IL35080A - Derivatives of p-1-(thio)-ureido-alkyl phenylsulphonyl-2-imino-imidazolidines,their preparation and pharmaceutical compositions containing them - Google Patents

Description

Y*3sY» R»*i»imfc( ι»η)1-κ*ικ3 Ys> nisnn nnVifi ^Γ,Ί a»V»:>an firnpn . »·ν»Ρ3ητ New derivatives of p-I-(Thio-ureidoalkyl phenylsulphonyl-2~iminoimidaz0lidines, their preparation and pharaaceutical compositions containing them CIBA-GEIGY A.G.

C: 33234 4-3126* PROCESS FOR THE PRODUCTION OF NEW DERIVATIVES OF p-AMI OALKYL BENZENESULPHONAMIDE The present invention relates to nev7 derivatives of p-aminoalkyl benzenesulphonamide, to a process for the production thereof, to medicaments containing the new compounds, and to the use thereof.

It has been found that p-substituted phenylsulphon 2-imino-imidazolidines of the general formula I: wherein R^ represents an optionally branched alkyl radical having 1-6 carbon atoms, an allyl radical, a cycloalkyl radical or cycloalkenyl radical having - 8 carbon atoms , R£ represents hydrogen, an ethyl group or a methyl group, an optionally branched alkyl group having 1 - 6 carbon atoms, a cycloalkyl group or cycloalkenyl group having in each case at most 8 carbon atoms , an alkenyl group having 3 - 5 carbon atoms or a phenyl group, R^ represents hydrogen, an optionally branched alkyl group having 1 - 6 carbon atoms, a phenyl group, 35080/2 — A' and together represent a polymethylene chain having 4-7 carbon atoms, which can be interrupted by an oxygen atom, X represents oxygen or sulphur, A represents a straight or branched chain alkylene group having 2 or 3 chain members, as well as their addition salts with inorganic or organic acids, have an hypoglycaemic action in warm-blooded animals. , In the compounds of the general formula I, R^ may 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, methylpentyl, a dimethylbutyl , an ethylbutyl group; as the cycloalkyl group, R^ can denote the cyclopentyl group, which can be optionally ' \ \ substituted by alkyl radicals having 1-3 carbon atoms, the cyclohexyl group, V7hich can be substituted by : ethyl or methyl, and the cycloheptyl group optionally ! substituted by methyl, as well as the cyclooctyl group; as the cycloalkenyl group, can denote the 2-cyclopenten-l-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.

The subs ituent embraces the same alkyl groups as stated under , cycloalkyl or cycloalkenyl groups; as the alkenyl group, can denote the allyl, 1-methyl- allyl, 2-methylallyl group, the 2- or 3-butenyl group or the 2-, 3- or 4-pentenyl group.

Using the process according to the invention, compounds of the general formula I are produced by reacting a compound of the general formula II: wherein R^, and . have the meaning given under formula I, iV7ith an isocyanate or isothiocyanate of the general formula III: w .herein R3¾ - N = C = X (III)',' R^ and X have the meaning given under the general formula I; or with a reactive derivative of a carbamic acid or thiocarbamic acid of the general formula IV: wherein R^, ^ and X have the meaning given under formula I; and, optionally, converting the obtained reaction products into the salt of an inorganic or organic acid.

Suitable as reactive derivatives of a carbamic acid or thiocarbamic acid of the general formula III are, e.g. the halides, especially the chlorides, the lower alkyl esters, particularly the methyl or ethyl esters, the phenyl ester, the amides, the lower mono- or dialkyl-amides, in particular the N-methyl amides and the Ν,Ν-dimethylamides , the diphenylamides , also the N-acylamides such as, e.g. the acetyianiides and the benzoylamides .

The reaction is performed, e.g. at room temperature, or by heating in an inert organic solvent. Suitable as such are, e.g. hydrocarbons such as benzene, toluene or xylene, etheis such as diethyl ether, dioxane or as ^methylene chloride, and lower ketones such as acetone or methyl ethyl ketone. The reaction can, in general, be carried out without the addition of condensing agents; optionally, however, such agents, e.g. alkali metal alcoholates and alkali metal hydroxides, can be added.

A halide of a carbamic acid or thiocarbamic acid of the general formula IV is reacted according to the invention preferably in the presence of an acid-binding agent. As such 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.

In addition to inorganic bases or salts, organic bases are also suitable such as, e.g. pyridine, trimethyl-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 carbamic or thiocarbamic acid chloride, 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 V: wherein R represents a simple alkyl or aryl radical, e.g. a methyl or a phenyl group, and a s has the meaning given in formula I, V7ith 2-amino-2-imidazoline derivatives of the general formula VI: wherein R^ and R2 have the meaning given under formula I; and afterwards hydrolytically splitting off the protective acyl group (R-CO-) . The N-acyl compounds derived from formula II, obtained as intermediate product, have likewise not been described hitherto in the literature.

Suitable reactive derivatives of a sulphonic acid of the general formula V are halides, especially chlorides and anhydrides of the general, formula Va: wherein R has the meaning given under formula V.

The anhydrides of the general formula Va can be obtained in a simple manner by the reaction of corresponding substituted sulphonic acid halides with salts of correspondingly substituted sulphonic acids .

Using a further process, starting materials of the general formula II are obtained by reacting substituted p- (aminoalkyl) -benzenesulphonamides (produc analogously to the method of E.Miller, J.Amer. Chem.

Soc. 62, 2101 (1940)) of the general formula VII: wherein has the meaning given under formula I, with substituted N- (2-bromoalkyl) -cyar.oamides in an alkaline medium.

