IL35224A - P-aminoalkyl phenylsulphonyl-2-imino-imidazolidine derivatives,their production and pharmaceutical compositions containing them - Google Patents

Description

35224/3 o' ^san mnpm 'Twain pis , J ^IT«TB»R |niR p-Aminoalk l p ©aylei^pj¾onyl-2-iiain derivatives,, their production and pharmaceutica compositions containing them CIBA-G3IQY AG 0/ 33434 PROCESS FOR THE PRODUCTION OF NEW p-AMINOALKYL - BENZENESULPHONAMIDE DERIVATIVES "' The present invention relates to new derivatives of p-aminoalkyl benzenesulphonamide , to processes for their production, to medicaments containing the new compounds, and to the use thereof.

It has been found that p-substituted phenylsulphonyl 2-imino-imidazolidines of the general formula I: R, wherein R^ represents an optionally branched alkyl radical having 1-6. carbon atoms, an alkenyl radical having 3-5 carbon atoms, a cycloalkyl radical or cycloalkenyl radical having in each case 5-8 carbon atoms, a phenylalkyl radical having at most 9 carbon atoms, R2 represents hydrogen, an ethyl group or a methyl group, R^ represents an optionally branched alkyl group having 1-6 carbon atoms, m represents 2 or 3, n represents 1, 2, 3 or 4, Y represents oxygen or sulphur, and Z represents oxygen, sulphur, a sulphoxide or a sulphone. grouping, acids have a hypoglycaemic action on warm-blooded animals, in combination with a favourable therapeutic index.

In the compounds of the general formula I, can have, e.g. the following meanings: as the alkyl group, can denote the methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert .butyl, isobutyl, pentyl, isopentyl, 2 , 2-dimethylpropyl , 1-methylbutyl , 1-ethylpropyl or the 1, 2-dimethylpropyl group, or a straight-chained or branched hexyl radical, e.g. an n-hexyl, a methylpentyl , a dimethylbutyl , an ethylbutyl group as the alkenyl group, can denote the allyl, 1-methylallyl, 2-methylallyl, the 2- or 3-butenyl or the 2- , 3- or 4-pentenyl group; as the cycloalkyl group, can denote the cyclopentyl group which may be optionally substituted by alkyl radicals having 1-3 carbon atoms, the cyclohexyl group which may be substituted by ethyl or methyl, and the cycloheptyl group optionally substituted by methyl, as well as the cyclooctyl group; as the cycloalkenyl group, R^ can denote the 2-cyclopenten-1-yl, the 2-cyclohexen-l-yl , the 3-cyclohexen-l-yl , the 2-methyl-2-cyclohexen-l-yl, the 3-cyclohepten-l-yl group, or a cyclooctenyl group; as the phenylalkyl group, R^ can denote the benzyl, the phenylethyl or the a-methylphenylethyl group.

The substituent R^ embraces the same alkyl groups as those given under R^ .

Using the process according to the invention, d he ra form a ar b reacting an amine of the general formula II wherein R^, R2 and m have the meanings given under formula I, with a carboxylic acid or thiocarboxylic acid of the general formula III: Y R3 - Z - CnH2n " ^ " 011 (III> wherein 1 R^, Z, n and Y have the meanings given under the general formula I, or with a reactive derivative of such a carboxylic acid or thiocarboxylic acid; and, optionally, converting the obtained reaction products into the salt of an inorganic or organic acid.

The reaction of an amine of the general formula II with a carboxylic acid or thiocarboxylic acid of the , general formula III can be performed, e.g. by first converting the amine into the ammonium salt of an acid corresponding to formula III; and then converting the ammonium salt, by dry heating, into the amide of the general formula I. According to a preferred embodiment of the process according to the invention, an amine of the general formula II is reacted with a carboxylic acid or thiocarboxylic acid of the general formula III in the presence of a water-splitting agent in an inert solvent. A particularly suitable water-splitting agent is, e.g. Ν,Ν' -dicyclohexylcarbodiimide . As a water-splitting agent, it is also possible to use carbonyldipyrazole .

Suitable inert solvents are, e.g. hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, trichloroethylene and lower ketones such as acetone or methyl ethyl ketone .

Suitable reactive derivatives of a carboxylic acid or thiocarboxylic acid of the general formula III are, e.g. halides, especially chlorides, lower alkyl es-ters, especially methyl or ethyl ester, phenyl ester, amides, lower mono- or dialkylamides , especially N-methylamides and Ν,Ν-dimethylamides , diphenylamides , also N-acylamides such as, e.g acetylamides and benzoylamides .

The reaction of the aforementioned reactive derivatives of carboxylic or thiocarboxylic acids is performed, e.g. at room temperature, or by heating, in one of the above already mentioned organic solvents. In general, the reaction may be carried out without the addition of. condensation agents; optionally, however, such agents, e.g. alkali metal alcoholates and alkali metal hydroxides, can be added.

