IL31800A - 1-phenylsulphonyl-2-imino-imidazolidine derivatives and processes for their preparation - Google Patents

Description

Tnasn o"»3*Vnm 7»η»* τιπ·»·κ l-Phenylsulphonyl-2-iminq-imida2olidine derivatives and processes for their preparation CIBA-GEIOY AG 0:30093 GEIGY A.G., BASLE, SWITZERLAND 4-2781* The present invention concerns new benzenesulphonamide derivatives, processes for the production thereof, pharmaceuticals containing the new compounds, and the use thereof.

Compounds of general formula I NH wherein R^ represents an alkyl group with 1 - 4 carbon atoms, an alkenyl group with 3 - 4 carbon atoms or a cycloakyl group with 5 - 7 carbon atoms, R2 represents hydrogen, the methyl or ethyl group, and X represents hydrogen, a halogen atom with an atomic group, or the acetyl group, and the addtion salts thereof with inorganic or organic acids, have hitherto not been known.

It has now been found that these compounds possess valua- ble pharmacological properties, in particular 1- (p-chloro-phenyl- sulphonyl) -2-irnino-3-butyl-imidazolidine , 1- (p-methoxyphenyl- sulphonyl) -2-imino-3-butyl-imidazolidine , 1- (p- tolylsulphonyl) - 2-imino-3-butyl-imidazolidine, 1- (p-acetylphenyl sulphonyl) - 2- imino-3-butyl-imidaz olidine , 1- (p-methylthio-phenylsulphonyl) - 2-imino- 3-cyclohexyl-imidazolidine, 1- (p-acetylphenyl sulphonyl) - 2-imino-3-allyl-imidazolidine and 1- (p-tolylsulphonyl) -2-imino- 3-propyl-5-ethyl-imidazolij?idine exhibit hypoglycemic activity when administered orally or parenterall , thus characterising them as suitable for treating diabetes. The hypoglycemic acti- vity was determined by standard tests on warm-blooded animals, e. g. rats.

In the compounds of general formula I , as lower alkyl group can be, e. g. the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl or isobutyl group.

As alkenyl group: the allyl, l-methyiallyl , 2-methyl- allyl or the 2-butenyl group; as cycloalkyl group: - metbyi , cyclopentyl , cyclohexyl, ryrl nhpyyl --methyl , cycloheptyl, cyclobutyl group.

Compounds of general Formula I are produced by a first process according to the invention by condensin compounds of general Formula II wherein X, R-^ , and Rg have the meanings given under Formula I, and R^ represents hydrogen, an arylmethyi } diarylmethyl or a triarylmethyl group, the methyl or the allyl group, with a reactive cyanic acid derivative, whereby ring closure takes place and, depending on the starting material, R3-halide .splits off, and optionally converting the compound obtained into an addition salt with an inorganic or organic acid. 3 as arylmethyi, diarylmethyl or triarylmethyl group is, for example, the benzyl, benzhydryl, the trityl group, the methyl or allyl grou .

• Suitable as reactive cyanic acid derivatives are cyanogen halides such as cyanogen chloride or cyanogen bromide, or cyanic acid esters, in particular cyanic acid phenyl esters. The reaction is preferably performed in the presence of a water miscible or water non-mi scible inert organic solvent in the presence or absence of water. Suitable inert organic solvents are, e.g., hydrocarbons such as benzene, toluene or xylene; lower alkanols such as methanol or ethanol , ethereal liquids such as ether, dioxane or tetrahydrofuran; chlorinated hydrocarbons such as methylene chloride; and lower ketones such as acetone or methyl ethyl ketone; carboxylic acid esters such as ethyl acetate; carboxylic acid nitriles such as acetonitrile; or sulphones such as tetrahydro-thiophene-1 , 1-dioxide . The reaction can be performed in the presence or absence of an acid binding agent. Inorganic bases or salts can be used as acid binding agents, e.g. alkali metal hydroxides, hydrogen carbonates carbonates or phosphates, as well as the corresponding sodium or potassium compounds. Also calcium carbonates as well as calcium phosphates and magnesium carbonate can be used.