The preparation of the starting compounds of the general formula III and of the general formula IV is carried out us ng the generally known preparation methods for isocyanates and isothiocyanates . and carbamic acid derivatives and thiocarbamic acid derivatives, respectively The new active substances, or the pharmaceutically acceptable salts thereof, can be administered orally or parenterall . For salt formation, it is possible to use physiologically harmless inorganic or organic jacids , such as, e.g. hydrochloric acid, hydrobromic j acid, sulphuric acid, phosphoric acid, methane- sulphonic acid, acetic acid, lactic acid, succinic acid, tartaric acid and maleic acid; but also hypoglycaemic sulphonyl ureas such as, e.g. p-toluene- sulphonylbutyl urea, p-chlorobenzenesulphonylpropyl urea, and p- [ 2- (2-methoxy-5-chlorobenzamido) -ethyl j - phenylsulphonyl-cyclohexyl urea. The daily dosages are between 10 and 400 mg/kg for warm-blooded animals. Suitable dosage units such as dragees or tablets preferably contain 10-200 mg of an active substance according to the invention, whereby the content of active substance is 20-80% by weight, Tablets and dragees are produced by combining the active substance, e.g. it 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. The tablets and dragee-cores are coated, e.g. with concentrated sugar solutions which may also contain, e.g. gum arable, 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. to distinguish between . varying 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 preferably contain the active substance 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 stabilisers may also be added.

The following prescriptions further illustrate the production of tablets and dragees: a) 1000 g of 1- [p- (2- (3-butylureido) -ethyl) -phenyl sulphonyl ] -2--imino-3-cyclohexyl-imidazolidine are 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 starch 60.0 g of talcum, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are mixed in; and the mixture is pressed into 10,000 tablets each weighing 200 mg and each containing 100 mg of active substance. Optionally, the tablets may be provided with grooves for more precise adjustment of the dosage amount. b) A granulate is prepared from 1000 g of 1- [p- (2- (3-butyl -thio-ureido) -ethyl) -phenyl-sulphonyl imino- 3-cyclohexyl-imidazolidine , 345.0 g of lactose and the aqueous solution of 6.0 g of gelatine.

After drying, the granulate is mixed 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; the mixture is then 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 100 mg of active substance.

The following examples further illustrate the production of the new compounds of the general formul and of intermediate products not described hitherto; but these examples in no way represent the only embodiments thereof. The temperatures are given in degrees Centigrade.

Example 1 a) An amount of 39.8 g of 1- [ p- (2-aminoethyl) - phenyl sulphonyl ] - 2- imino-3-n-buty1- imidazolidine- dihydrochloride is dissolved in 100 ml of water, and the base liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of n-propylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. 1- [p- (2- (3-n-propylureido) -ethyl-phenylsulphonyl] -2-imino-3-n-butyl-imidazolidine melts at 164-166°. b) The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] -2- imino-3-butyl- imidazolidine-dihydrochloride , is obtained by two processes: 1) An amount of 36.65 g of 1- [p- (2-acetaminoethyl) -phenylsulphonyl ] -2-imino-3-butyl- zolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2-imino-3-butyl-imidazolidine-dihydrochloride crystallises out in the. cold state, M.P. 231-233°. 1- [p- (2-Acetamidoethyl) - phenylsulphony1 ] -2- imino-3-buty1-imidazolidine can be produced as follows: To a solution of 8.5 g of sodium hydroxide in 85 ml j of water are added 17.8 g of l-butyl-2-imino-imidazolidine-hydrochloride . To the obtained clear solution is added a solution of 26.6 g of p- (2-acetamidoethyl) -benzenesulphochloride in 100 ml of acetone, whereby a rise in temperature occurs. The mixture is subsequently heated for half an hour to 90°, and then concentrated to dryness in vacuo. The residue is recrystallised from ethyl acetate. The pure 1- [p- (2-acetamidoethyl) -phenylsulphonyl ] -2-imino-3 butyl-imidazolidine melts at 130 - 131°.

The 1- [p- (2-acetamidoethyl) -phenylsulphonyl ] -2-imino- imidazolidines required in the following examples for the production of the starting material are obtained, in an analogous manner, by the reaction of p- (2-acetamidoethyl) -benzenesulphochloride with correspondingly substituted 2-imino-imidazolidines .

I 2) A mixture of 100 ml of dimethylsulphoxide , 11.2 g of powdered potassium hydroxide, 23.65 g of p-(2- aminoethy1) -benzenesulphonamide hydrochloride [Lit.: Έ .Miller et al, J .Arner . Chem . Soc .62 , 2101, (1940)] and 16 g of N- (2-chloroethyl) -N-butylcyanamide is heated, whilst being stirred, for one hour in an oil bath at 110°. After cooling, the mixture is poured on to water . The obtained cloudy solution is rendered alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-butyl-imidazolidine dihydrochloride precipitates, M.P. 231-233°.

Example 2 In an analogous manner to Example 1 are obtained: from 38.4 g of 1- [p- (2-amino-ethyl) -phenylsulphonyll-2-imino- 3-isopropyl-imidazolidine-dihydrochloride and 12.5 g of cyclohexyl-isocyanate the 1- [p- (2- (cyclohexyl^ureido) -ethyl) -phenylsulphonyl ] -2-imino-3-isopropyl- imidazolidine , M.P. 158 - 158°. from 42.5 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-n-butyl-4-e hyl-imidazolidine-dihydrochloride and 12.5 g of cyclohexyl-isocyanate the 1- [p- (2- (cyclohexyl-ureido) -ethyl)-phenylsulphonyl ] -2-imino-3-n-butyl-4-ethyl-imidazolidine , M.P. 98 - 99°. from 43.7 g of 1- [p- (2-amino-propyl) -phenylsulphonyl ] -2 imino-3-cyclohexyl-imidazolidine-dihydrochloride and 12 cyclohexyl-isocyanate the 1- [p- (2- (cyclohexyl-ureido) -propyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazoli M.P. 201 - 202°.

