,5benzodioxepin-6-carboxylic acid were introduced into a balloon flask provided with a condenser The mixture was heated at 45-50 C and the excess of thionyl chloride was removed under vacuum The residue was treated with petroleum ether, then 55 dried off, washed and dried 94 g of 8-ethylsulphonyl-2 H-3,4-dihydro-l,5benzodioxepin-6-carbonyl chloride was obtained (M P = 108-110 C; Yield = 98 %) .

1,571,447 N-( -ethyl-2-pyrrolidinylmethyl)-8-ethylsulphonyl-2 H-3,4-dihydro-1,5benzodioxepin-6carboxamide hydrochloride 39.5 g of 1-ethyl-2-aminomethylpyrrolidine in 282 ml of chloroform was introduced into a balloon flask provided with an agitator and a thermometer 94 g of 8-ethylsulphonyl-2 H-3,4-dihydro 1,5-benzodioxepin-6-carbonyl chloride was 5 added in portions, the temperature being maintained at from 5 to 10 C The mixture was heated and then poured into water The aqueous phase was cooled, filtered and treated with 30 ml of caustic soda The precipitate was extracted by methylene chloride and the organic phase was dried over potassium carbonate The solvent was distilled off, and the residue was dissolved in isopropyl alcohol and 10 treated with a solution of hydrochloric acid in isopropyl alcohol The precipitate was dried off, washed with alcohol and dried 98 g of N-(l-ethyl-2pyrrolidinylmethyl)-8-ethylsulphonyl-2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxamide was obtained (M P = 141-142 C; Yield = 73 %).

EXAMPLE 44 15

5-l( 4-Methyl-1 -piperazinyl)carbonyll-6,7-dibromo-8-nitro-1,4benzodioxane 6,7-Dibromo-1,4-benzodioxane-5-carboxylic acid 1440 ml of acetic acid and 360 g of 1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator, an introduction funnel and a condenser The mixture was heated to 55 C, then a solution of 700 g of 20 bromine in 360 ml of acetic acid was added in portions The mixture was heated to C, then cooled to 15 C The precipitate was dried off, washed with acetic acid and dried 332 g of 6,7-dibromo-l,4-benzodioxane-5-carboxylic acid was obtained (M.P = 212 C) The structure was confirmed by NMR analysis.

6,7-Dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid 25 166 g of 6,7-dibromo-l,4-benzodioxane-5-carboxylic acid and 500 ml of acetic acid were introduced into a balloon flask The mixture was heated to 37 C and a solution of 60 ml of nitric acid (specific gravity = 1 49) in 60 ml of acetic acid, together with sulphuric acid as catalyst, was added After heating at 50 C, the mixture was poured in cold water, under agitation The precipitate was dried off, 30 washed with water and dried 107 g of 6,7-dibromo-8-nitro- 11,4benzodioxane-5carboxylic acid was obtained (M P = 237 C) The acid was purified by treatment with a solution of 50 g of sodium bicarbonate in 500 ml of water and precipitation by hydrochloric acid The precipitate was dried off, washed and dried Crystals were obtained (M P = 238 C; Yield = 51 %) The structure was confirmed by NMR 35 analysis.

6,7-Dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride 96 g of 6,7-dibromo-8-nitro-l,4-benzodioxane-5-carboxylic acid and 200 ml of thionyl chloride were introduced into a balloon flask provided with an agitator and a thermometer The mixture was heated under reflux, then the excess of thionyl 40 chloride was removed under vacuum The residue was dissolved in l O Oml of isopropyl ether, then the solvent was removed and the product air-dried 91 g of 6,7dibromo-8-nitro-l,4-benzodioxane-5-carbonyl chloride was obtained (M P = 215 C; Yield = 91 %).

5-l( 4-Methyl-1-piperazinyl)carbonyll-6,7-dibromo-8-nitro-1,4benzodioxane 45 400 ml of methyl ethyl ketone and 1 lg of methylpiperazine were introduced into a balloon flask provided with an agitator and a thermometer The mixture was cooled to 10 C and then 41 g of 6,7-dibromo-8-nitro-l,4-benzodioxane-5carbonyl chloride was added in portions, with the temperature being maintained below 20 C After agitation of the mixture, the crystals were dried off, washed with 50 methyl ethyl ketone and dried, then dissolved in water and reprecipitated by addition of 50 ml of 20 % ammonia The crystals were dried off, washed with water and dried 33 g of 5-l( 4-methyl- 11-piperazinyl)carbonyll-6,7-dibromo-8nitro-1,4benzodioxane was obtained (M P = 164 C; Yield = 69 6 %) The structure was confirmed by I R and NMR analysis 55 EXAMPLE 45.

N-( l-ethyl-2-pyrrolidinylmethyl)-6,7-dibromo-8-nitro 1,4-benzodioxane-5carboxamide In a similar manner, by substituting l-ethyl-2-aminomethylpyrrolidine for methylpiperazine, N-(l-ethyl-2-pyrrolidinylmethyl)-6,7-dibromo-8-nitro 1, 4-benzo 60 1,571,447 dioxane-5-carboxamide was obtained (M P = 213 C; Yield = 65 %) The structure was confirmed by NMR analysis.

EXAMPLE 46.

N-( 1-ethyl-2-pyrrolidinylmethyl)-8-amino 1,4-benzodioxane-5-carboxamide 8-Amino-I,4-benzodioxane-5-carboxylic acid 5 400 ml of water, 98 5 g of 6,7-dibromo-8-nitro-l,4-benzodioxane-5carboxylic acid, l O Oml of caustic soda and O lg of Pd/C were introduced into an autoclave, then hydrogen under a pressure of 40 kg/cm 2 was introduced while heating at 50 C.

The mixture was filtered, then treated with 95 ml of hydrochloric acid The precipitate was dried off, washed and dried 42 g of 8-amino-l,4benzodioxane-5 10 carboxylic acid was obtained (M P = 186 C; Yield = 83 7 %).

N-( 1-ethyl-2-pyrrolidinylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide According to the method described in Example 2, 42 g of 8-amino-l,4-benzodioxane-5-carboxylic acid was treated with methanol and the resulting compound treated with 33 g of 1-ethyl-2-aminomethylpyrrolidine and then with a solution of 15 13 g of hydrochloric acid in absolute alcohol 49 g of N-(l-ethyl-2pyrrolidinylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride was obtained (M.P = 173 C; Yield = 60 %).

EXAMPLE 47.

5-l( 4-Methyl-l-piperazinyl)carbonyll-8-chloro-1,4-benzodioxane 20 8-Chloro-1,4-benzodioxane-5-carboxylic acid 29.3 g of 8-amino-l,4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer The mixture was heated to 40 C and then cooled to 5 C, and a solution of 10 5 g of sodium nitrite in 20 ml of water was added in portions, with the 25 temperature being maintained at from 5 to 10 C The mixture was agitated and then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (specific gravity = 1 18), with the temperature being maintained below 30 C The precipitate was dried off, washed with hydrochloric acid and water, and dissolved in 300 ml of water and 25 g of sodium bicarbonate The solution was filtered and 30 treated with hydrochloric acid The precipitate was dried off, washed with water and dried 20 g of 8-chloro-l,4-benzodioxane-5-carboxylic acid was obtained (M P = 195 C; Yield = 62 %).