Suitable starting materials of the general formula II are those compounds which are correspondingly substituted according to the defiiitions of the symbols X, R-^ , and as given after formula I. One such group of starting materials are the N-(2-ami-no-ethyl) -benzenesulphonamides the benzene ring of which being substituted in para-position by the radical X and the amino group thereof being substituted by the radical . These starting materials can be prepared, for example, by reacting a 1-phenylsul-phonyl-aziridine substituted by the radical X, with an amine containing the radical R^ and R-^ . Examples of such aziridines have been described in the literature, e. g. 4 ' - (aziridine-l-yisul-phonyl) -acetanilide [cp. R, Lehmann et al . , Bull .Soc .Chim . Beiges 55, 52 - 97 (1946); C.A. 41, 5475 (1947)].

Further aziridines of this type can be prepared analogously.

A second group of starting materials corresponds to the first group, however having a lower alkyl group substituted in the ethylene moiety. These compounds are prepared as follows: benze-sulphonyl chloride substituted in para-position by the radical X, is used as starting material, which is reacted with a 2-alkyl-aziridine [cf. A. Weissberger, Heterocyclic Compounds with Three and Four-Membered Rings, Part One, John Wiley & Sons Inc., London (1964)] in the presence of diluted sodium hydroxide solution. Substituted l-phenylsulphonyl-2-alkyl-aziridines are obtained which nylsulphonyl-aziridines , with an amine containing the radical and .

Compounds of general formula I wherein is in 5 -position are produced by a second process according to the invention by condensing and cyclisxng a compound of the general formula III wherein X and R2 have the meanings as defined in formula I, with a compound of general formula IV, H " f ' Rl (IV) C s N wherein R^ has the meaning given in formula I , or with an alkali metal or alkaline earth metal derivative thereof, and optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

Suitable alkali metal and alkaline earth ir.etal derivatives of general Formula IV are the sodium, potassium, lithium and calcium derivatives. The condensation is preferably performed in an ethereal liquid, e.g. in " ether, tetrahydrcfuran , dioxane, anisole or ethyleneglycol-dimethylether.

Suitable starting materials of the general Formula III are, e.g., those . compounds vhich are correspondingly substituted according -to the definitions of the symbols R2 and X as given after formula I . A method for producing such compounds has already been described following the first process.

Compounds of general formula I are produced by a third process according to the invention by condensing and cyclising a compound of general formula V wherein X has the meaning given under formula I, with a reactive ester of a hydroxy compound of general formula VI (VI) I I HC CH HO N-R, I 1 C=N wherein R-^ and R2 ' have the meanings given under formula I, and optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

Suitable reactive esters of hydroxy compounds of Formula VI are e.g. halides, particularly chlorides or bromides, furthermore, sulphonic acid esters such as the o- and p-toluene-sulphonic acid esters or methanesulphcnic acid esters. The condensation is performed preferably in a solvent iscible or non-miscible with water and in the presence or absence of water. Suitable solvents are e.g. alkanols such as.butanol; ethereal liquids, such as dioxane, diethyleneglycol mono ethyl ether; carbox>/3ic acid amides, such as N, -dimethylforr.a ide ; or sulphcxides such as dimethylsulphoxiae . The condensation is advantageously carried out in the presence of an acid binding agent. Such acid binding agents are named following the first process of this invention. Furthermore also tertiary organic bases such as N, -dii sopropyl-ethyl-a ine can be used.

Suitable starting materials for the third process are, e.g., the reactive esters, mentioned hereinbe ore, of a hydroxy compound of general Formula VI in which the symbols R^ and correspond to the definitions given after Formula I. One class of bromides of general Formula VI can be obtained, e.g., by reacting l-alkyi aziridines [cf. A. Weissberger, Heterocyclic Compounds v/ith Three and Four-Membered Rings, Part One, John Wiley Sons Inc., London (1964)] v/ith cyanogen bromide in dicxane.

Compounds of general Formula I are prepared by a fourth process according to the invention by condensing and cyclising a reactive ester of a compound of general Formula VII C ≡ N wherein X and R2 have the meanings given under formula I , with an amine of general formula VIII Rt - H2 (VIII) wherein R, has the meaning given under formula I, and. optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

Suitable reactive esters, of hydroxy compounds of general Formula VI are e.g. halides, particularly chlorides or bromides , or sulphcnic acid esters, in particular a benzenesulphonic acid ester which is substituted in para-position by the radical X . The condensation is performed preferably in a solvent. Suitable solvents are, e.g. , the same solvents used in the third process.