A halide of a carboxylic acid or thiocarboxylic acid of the general formula III is reacted according to the invention preferably in the presence of an acid-binding agent. As acid-binding agents, it is possible to use inorganic bases or salts such as, e.g. an alkali hydroxide, alkali acetate, alkali hydrogen carbonate, alkali carbonate and alkali phosphate, such as sodium hydroxide, sodium acetate, sodium hydrogen carbonate, sodium carbonate and sodium phosphate, or the corresponding potassium compounds. It is also .possible to use calcium oxide, calcium carbonate, as well as calcium phosphate and magnesium carbonate.

Also suitable, in place of inorganic bases or salts, 1 · , ■ are organic bases such as, e.g. pyridine, trimethylamine o or triethylamine, diisopropylamine, or collidine.

Added in excess, these can also be used as solvent.

Instead of amines of the general formula II, it is also possible to use, for the reaction according to the invention with a carboxylic acid or thiocarboxylic acid, N-alkali metal derivatives of these compounds such as, e.g. sodium, potassium or lithium derivatives.

The starting compounds of the general formula II are, for their part, new compounds and can be produced, e.g. by reacting a reactive derivative of a sulphonic acid of the general formula IV:. substituted sulpbohic acids.

The carboxylic acids or thiocarboxylic acids of the general formula III can be obtained in a simple manner by reacting alcoholates or thiolates of the general formula VI: R3 - Z1 - Me (VI), wherein has the meaning given under the general formula I, Z' denotes oxygen or sulphur, and Me denotes a monovalent metal, with halogen-alkanoic acids or their lower alkyl esters of the general formula VII: Hal - C H0 - COOR (VII) n 2n and, if an ester has been used as starting material, ' optionally saponifying this, and converting the obtained acid into another reactive derivative.

The carboxylic acids of the general formula III (obtained with thiolates of the general formula VI), in which Z represents a sulphur atom, can be converted by oxidation, e.g. with hydrogen peroxide or with potassium permanganate, into the corresponding carboxylic acids of the general formula III, wherein Z represents the sulphoxide or sulphone grouping.

For the preparation of derivatives of carboxylic or thiocarboxylic acids of the general formula III, wherein n is equal to 2, there is also the possibility of addition of corresponding alkanols or alkanethiols to acrylic acid derivatives.

Using a further process, starting materials of the general formula II are obtained by reacting substituted p- (aminoalkyl) -benzenesulphonamides (produced analogously to the method of E. Miller, J.Amer. Chem. Soc . 62 , 2101 (1940)) of the general formula VIII: V;· wherein m has the meaning given under formula I, with substituted N- (2-bromoalkyl) -cyanamides in alkaline medium.

The new substances, or the pharmaceutically acceptable salts thereof, can be administered orally or parenterally. For salt formation, it is possible to use physiologically harmless inorganic or organic acids such as, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, lactic acid, succinic acid, tartaric acid and maleic acid, but also hypoglycaemic sulphonyl ureas such as, e.g. p-toluenesulphonylbutyl urea, p-chlorobenzenesulphonyl-propyl urea and p- [ 2- (2-methoxy-5-chlorobenzamido) -ethyl ] -phenylsulphonyl-cyclohexyl urea. The daily dosages are between 0.10 end 100 mg/kg for warm-blooded animals.

Suitable dosage units, such as dragees and tablets, contain preferably 10-200 mg of an active substance according to the invention, whereby the content of active dragees are produced by combining the active substance, e.g. with solid pulverulent carriers such as lactose; saccharose, sorbitol or mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives. or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights. Tablets and dragdie cores are coated, e.g. with concentrated sugar solutions which may also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. for identification of the various dosages of active substance.

Other suitable dosage units for oral administration are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener, such as glycerin.

The hard capsules contain the active substance prefereably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilisers such as sodium metabisulphite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stabilisers can be added.

The following prescriptions serve to further illustrate the production of tablets and dragees: a) An amount of 1000 g of 1- [p- (2-ethoxyacetamido-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine is mixed with 500 g of lactose and 270 g of potato starch; the mixture is then moistened with an aqueous solution of 8.0 g of gelatine, and granulated through a sieve.