Example 3 Starting with 39.8 g of 1- [ p~ (2-aminoethyl) - phenylsulphoiiyl] -2-imino-3-n .butyl-imidazolidine- j dihydrochloride are obtained, analogously to Example 1, the following: a) with 8.5 g of isopropylisocyanate, 1- [p- (2- (3-isopropylureido) -ethyl) -phenylsulphonyl ] -2- imino-3-n-butyl-imidazolidine , .P. 151-152° (from ethyl acetate); b) with 9.9 g of n-butylisocyanate , 1- [ p- (2- (3-n-butylureido) -ethyl) -phenylsulphonyl1-2-imino-3-n-butyl-imidazolidine , M.P. 158-159° (from ethyl acetate) c) with 11.5 g of n-butylisothiocyanate, 1- [p~ (2- (3-n-butyl~ 2- thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-butyl-imidazolidine , M.P. 183-184° (from ethyl acetate) d) with 11.1 g of cyclopentylisocyanate , 1- [p- (2- (3- cyclopentylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-butyl-imidazoiidine , M.P. 176-177° (from ethyl acetate); e) with 11.9 g of phenylisocyanate . 1- (p- (2- (3-phenylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-butyl- midazolidine hemihydrate, M.P. 210-211° (from ethyl acetate) ; ■f) with 13.5 g of phenylisothiocyanate , 1- { p- (2- (3 - phenyl-2- hioureido) -ethyl) -phenylsulphonyl ) -2-imino-3-n-but l-imidazolidine containing 1/4 mole of hydrogen, M.P. 195-196° (from ethyl acetate); Example 4 a) 38.4 g of 1~ [ p- (2-aminoethyl) -phenylsulphonyl ]- 2- imino-3-n-propyl-imidazolidine dihydrochloride are dissolved in 100 ml of water; and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 12.5 g of cyclohexylisocyanate , and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [p- (2- (3-cyclohexylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-propyl-imidazolidine melts at 185-186°. b) The starting material: 1- [ - (2-aminoethyl) -phenylsulphonyl ] - 2-imino- 3- ropyl- imidazolidine dihydrochloride, is produced by two processes: 1) An amount of 35.2 g of 1- [ p- (2-acetaminoethyl) -phenyl-sulphonyl ] -2-imino-3-propyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [ p- (2-aminoethyl) -benzenesulphonyl ] - 2-imino-3-propyl—imidazolidine dihydrochloride , M.P. 255-256 , crystallises out in the cold state. 2) A mixture of 100 ml of dimethylsulphoxide , 11.2 g of powdered potassium hydroxide, 23.65 g of p- (2-aminoethyl) -phenylsulphonamide hydrochloride ![Lit.: E.Miller et al , J.Ame .Chem.Soc .62, 2101, (1940)] and 16 g of - (2-chloroethyl) - -propyl-cyanamide is heated, whilst being stirred, for 1 hour in an oil-bath at 110°. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is rendered alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid.

As a result of cooling and, if necessary, dilution with ether, 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-propyl-imidazolidine dihydrochloride , M.P. 255-256°, precipitates.

Example 5 a) 39.8 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2-imino-3- isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base liberated with 150 ml of 2-n. sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. Ί the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of n-propylisocyanate , and stirring is maintained for one hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [p- (2- (3-n-propylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-isobutyl-imidazolidine melts at 154-156°. b) The starting material: 1-· [p- (2-aminoethyl) -phenylsulphonyl ] - 2-imino-3-isobutyl-imidazolidine-dihydrochloride monohydrate, is produced by two processes 1) An amount of 36.65 g of 1- [ p- (2-acetaminoethyl) -phenylsulphonyl ] -2-imino-3-isobutyl-imidazolidine is dissolved in 370 ml of 2-n. hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [ p- (2-aminoethyl) -benzenesulphonyl ] -2-imino-3-isobutyl-imidazolidine-dihydrochloride monohydrate, M.P. 151-152, crystallises out in the cold state. 2) A mixture of 100 ml of dimethylsulphoxide , 11.2 g of powdered potassium hydroxide, 23.65 g of p- (2-aminoethyl) -benzenesulphonamide hydrochloride j [Lit.: E.Miller et al, J . Amer . Chem . Soc . 62, 2101, (1940)] and 20.5 g of N- (2-bromoethyl) -N-isobutyl-cyanamide is heated, whilst being stirred, for 1 hour in an oil-bath at 110°. After the mixture has cooled, it is poured on to wate . The obtained cloudy solution is made alkaline v.7ith concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by e\aporation . The obtained oil (free base) is dissolved in alcohol and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, l-[p-(2-aminoethyl) -phenylsulphonyl ] -2-imino-3-isobutyl-imidazolidine-dihydrochloride monohydrate, M.P. 151^152°, precipitates .

Example 6 In an analogous manner to Example 4 is obtained, jstarting with 39.8 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2-iinino-3-isobutyl-imidazolidine-hydrochloride with 12.5 g of cyclohexylisocyanate, l-[p-(2-(3- cyclohexylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-isobutyl-imidazolidine , M.P. 171-172.5° (from acetyl acetate) .

Example 7 a) 41.0 g of 1- [p- (2-aminoethyl) -phenylsulphonyl ] -2- imino-3-cyclopentyl- imidazolidine-dihyd ochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 5.7 g of methylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. 1- [p- (2- (3-me hylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine melts at 129-130°. b) The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2-irnino-3- cyclopentyl- imidazolidine-dihydrochloride, is obtained by two processes: 1) An amount of 37.8 g of 1- [p- (2-acetaminoethyl) -phenylsulphonyl ] - 2-imino-3-cyclopentyl- i idazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is thenconcentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [p- (2-aminoethyl) -benzenesulphonyl ] - 2- imino-3-cyclopentyl- imidazolidine-dihydirochloride , M.P. 270°, crystallises out in the cold state. 2) A mixture of 100 ml of dimethylsulphoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p- (2-aminoethyl) -phenylsulphona ide-hydrochlo ide ! [Lit.: E.Miller et al, J .Amer . Chem . Soc . 62, 2101, (1940)] and 17.2 g of N- (2- chloroethyl) -N-cyclopentyl-cyanamide is heated, whilst being stirred, for 1 hour in an oil bath at 110°. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, 1- [p- (2-aminoethyl) -phenylsulphonyl ] --2-imino-3-cyclopentyl-5_midazolidine-dihydrochloride, M.P. 270°, (decomposition) precipitates.