5-l( 4-Methyl-l-piperazinyl)carbonyll-8-chloro-I,4-benzodioxane According to the method described in Example 33, 20 g of 8-chloro-l,4benzo 35 dioxane-5-carboxylic acid was treated with thionyl chloride and the resulting 8chloro-l,4-benzodioxane-5-carbonyl chloride (M P = 83 C) was treated with 10 5 g of methylpiperazine 14 g of 5-l( 4-methyl-l-piperazinyl)-carbonyll-8chloro-1,4benzodioxane was obtained (M P = 260 C with decomposition; Yield = 50 5 %).

EXAMPLE 48 40

N-( 1-Ethyl-2-pyrrolidinylmethyl)-8-acetamido 1,4-benzodioxane-5carboxamide 8-Acetamido-1,4-benzodioxane-5-carboxylic acid 43 g of 8-amino-l,4-benzodioxane-5-carboxylic acid and 72 ml of acetic acid were introduced into a balloon flask and 24 5 ml of acetic anhydride was added in portions The mixture was heated at 60-70 C, then cooled The precipitate was 45 dried off, washed with acetic acid and water and dried 44 g of 8acetamido-l,4benzodioxane-5-carboxylic acid was obtained (M P = 233 C; Yield = 84 %).

N-( -ethyl-2-pyrrolidinylmethyl)-8-acetamido-1,4-benzodioxane-5carboxamide According to the method described in Example 31, the 8-acetamido-l,4benzodioxane-5-carboxylic acid was treated with isobutyl chloroformate and 1 50 ethyl-2-aminomethyl-pyrrolidine N-( 1 -ethyl-2-pyrrolidinylmethyl)-8acetamido1,4-benzodioxane-5-carboxamide was obtained The structure was confirmed by NMR analysis.

EXAMPLE 49.

N-(diethylaminoethyl)-7-nitro-8-acetamido-1,4-benzodioxane-5-carboxamide 55 42 g of 8-acetamido-1,4-benzodioxane-5-carboxylic acid, 75 ml of acetic acid and 75 ml of acetic anhydride were introduced into a balloon flask; then a solution of 17 5 ml of nitric acid (specific gravity = 1 49) in 17 ml of acetic acid was added, 1,571,447 with the temperature being left rising After dissolution and crystallization, 50 ml of acetic acid was added The mixture was agitated at 40-45 C and then cooled to C The precipitate was dried off, washed with acetic acid and water and dried.

13.5 g of a 50 % mixture of 7-nitro-8-acetamido- 11,4-benzodioxane-5carboxylic acid and 6-nitro-8-acetamido-1,4-benzodioxane-5-carboxylic acid was obtained The 7 5 nitro-8-acetamido 1,4-benzodioxane-5-carboxylic acid was separated and then treated, according to the process of Example 31, with isobutyl chloroformate and diethylaminoethylamine N-(Diethylaminoethyl)-7-nitro-8-acetamido-1,4benzodioxane-5-carboxamide was obtained The structure was confirmed by NMR analysis 10 EXAMPLE 50.

N-( 1-allyl-2-pyrrolidinylmethyl)-7,8-azimido 1,4-benzodioxane-5carboxamide 7,8-Azimido-I,4-benzodioxane-5-carboxylic acid 13 g of a 50 % mixture of 7-nitro-8-acetamido-l,4-benzodioxane-5carboxylic acid and 6-nitro-8-acetamido-1,4-benzodioxane-5-carboxylic acid, 90 ml of water, 15 mi of sodium hydroxide, some Raney nickel, and hydrogen under a 50 kg/cm 2 pressure were introduced into an autoclave At the end of the hydrogen absorption the nickel was filtered off and the solution was treated with 12 ml of hydrochloric acid and then with a solution of 3 5 g of sodium nitrite in 10 ml of water, at a temperature of from 20 to 25 C The resulting precipitate was dried off, and then 20 treated with an aqueous sodium hydroxide solution The mixture was acidified and the resulting precipitate was dried off, washed and dried 3 g of 7,8azimido- 11,4benzodioxane-5-carboxylic acid was obtained (M P = 260 C with decomposition; Yield = 59 %).

N-( 1-allyl-2-pyrrolidinylmethyl)-7,8-azimido-1,4-benzodioxane-5carboxamide 25 The 7,8-azimido 1,4-benzodioxane-5-carboxylic acid was treated with Nhydroxyphthalimide together with dicyclohexylcarbodiimide The resulting phthalimide carboxylate was treated with l-allyl-2-aminomethylpyrrolidine to produce N-( 1 -allyl-2-pyrrolidinylmethyl)-7,8-azimido 1,4-benzodioxane-5carboxamide, the structure of which was confirmed by NMR 30 EXAMPLE 51.

N-( 2-pyrimidinyl)-6-chloro 1,4-benzodioxane-5-carboxamide 6-nitro-1,4-benzodioxane-5-carboxylic acid 1600 ml of acetic acid, 1600 ml fo acetic anhydride and 1000 lg of 1,4benzodioxane-5-carboxylic acid were introduced into a 6 litre balloon flask provided with 35 an agitator and a 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 introduction, the mixture was stirred at 40-45 C for 2 hours, then cooled to 5 C The precipitate was dried off, washed with 600 ml of acetic acid and then with water, and dried at 40 C 700 g of 7-nitro-l,4-benzodioxane-5-carboxylic acid was collected, the 40 structure of which was confirmed by NMR (M P 246 C) The mother-liquors were diluted with 25 litres of water, and the resulting precipitate was dried off, washedwith water and dried to produce 6-nitro-l,4-benzodioxane-5-carboxylic acid (M P.

188 C).

6-Amino-1,4-benzodioxane-5-carboxylic acid hydrochloride 45 g of 6-nitro-l,4-benzodioxane-5-carboxylic acid, 1950 ml of ethanol and some Raney nickel were introduced into an autoclave The mixture was hydrogenated under a hydrogen pressure of 35 kg/cm 2 at 600 C for one hour, then cooled The nickel was filtered off and the solution was acidified with 150 ml of an ethanolic solution of hydrochloric acid ( 23 g/l O Oml) The precipitate was filtered and dried 50 g of 6-amino-1,4-benzodioxane-5-carboxylic acid hydrochloride was obtained (M.P 160 C; Yield 57 5 %).

6-Chloro-1,4-benzodioxane-5-carboxylic acid 58 g of 6-amino-l,4-benzodioxane-5-carboxylic acid hydrochloride and 116 ml of water were introduced in a 500 ml balloon flask provided with a stirrer, a 55 thermometer and a dropping funnel 28 ml of hydrochloric acid (specific gravity = 1.18) was added and the mixture was cooled to a temperature of from 0 to O 5 C.