After drying of the granulate, 60.0 g of potato sotarch, 60.0 g of talcum, 10.0 g of magnesium stearate and .0 g of colloidal silicon dioxide are mixed in; the mixture is then pressed to form 10,000 tablets each weighing 200 mg and each containing 100 mg of active substance. Optionally, the tablets may be provided with grooves for a more precise adjustment of the dosage amount. b) A granulate is produced from 1000 g of l-[p-(2-ethoxyacetamidoethyl) -phenylsulphonyl ) -2-imino-3-cyclohexyl-imidazolidine , 345 g of lactose, and the aqueous solution of 6.0 g of gelatine; the granulate is then mixed, after being dried, with 10,0 g of colloidal silicon dioxide, 40.0 g of talcum, 40.0 g of potato starch and 5.0 g of magnesium stearate; and the mixture is pressed into 10,000 dragee cores. These are subsequently coated with a concentrated syrup made from 533.0 g of crystallised saccharose, 20.0 g of shellac, 75.0 g of gum arabic, 250 g of talcum, 20 g of colloidal silicon dioxide and 1.5 g of dyestuff; and then dried. The obtained dragees each weigh 240 mg and each contain The following examples further illustrate the production of the new compounds of the general formu and of intermediate products not described hitherto; the examples in no way constitute, however, the only embodiments thereof. The temperatures are given in degrees Centigrade.

Example 1 To a solution of 35.6 g of 1- [p- (2-aminoalkyl) -phenyl- sulphonyl ] -2-imino-3-methyl-imidazolidine dihydrochloride , M.P. 230-235°, in 100 ml of water are added 150 ml of 2-n sodium hydroxide solution; and the liberated base is extracted with methylene chloride. To the extract, dried with sodium sulphate, are added at 0° 20.6 g of Ν,Ν' -dicyclohexylcarbodiimide . To the whole is then added dropwise at 0°, over 5 minutes, a solution of 9.0 g of methoxyacetic acid in 30 ml of methylene chloride.

After 2 hours stirring at 0°, the precipitated Ν,Ν' -dicyclohexyl urea is filtered off, and the clear filtrate concentrated by evaporation. The thus obtained crude 1- [ p- (2-methoxyacetamidoethyl) - phenylsulphonyl ] - 2-imino-3-methyl-imidazolidine is recrystallised from ethyl acetate/acetone. It contains 1 1/2 moles of crystal water and melts at 159-160°.

In an analogous manner are obtained, with in each case 20.6 g of Ν,Ν' -dicyclohexylcarbodiimide and 9.0 g of methoxyacetic acid, the following: a) from 38.2 g of 1- [p- (2-aminoethyl)-phenylsulphonyl ] -2-imino-3-allyl-imidazolidine dihydrochloride, M.P. 232-233°, is obtained: 1- [ p- (2-inethoxyacetamidoethyl) -phenylsulphonyl ] -2-imino 3-allyl-imidazolidine, M.P. 103-104° (from ether/petroleum ether); b) from 39.8 g of 1- [p- (2-aminocthyl) -phenylsulphonyl ] -2- imino-3-butyl-imidazolidine dihydrochloride, M.P. 231-233°, is obtained: 1- [ - (2-methoxyacetamidoethyl) -phenylsulphonyl ] - 2-imino- 3-butyl-imidazolidine; c) from 42.6 g of 1- [p- (2-aminoethyl) -phenylsulphonyl. ] -2- imino-3- (3-methylpentyl (2) ) -imidazolidine dihydrochloride (crude product) is obtained: 1- [p- (2-methoxyacetamidoethyl) -phenylsulphonyl ]- 2-imino-- 3- (3-methylpentyl (2)) -imidazolidine, M.P. 137-138° (monohydrate; from ethyl acetate/acetone); d) from 41.0 g of 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine dihydrochloride, M.P. 270°, is obtained: 1- [p- (2-methoxyacetamidoethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine, M.P. 151-151.5° (monohydrate; from ethyl acetate) ; e) from 42.4 g of 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine dihydrochloride, M.P. 247-250°, is obtained: 1- [p- (2-methoxyacetamidoethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine, M.P. 150-151° (monohydrate; from ethyl acetate) ; f) from 43.8 g of 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3- (4-methylcyclohexyl) -imidazolidine dihydrochloride, M.P. 260°, is obtained: 1- [p- (2-inethoxyacetamidoethyl) -phenylsulphonyl ] -2-imino 3- (4-methylcyclohexyl)-imidazolidine, M.P. 159-160° Example 2 To a solution of 42.3 g of 1- [p- (2-aminoethyl) -phenyl- sulphonyl ] -2-imino-3-cyelohexyl-imidazolidine dihydrochloride , M.P. 247-250°, in 200 ml of water are added 300 ml of 2-n sodium hydroxide solution, and the whole is extracted with methylene chloride. To the extract dried with sodium sulphate are added 50.5 g of triethylamine . An addition is then made dropwise at room temperature, within 20 minutes, of a solution of 13.5 g of ethoxy-acetyl chloride in 100 ml of methylene chloride; the obtained mixture is then stirred for one hour at room temperature. The reaction solution is then washed first with 100 ml of 2-n sodium hydroxide solution, and afterwards twice with 100 ml of water. The combined aqueous phases are extracted twice with methylene chloride, and the obtained methylene chloride extracts combined with the washed reaction solution. By concentration by evaporation of the methylene chloride solution (dried with sodium sulphate) is obtained the crude l-[p-(2-ethoxyacetamidoethyl) -phenylsulphonyl] -2-imino-3-cyclohexyl-imidazolidine which, after recrystallisation from ethyl acetate/petroleum ether, melts at 111-113°.