Example 8 Analogously to Example- 7 is obtained, starting I with 41.0 g of 1- [ p- (2-aminoethyl) - phenylsulphonyl ] - 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride , the follov?ing : a) with 9.9 g of n-butylisocyanate , 1- (p- (2- (3-n-butylureido) -ethyl) -phenylsulphonyl ] -2-imino-3- cyclopentyl- imidazolidine , M.P. 134-136° (from ethyl acetate) .

Example 9 a) 42.4 g of 1- fp- (2-aminoethyl) -phenylsulphonyl ] -|2-imino-3- cyclohexyl- imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 9.9 g of n-butylisocyanate , and stirring is maintained for one hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. 1- [p- (2·- (3-n-butylureido) -ethyl) -phenylsulphonyl ] -2- imino-3- cyclohexyl- imidazolidine melts at 161.5° - 162°. b) The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] -2- imino-3-cyclohexyl- imidazolidine-dihydrochloride , is obtained by two processes: 1) An amount of 39.2 g of 1- [ p- (2-acetaminoethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl- imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [p- (2-aminoethyl) -pheny1su1phony1 ] - 2- imino-3 - cyc1ohexy1- linidazo1idine-dihydrochlori.de, M.P. 247-250°, crystallises out in the cold state. 2) A mixture of 100 ml of dimeth lsulphcxide , 11.2 g of powdered potassium hydroxide, 23.65 g of p- (2-aminoethyl) benzenesulphonamide hydrochloride [Lit.: E .Miller et al, J.Amer .Chem.Soc._62, 2101, (1940)] and 23,1 g of N- (2-bromoethyl) -N- cyclohexylcyanamide is heated, whilst being stirred, for one hour in an oil-bath at 110°. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2~imino-3-c clohex l- imidazolidine-dihydrochloride , M.P. 247-250°, precipitates.

Example 10 Starting with 42.4 g of 1- [p- (2-aminoethyl) -phenyl-sulphonyl ] - 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride , the following are obtained analogously to Example 9 : a) with 11.5 g of n-butylisothiocyanate , 1- [p- (2- (3-n-butyl— 2- hioureido) -ethyl) -phenylsulphony 2- imino-3-cyclohexyl-imidazolidine , M.P. 186-187° (from ethyl acetate) ; b) with 11.9 g of phenylisocyanate, 1- [p- (2- (3-phenyl- 2-thioureido) -ethyl) -phenylsulphonyl ] · 2- imino-3-cyclohexyl-imidazolidine , M.P. 210.5 - 212° (from ethyl acetate) ; c) with 13.5 g of phenylisothiocyanate , - [ p- (2- (3-phenyl-2-thioureido) -ethyl) -phenylsulphonyl ] ■ - imino-3-cyclohexyl-imidazolidine , M.P. 188-189° (from ethyl acetate) .

Example 11 43.8 g of 1- [p- (2-aminoethyl) - phenyIsulphonyl ] -2- imino-3- (4-me hylcyclohexyl) - imidazolidine-dihydrochlo ide are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution.

It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of n-propyl- isocyanate, and stirring proceeds for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [ p- (2- (3-n-propylureido) -ethyl) - 3- phenylsulphonyl ] - 2-imino-/(4-methylcyclohexyl) - imidazolidine , containing 1/4 mole of water, melts at 162.5 - 163°.

The starting material: 1- [ p- (2-aminoethyl) -benzene- sulphonyl ] -2-imino-3- (4-methylcyclohexyl) -imidazolidine-- dihydrochloride is obtained by two processes: a) An amount of 40.7 g of 1- [ p- (2-acetaminoethyl) -· phenylsulphonyl ] --2-imino-3- (4-methylc clohexyl) - imidazolidin is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- fp- (2-aminoethyl) -benze!ie-sulphonyl ] -2-imino-3- (4-methylcyclohexyl) -imidazolidine-dihydrochloride , M.P. 260°, (with decomposi ion), crystallises out in the cold state. b) A mixture of 100 ml of dimethylsulphoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p- (2-aminoethyl) -benzenesulphonamide-hydrochloride [Lit.: E. Miller et al, J. Amer . Chem . Soc . _62, 2101, (1940)] and 200 g of 2-chloroethyl- (4-rcethylcyclohexyl) -cyanamide is heated, whilst being stirred, for one hour in an oil-bath at 110°. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered, and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, 1- [p- (2-aminoethyl) -benzenesulphonyl ] - 2-imino-3- (4-methyi-cyclohexyl) -imidazolidine-dihydrochloride, M. P . 260° (with decomposition) precipitates.

Starting with 49.8 g of 1- [ p- (2-aminoethyl) - obtained analogously to Example 11: a) with 11.5 g of n-butylisothiocyanate , 1- [p- (2- (3-n-butyl-2-thioureido) -ethyl) - phenylsulphony1 ] -2-imino-3- (4-methyl cyclohexyl) -imidazolidine , M.P. 170-171° (from ethyl acetate) with 12,5 g of cyclohexylisocyanate, l-[p-(2- (3-cyclohexylureido) -ethyl) -phenylsulphonyl ] -2--imino-3- (4-methylcycl.ohexyl) -imidazolidine, M.P. 179-182° (from ethyl acetate) ; c) with 11.9 g of phenylisocyanate , l-[p-(2-(3-phenylureido) -ethyl) -phenylsulphony! ] -2- imino-3- (4-methylcyclohexyl) -imidazolidine, M.P. 213-214° (from ethyl acetate) ; d) with 13.5 g of phenylisothiocyanate , l-[p-(2-(3-phenyl-2- hioureido) -ethyl) -phenylsulphonyl ] -2-imino-3- (4-methylcyclohexyl)-imidazolicline, M.P. 181.5 -182.5° (from ethyl acetate).