A solution of 17 5 g of sodium nitrite in 38 ml of water was added at a temperature within the range 0 to 5 C The mixture was stirred for one hour 20 g of cuprous chloride and 75 ml of hydrochloric acid were then added The mixture 60 1,571,447 was allowed to stand overnight and then filtered.

The solid 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 36 B 6 caustic soda), then addition of 25 ml of hydrochloric acid 40 g of 6-chloro-l,4benzodioxane-6carboxylic acid was obtained (M P 162 C; Yield 74 %) 5 6-chloro-1,4-benzodioxane-5-carbonyl chloride 56 m 1 of thionyl chloride and 28 g of 6-chloro-l,4-benzodioxane-5carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a condenser and a thermometer The mixture was heated at the reflux temperature for 30 minutes The excess of thionyl chloride was removed by distillation under reduced 10 pressure 28 5 g of 6-chloro-l,4-benzodioxane-5-carbonyl chloride was obtained (M.P 50 C; Yield 93 %).

N-( 2-pyrimidinyl)-6-chloro-1,4-benzodioxane-5-carboxamide 280 ml of methyl ethyl ketone and 13 g of 2-amino-pyrimidine were placed in a 500 ml balloon flask provided with a stirrer and a thermometer The mixture was 15 cooled to 10 C, 28 g of ground 6-chloro-l,4-benzodioxane-5-carbonyl chloride was added and the mixture was stirred for 2 hours, the temperature being allowed to rise to 20 C The resulting solid was filtered off, washed with 30 ml of methyl ethyl ketone and dissolved in 250 ml of boiling water The solution was treated with l Oml of 36 Be caustic soda After filtration, 12 g of product was obtained It was 20 recrystallized from 150 ml of ethanol 9 5 g of N-( 2-pyrimidinyl)-6chloro-1,4-benzodioxane-5-carboxamide was obtained (M P = 223 C with decomposition) The structure was confirmed by NMR analysis.

EXAMPLE 52.

* 5-l( 4-Methyl 1 -piperazinyl)carbonyll 6-nitro 1,4-benzodioxane hydrochloride 25 360 ml of methyl ethyl ketone and 16 g of N-methylpiperazine were introduced into a 500 ml balloon flask provided with a stirrer and a thermometer The mixture was cooled to 10 C and 36 5 g of 6-nitro-l,4-benzodioxane-5-carbonyl chloride was then added in portions The mixture was maintained under stirring at ambient temperature for one hour The precipitate was dried off, washed with 150 ml of 30 methyl ethyl ketone, dried and then dissolved in 210 ml of cold water The solution was acidified to p H 1 by addition of hydrochloric acid, treated with carbon black and filtered The base was precipitated by addition of 15 ml of caustic soda The precipitate was washed with water and dried 24 g was obtained (M P = 221 C).

The base was then treated with 168 ml of ethanol containing 8 ml of water and 35 8 ml of hydrochloric acid (specific gravity = 1 18) After crystallization, the solid was filtered off, washed and dried 19 5 g of 5 l( 4-methyl-l-piperazinyl) carbonyll-6nitro-l,4-benzodioxane hydrochloride was obtained (M P 205 C with decomposition) The structure was confirmed by NMR analysis.

EXAMPLE 53 40

N,N-diethyl-7-cyclohexylsulphamoyl 1,4-benzodioxane-5-carboxamide 7-Cyclohexylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 250 mi of water and 300 ml of cyclohexylamine were placed in a 1 litre balloon flask 139 g of moist 7-chlorosulphonyl-l,4-benzodioxane-5-carboxylic acid was added portionwise, the temperature being maintained at from 20 to 30 C The 45 mixture was stirred at room temperature for 3 hours and then the solution was treated with 30 g of carbon black 3 S After filtration, 300 ml of hydrochloric acid (specific gravity = 1 18) was added The precipitate was recrystallized, washed with water and dried 92 g of 7-cyclohexylsulphamoyl-l,4-benzodioxane-5carboxylic acid was obtained (M P 150 C) 50 N,N-Diethyl-7-cyclohexylsulphamoyl-1,4-benzodioxane-5-carboxamide 34.1 lg of 7-cyclohexylsulphamoyl-1,4-benzodioxane-5-carboxylic acid, 35 m 1 of water and 10 5 g of triethylamine were introduced into a 250 mi balloon flask provided with a stirrer and a thermometer 1 O Oml of acetone was added and the mixture was cooled to 10 C 14 g of isobutyl chloroformate was added and the 55 mixture was stirred for 30 minutes at room temperature 8 g of diethylamine was introduced at a temperature of from 15 to 20 C After stirring during 3 hours, the solvent was removed under vacuum The residue was washed with water, dried and dissolved in 180 ml of absolute ethanol and the solution was treated with 3 g of carbon black After filtration and crystallization, 23 g of N,N-diethyl-7cyclohexyl 60 1,571,447 sulphamoyl-l,4-benzodioxane-5-carlioxamide was obtained (M P 201 C) The structure was confirmed by IR and NMT analyses.

EXAMPLE 54.

N-( 4-methyl 1 -piperazinyl)-7-nitro 1,4-benzodioxane-5-carboxamide hydroS chloride 5 7-Nitro-1,4-benzodioxane-5-carbonyl chloride 112 ml of thionyl chloride and 55 g of 7-nitro-l,4-benzodioxane-5carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a thermometer and a reflux condenser The mixture was stirred and 1 ml of dimethylformamide was added with heating After stirring for I hour at the reflux 10 temperature, the excess of thionyl chloride was removed by distillation under vacuum 61 g of 7-nitro-l,4-benzodioxane-5-carbonyl chloride was obtained (M P.

108 C; Yield near 100 %).

N-( 4-methyl-l-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide 33 g of 1-amino-4-methylpiperazine was dissolved in 630 ml of methyl ethyl 15 ketone The mixture was cooled to 10 C and 61 g of 7-nitro-l,4benzodioxane-5carbonyl chloride was introduced in portions The mixture was stirred for 2 hours and the solid was then filtered off and washed with 150 ml of methyl ethyl ketone.

The resulting product was purified by transformation into the base (M P 212 C) and crystallization by treatment with ethanolic hydrogen chloride 45 g of N-( 4 20 methyl 1 -piperazinyl)-7-nitro 1,4-benzodioxane-5-carboxamide was obtained (M.P 210 C with one mole of water) The structure was confirmed by NMR and IR analyses.

EXAMPLE 55.

N(l-allyl-2-pyrrolidinylmethyl)-6,7-azimido-1,4-benzodioxane-5carboxamide 25 hydrochloride 6,7-Dinitro-I,4-benzodioxane-5-carboxylic acid ml of nitric acid (specific gravity = 1 49) was placed in a 500 ml balloon flask provided with a mechanical stirrer and a thermometer 90 g of 1,4benzodioxane-5carboxylic acid was added at -10 C The mixture was maintained for 2 hours at 30 room temperature, then 1 litre of iced water was added The precipitate was filtered off, washed with water, dried at 50 C, and purified by recrystallization from acetic acid 87 g of 6,7-dinitro-l,4-benzodioxane-5-carboxylic acid was collected (M.P 211 C).