In an analogous manner are obtained with, in each case, 50.5 g of triethylamine: a) from 43.7 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine dihydrochloride, M.P. 270°, and 13.5 g of ethoxyacetyl chloride: cyclopentyl-imidazolidine, M.P. 105- 106 .5 (from ethyl acetate) ; b) from 41 .0 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2-imino-3-cyclopentyl-imidazolidine dihydrochloride, M.P. 270° , and 13 .7 g of methylthioacetic acid chloride: 1- [p- (2-methylmercaptoacetamidoethyl) -phenylsulphonyl ] - 2-imino-3-cyclopentyl-imidazolidine, M.P. 106-107° (purified by chromatography on the 20-fold amount of silica gel (grain size 0 .05 -0.2 mm) with chloroform + 57o methanol as solvent, and subsequent recrystallisation from ethyl acetate) .

Example 3 An amount of 39.8 g of 1- [p- (2-aminoethyl) -phenyl-sulphonyl ) -2-imino-3-butyl-imidazolidine dihydrochloride , M.P. 231-233°, is suspended, with stirring, in a mixture of 500 ml of methylene chloride and 100 ml of 50% aqueous potassium carbonate solution. The mixture is stirred for 30 minutes. To the mixture, cooled with ice, is then added dropwise a solution of 17.0 g of 2-ethylmercaptopropionic acid chloride in 100 ml of methylene chloride, and stirring proceeds for a further 30 minutes. The organic phase is then separated, washed with water, and the methylene chloride evaporated off. The thus obtained 1- [p- (2- (2-ethylmercapto-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-butyl^ imidazolidine melts, after recrystallisation from ethyl acetate, at 113-114°.

Example 4 An amount of 43.7 g of 1- [p- (2-aminoethyl) -phenyl-sulphonyl ] -2-imino-3- (4-methylcyclohexyl) -imidazolidine dihydrochloride, M.P. 260°, is suspended, with stirring, in a mixture of 500 ml of methylene chloride and 100 ml of a 50% aqueous potassium hydroxide solution, and stirring then proceeds for a further 30 minutes.

To the suspension, whilst it is being cooled with ice, is then added dropwise a solution of 15.0 g of 2-methyl-mercaptopropionic acid chloride in 100 ml of methylene chloride; stirring is continued for a further 30 minutes. The organic phase is separated, washed with water, and the methylene chloride evaporated off. The residue is dissolved in ethyl acetate, and the solution repeatedly extracted with 2-n hydrochloric acid. The combined acid extracts are made alkaline, whilst being cooled with ice, with cone, aqueous sodium hydroxide solution. The precipitated crude product is taken up with methylene chloride, the methylene chloride solution dried with sodium sulphate, and concentrated by evaporation. The thus obtained crude 1- [p- (2- (2-methylmercaptopropion-amido) -ethyl) -phenylsulphonyl ] -2-imino-3- (4-methylcyclohexyl) -imidazolidine is purified by recrystallisation from ethyl acetate. It melts at 157-158°.

In an analogous manner is obtained from 44.5 g of 1- [ p- (2-aminoethyl) rphenylsulphonyl ] -2-imino-3- (2- phenylethyl) -imidazolidine dihydrochloride and 16.0 of 3-ethylmercaptopropionic acid chloride: 1- [p- (2- (3-ethylmercaptopropionamido) -ethyl) -phenylsulphonyl ] -2-imino-3- (2-phenylethyl) -imidazol Example 5 An amount of 41.5 g of 1- [ p- (2-aminoethyl) -phenyl-sulphonyl ] -2-imino-3-isobutyl-imidazolidine dihydrochloride monohydrate, M.P. 151-152°, is suspended, with stirring, in a mixture of 500 ml of methylene chloride and 100 ml of 50% aqueous potassium hydroxide solution; stirring proceeds for a further 30 minutes. To the suspension, cooled with ice, is then added dropwise a solution of 17.0 g of 3-ethylmercaptopropionic acid chloride in 100 ml of methylene chloride; stirring continues for a further 30 minutes. The methylene chloride phase is separated, washed with water, and the methylene chloride evaporated off. The thus obtained crude l-[p-(2- (3-ethylmercaptopropionamido) -ethyl) -phenysulphonyl ] -2-imino-3-isobutyl-imidazolidine is purified by recrystallisation from ethyl acetate. It melts at 135-137°.