Advantageously the reaction is performed in the presence of an acid binding agent. Suitable acid binding agents are preferably bases of general Formula VIII which are present in excess.

Suitable starting materials for this process are, e.g.}the reactive esters of a hydroxy compound of general Formula VII, listed hereinbefore, in which the symbols X and R 2 correspond to the definitions given after Formula .1· One class of such compounds are produced e.g.- as follows: Aziridine is reacted with cyanogen bromide in ether to give -(2-bromoethyl) -cyana ide , which is then condensed in acetone in the presence of dilute sodium hydroxide solution while splitting off hydrogen chloride, with a benzenesulphcnyl chloride, which is substituted in para-position by the radical X , to yield the corresponding N- ( 2-chloroethyl) - -cyanobenzene-sulphcnamide.

A compound of general formula I is prepared by a fifth pro-cess according to the invation by cyclising by heating an addition salt of general formula IX wherein X, and R2 have the meanings given under formula I, and Y represents halogen, and optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

As halogen, Y can -represent , e.g., bromide or chlorine.

The condensation can be performed by heating with or without a solvent. Suitable solvents are liquids with a high boiling point, e.g. ethers such as diethyleneglycoldirnethylethe , or carboxylic acid amides such as N ,N-dimethyl- ormamide .

Suitable starting materials for this process are compounds of general Formula IX, in which the" symbols X, Y, ^ and R2 correspond to the definitions given after Formulas I and IX. One class of such starting materials can be produced, e.g., by condensin benzenesulphonyl chlorides, which are substituted by the radical X in para-position, with di sodium cyanamide in water to obtain the sodium derivative of the corresponding -cyanobenzenesulphcnamides ; these condensation products are then reacted with N-( 2-chloroethyl) -amino-hydrochlorides which are substituted at their nitrogen atom by the radical According to a sixth process, compounds of general Formula I are obtained by reacting a reactive functional derivative cf a sulphonic acid of general Formula X wherein χ has the meaning given under Formula with a compound of general Formula XI H wherein R^ and R2 have the meanings given under formula I , and optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

A suitable reactive functional derivative of a sulphonic acid of general Formula X is, e.g., a halide, in particular a chloride, or also an anhydride of general Formula X a wherein X has the meaning given under Formula I The reaction is performed preferably in an inert organic solvent miscible or non-miscible with water and in the presence or absence of v/ater. Suitable inert organic solvents are, e.g., carbohydrates such as benzene, toluene or xylene, ethereal • hydrocarbons such as methylenechloride, and lower ketones such as acetone or methylethyl ketone. It is advantageous to add an acid binding agent to the reaction solution. Suitable as such acid binding agents are, e.g., the inorganic bases or salts that were mentioned following the first process. Furthermore also organic bases such as pyridine, trimethyl or triethyl amine, Ν,Ν-diisopropyl-ethyl amine or collidine can be used, which, when added in excess, can also serve as solvent.

Suitable starting materials for this process are, e.g., compounds •^o of general Formula XI , in which the symbols and correspond to the definitions given after Formula I. and1 1-methyl-/ 1-cyclohexyl- and ±^-g---&y-al^ohox l^o kyj*-)--2-amino- imidazoline are described in the literature. Other starting materials of this type can be produced analogously. According to a first process, ethylenediamines which are substituted at a nitrogen atom by a radical are used as starting material ·, these ethylenediamines reacted with carbon disulfide yield the corresponding 2-imidazolidinethicnes , which, with methyl iodide, are converted to the corresponding 2-methylthio-2-imidazolinium iodides, which are then reacted with ammonia. According to a second process, these same starting materials are obtained when the ethylenediamines, substituted at a nitrogen atom by the radical R]_, are reacted with cyanogen chloride, or according to a third process, v/hen the same ethyleneciamine is condensed with a salt of an S-methylisothiourea to the corresponding l-(2-aminoethyl) -guanidines and these are cyclised by heating.

These compounds can be produced by a fourth process by reacting the 2-imino-imidazolidine with an R^-halide.