6,7-Diamino-1,4-benzodioxane-5-carboxylic acid 35 g of 6,7-dinitro-l,4-benzodioxane-5-carboxylic acid, 500 ml of water and ml of caustic soda were introduced into a 1 litre autoclave and hydrogenated under a 80 kg/cm 2 pressure in presence of Raney nickel The mixture was heated to C for 2 hours, then cooled and filtered; the nickel was washed on the filter with 200 ml of water and the filtrates were kept all together A sample was acidified with 40 hydrochloric acid to form 6,7-diamino-l,4-benzodioxane-5-carboxylic acid dihydrochloride, which was filtered, washed and dried (M P 153 C).

6,7-Azimido-1,4-benzodioxane-5-carboxylic acid The filtrate obtained in the preceding step was introduced in a 2 litre balloon flask provided with a mechanical stirrer and a thermometer A solution of 35 g of 45 sodium nitrite in 70 ml of water was added dropwise at a temperature from 20 to C The crystallized product was filtered off, washed with water and dried at C 96 g of 6,7-azimido-l,4-benzodioxane-5-carboxylic acid was obtained (Yield 87 %) The structure was confirmed by NMR analysis.

6,7-Azimido-1,4-benzodioxane-5-(N-phthalimide carboxylate) 50 74 g of 6,7-azimido-l,4-benzodioxane-5-carboxylic acid, 1 litre of dimethylformamide, 57 g of N-hydroxyphthalimide and 74 5 g of dicyclohexylcarbodiimide were heated at a temperature of 90 C for 30 minutes After cooling to 20 C, the crystals were filtered off and washed with 150 ml of dimethylformamide The filtrates were evaporated under vacuum and the residue was treated with 400 ml of 55 methanol The solid was filtered, washed and dried 80 g of 6,7-azimido-l,4benzodioxane-5-(N-phthalimide carboxylate) was obtained (M P above 250 C; Yield 65.6 %).

1,571,447 N-( -allyl-2-pyrrolidinylmethyl)-6,7-azimido-1,4-benzodioxane-5carboxamide hydrochloride 92 g of 6,7-azimido- 11,4-benzodioxane-5-(N-phthalimide carboxylate) and Oml of dimethylformamide were introduced into a 1 litre balloon flask provided with a mechanical stirrer and a thermometer 45 g of 1-allyl-2-aminomethylpyrrol 5 idine was added under 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 After filtration, 50 ml of an ethanolic solution of hydrochloric acid was added to the filtrate The product was filtered, washed and recrystallized 50 g of N( 1 -allyl-2-pyrrolidinylmethyl)-6,7-azimido 1,4-benzodioxane-5carboxamide hydro 10 chloride was obtained (M P 255 C) The structure was confirmed by IR and NMR analyses.

EXAMPLE 56.

5-l( 4-methyl-1-piperazinyl)carbonyll 6,7-dinitro-1,4-benzodioxane 6,7-Dinitro-1,4-benzodioxane-5-(N-phthalimide carboxylate) 15 54 g of 1,4-benzodioxane-6,7-dinitro-5-carboxylic acid and 400 ml of dimethylformamide were introduced into a 1 litre balloon flask provided with a mechanical stirrer and a thermometer 34 2 g of N-hydroxyphthalimide and 44 4 g of dicyclohexylcarbodiimide were added under stirring The mixture was heated to 90 C for 30 minutes, then cooled to 10 C After filtration, the filtrate was evaporated under 20 vacuum and the residue recrystallized from methanol 67 5 g of 6,7-dinitrol,4benzodioxane-5-(N-phthalimide carboxylate) was obtained (M P 225 C; Yield:

81.3 %).

l( 4-methyl)-1-piperazinyl)carbonyl J-6, 7-dinitro-1,4-benzodioxane 67 g of 6,7-dinitro-l,4-benzodioxane-5-(N-phthalimide carboxylate) was 25 dissolved in 400 ml of dimethylformamide 20 g of N-methylpiperazine was added and the mixture was stirred for 2 hours After evaporation of the solvent under vacuum, I litre of water was added to the residue The solid was filtered and recrystallized from dimethylformamide 40 g of 5 l( 4-methyl)-1piperazinyl)carbonyll-6,7-dinitro-l,4-benzodioxane was obtained (M P 254 C) The structure 30 was confirmed by NMR analysis.

EXAMPLE 57.

N-( -piperidinopropyl)-6,7-diacetamido 1,4-benzodioxane-5-carboxamide In the same manner as described in Example 53, 6,7-diacetamido-l,4-benzodioxane-5-carboxylic acid (prepared by acetylation of 6,7-diamino-l,4benzo 35 dioxane-5-carboxylic acid) was condensed with 1-piperidinopropylamine in the presence of isobutyl chloroformate N-( 1-piperidinopropyl)-6,7diacetamido-1,4benzodioxane-5-carboxamide was obtained (M P = above 250 C with decomposition) The structure was confirmed by NMR analysis.

EXAMPLE 58 40

5-l( 4-Methyl-l-piperazinyl)carbonyll-7-amino 1,4-benzodioxane In the same manner as described in Example 2, 7-amino-1,4-benzodioxane-3carboxylic acid was treated with methanol, then the resulting carboxylic ester was reacted with N-methyl-piperazine 5-l( 4-Methyl-l-piperazinyl)carbonyll-7amino1,4-benzodioxane was obtained (M P 170 C) 45 EXAMPLE 59.

N( 1 -ethyl-2-pyrrolidinylmethyl) 1,4-benzodioxane-5-carboxamide hydrochloride In the same manner as described in Example 17, by reaction of 1,4-benzodioxane-5-carbonyl chloride with 1-ethyl-2-aminoethylpyrrolidine, N(lethyl-2pyrrolidinylmethyl)-l,4-benzodioxane-5-carboxamide hydrochloride was obtained 50 (M.P 149-150 C).

The compounds whose synthesis is described in the above Examples, are summarized in Table I.

1,571,447 z:

U 11 :z C) f X U m W U U P c P 4 z PP z W z z 0 Q J m 1 I1,571,447 )l k%,514 ki.ll 1 '_i TABLE I (Continued) R A N' ExX Y Z A N'B NR, R 2 6 H H H -(CH 2)2NH J 7 -As 7 H SO 2 N 2 H -(CH 2)2NH J 77 syCH 2-CH=CH 2 8 H 502 NHCH 3H -(CH 2)2NH ip 711 C 2 H, 9 H H H -(CH 2)ARNH 3-IH.