In an analogous manner are obtained: a) from 42.5 g of 1- [p- (2-aminoethyl) -phenylsulphonyl] -2-imino-3- (1 , 2-dimethylbutyl)-imidazolidine dihydrochloride and 15.0 g of ethylmercaptoacetyl chloride: 1- [p- (2-ethylmercaptoacetamidoethyl) -phenysulphonyl ] -2-imino-3- (1 , 2-dimethylbutyl) -imidazolidine , M.P. 75-78°.

Purification of the crude product is performed by chromatography on the 20-fold amount of silica gel (grain-size 0.2-0.5 mm) with chloroform + 5% methanol as solvent, and subsequent recrystallisation from methylene chloride/ether - - b) from 38.1 g of 1- [p- (2-aminoethyl) -phenylsulphonyl ]- 2-imino-3-allyl-imidazolidine dihydrochloride^ M.P. 232-233° and 14.5 g of ethylmercaptoacetyl chloride: 1- [ p- (2-ethylmercaptoacetamidoethyl) -phenylsulphonyl ] - 2-imino-3-allyl-imidazolidine, M.P. 100-102° (purification by chromatography and recrystallisation analogously to a) ) .

Example 6 To a solution of 42.3 g of 1- [p- (2-aminoethyl) -phenyl sulphonyl ] -2-imino-3-cyclohexyl-imidazolidine dihydrochlo M.P. 247-250°, in 100 ml of water are added 150 ml of 2-n sodium hydroxide solution, and the free base is taken up in methylene chloride. To the methylene chloride solution dried with sodium sulphate are added portionwise at room temperature 36 g of 3-methylmercapto-propionic acid and 60 g of N, 1 -dicyclohexylcarbodiimide . The solution is allowed to stand for 1 hour at room temperature, and is then concentrated by evaporation to dryness . The residue is shaken with a mixture of ethyl acetate and 2-n hydrochloric acid. The insoluble Ν,Ν' -dicyclohexyl urea is filtered off, the aqueous acid phase separated, and from this is then liberated the base, whilst ice cooling is applied, by the addition of concentrated aqueous sodium hydroxide solution; and it is taken up with methylene chloride. By concentration by evaporation of the methylene chloride solution (dried with sodium sulphate) is obtained crude l-[p-(2-(3-methylmercaptopropionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine which, after recrystallisation from methylene chloride/ethyl acetate, melts at 160-162°.

The following is obtained in an analogous manner: a) from 37.1 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-ethyl-imidazolidine dihydrochloride, M.P. 242-244C 45.0 g of 3-methylsulphonylpropionic acid and 60.0 g of Ν,Ν' -dicyclohexylcarbodiimide is obtained: 1- [ p- (2- (3-methyl.sulphonylpropionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-ethyl- imidazolidine , M.P. 181-184° (from methanol/ether) ; b) from 39.7 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl-2-lmino-3-butyl-imidazolidine dihydrochloride, M.P. 231-233 50.0 g of 3-ethylsulphonylpropionic acid and 60.0 g of Ν,Ν' -dicyclohexylcarbodiimide is obtained: 1- [p- (2- (3-ethylsulphonylpropionamido) -ethyl) -phenyl-sulphonyl ] -2~imino-3-butyl-"imidazolidine, M.P. 149-151° (from methanol) .

Example 7 To a solution of 37.1 g of 1- [p- (2-aminoethyl) -phenyl-sulphonyl ] -2-imino-3-ethyl-imidazolidine dihydrochloride , M.P. 242 - 244°, in 100 ml of water are added 150 ml of 2-n sodium hydroxide solution, and the base is taken up with methylene chloride. The methylene chloride solution (dried with sodium sulphate) is concentrated by evaporation to dryness, and the residue dissolved in 300 ml of tetrahydrofuran . To this solution are added portionwise, at room temperature, 36.0 g of 3-methylthiopropionic acid and 60.0 g of Ν,Ν' -dicyclo-hexylcarbodiimide ; the solution is allowed to stand for 1 hour at room temperature, and is then concentrated by evaporation to dryness . The residue is treated analogously to Example 6. The obtained l-[p-(2-(3-methylthiopropionamido) -ethyl) -2-imino-3-ethyl-imidazolidine melts, after recrystallisation from ethyl acetate, at 137-139°.

Example 8 To a solution of 41.0 g of 1- [p- (2-aminoethyl) - phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine dihydrochloride, M.P. 270°, in 100 ml of water are added 150 ml of 2-n sodium hydroxide solution; and the base is taken up with methylene chloride. The methylene chloride splution is dried with sodium sulphate, the methylene chloride distilled off, and the 1- (p- (2-aminoethyl) -phenylsulphonyl] -2-imino-3-cyclopentyl-imidazolidine remaining behind dissolved in 300 ml of dioxane. To this solution are added portionwise, at room temperature, 45.0 g of 3-methylsulphonyl-propionic acid and 60.0 g of Ν,Ν' -dicyclohexyl-carbodiimide . The solution is allowed to stand for 1 hour at room temperature, and is then concentrated by evaporation to dryness. The obtained residue is processed analogously to Example 6. By this means is obtained 1- [p- (2- (3-methylsulphonylpropionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine, M.P. 180-181° (from methanol/ether) .