Another class of starting materials of the general Formula XI are 2-amino- -methyl-2-imidazolines which are substituted in 1-position by radical Rj_ . Such Compounds are obtained, e.g., as follows: 2-chloro-propionyl chlorides are reacted with amines whic have the radical bound to the nitrogen atom, to yield N-R^- 2-chloro-propionamides ; which asides, with benzylamirie, yield N-R i~( 2-benzylamino) -prcpiona ides ,which are reduced with lithium aluminium hydride to N-R-^- ' -benzyl-1 , 2-propane-diamines $ the reduction products can be debenzylated with palladium charcoal and hydrogen to the corresponding K-R]-l , 2-propane-diamines which, with cyanogen bromide, condense with ring closure.

Homologous l-R-^-2-amino-4-ethyl-2-iffiidazolines can be produced analogously by starting from 2-chloro-butyryl chloride.

Compounds of general formula I but wherein represents specifically an alkyl group with 3 or 4 carbon atoms other r than the tertial-ty butyl group are produced by a seventh process according to the invention by reducing a compound of general formula XII N - H wherein X and R2 have the meanings given -under Formula I, and represents a lower alkenyl group with 3 to 4 carbon atoms and optionally converting the compound obtained into an addition salt with an inorganic or organic acid.

The reduction is preferably performed in a solvent with hydrogen in the presence of a catalyst. Suitable catalysts are, for example noble metal catalysts such as palladium, which can be used, e.g., on charcoal, as well as Raney nickel. Solvents which can be used are, e.g., alkanols such as methanol or ethanol, and also dioxane. The reduction is advantageously performed at normal pressure and temperature.

Suitable starting materials of general Formula XII are those compounds which are correspondingly substituted according to the definitions of the symbols X, and R2 as given after Formulas I and XII Such compounds can, e.g., be produced according to the first process according to the invention.

If desired, the compounds of general Formula I obtained according to the processes of the inventim are subsequently converted into their salts with inorganic as well as organic acids. These salts are produced, e.g., by reacting the compounds of general Formula - organic or organic solvent such as methanol, ethanol , diethyl ether, chloroform or methylene chloride.

For- use as pharmaceuticals, in place of the free compounds of general Formula I, the pharmaceutically acceptable salts thereof with acids can be used. Suitable addition salts are salts which are derived from, e.g., hydrochloric acid, hydrobrcmic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, β-hydroxy-ethane sulphonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid as well as salts derived from sulphonyl ureas which lower the blood sugar rate, such as 1-toluolsulphonyl-butyl-urea, 1-chlorobenzenesulphonyl-propyl-urea and l-[ 2- ( 2-methoxy-5- chloro-benzamido) -ethyl] -phenyl sulphonyl-cyclohexyl-urea.

The new active substances are preferably administered orally.

The daily dosages vary betv/een about 100 and 500 mg for adult patients of normal weight. Suitable forms of dosage units such as dragees or tablets preferably contain 50-500 mg of an active substance according to the invention, that is from 20 to 80%- of a compound of general Formula I.

They are produced by combining the active substance with, e.g. , solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or Relatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols to form tablets or dragee cores. The latter are coated with, e.g. concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily 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 forms of dosage units are hard gelatine capsules and also soft closed capsules made of gelatine and a softener as glycerin. The former contain the active substance advantageously in the form of granulate, for example, in admixture with diluents such as maize starch, and/ or lubricants such as talcum or magnesium stearate and, optionally stabilising agents such as sodium metabisulphite or ascorbic acid. In soft capsules the active sub stance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols } to which stabilising agents can also be added.

The following prescriptions further illustrate the production of tablets and dragees: a) 1000 g of l-(p-chloro-phenyl) -2-imino-3-butyl-imidazolidine are mixed with 500 g of lactose and 270 g of potato starch, the mixture is moistened with an aqueous solution of 8.0 g of gelatine and granulated through a sieve. After drying, 60.0-g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and 20.0g of colloidal silicium dioxide ' are mixed in and the mixture is pressed into 10,000 tablets each weighing 200 mg and containing 100 mg of active substance. If desired the b) A granulate is produced f om I,GOO g of 1- (p-methcxy-pheny sulphonyD-2-ir;ino- 3-tert-butyl-imidazolidine , 345.0 g of lactose the aqueous solution of 6.0 g of .gelatine. After drying, the gr ulate is mixed with 10.0 g of colloidal silicium dioxide, 40.0 g talcum, 40.0 g of potato starch ana 5.0 g of magnesium stearate and pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made fro 533.0 g of crystalline saccharose, 20.0 g of shellac, 75.0 g of gum arabic, 250.0 g of talcum, 20.0 g of colloidal silicium dioxide and 1.5 g of dyestuff , and dried. The dragees obtained each weigh 240 mg and contain 100 mg of active substance.