(L) 11 (D)H 502 C 2 H,H -(CH 2)2 NH C 2 H, TABLE I (Continued) R A NI Ex X Y Z A N' f B NR, R 13 H SO 2 NH 2 H -(CH) NH S CH, 14 H so 2 C 2 H, H -(CH 2)2 NH -h i 7 l77 CH 2-CH =CH 2 H H H -(CH 2)3 NH i 7 JC 2 H, 16 H so 2 NHCH, H -(GCH 2)2 NH CH, 17 H H H -(CH 2)2 NH -CH 2-CH 2N-C 2 H, C 2 H, tci t-h TABLE 1 (Continued) R N' Ex X y z A NR' B NRI R is H 502 C 2 H, H -(CH 2)2 _ NH C 2 H, 19 H SO N(CH,), H -(CH NH CH, 2 2)2 _ H 502 NHCH,, H -(CH 2)2 _ NH 21 H 502 MCH,)2 H -(CH 2)2 _ NH Icy,? C 2 H, 22 (D) H SO, NHCH, H -(CH 2)2 _ NH gypsy C 2 H, 23 (L) o t A -Pl 4:1 j t.i \ O z z EM ell C 14 CA en 1,571,447 P 4 e P 4 z m z 4 z z l.

z U N U 11 U 1 r.

U m m X z:

U W ;a 0 :3 r.

0 U W m C ETABLE I (Continued) R IF '% A NRI B NRI R 2 -WH 2)2 _ CH, \".-i -(CH,r , CH 3 2)2 _ -A \_J LA j 4 I b.

TABLE 1 (Continued) R f A NR' B NR, R 2 -(CH 2)2 _ NH e# C 2 H, I? J 3 )v -(CH 2)2 _ \-i t^ P.

P.

-j W hi 1,571,447 3-1 0 :i r.

z r_l 0 U W 4 on TABLE I (Continued) R / NI Ex X Y Z A NR' B NR, R 46 NH 2 H H -(CH 2)2 NH J 77 C 2 H, 47 cl H H -(CH 2)2 CH, 48 NHCOCH, H H -(OH 2)2 NH J 77 l C 2 H, 49 NHCOCH, NO 2 H -(OH 2)2 NH -CH 2CH 2N-C 2 H,02 H 3 H-C 2 2 N d YCH 2-CH=CH 2 TABLE I (Continued) R NI Ex X Y Z A NR' B NR 1 R 2 51 H H cl -(CH 2)2 H 52 H H NO 2 -(CH 2)2 CH, 53 H H -(C H 12)2 N-C 2 H, C 2 H, 54 H NO 2 H -(C 12)2 NH H Rl-(Gi 12)2 NH CH 2-CH =CH 2 t Jli i.h :2 P P.

j TABLE I (Continued) C-^I -43 -.b Compounds according to the invention may be used in various forms such as capsules, tablets, pills, granules and injectable solutions, the preparation of which is known per se Substances that do not react with the compounds may be used, e g.

lactose, magnesium stearate, starch, talc, celluloses, levilite, alkali metal lauryl sulphates, saccharose and other vehicles used in medicinal preparations.

Compounds according to the invention may be administered at dosages of 50 to 900 mg per day It is advantageous to use 50 to 300 mg per day and preferably 100 to 150 mg per day The following examples concern pharmaceutical compositions prepared by methods known per se and containing compounds of the invention.

37 1,571,447 37 EXAMPLE 60.

Tablets of the following composition are prepared:

Form 1 Form 2 Form 3 N-( 1-ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4-benzodioxane-5-carboxamide 50 mg 50 mg 50 mg 5 Dried starch 30 mg 30 mg 20 mg Lactose 80 mg 80 mg 120 mg Methylcellulose 1500 cps 1 3 mg 1 2 mg 1 2 mg Magnesium stearate 3 mg 2 5 mg 3 mg Levilite 8 mg 6 3 mg 5 8 mg 10 EXAMPLE 61.

Tablets of the following composition are prepared:

N-( 1 -methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane-5-carboxamide 50 mg Dried starch 20 mg 15 Lactose 80 mg Methylcellulose 1500 cps 1 3 mg Levilite 6 mg Magnesium stearate 3 mg EXAMPLE 62 20

Tablets of the following compositions are prepared:

Form 1 Form 2 N-( 1 -allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl1,4-benzodioxane-5-carboxamide 50 mg 50 mg Dried starch 15 mg 10 mg 25 Lactose 50 mg 62 mg Methylcellulose 1500 cps 1 mg 1 mg Levilite 5 mg 5 mg Magnesium stearate 2 mg 2 mg 1,571,447 EXAMPLE 63.

Tablets of the following composition are prepared:

N-( 1-methyl-2-pyrrolidinylmethyl)-7-sulphamoyl1,4-benzodioxane-5-carboxamide 50 mg Dried starch 10 mg Lactose 50 mg Methylcellulose 0 94 mg Levilite 6 mg Magnesium stearate 2 mg EXAMPLE 64.

Tablets of the following composition are prepared:

N-( l-methyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl1,4-benzodioxane-5-carboxamide 50 mg Dried starch 10 mg Lactose Codex 50 mg Methylcellulose 1500 cps 0 55 mg Levilite 4 mg Magnesium stearate 2 mg EXAMPLE 65.

Capsules of the following composition are prepared:

N-( l -ethyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl-1,4-benzodioxane-5-carboxamide 50 mg Dried starch 15 mg Lactose 50 mg Methylcellulose 1500 cps 1 mg Levilite 5 mg Magnesium stearate 2 5 mg Tablets are prepared by mixing the selected compound with starch and lactose by the successive dilution method Granules are prepared from this mixture and methylcellulose, Levilite, magnesium stearate and talc are added to granules before compressing Methylcellulose may be replaced by any suitable granulating agent such as ethylcellulose, polyvinylpyrrolidone, starch paste or gum-arabic Starch may also be replaced by another partition agent such as maize-starch, carboxymethyl amyloids, alginates or microcrystalline cellulose.

Injectable solutions may be prepared by dissolving a compound according to 39 1,571,447 39 the invention in hydrochloric, levulinic, gluconic or glucoheptonic acid The solution, prepared under sterile conditions, is made isotonic by an alkali metal chloride such as sodium chloride, then preservatives are added.

The same solution may be prepared without preservatives: an ampoule is filled under nitrogen atmosphere, then sterilized for half an hour at 1000 C 5 Compounds of the invention have been found to possess attractive anxiolytic, psychostimulant, disinhibiting and indeed thymoanaleptic effects, giving rise to properties suitable for therapeutic uses in the psychofunctional sphere and in particular in gastro-enterology, cardiology, urology, rheumatology and gynaecology Their low level of toxicity is compatible with use in human therapy, 10 without the danger of secondary effects.

The acute toxicity of the compounds of the invention was determined in Swiss mice by parenteral (intravenous, intra-peritoneal and subcutaneous) and by oral administration Lethal doses 50 are shown in Table II.

The numbering of the compounds in the following tables corresponds to the 15 numbers of the Examples.