Example 13 " Analogously to Example 11 are obtained: from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] ~2-imino- 3-cyclohexyl-imidazolidine-dihydrochloride and 7.7 g of ethyl- isothiocyanate the 1- [p- (2- (3-ethyl-2- thioureido) -ethyl) - phenylsulphonyl ] -2-imino- 3-cyclohexyl-imidazolidine , M.P. 140°. from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] ~2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 7.3 g methyl-isothiocyanate the 1- [p- (2- (3-methyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine , M.P. 187 - 188°. from 40.9 g 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 7.7 g cf ethyl-isothiocyanate the 1- [p- (2- (3-ethyl--2- hioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl.-imidazolidine , M.P. 178°. from 40.9 g 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine-dihydrocb.ioride and 7.3 g of methyl-isothiocyanate the 1 - [p- (2- (3-methyl-2- hioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine , M.P. 179°. from 39.7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino- 3-n-butyl-imidazolidine-dihydrochloride and 13.7 g of cyclo-pentyl-isothiocyanate the' 1- [p- (2- (3-cyclopentyl-2- hioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-butyl-imidazolidine , M.P. 206 - 207°. from 35.5 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-methyl-imidazolidine-dihydrochloride and 11.5, g of n-butyl-isothiocyanate the 1- [p- (2- (3-n-butyl-2- hioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-methyl-imidazolidine , M.P. 174.5 - 176°. from 38.1 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-allyl-imida2olidine-dihydrochloride and 11.5 g n-Butyl-isothiocyanate the 1- fp- (2- (3-n-butyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-allyl-imidazolidine , M.P. nfi-ni°. from 42.5 g 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3- (1.2-dimethyl-butyl) -imidazolxdine-dihydrochloride and 8.7 g of ethyl-isothiocyanate the 1- [p- (2- (3-ethyl-2- thio-ureido) -ethyl) -phenylsulphonyl ] -2-imino-3- (1.2-dimethyl-butyl) -imidazoledine , M.P. 122.5 - 124°. from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino- 3-cyclopentyl-imidazol.idine-dihydrochloride and 10,1 g of n-propyl-isothiocyanate the 1- [p- (2- (3-n-propyl-2- thio- ureido) -ethyl) -phenylsulphonyl ] -2-imino-3.-cyclopen.tyl- imidazolidine , M.P. 184.5 - 185°. from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imirio-3-cyclopentyi-imidazolidine-dihydrochloride and 10.1 g of isopropyl-isothiocyanate the 1- fp- (2- (3-isopropyl-2-thio-ureido) -ethyl) -phenylsulphonyl ] ~2-imino-3-cyclopentyl-imidazolidine , M.P. 196 - 197°. from 40.9 g of 1- [p-(2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 11.5 g of n-butyl-isothiocyanate the 1- [p- (2- (3-n-butyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine , M.P. 179 - 180°. from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine-dihydrochloride and 11.5 g of sec butyl-isothiocyanate the 1- [p- (2- (3-sec . butyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyc Icpentyl-imidazolidine , M.P. 191 - 192°. from 40.9 g of 1- [p- (2-amino-e thyl) -phenylsulphonyl ] -2 -lining - 3-cyclopentyl-imidazolidine-dihydrochloride and 11.5 of ter . butyl-isothiocyanate · the 1- [p- (2- (3-tert . butyl-2-I thioureido) -e hyl) -phenylsulphonyl ] --2-imino-3-cyclopentyl- imidazolidine, M.P. 190 - 191° (decomposition). from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino 3-cyclopentyl-imidazolidine-dihydrochloride and 12.9 g of isopentyl-isothiocyanate the 1- [p- (2~ (3- isopentyl-2- thio- ureido)-ethyl) -phenylsulphonyl ] ~2-imino-3-cyclopentyl- imidazolidine , M.P. " from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino 3-cyclohexyl-imidazolidine-dihydrochloride and 10.1 g of n-propyl-isothiocyanate the 1- [p- (2- (3-n-propyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino~3-cyclohexyl- imidazolidine, M.P. 174 - 175°. from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 10.1 g of isopropyl-isothiocyanate the 1- [p- (2- (3-isopropyl-2- thioureido) -ethyl) -phenylsulphonyl j -2-imino-3-cyclohexyl-imidazolidine, M.P. 186 - 187°. from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imi^j" 3-cyclohexyl-imidazolidine-dihydrochloride and 9.9 g of cyclopropyl-isothiocyanate the 1- [p- (2- (3-cycIopropyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino~3-cyclohexyl-imidazolidine , M.P. 116.5 - 118°. from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino 3-cyclohexyl-imidazolidine-dihydrochloride and 11.5 g of sec. butyl-isothiocyanate the 1- [p- (2- (3-sec . butyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine , M.P. 186 - 187°. from 42.3 g of 1- fp- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 11.5 g of tert . butyl-isothiocyanate the 1- [p- (2- (3-tert butyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine , M.P. 201 - 202°. from 42,3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 12 of isopentyl-isothiocyanate the 1- [p- (2- (3-isopentyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-lmino-3-cyclo-hexyl-imidazolidine , M.P. H5'S"- '^Η-"*0 ■ from 42.3 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2- -ί^' imino-3-cyc lohex l- imidazolidine-dihydrochloride and 14.3 g of ri-hexyl-isothiocyanate the 1- [p- (2- (3-n-hexyl- 2- thioureido) -e hyl) -phenylsulphonyl ] -2-imino-3-cyclo-hexyl-imidazolidine , M.P. 172.5 - 173°. from 42.1 g of 1- fp- (2-amino-ethyl) --phenylsulphonyl ] -2-iroino- 3-cyclohexen-3-yl-imidazolidine-dihydrochloride and 11.5 g of n-butyl-isothiocyanate the 1- [p- (2- (3-n-butyl--2- thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexen-3-yl-imidazolidine , M.P. 149 - 151°. from 43,7 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 8.7 g of ethyl-isothiocyanate the 1- [p- (2~ (3-ethyl-2-thioureido) -propyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine , M.P. 162 - 163°.