The following examples further illustrate the production of the new compounds of general Formula I and intermediates thereof which have not been hitherto described, but are by no means the sole methods of performing same. The temperatures are given in degrees centigrade. If not otherwise denoted by an alkyl group is meant a straight chain n-alkyl group.

Example 1 a) 25.6 g of -( 2-propylamino-ethyl) -p-toluenesulphcn- amide are dissolved in ICO. ml of 2 N sodium hydroxide solution and, while cooling at 20-30°, 10.6 g' of cyanogen bromide are added. The reaction mixture is allowed to stand for 10 minutes and the crystals .vhich have precipitated are then filtered. The crude product is recrystallized from ethyl acetate to yield l-(p-tolylsulphonyl) -2-imino-3-propyl-i idzolidine melt ng at 95 - 96 °.

The starting material is produced as follows: b) A solution of 190.5 g of p-toluenesulphonyl chloride in 250 ml of acetone is added dropv/ise during 20 minutes with stirring to a solution of 43.0 g of aziridine in 300 ml of 4 N sodium hydroxide solution which has been cooled to -10°, The reaction mixture is stirred for 2 hours at 0-10° with cooling. 2 liters of water are then added to the mixture and it is extracted three times with 500 ml of ether. The ether extract is dried over sodium sulphate and concentrated under vacuum.

The residue, crude 1- (p-tolyl sulphonyl) -aziridine , melts at 54-56°. c) A solution of 19.7 g of 1- (p-tolyl sulphonyl) -aziridine in 100 ml of dioxane and 15 ml of water is added dropwise at room temperature to 100 ml of propylamine, ana the reaction mixture is refluxed for one hour. It is then concentrated under vacuum. Recrystailization of the residue from ethyl acetate/petroleum ether yields pure - ( 2-propylaminc-ethyl) -p-toluene-sulphonamide , m.p. 39-41°.

* Example 2.

Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following end products are obtained: a) with 27.0 g of -( 2-tert . butylamino-ethyl) -p-toluene sulphcnamide j m.p. 67-68° (from ethyl acetate/ether), l-(p- tolylsulphonyl) -2-imino-3-tert . but l-imidazolidine , m . p . 130-131°, [the starting- product is produced analogously to / Example 1 c) from 19.7 g of l-(p-tolylsulphonyl) -aziridine and 100 ml of tert . butylamine] and b) with 29.6 g of N-( 2-cyclohexylamino-ethyl) -p-toluene sulphonamide , m.p. 65-66° (from ether),, l-(p-tolylsulphonyl) -2-imino-3-cyclohexyl-imidazolidine , m.p. 118-120°, [ the starting product is produced analogously to Example 1 c) from 19.7 g of l-(tolylsulphonyl) -aziridine and 100 ml of cyclo-hexylamine] .

Example 3 a) 24.4 g of l'i- ( 2-methylamir.c-ethyl) -p-methoxy-benzer.e- sulphonamide are dissolved, in 100 ml of 2 sodium hydroxide solution and while cooling at 20-30°, 10.6 g of cyanogen bromide are added thereto. The reaction mixture is allowed to stand for 3 hours and then the crystals which have precipitated are filtered. The crude product is recrystallized from methanol to obtain l-(p-methoxy-phenyisulphonyl) -2-imino-3- methyl-imidazolidine melting at 104--1070.

The starting material is produced as follows: b) A solution of 20.6 g of p-ir.ethoxy-benzenesul henyl chloride in 250 ml of acetone is added dropwise during 20 minutes with stirring to a solution of 4.3 g of aziridine in 300 ml of 4 N sodium hydroxide solution which has been cooled to -10°. The reaction mixture is stirred for 2 hours at 0-10° with cooling. Then 2 liters of water are added to the mixture and it is extracted three times with 500 ml of ether. The ether extract is dried over sodium sulphate and concentrated under vacuum. The residue, l-(p-methoxy-phenylsulphcnyl) -aziridine, melts at 45-46° (from ethyl.acetate/petroleum ether). c) A solution of 21.3 g of l-(p-methoxy-phenylsulphonyl) aziridine in ICC mi of dioxane and 15 ml of water is added dropwise at room temperature to 300 ml of 33o ethylamine in ethanol, and the reaction mixture is refluxed for one hour. It is then concentrated under vacuum. The residue is purified by elution chromatography on silica gel. From the chlorofor ethanol fraction (9:1) ΙΪ- ( 2-r:ethyla:iinc-ethyl) -p-rr.ethoxy-benzenesulphona.T;ide is obtained, hich rcelts at 68-69° after recrystallization from ethyl acetate.