1,571,447 TABLE II TOXICITY LD 50 Mice mg/kg (base) Compound I V IP SC P O 1 171 5-172 522-540 1344-1440 2 48-49 6 312-320 594-624 O % at 3000 mg/kg 3 120-120 4 220 8-225 6 7 96 6-100 8 84 6-90 322-328 1450-1485 35 % at 2000 mg/kg 150-157 5 350-363 1260-1360 11 168-184 442-450 12 147-154 480 1225-1230 1400-1470 13 64-67 5 234-240 430-437 0 % at 3000 mg/kg 14 146-157 325-338 420-442 2900-3491 79 7-86 2 224-227 572-613 756 16 88-96 380-396 925-1014 2760-2900 17 49 1 241 575 544-679 72 5-76 180-184 5 476-499 5 1190-1200 21 196-208 22 83 6-86 23 115 5-126 1,571,447 TABLE II TOXICITY (Continued) LD 50 Mice mg/kg (base) Compound IV IP SC PO 24 216-232 160-168 26 105-116 27 80-83 6 28 141-154 3875-418 1620-1850 2100-2400 39 164-175 896-957 960 1560-1600 Compounds of the invention are moreover virtually devoid of cataleptic activity They were administered subcutaneously to rats The criterian in respect of the cataleptic state was immobility of the animal for 30 seconds, the front limbs of the animal being spread apart and arranged carefully on wood cubes which were 4 cm in height, thus putting the animal into an unusual and uncomfortable position.

Cataleptic activity was measured at the maximum of the effect The results are given in Table III.

42 1,571,447 42 TABLE III CATALEPTIC ACTIVITY Compound ED 50 SC Rat mg/kg 1 Effect of 40 % at 200 mg/kg 2 Inactive at 200 mg/kg 3 325 mg/kg Effect of 30 % at 200 mg/kg 7 Inactive at 200 mg/kg 8 Effect of 10 % at 200 mg/kg Inactive at 200 mg/kg 11 Inactive at 200 mg/kg 12 Inactive at 200 mg/kg 13 Inactive at 200 mg/kg 14 Effect of 10 % at 200 mg/kg Inactive at 200 mg/kg 16 Inactive at 200 mg-/kg 17 389 mg/kg Inactive at 200 mg/kg 21 Inactive at 200 mg/kg 24 Effect of 30 % at 200 mg/kg Inactive at 200 mg/kg 28 Inactive at 200 mg/kg 39 Inactive at 200 mg/kg From these results it will be seen that the compounds of the invention are virtually devoid of cataleptic activity in a rat This property permits clinical usage of the compounds of the invention, with a high degree of tolerance in respect of the extrapyramidal system The compounds of the invention are also found to be 5 particularly active in a dog in respect of the central emetic agent such as apomorphine The experimental procedure followed was that of CHEN and ENSOR The compounds of the invention were administered subcutaneously 30 minutes before apomorphine ( 1100,tg/kg/SC); the animal was observed half an hour after the injection of the alkaloid 10 The results are given in Table IV.

TABLE I V: ANTIEMETIC ACTIVITY ED 50 ag/kg/SC Dog Effect of 8 % at 5 ttg/kg/SC 5.5 1.5 3.5 3.9 2.3 3.5 The interest aroused by the experiments carried out on laboratory animals has been found to be very largely justified when carrying out human clinical tests of the compounds of the invention.

The following can be quoted by way of example:

The case of a 38 year old patient suffering from Hodgkins disease; subjected to repeated chemo therapy as an out-patient, once a week; each session was accompanied by fits of nausea and then very substantial vomiting, persisting for 24 hours in spite of the usual treatments.

Treatment, 24 hours before the beginning the perfusion and 4 hours afterwards, with 50 mg of N-( I -ethyl-2-pyrrolidinylmethyl-7methylsulphamoyl 1,4benzodioxane-5-carboxamide totally suppressed the nausea and vomiting attacks.

The product was perfectly well tolerated and no secondary effect was observed.

A 28 year old data-processing engineer suffered from a characterial neurosis with bouts of anxiety culminating in three attempts at suicide Analytical treatment for 18 months made it possible to achieve social reintegration but had little effect on the anxiety aspect.

The administration of 50 mg of N-( 1-methyl-2-pyrrolidinylmethyl)-7methylsulphamoyl-1,4-benzodioxane-5-carboxamide three times per day, caused in a few days the complete disappearance of any anxiety, without any troublesome sedative action The product was perfectly well tolerated, and no secondary effect was observed.

A 78 year old subject had been suffering for 8 months from severe reactional depression (close bereavement) The existence of a prostatic adenoma contraindicated the use of tricyclics He was treated three times a day with 50 mg of N-( 1methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-l,4 benzodioxane 5 carboxamide, and in three weeks, as his condition had substantially improved, he was able to leave hospital The treatment, which has been continued at home for 3 months, Compound 8 1,571,447 411 makes it possible to maintain an excellent psychic balance, with the resumption of normal activity in a retired person of this age.

The product was perfectly well tolerated, and no secondary effect was observed.

A 42 year old subject underwent a hysterectomy for a fibroma 5 months ago S Some days after the operation, hot flushes ( 10 to 20 a day) appeared with attacks of sweating which awoke the patient during the night and caused her to be embarrassed during her work.

She was treated with N-(l-ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl1,4-benzodioxane-5-carboxamide at a single dose of 100 mg a day, the symptoms 10 disappeared within 4 days Only one hot flush still persisted during the day occurring every 2 or 3 days.

The product was perfectly well tolerated and no side-effects were observed.

A 47 year old patient suffered, after the menopause, from repeated attacks of cystitis with frequency and severe urgency such that no social life was possible The 15 patient consulted general practitioners and specialists All the tests were negative and all treatment was without effect in this classical case of cystitis.

She was treated for some days with N-(l-methylsulphamoyl-1,4-benzodioxane-5-carboxamide at a dose of 150 mg a day and the symptoms completely disappeared and her psychological state became normal 20

Claims (1)