Example 14 a) 41.1 g of 1- [ p- (2 -aminoethyl) -phenylsulphonyl ] -I 2- irnino-3 -n-buty1-4 -me hy]-—imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of n- propylisocyanate , and stirring is maintained for one hour . The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The l-[p~(2- (3-n-propylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-but;yl-4-methyl-imidazolidine melts at 109-112°. b) starting material: 1- [ p- (2-aminoethyl) phenylsulphonyl ] -2- imino-3-buty1-4-meth l-imidazolidine-dihydrochloride is produced by the following process: An amount of 38.0 g of 1- [p- (2-acataminoethyl) -phenylsulphonyl ] -2-i:nino-3-butyl-4-methyl-imidazol is dissolved in 370 ml of 2-n hydrochl acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [ p- (2-amino-ethyl) - phen lsulphonyl ] - 2- imino-3-bu y1-4-methy 1-imidazolidine-dihydrochloride , M.P 240° (decomposition), crystallises out in the cold state.

Example 15 Starting with 41.1 g of 1- [p- (2-aminoethyl) -phenylsulphon l ] - 2~imino~3-n-bu yl- -me hyl-imidazolidine-dihydrochloride are obtained, analogous to Example 14, with 12.5 g of cyclohexylisocyanate , the 1- [ p" (2- (3-cyclohexylureido) -ethyl) -phenyl-sulphonyl ] -· 2- imino-3-n-buty1-4-me hy1- imidazolidine , M.P. 137-138° (from ethyl acetate).

Example 16 a) An amount of 41.1 g of 1-* [ p- (2-amincethyl) - pheny1su1phony1 ] -2- imino-3-n-buty1-5 -me hy1 - imidazo1idine- dihydrochloride is dissolved in 100 ml of water, and the base liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 11.3 g of isoamyl-isocyanate , and stirring is maintained for one hour. The reaction, mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [ p- (2- (3- isoamyl-ureido) -ethyl) phenylsulphonyl ) -2- iinino-3-n-butyl--5-me hyl-imidazolidine melts at 117 - 118°. b) The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] -2- irnino-3 -butyl- 5-methyl- imidazolidine-dihydrochlori.de is produced, analogously to Example 14 b) , from 38.0 g of 1- [ p- (2-acetaminoethyl) - phenylsulphony1 ] -2-imino-3-buty1-5- ethy1- imidazolidine-dihydrochloride , M.P. 255-257°.

Examnle 17 39.7 g of 1- [ p- (2-aminoethyl) -phenylsulphonyl ]- 2- iraino-3-n- propyl- 5 -methyl- imidazolidine-dihydrochlo ide are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 11.1 g of cyclopentylisocyanate , and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [p- (2- (3-cyclopentylureido) -ethyl)-phenylsulphonylj-2-imino-3-n-p cpyl-5-methyl-imidazolidine melts at 137-138°.

The starting material: 1- [ p- (2-aminoethyl) -benzenesulphonyl ] -2-imino-3- propyl-5-methyl-imidazolidine-dihydrochloride is produced as follows: An amount of 36,6 g of 1- [ p- (2-acetaminoethyl) -phenylsulphonyl ] - 2- imino-3- propyl- 5 -me hy1-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1- [ p- (2-aminoethyl) -benzenesulphonyl ] - 2- imino-3-propy1-5 -methyl-imidazolidine-dihydrochloride , M.P. 241-242°, crystallises out in the cold state.

Example 18 39.8 g of 1- [ - (2-amiaoethyl) -phenylsulphonyl ] - 2- imino-3-n-prop 1-5 -me hyl-imidazolidine-dihyd ochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 12.5 g of cyclohexyl-isocj^anate , and stirring is maintained for 1 hour.

The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- { p- (2- (3-cyclohexylureido) -ethyl) -phenylsulphonyl ] -2-imino~3-n-propyl-5-methyl-imidazolidine melts at 99.5 - 100.5°.

The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2- imino-3-n- propyl-5 -meth 1- imidazolidine-dihydrochloride is produced analogously to Example 17.

Example 19 a) 39.8 g of 1- [ p- (2-aminoet-hyl) - phenylsulphonyl ] - 2- imino-3-n-bu yl- imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 14 g of 4--cyclohex-3-enyl~ isothiocyanate , and stirring is maintained for 1 hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [ p- (2- (3-cyclohex-3-enyl-2-thioureido) -ethyl) -phenylsulphonyl ] -2-imino-3--n-butyl-imidazolidine melts at 182-183°. b) The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] -2-imino-3-n-butyl-imidazolidine-dihydrochloride is obtained according to the instructions given in Example lb) .

Example 20 39.8 g of 1- [ p- (2-aminoethyl) -phen Isulphonyl ] - 2-:imino-3-- isobuty1- iniidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 9.9 g of n-butylisocyanate , and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1~ [p- (2- (3-n-butylureido) -ethyl) -phenylsulphonyl ] -2- imino-3- isobutyl- iniidazolidine melts at 144 - 144.5°.

The starting material: 1- [p- (2-aminoethyl) -phenyl-sulphonyl ] - 2- imino-3-isobuty1-imidazolidine-dihydrochloride is produced analogously to Example 5 b) .

Example 21 a) 41.0 g of 1- [ ρ- (2-aminoethyl) -phenylsulphonyl ] - 2- imino-3- cyclopentyl- imidazolidine -dihyd ochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride.

To the methylene chloride solution (dried with sodium sulphate) are added 14.1 g of cyclohexylisothiocyanate , and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate.

The 1- [p- (2- (3-cyclohe>:yl-2-thioureido) -ethyl) - phenylsul honyl ] -2- imino-3- cyclopentyl- imidazolidine melts at 215-216°. b) The starting material: 1- [ - (2-aminoethyl) - phenylsulphonyl. ] - 2- imino-3 -cyclopentyl- imidazolidine- dihydrochloride is obtained according to the instructions given in Example 7 b).