Example 9 The base, liberated from a solution of 41.0 g of ί- (p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine dihydrochloride, M.P. 270°, in 200 ml of water by the addition of 300 ml of 2-n sodium hydroxide solution, is taken up with methylene chloride; the methylene chloride solution is then dried with sodium sulphate, and the methylene chloride distilled off.

The 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine remaining behind as oil is well mixed at 30-40°, under nitrogen, with 21.2 g of methoxydithioacetic acid benzyl ester by shaking; the mixture is then heated for 1/2 hour in a water-bath to about 80°, whereby the colour of the dithio ester' gradually disappears, and the product crystallises.

The formed benzylmercaptan is afterwards removed by washing four times with 100 ml of petroleum ether each time. The thus obtained crude 1- [p- (2-methoxythio-acetamidoethyl) -phenylsulphonyl ] -2-imido-3-cyclopentyl-imidazolidine melts, after recrystallisation from ethyl acetate, at 127-128°.

In an analogous manner is obtained, from 42.4 g of 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine dihydrochloride, M.P. 247-250°, and 21.2 g of methoxydithioacetic acid benzyl ester: 1- [ p- (2-methoxythioacetamidoethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine, M.P. 146-147° (from acetone) .

The methoxydithioacetic acid benzyl ester used as starting material can be obtained according to the following prescription: An amount of 3.8 g of hydrogen chloride is dissolved at -10° in a mixture of 7.1 g of methoxyacetonitrile and 13.3 g of benzylmercaptan; the solution is then allowed to stand for several days at -5° to -10° until it has been converted into a crystal cake. The formed methoxythioacetimidobenzyl ester hydrochloride is washed with petroleum ether, and dried in vacuo. The substance melts at 137-141° (decomposition) .

Into a suspension of 23.2 g of methoxythioacetimidobenzyl ester hydrochloride in 60 ml of abs . pyridine is fed, whilst cooling is applied with an acetone/ dry ice mixture, hydrogen sulphide until saturation is obtained. The temperature is then allowed to rise to 0°, and stirring proceeds for a further 1 hour at this temperature. To the whole are then added dropwise within 10 minutes, with ice cooling, 120 ml of water; the formed emulsion is poured into a mixture of 270 ml of cone, hydrochloric acid and 430 ml of water, and the precipitated red-yellow oil is taken up with ether.

The ethereal solution is washed with water, and dried with sodium sulphate. The crude methoxydithioacetic acid benzyl ester, remaining behind after the ether has been distilled off, is distilled in high vacuum, B.P. 110-120°/0.01 mm.