1. WHAT WE CLAIM IS:-

   1 Novel substituted 2,3-alkylene bis (oxy) benzamides having the following general formula:

   z /R 1 and their pharmaceutically acceptable acid-addition salts, their quaternary 25 ammonium salts, their N-oxides, and dextrorotatory and levorotatory isomers thereof, in which A represents a C 1, alkylene chain optionally substituted by a C,, alkyl, C 2,4 alkenyl, or C 1,4 hydroxyalkyl group; R represents a hydrogen atom, a C,-4 alkyl group or a radical having the general formula (II) 30 2 R, -q Bn N (II) R,, in which n is O or 1; B represents a C 1, alkylene chain, which may or may not be substituted by a C 1 _ 4 alkyl group or C 2 _ 4 alkenyl group and 35 R, represents a hydrogen atom, a C 1 _ 4 alkyl, C 24 alkenyl or C 24 alkynyl group or a substituted alkyl group or R 1 is joined to B to form a saturated or unsaturated nitrogenous heterocycle; R 2 represents a hydrogen atom; a C 1,4 alkyl, C,-4 alkenyl or C,-4 alkynyl group; a substituted alkyl group, a substituted or unsubstituted saturated or 40 unsaturated heterocycle comprising one or more heteroatoms, or a phenyl, adamantyl, cycloalkyl, bicycloalkyl or cycloalkenyl group, connected to the nitrogen atom of formula (II) directly by a carbon atom of the ring or by means of a substituted or unsubstituted alkylene chain; or R 2 and R 1 are connected together to form, together with the N atom of 45 formula (II), a heterocycle, which may optionally contain other heteroatoms, in which, when the heterocycle contains another nitrogen atom, that is optionally substituted by a C 1,4 alkyl, C 2,4 alkenyl, C 2,4 alkynyl, phenyl, benzyl, cycloalkyl, 1,571,447 cycloalkenyl, cycloalkanealkyl, cycloalkenealkyl, adamantyl or bicycloalkyl group, or an alkyl group substituted by a hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio group; R' represents a hydrogen atom, or a C 1 _ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, adamantyl, pyrimidinyl, pyrazinyl, diazepinyl, quinuclidinyl, azabicycloalkyl, 5 diaza-bicycloalkyl, bicycloalkyl, substituted or unsubstituted phenyl or aralkyl group or R' and B are connected together to form a monoaza substituted or unsubstituted heterocycle, or R' and R, are joined together to form a saturated or unsaturated substituted or unsubstituted diaza heterocycle; X represents a hydrogen or halogen atom, or a hydroxy, nitro, amino, 10 substituted amino, C,_ 4 alkoxy or C,_ 4 alkyl group, Y represents a hydrogen or halogen atom, a hydroxy, amino, substituted amino, nitro, C,_ 4 alkoxy, C,_ 4 alkylsulphonyl, adamantylsulphonyl, or cycloalkyl sulphonyl group or a group of formula SO 2 NR 3 R 4 in which each of R 3 and R 4, which can be identical or different, is a hydrogen atom or a C,4 alkyl, C 24 alkenyl, 15 C 2 _ 4 alkynyl, phenyl, benzyl, cycloalkyl, cycloalkanealkyl, cycloalkenealkyl, bicycloalkyl, adamantyl, pyrimidinyl or pyrazinyl group or an alkyl group having a hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio substituent, or R 3 and R 4, together with the nitrogen atom to which they are attached, form a heterocycle which may optionally contain another heteroatom;

   20 Z represents a hydrogen or halogen atom or a hydroxy, amino, substituted amino, nitro, or a C,_ 4 alkoxy group; or X and Y or Y and Z are connected together through a substituted or unsubstituted carbon chain or through a heteroatom to form a ring; provided that when A is -CH 2-CH 2 or -CH 2-, at least one of X, Y, Z, R 25 and R' is other than a hydrogen atom.

   2 A compound according to Claim 1, in which R is a dialkylaminoalkyl group.

   3 A compound according to Claim 2, in which R is a diethylaminoethyl group.

   4 A compound according to Claim 1, in which R is a l-alkyl-2-pyrrolidinylalkyl group 30 A compound according to Claim 4, in which R is a 1-ethyl-2-pyrrolidinylmethyl group.

   6 A compound according to Claim 4, in which R is a l-methyl-2pyrrolidinylmethyl group.

   7 A compound according to Claim 1, in which R is a 1-cycloalkyl-3-pyrroli 35 dinyl group.

   8 A compound according to Claim 7, in which R is a l-cyclohexyl-3-pyrrolidinyl group.

   9 A compound according to Claim 1, in which R is a l-alkenyl-2pyrrolidinylalkyl group 40 A compound according to Claim 9, in which R is a 1-allyl-2-pyrrolidinylmethyl group.

   11 A compound according to Claim 1, in which R' and R, are linked together so as to form a saturated dinitrogenous heterocycle and R 2 is a heterocyclic group.

   12 A compound according to Claim 11, in which R' and R, are linked together 45 so as to form a piperazine and R 2 is a 2-pyrimidinyl group.

   13 A compound according to Claim 1, in which R' and R, are linked together so as to form a saturated dinitrogenous heterocycle and R 2 is an alkyl group.

   14 A compound according to Claim 13, in which the heterocycle is a piperazinyl ring and the alkyl group is a methyl group 50 A compound according to Claim 1, in which R', R, and R 2 are linked together so as to form a diazabicycloalkane residue.

   16 A compound according to Claim 15, in which the diazobicycloalkane is diazabicyclo l 4 5 0 l nonane.

   17 A compound according to Claim 1, in which R, and R 2 are joined to form a 55 heterocycle.

   18 A compound according to Claim 17, in which the heterocycle is piperidinyl.

   19 A compound according to Claim 1, in which R is a l-aralkyl-2-pyrrolidinylalkyl group 60 A compound according to Claim 19, in which R is a l-benzyl-2-pyrrolidinylmethyl group.

   21 A compound according to Claim 1, in which R' is an alkyl group.

   22 A compound according to Claim 21, in which R' is a butyl group.

   23 A compound according to Claim 21, in which R' is an ethyl group 65 1.571 447 46 1,571 447 46 24 A compound according to Claim 1, in which R and R' are both alkyl groups.

   A compound according to Claim 24, in which R and R' are both ethyl groups.

   26 A compound according to Claim 1, in which R' is an aralkyl group 5 27 A compound according to Claim 26, in which R' is a benzyl group.

   28 A compound according to Claim 1, in which R' is an adamantyl group.

   29 A compound according to Claim 1, in which R, and B are joined to form a heterocycle and R, is an aralkyl group.

   30 A compound according to Claims 1 and 29, in which the heterocycle is 10 piperidinyl and the aralkyl group is a benzyl group.

   31 A compound according to Claim 1, in which R' is a pyrimidinyl group.

   32 A compound according to Claim 1, in which R has the formula -N R, 33 A compound according to Claim 32, in which R is an alkyl piperazinyl is residue.

   34 N-( 1 I-allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4benzodioxane-5carboxamide.

   N-( 1 I-ethyl-2-pyrrolidinylmethyl)-7-sulphamoyl 1,4-benzodioxane-5carboxamide 20 36 N-( 1-methyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide.

   37 1 -( 2,3-Ethylenedioxy-5-sulphamoylbenzoyl)-4-( 2-pyrimidinyl) piperazine.

   38 N-( 1-Methyl-2-pyrrolidinylmethyl)-7-dimethylsulphamoyl 1,4-benzodioxane-5-carboxamide 25 39 N-( 1-Benzyl-2-pyrrolidinylmethyl) 1,4-benzodioxane-5-carboxamide.

   N-( 1 -Allyl-2-pyrrolidinylmethyl)-7-sulphamoyl 1,4-benzodioxane-5carboxamide.

   41 N-( 1-Ethyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1,4-benzodioxane5-carboxamide 30 42 N-( 1-Ethyl-2-pyrrolidinylmethyl)-2,3-imethylenedioxy-benzamide.

   43 N-( 1 I -Ethyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane5carboxamide.

   44 N-( 1 -Methyl-2-pyrrolidinylmethyl)-7-sulphamoyl 1,4-benzodioxane-5carboxamide 35 N-( 1-Allyl-2-pyrrolidinylmethyl)-7-ethylsulphonyl 1,4-benzodioxane-5carboxamide.