Example 22 a) 42.4 g of 1- [ p- (2-arninoe iihyl) -· phenylsulphonyl ] - 2- imino-3 - cyclohexy1- imidazolidine- dihyirochlor ide are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution..' It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 12.7 g of cyclopentyl-isothiocyanate , and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallised from ethyl acetate. The 1- [p- (2·- (3-cyclopentyl-2-thioureido) -ethyl) -phenylsulphonyl ] - 2- imi.no-3-cyclohexyl-imidazolidine melts at 206-207°. b) The starting material: 1- f p- (2-aminoethyl) -pheny lsulphony l. ] - 2- imino-3 -cyclohexyl- imidazolidine-dihydrochloride is obtained according to the instructions given in Example 9 b) .

Example 23 Starting with 42.4 g of 1- [p<- (2-aminoethyl) -phenyl-sulphonyl ] -2 - imino-3- cyclohexy1- imidazolidine-dihydrochlori.de are obtained, analogously to Example 22, the following: a) with 14 g of cyclohex-3-enyl-isothiocyanate , 1- f - (2- (3-cyclohex-3-enyl-2- hioureido) -ethyl) -phenylsulphonyl ] -2- imino-3- cyclohexy1- imidazolidine , M.P. 208.5 - 209.5° (from ethyl acetate). b) with 14 g of cyclohexylisothiocyanate , 1- [p- (2- (3-cyclohexyl-2-thioureido) -ethyl) -phenylsulphonyl ] 2-imino-3-cyc.lohexyl-imidazolidine, M.P. 214-215° (from ethyl acetate) .

Example 24 a) 39.8 g of 1- [p- (2-aminoethyl) - phenylsulphony1 ] -2- imino-3-n-butyl-imida∑:olid'ine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride.

To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine.

At room temperature are then added the solution of 23.2 g of diphenylcarbamic acid chloride in 100 ml of methylene chloride, and stirring is maintained for 4 hours at room temperature. The whole is then washed twice with 30 ml of water each time. The aqueous phases are extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases yield, after being dried with sodium sulphate, filtered, and concentrated by evaporation, 1- [ p- (2- (3-dipheiiyl-ureido) -ethyl) -phenyIsulphony1 ] - 2-imino-3-n-butyl-imidazolidine which, recrystallised from ethyl acetate, melts at 96.5 - 93°. b) The starting material : 1- [p- (2-aininoethyl) -phenylsulphonyl ] -2~imino-3-n-butyl-imidazolidine-dihydrochloride is obtained according to the instructions given in Example 1 b) .

' Example 25 a) 39.8 g of 1- [p- (2-anvinoethyl) -phenylsulphonyl ] -2- imino-3 -n-butyl- imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To "the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylainine . At room temperature is then added dropwise the solution of 14.8 g of piperidino- carbonyl chloride in 100 ml of methylene chloride, and the whole is stirred for 4 hours at room temperature; it is then washed twice with 30 ml of water each time. The aqueous phases are extracted twice with 100 mi of methylene chloride. The combined methylene chloride phases yield, after drying with sodium sulphate, filtration, and concentration by evaporation, 1- [ p- (2- (3 - piperidino- carbamido) -ethyl) -phenylsulphonyl ] - 2- mino-3-n-bu yl- midazolidine which, recrystallised from ethyl acetate, melts at 179.5 -180.5°. b) The starting material: 1- [ p- (2-aminoethyl) -pheny1su1phony1 ] - 2- imino-3-n-buty1- imidazo1idine-dihydrochlor i de is obtained according to the instructions given in Example lb).

- Example 26 a) 39.8 g of 1- [ p- (2-aminoethyl) - phenylsulphon 1 ] - 2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethyiamine . At room temperature are then added the solution of 9.8 g of dimethylcarbamic acid chloride in 100 ml of methylene chloride, and the whole is stirred for 4 hours at room temperature; it is then washed twice with 30 ml of water each time. The aqueous phases are extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases yield, after being dried with sodium sulphate, filtered^ and concentrated by evaporation, 1- [ p- (2- (3-dimethylureido) -ethyl) -phenylsulphonyl ] -2- imino-3- isobutyl- imidazolidine which, recrystallised from ethyl acetate, melts at 132-135°. b) The starting material: 1- [ p- (2-aminoethyl) -phenylsulphonyl ] - 2- imino-3- isobutyl- imida olidine-dihydrochlo ide is obtained according to the instructions given in Example 5b) .

Example 27 Analogously to Example 28 are obtained: from 39.6 g of 1- [p- (2-amino-ethyl)-phenylsulphonyl ] -2-imi.no-3-n-butyl-imidazolidine-dihydrochloride and 15.0 g of morpholino-carbonylchloride the 1- [p- (2- (morpholino-carbamido) --e hyl ) -phenylsulphonyl ] -2-imino-3-n-butyl-imidazolidine , M.P. 176 - 177°. from 42.5 g of 1- fp- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 13.9 g of -n-butyl-N-methylamino-carbonylchloride the 1- [p- (2- (3-n-butyl-3-methyl-ureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazo-lidine, M.P. 134 - 136°. from 39.6 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-n--butyl-imidazolidine-dihydrochloride and 13.9 g of N-n-butyl-N-methyl-arnino-carbonylchloride the. 1- [p- (2- (3-n-butyl-3-methylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-n-butyl-imidazolidine , M.P. 136 - 137°.

Example 28 a) 41.0 g of 1- [ - (2-aminoethyl) -phenyl-sulphonyl ] - 2- imino-3 -cyclopentyl- imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution.

The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) is added dropwise, at room temperature, the solution of 23.2 g of diphenylcarbamic acid chloride in 100 ml of methylene chloride; the whole is then stirred for 4 hours at room temperature, and afterwards washed twice with 30 ml of water each time.

The aqueous phase is extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases yield, after being dried with sodium sulphate, filtered, and concentrated by evaporation, l-[p- (2- (3-diphenylureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl- imidazolidine-hydrochloride which, recrystallised from ethyl acetate, melts at 209-210°. b) The starting material: 1- [p- (2-aminoethyl) -phenyl-sulphonyl ] - 2- imino-3-cyclopentyl-imidazolidine-dihydrochloride is obtained according to the instructions given Example 29 39.7 g of 1- [ p- (2-amin ethyl) -phenylsulphonyl ] - 2- imino-3-n-buty1- imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide sclution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine .

At room temperature is then added the solution of g of 1-morpholinylcarbonyl chloride in 100 ml of methylene chloride, and stirring is maintained for 4 hours at room temperature; the whole is then washed twice with 30 ml of water each time. The aqueous phases are extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases yield, after drying with sodium sulphate, filtration, and concentration by evaporation, 1- [ p- (2- (l-morpholinyl-carbonamido) -ethyl) -phenylsulphonyl ] - 2- imino- 3-n-butyl-imidazolidine which, recrystallised from ethyl acetate, melts at 176-177°.

The starting material: 1- [ p- (2-amirioethyl) -phenyl-sulphonyl ] - 2-imino-3-n-butyl-imidazolidine-dihydrochloride is obtained according to the instructions given in Example 1 b) .

Exampl- 30 g of 1- [p- (2- (3-ethyl-2-thioureido) -ethyl)-phenylsulphonyl ] -2-imino-3-cyclopentyl-imidazolidine , M.P. 178°, are dissolved in 100 ml of 2-n. hydrochloric acid, vzhile slightly heating. After cooling with ice-water the 1- [p- (2- (3-ethyl-2- thio-ureido) -ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentyl-imida-zolidine-hydrochloride precipitates, M.P. 166 - 168°.

Claims (16)

1. What we claim is: 4-3126* 1. p-Subs ifcu ed phenylsulfony1-2 -imino-imidazolidinones having the formula I wherein R, represents an optionally branched alkyl group having from 1 to 6 carbon atoms, an allyl group, or a cycloalkyl or cycloalkenyl group having, in both cases, from 5 to 8 carbon atoms. R2 represents a hydrogen atom or a methyl or ethyl group, A represents a straight or branched chain alkylene group having 2 or 3 chain members , X represents an oxygen or sulphur atom and represents an optionally branched alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms, a phenyl group or a cycloalkyl or cycloalkenyl group having, in both cases, from 5 to 8 carbon atoms, while R^ represents a hydrogen atom, an optionally branched alkyl group having from 1 to 6 carbon atoms or a phenyl group, or R~ and R, together represent a polymethylene chain having from 4 to 7 carbon atoms, said chain being optionally interrupted by an oxygen atom.

2. p-Substituted phenylsulfonyl-2-imino- imidazolidisenes having the formula I as illustrated in claim 1 wherein represents an n-butyl, cyclopentyl, cyclohexyl or 4- methyl-cyclohexyl group, R represents a hydrogen atom, A represents an ethylene group, X represents an oxygen or sulphur atom, R^ represents an ethyl, n-propyl or n-butyl group and. R^ represents a hydrogen atom.

3. 1- [p- (2- (3 -n-butyl-2 -thioureido) -ethyl) -phenylsulfonyl ] - 2-imino-3-n-butyl-imidazolidine .

4. . 1- [p- (2- (3 -n-butylureido) -ethyl) -phenylsulfonyl ] -2-imino- 3-cyelohexyl-imidazoiidine .

5. 1- [p- (2- (3-n-butyl-2-thioureido) -ethyl) -phenylsulfonyl ] -2 -imino-3 -cyclohexyl-imidazolidine .

6. 1- [p- (2- (3-n-propylureido) -ethyl) -phenylsulfonyl ] -2-imino-3- (4-methylcyclohexyl) - imidazolidine .

7. 1- [p- (2- (3-ethyl-2-thioureido) -ethyl) -phenylsulfonyl ] -2-imino-3 -cyclopentyl-imidazolidine .

8. The pharmaceutically acceptable acid addition salts of a p-substituted phenylsulfonyl-2-imino-imidazolidia&ne as claimed in any one of claims 1 to 7.

9. 1- [p- ( · (3-ethyl-2-thioureido) -ethyl) -phenylsulfonyl ] -2-imino-3-cy lopcntyl- imi dazolidit3_ane hydrochlo ide .

10. Process for the production of p-substituted phenylsulfonyl-2 -imino-imidazol.idi.nes having the formula I as defined in claim: 1 and their pharmaceutically acceptable acid addition salts which comprises reacting the corresponding compound havins the formula II Nil with an isocyanate or isothiocyanate having the formula III R3 - N = C = X (III) wherein R^ and X have the meanings given in claim 1, or with a reactive derivative of a carbamic acid or thiocarbamic acid having the formula IV wherein RQ , R, and X have the meanings given in claim 1 and, when required, converting an acid addition salt of a p-substituted pheny lsulfonyl-2-imino-imidazolidlne having the formula I thus obtained into the free base or converting a p-substituted phenylsulfonyl-2-imino-irnidazolidine having the formula I or an acid addition salt thereof thus obtained into, or into an other, pharmaceutically acceptable, acid addition salt thereof.

11. Λ p--subs ituted phenylsulfonyl-2-imi no-imidazolidine or pharmaceutically acceptable acid addition salt thereof when- ever prepared by a process as claimed in claim 10.

12. Process as defined in claim 10 substantially as hereinbefore described with reference to any one of the Examples 1,3 to 11, 14 to 26, 28 and 29.

13. Process as defined in claim 10 substantially as hereinbefore described with reference to any one of the Examples 2, 12, 13, 27 and 30.

14. A p-substituted phenylsulfonyl-2 -imino-!midazolidine having the general formula I as defined in claim 1. or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with reference to any one of Examples 1, 3 to 11, 14 to 26, 28 and 29.

15. A p-substituted phenylsulfonyl-2-imino-imidazolidine having the general formula I as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with reference to any one of Examples 2, 12, 13, 27 and 30.

16. A pharmaceutical composition comprising a p-substituted phenylsulfonyl-2-imino-imidazolidine derivative or pharmaceutically acceptable acid addition salt thereof as claimed in any one of claims 1 to 9 together with a pharmaceutically acceptable diluent or carrier therefor. 13.7.70 - 56 - GB etc.