Example 10 Analogously to Example 1, with the use, each time, of 20.6 g of Ν,Ν' -dicyclohexyl-carbodiimide, are obtained: from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 11.8 g of propoxy- acetic acid, 1- [p- (2-propoxyacetamido)-ethyl) -phenyl- sulphonyl ]-2-imino-3-cyclohexyl-imidazolidine , M.P. 100 - 102°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl] -2- imino-3-cyclohexyl-imidazolidine-dihydrochloride and 11.8 g of isopropoxy-acetic acid, 1- [p- (2-isopropoxy-acetamido)- ethy1) -pheny1- sulphony1 ] -2-imino- 3-eye1ohexy1- imidazo1id- ine, M.P. 105 - 107°; from 43.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] - 2-imino-3- (2-methy1-eye1ohexy1) -imidazolidine-dihydro- chloride and 10.4 g of 3-methoxy-propionic acid, l-[p-(3- methoxy-propionamido) -ethyl) -phenylsulphonyl ] -2- imino-3. (2-methyl-cyclohexyl-imidazolidine, M.P. 130 - 132°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] - 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 11.8 11.8 g of 3-ethoxy-propionic acid, 1- [p- (2- (3-ethoxy-prop- ionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl- imidazolidine, M.P. 130 - 132°; from 43.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3- (2-methyl-cyclohexyl) -imidazolidine-dihydrochlor- ide and 13.2 g of 3-isopropoxy-propionic acid, l-[p-(2- (3-isopropoxy-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3- (2-methyl-cyclohexyl) -imidazolidine, M.P. 128 - 130° from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and .6 g of methylmercapto-acetic acid, 1- [p- (2-methylmercapto acetamido-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine, M.P. 120 - 121° ; from 39.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3-sec .butyl-imidazolidine-dihydrochloride and .6 g of methylmercapto-acetic acid, 1- [p- (2-methylmercapto-acetamido)-ethy1)-pheny1sulphony1 ]-2-imino-3-sec .butyl- imidazolidine, M.P. 104 - 105° from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 12.0 g of ethylmercapto-acetic acid, 1- [p- (2-ethylmercapto-acetamido)-ethyl)-pheny1sulphonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. 128 - 130°; from 39.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] - 2-imino-3-sec .butyl-imidazolidine-dihydrochloride and .6 g of 2-methylmercapto-acetic acid, l-[p-(2-(2-methylmercapto-propionamido) -ethyl) -phenylsulphonyl ] -2- from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 10.6 g of 3-methylmercapto-propionic acid, l-[p-(2-(3-methylmercapto-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine, M.P. 132 - 133°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl] 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 16.2 g of 3-tert .butylmercapto-propionic acid, l-[p-(2-(3- tert .butylmercapto-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine , M.P. 142 - 146° from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl] 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 13.4 g of propylmercapto- acetic acid, 1- [p- (2-propyl-mercapto-acetamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine, M.P. 110 - 111°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 13.4 g of isopropylmercapto-acetic acid, l-[p-(2-iso-propylmercapto-acetamido) -ethyl) -phenylsulphonyl] -2-imino-3-cyclohexyl-imidazolidine, M.P. 125 - 126°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 14.8 g of tert .butylmercapto-acetic acid, l-[p-(2- - - - - 2-imino-3-cyclohexyl-imidazolidine , M.P. 140 - 141°; from 35.5 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3-methyl-imidazolidine-dihydrochloride and 13.4 g of 2-ethylmercapto-propionic acid , 1- [p- (2- (2-ethylmercapto-propionamldo) -ethyl) -phenylsulphonyl ] -2-imino-3-methyl-imidazolidine, M.P. 140 - 142°; from 39.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-isobutyl-imidazolidine-dihydrochloride and 16.6 g of 3-ethylsulphonyl-propionic acid, 1- [- (2- (3-ethylsulph-onyl-propionamino) -ethyl) -phenylsulphonyl ]-2-imino-3-iso-butyl-imidazolidine , M.P. 176 - 177°; from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 13.4 g of methylsulphonyl-acetic acid, 1- [p- (2- (methyl-sulphonyl-acetamido)-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine , S.P. 147°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and .2 g of ethylsulphonyl-acetic acid, 1- [p- (2-ethylsulph-onyl-acetamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclo-hexyl-imidazolidine, M.P . 144 - 146° ; from 35.5 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] - 2-imino-3-methyl-imidazolidine-dihydrochloride and 16.6 g onyl-propionamido) -ethyl) -phenylsulphonyl]-2-imino-3-methyl-imidazolidine, M.P. 162 - 163°; from 39.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] - 2-imino-3-isobutyl-imidazolidine-dihydrochloride and 15.0 g of 3-ethylsulphinyl-propioni.c acid, 1- [p- (2- (3-ethyl-sulphinyl-propionamido) -ethyl) -phenylsulphonyl ] -2-imino- 3-isobutyl-imidazolidine, M.P. 141 - 143°; from 40.9 g of 1- [p- (2-amino-ethyl)-phenylsulphonyl ]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 12.2 g of methylsulphinyl-acetic acid, 1- [p- (2- (methyl-sulphinyl) -acetamido) -ethyl) -phenylsulphonyl ]-2-imino- 3-cyclopentyl-imidazolidine, M.P. 141 - 142°; from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 13.6 g of 3-methylsulphinyl-propionic acid, l-[p-(2- (3-methylsulphinyl-propionamido) -ethyl) -phenylsulphonyl} -2-imino-3-cyclopentyl-imidazolidine, M.P. 146 - 147°; from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]- 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 13.6 g of ethylsulphinyl-acetic acid, 1- [p- (2-iethyl-sulphinyl-acetamido) -ethyl) -phenylsulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, M.P. 133 - 134°; from 42.3 g of 1- [p- (2-amlno-ethyl) -phenylsulphonyl ]-2-imino-3-cyclohexyl-imldazolidine-dihydrochloride and 17.8 g of 3-tert .butylsulphinyl-propionic acid, l-[p-(2-(3-tert .butylsulphinyl-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine, M.P. 125 - 127°; from 43.7 g of 1- [p- (2-amino-propyl) -phenylsulphonyl ]-2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 9.0 g of methoxy-acetic acid, 1- [p- (2-methoxy-acetamido)-propyl-phenylsulphonyl ]-2-imino-3-cyclohexyl-imidazolidine , M.P. 120 - 121°; from 43.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-4-methyl-imidazolidine-dihydrochloride and 10.4 g of ethoxy-acetic acid, 1- [p- (2-ethoxy-acetamido) -ethyl) -phenylsulphonyl] -2-imino-3-cyclohexyl-4-methyl-imid-azolidine, M.P. 115 - 117°; from 43.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-4-ethyl-imidazolidine-dihydrochloride and 13.4 g of 3-ethylmercapto-propionic acid, 1- [p- (2- (3-ethylmercapto-propipnamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-4-ethyl-imidazolidine , an oil; from 43.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cycloheptyl-imidazolidine-dihydrochloride and 12.0 g of 2-methylmercapto-propionic acid, l-[p-(2-(2- - - - - - imino-3-cycloheptyl-imidazolidine, M.P. 167 - 169°; from 43.1 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-benzyl-imidazolidine-dihydrochloride and 12.0 g of 2-methyl-mercapto-propionic acid, 1- [p- (2- (2-Methyl-mercapto-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-benzyl-imidazolidine, M.P. 141 - 143°; from 44.5 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3- (β-phenyl-ethyl) -imidazolidine-dihydrochloride und 13.4 g of 3-ethylmercapto-propionic acid, l-[p-(2-(3-ethylmercapto-propionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-(/3-phenyl-ethyl)^imidazbliaine, M.P. 102 - 103°; from 42.1 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ]-imino-3- (3-cyclohexen-l-yl) -imidazolidine-dihydrochloride and 9.0 g methoxy-acetic acid, 1- [p- (2-methoxy-acetamido)-ethyl) -phenylsulphonyl ]-2-imino-3- (3-cyclohexen-l-yl) -imidazolidine .