   46 N-( 1-Ethyl-2-pyrrolidinylmethyl)-2 H-3,4-dihydro 1,5-benzodioxepin-6carboxamide.

   47 N-( 1 -Methyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl 1,4-b enzo 40 dioxane-5-carboxamide.

   48 N-(Diethylaminoethyl)-1,4-benzodioxane-5-carboxamide.

   49 N-( 1-Cyclohexyl-3-pyrrolidinyl)-7-methylsulphamoyl 1,4-benzodioxane-5carboxamide.

   50 N-( 1 -Ethyl-2-pyrrolidinylmethyl)-7-dimethylsulpharnoyl 1,4-benzo 45 dioxane-5-carboxamide.

   51 N-( 1-Ethyl-2-pyrrolidinylmnethyl)-8-methylsulphamoyl-2 H-3,4-dihydro 1,5benzodioxepin-6-carboxamiide.

   52 N-( 1-Ethyl-2-pyrrolidinylniethyl)-2,3-methylenedioxybenzamide.

   53 4 ( 1,4-B enzodioxane-7-ethylsulphonyl-5-carbonyl) 1,4-diazabicyclo so l 4.3 O 1 nonane.

   54 5-l( 4-Methyl 1-ierazinyl)carbonyll-7-nitro-1 I,4-benzodioxane.

   5-l( 4-Methyl-1-piperazinyl)carbonyll-7-( 1-adamantyl)sulphamoyl 1,4benzodioxane.

   56 N-(Piperidinoethyl)-7-chloro-1,4-benzodioxane-5-carboxamide 55 57 N-butyl-7-l( 1-adamantyl)sulphamoyll 1,4-benzodioxane-5-carboxamide.

   58 N-( 1 I-Ethyl-2-pyrrolidinylmethyl)-8-methoxy-1 I,4-benzodioxane-5carboxamide.

   47 1,571,447 ' 47 59 N-( 1 -Ethyl-2-pyrrolidinylmethyl)-8-methoxy-7-sulphamoyl 1,4-benzodioxane-5-carboxamide.

   4-( 1,4-B enzodioxane-5-carbonyl) 1,4-diazobicyclol 4 3 01 nonane.

   61 N-benzyl-7-diethylsulphamoyl-1,4-benzodioxane-5-carboxamide.

   62 N-( 1 -Benzyl-4-piperidyl)-7-methylsulphamoyl 1,4-benzodioxane-5carbox 5 amide.

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

   64 N-( l-B enzyl-2-pyrrolidinylmethyl)-7-diethylsulphamoyl 1,4-benzodioxane-5-carboxamide.

   65 N-( 1-Benzyl-4-piperidinyl)1,4-benzodioxane-5-carboxamide 10 66 N-( 1-Ethyl-2-pyrrolidinylmethyl)-8-ethylsulphonyl-2 H-3,4-dihydro 1,5benzodioxepin-6-carboxamide.

   67 5 l( 4-methyl l-piperazinyl)carbonylll-6,7-dibromo-8-nitro 1,4-benzodioxane.

   68 N-( 1-Ethyl-2-pyrrolidinylmethyl)-6,7-dibromo-8-nitro 1,4-benzodioxane5 15 carboxamide.

   69 N-( l -Ethyl-2-pyrrolidinylmethyl)-8-amino 1,4-benzodioxane-5-carboxamide.

   5-l( 4-Methyl 1 -piperazinyl)carbonyll-8-chloro 1,4-benzodioxane.

   71 N-( l -Ethyl-2-pyrrolidinylmethyl)-8-acetamido 1,4-benzodioxane-5carbox 20 amide.

   72 N-(Diethylaminoethyl)-7-nitro-8-acetamido 1,4-benzodioxane-5-carboxamide.

   73 N-( 1-Allyl-2-pyrrolidinylmethyl)-7,8-azimido 1,4-benzodioxane-5carboxamide 25 74 N-( 2-Pyrimidinyl)-6-chloro-1,4-benzodioxane-5-carboxamide.

   5-l( 4-Methyl 1 -piperazinyl)carbonyll-6-nitro 1,4-benzodioxane.

   76 N,N-diethyl-7-cyclohexylsulphamoyl-1,4-benzodioxane-5-carboxamide.

   77 N-( 4-Methyl 1 -piperazinyl)-7-nitro 1,4-benzodioxane-5-carboxamide.

   78 N-( l -Allyl-2-pyrrolidinylmethyl)-6,7-azimido 1,4-benzodioxane-5carbox 30 amide.

   79 5-l( 4-Methyl 1 -piperazinyl)carbonyll-6,7-dinitro 1,4-benzodioxane.

   N-(Piperidinopropyl)-6,7-diacetamido 1,4-benzodioxane-5-carboxamide.

   81 5-l( 4-Methyl l -piperazinyl)-carbonyll-7-amino 1,4-benzodioxane.

   82 N-( 1-Ethyl-2-pyrrolidinylmethyl)-1,4-benzodioxane-5-carboxamide 35 83 A method of producing a compound of formula I, according to any one of Claims 1 to 82, comprising reacting a compound having the general formula:

   COD < X (III) z O X in which A, X, Y and Z are as defined in Claim I and D represents an organic residue capable of forming a reactive derivative, a hydroxy group or a halogen 50 atom, with an amine having the general formula:

   R / HN R' in which R and R' are as defined above, or one of its reactive derivatives.

   84 A method according to Claim 83, in which an acid halide reacts with an amine 55 A method according to Claim 83, in which an alkyl carboxylate reacts with an amine.

   86 A method according to Claim 83, in which a carboxylic acid reacts with an amine in the presence of an alkyl haloformate.

   87 A method according to Claim 83, in which a carboxylic acid reacts with an amine in the presence of an imidazolide.

   88 A method according to Claim 83, in which a carboxylic acid reacts with an amine in the presence of a phosphorus halide.

   89 A method as claimed in any one of Claims 83 to 88, including the further 5 step of converting the products by known means to their pharmaceutically acceptable acid-addition salts, their quaternary ammonium salts or their oxides.

   A method as claimed in Claim 83, substantially as hereinbefore described in any one of Examples 1 to 59.

   91 A compound as claimed in Claim 1 when prepared by a method as claimed 10 in any one of Claims 83 to 90.

   92 A pharmaceutical composition, containing as active principle a compound as claimed in any one of Claims 1 to 83 and 91, with a pharmaceutically acceptable carrier, optionally containing other conventional addition agents.

   93 A composition as claimed in Claim 92, in which the said compound is 15 dissolved or suspended in a pharmaceutically acceptable liquid carrier.

   94 A composition as claimed in Claim 92, in which the said compound is mixed with a pharmaceutically acceptable solid carrier.

   A composition as claimed in Claim 90 in the form of a tablet, capsule, suppository, solution, suspension or aerosol 20 96 A composition as claimed in Claim 90 substantially as hereinbefore described in any one of Examples 60 to 65.

   For the Applicants D YOUNG & CO, Chartered Patent Agents, 9 and 10 Staple Inn, London WC 1 V 7RD.

   Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.

   Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

   1,571,447