Claims (17)

4-3153* What we claim is :

1. p-Aminoalkyl benzenesulphonamide derivatives having the formula I NH (I) , wherein represents an optionally branched alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms, a cycloalkyl or cycloalkenyl group i having from 5 to 8 carbon atoms, or a phenylalkyl group having at most 9 carbon atoms, ! represents a hydrogen atom or a methyl or ethyl group, represents an optionally branched alkyl group having I S from 1 to 6 carbon atoms, I j m represents the integer 2 or 3, I n represents the integer 1,2,3 or 4, j Y represents an oxygen or sulphur atom, and j Z represents an oxygen or sulphur atom or a sulphoxide j or sulphone grouping. ί j i

2. ! 2. p-Aminoalkyl benzenesulphonamide derivatives as de- I fined in claim 1 wherein R represents a hydrogen atom, m represents the integer 2, and Y and Z both represent oxygen atoms.

3. p-AminoaIkyI benzenesulphonamide derivatives as defined i claim 2 wherein represents an optionally branched alkyl group having from 1 to 6 carbon atoms or a cycloalkyl group having from 5 to 8 carbon atoms, and n represents the integer 1 or 2.

4. 1- [p- (2-Ethoxyacetamidoethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine .

5. 1- [p- (2- (3-Ethylmercaptopropionamido) -ethyl) -phenylsulphonyl ] -2~imino- 3- isobutyl- imidazolidine .

6. 1- [p- (2- (3-MethyImercaptopropionamido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl- imidazolidine .

7. 1- [p- (2- (3-Ethoxypropionam.ido) -ethyl) -phenylsulphonyl 2- imino-3-cyclohexyl- imidazolidine .

8. The pharmaceutically acceptable acid addition salts of a p-aminoalkyl benzehesulphonamide derivative as claimed in any one of claims 1 to 3.

9. The pharmaceutically acceptable acid addition salts of a p-aminoalkyl benzenesulphonamide derivative as claimed in any one of claims 4 to 7. _ 35 _ · GB etc .

10. Process for the production of p-aininoalkyl benzene- sulphonamide derivatives having the formula I as defined in claim 1 which comprises reacting the corresponding comp with a thiocarboxylic or carboxylic acid having the . formula III wherein , Z, n and Y have the meanings given in claim 1 or with a reactive functional derivative thereof .

11. Process as defined in claim 10 wherein a p-amino-alkyl benzenesulphonamide derivative thus obtained is converted into a pharmaceutically acceptable acid addition salt thereof.

12. Process as defined in claim 10, substantially as herein before described with reference to any one of the Examples 1 to 9. - 36 - GB etc .

13. Process as defined in claim 10, substantially as hereinbefore described with reference to Example 10.

14. A p-aminoalkyl benzenesulphonamide derivative as defined in claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 9.

15. A p-aminoalkyl benzenesulphonamide derivative as defined in claim 1, substantially as hereinbefore described with reference to Example 10.

16. A p-aminoalkyl benzenesulphonamide derivative as defined in claim 1 or pharmaceutically acceptable acid addition salt thereof whenever prepared by a process as claimed in claim 10 or 11.

17. A pharmaceutical composition comprising a p-aminoalkyl benzenesulphonamide derivative as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carr ier therefor. 19.8.1970/GSG/jh/ GB et