Example 4~ . Analogously to Example a) , starting from 10.6 g of cyanogen bromide, the following end products are obtained; a) with 28.6 g of U-( 2-butylamino-ethyl) -p-metnoxy-beiizenesulphonamide , m.p. 66-68° (from ether), 1- (p-methoxy-phenyl sulphonyl) -2-imino-3-butyl-imidazolidine , m.p. 85-86^ [the starting material is produced analogously to Example 5 c) from 21.3 g of l-(p-methcxy-phenylsulphonyl) -aziridine and 500 ml of butylamine] and b) with 28.6 g of N-( 2-tert .butylamino-ethyl) -p-methoxy-benzenesulphonamide 5 m.p. 97-99° (from ether, 1- (p-methoxy-phenyl sulphonyl) -2-imino- 3-1ert .butyl-imidazol dine , m. . 107 -108° (from me hanol) j_ the starting product is produced analogously to Example 3 c) from 21.3 g of l-(p-methoxy-phenyl-sulphonyl) -aziridine and 500 ml of tert. butylamine].

Analogously to Example 3- a) , starting from 10.6 g of cyanogen bromide-, the following end product is obtained: a) with 23.8 g of N-( 2-p opyl amino-ethyl ) -p-methylthio-benzenesulphonamide , m.p. 79-81° (from ethyl acetate), l-(p-.7;-et-hylthio-phenyl sulphonyl) -2-irr.ino- 3-propyl-i!rid zoliai e . b) The starting material for a) is produced as follows: Analogously to Example' 5 b), 22.3 g of p-methylthic-benzenesulphonyl chloride and .3- g of aziridine yield l-(p-methylthio-phenylsulphonyl) -aziridine (crude product); 22.9. g of the latter are converted analogously to Example .3 c) with 500 ml ' of propylamine to l-( 2-propylamino-ethyl) -p-methylthio-benzenesulphonamide .

Analogously to Example 1 a)', starting from 10.6 g of cyanogen bromide, the -following end products are obtained: a) with 30.2 g of ft- ( 2-butylamino-ethyl) -p-methylthio- benzenesulphonam de , m.p. 88-89° '(from ether), · l-(p-methyl- thio-phenyl sulphonyl) -2-imino-3-butyl-i!nidazolidine , m.p. 87-88° (from ether) [the starting material is produced analogously to Example 1 c) from 22.9 g of 1- (p-methylthiOTphenyl- sulphonyl) -aziridine and 500 ml of butylamine J and b) with 30.2 g of N- ( 2-tert . butylamino-ethyl) -p- methylthio-phenyl sulphonamide (crude product), l-(p-methyl- thio-phenyl sulphonyl) -2-imino-3-tert .butyl -imidazolidine , m.p. 138-139° (from ethyl acetate), i_tne starting material is produced analogously to Example 1 c) from 22.9 g of l-(p-metbylthio-phenyl sulphonyl ) -aziridine and 500 ml of tert. butylamine] .

In addition, analogously to Example 5 a) , starting from 10.6 g of cyanogen bromide, the following end product is obtained; . . c) with 32.8 g of N-( 2-cyclohexylamino-ethyl) -p-methyl-thio-benzenesulphonamide , m.p. 131-132° (from methanol), l-(p-methylthi o-phenyl sulphonyl) -2-imino-3-cyclohexyl-imidazoli dine, m.p. 129-130° (from ethyl acetate) ,[ the starting material is produced analogously to Example 5 c) from 22.9 g of l-(p-methylthio-phenyl'3ulphonyl) -aziridine and 300 ml of cyclohexylamine .

Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following is obtained: a) with 27.6 g of ΙΊ- ( 2-propylamirio-ethyl) -p-chloro- benzenesulphonamide (crude product), l-(p-chloro-phenylsulphon-yl) -2-imino-3-propyl-imidazolidine. This end product is purified by elution chromatography on silica gel, being eluted with chloroform/ethanol ( 9 : 1) , m.p. 6B-693. b) The starting material is obtained by starting from p-chloro-phenylsulphonyl chloride, which with aziridine, analogously to Example 1 b), yields l-(p-chloro-phenylsulphcnyl) aziridine (crude product) 21.7 g of this aziridine are converted with 300 ml of propylamine analogously to Example 1 c) to N- ( 2-propylamino-ethyl) -p-chloro-benzenesulphonamide .

Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following end products are obtained: a) with 29.0 g of N-( 2-butylamino-ethyl) -p-chloro-benzenesulphonamide (crude product), 1- (p-chloro-phenylsulphonyl) -2-imino-3-butyi-imidazolidine , m.p. 74-75°, [the starting material is produced analogously to Example 1 c) from 21.7 g of l-( p-chloro-phenylsulphonyl) -aziridine and 300 ml of butylamine] and b) with 31.6 g of N- ( 2-cyclohexylamino-ethyl) -p-chloro-benzenesulphonaraide , m.p. 83-84° (from ethylacetate/ether) , 1- (p-chloro-phenylsulphonyl) -2-imino- 3-cyclohexyl-imidazolidin m.p. 108-110°, [the starting material is produced analogously to Example 1 c) from 21.7 g of 1- (p-chloro-phenylsulphonyl) -aziridine and 300 ml of cyclohexylamine].

E ample 9 Analogously to Example la), starting from 10.6 g of cyanogen bromide, the foilcuing- end products are obtained: 'a) with 24.2 g of ( 2-propylariino-ethyl) - enzene- sulphonamide , in. p. 72-73° (from ethyl acetate), 1-phenyl- sulphonyl -2-imiri.c-3-propyl -imidazole dine , m.p. 69-70° (from ether), [the starting material is produced analogously to Example 1 c) from 18.3 g of 1-p.henylsuiphonyl-aziridine (cf. J. Kelles et al., German patent No. 695,331) and 300 ml of propylamine]; b) with 24.2 g of II- (2-iscpropylamino-ethyl) -benzene - sulphona ide , m.p. 59-60° (from ethyl acetate), 1-phenyl- sulphonyl-2-imino-3-isopropyl-imidazolidine , m.p. 71-72° (from ethyl acetate/ether), [the starting material is produced analogously to Example 1 c) from 18.3 g of 1-phenylsulphonyl-aziridine and 300 ml of isopropylamine}4 c) with 25.6 g of N-( 2-butylaminc-ethyi) -benzene- sulphonamide , m.p. 56-57° (from ether), 1-phenylsulphcnyl- 2-imino-3-butyl-imidazclidine, m.p. 84-85° (from ether), [the starting material is produced analogously to Example 1 c) from 18.3 g of 1-phenylsulphonyl-aziridine and 300 ml of butylamine] ¾ d) with 25.6 g of U- ( 2-tert . butyla ino-ethyl) -benzene-sulphonamide , m.p. 89-90° (from ethyl acetate), 1-phenyl-sulphonyl-2-imino-3-tert . butyl-imidazolidine , m.p. 9δ-100ΰ (from ethyl acetate/ether), [the starting material is produced analogously to Example 1 c) from 18.3 g of 1 -phenyl sulphonyl-, aziridine and 300 ml of tert . butylamine ] and. e) v/ith 28.2 g of N- ( 2-cyclohexylamino-ethyl) -berizene-sulphonamide , m.p. 79-80° (from ethyl acetate), 1-phenyl-sulphonyl-2-imino-3-cyclohexyl-imidazolidine , m.p. 94-95° (from ethyl acetate/ether), [the starting material is produced analogously to Example 1 c) from 18.3 g of l-phenylsulphonyl-aziridine and 300 ml of cyclohexylamine] .

Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following end product is obtained: a) with 29.8 g of N-( 2-tert . butylamino-ethyl) -p-acetyl-benzenesUlphonarr.ide , m.p- 116-117° (from .isopropanol) , l-(p-acetyl -phenylsulphonyl) -2-imi o-3-tert . butyl -imidazolidine , m.p. 144-146° (from isopropanol). b) The startin product for a) is produced starting from p-acetyl-benzenesulphonyl chloride, which with aziridiae analogously to Example 1 b) yields l-(p-acetyl-phenylsulphonyl) aziridine (crude product). 22.5 g of this aziridine are converted analogously to Example 1 c) with 300 ml of tert. butyl-amine to N- (tert . butyl-amino-ethyl) -p-acetyl-sulphonamide .

Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following end products are obtained: . . a) with 29.8 g of N- ( 2-butylamj no-ethyl) -p-acetyl- benzenesulphona.T.ide j m.p. 8S-S00 (from isoprcpanol), l-(p-acetyl -phenyl sulphonyl) -2-imino- 3-butyl-imidazolidine 3 m.p. 120-122° (from isoprcpanol), [the starting material is produced analogously to Example 1 c) from 22.5 g of l-(p- acetyl-phenylsulphonyl) -aziridine and 300 ml of butylamine] and b) with 40.7 g of N-( 2-cyclohexylamino-ethyl) -p-(Jr- acetyl -eyclo e y-l -iMJa-^^ m.p. 85-86° (from isopropanol) , l-(p-a cetyl-phenyl sulphonyl) -2-imino- 3-cyclo- hexyl-i idazolidine j m.p. 164-1.66° (from isopropanol), j_ the starting product is produced analogously to Example 1 c) from 22.5 g of l-( -acetyl-phenylsulphonyl) -aziridine and 300 ml of cyclohexylamine] .

E mple 12 Analogously to Example 1 a) starting from 10.6 g of cyanogen bromide } the following end product is obtained: a) with 27.4 g of ίί-( 2-butylamino-ethyi) -p-fiucro-benzenesulphonamide (crude product), l-(p-i'luoro-phenyisulphon 2-imino- 3-butyl-i idazolidine , m.p. 74-76°. b) The starting material for a) can be produced starting from p-fluoro-benzenesulphonyl chloride, which, analogously to Example 1 b) , is converted with aziridine to l-(p-flucro-phenyl sulphonyl) -aziridine , 20.1 g of which with 150 ml of butylamine yield, analogously to Example 1 c) , K-( 2-butylamino-ethyl) -p-fluoro-benzenesulphonamide.

Example I .

Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following end product is obtained: a) with 27.0 g of H-(l-nethyl-2-propylamino-ethyl)-p-toluenesulphcnamide , a. . 91-92°, 1- (p-tol lsulp onyl) -2-imino-3-propyl-5-methyl-imida∑:olidine , b.p. 183-189°/ 0.01 Torr. b) The starting material for a) can be produced starting from p-toluenesulphonyl chloride, which, analogously to Example l b), is converted with 2-methyl-aziridine to l-(p-tolylsulphon-yl) -2-methyl-aziridine , m.p. 63-65°, 21.1 g of which, analogously to Example 1 c) , with 150 ml of propylamine yield N-(l-methyl-2-propylamino-ethyl) -p-toluenesulphcnamide .

E ample- 14 Analogously to Example 1 a), starting, from 10.6 g of cyanogen bromide, the following end products are obtained: a) with 28. g of -(l-methyl-2-butylamino-ethyl) -p- toluenesulp.hcnamide , m.p. 73-75° (from ether), l-(p-tolyl- sulphonyl) -2-imino- 3-butyl-5-methyl-imid3Zolidine , b . . 173- 179°/0.01 Terr, [the starting material is produced analogously to Example- 1 c) from .21.1 g of l-(p-tolylsulphonyl) -2-methyl- aziridine and 150 ml of butylaminej b) with 28.4 g of N-(l-methyl-2-tert . butylamino-ethyl) -p-toluenesulphonamide , m. p . 82-83° (from ether), l-(p-tolyl-sulphonyl) -2-imino- 3-tert .butyl -5-methyl-imidazolidine , m. . 92-94° (from ether), [the starting material is produced analogously to Example 1 c) from 21.1 g of l-(p-tolylsulphon-yl) -2-methyl-aziridine and 150 ml of tert .butylaminej and c) with 31.0 g of N-(l-methyl-2-cyclohexylamino-ethyl) -p-toluenesulphonamide, m.p. 58-59° (from ether), l-(p-tolyl-sulphonyl) -2-imino-3-cyclohexyl-5-methyl-i idazolidine , m.p. 93-94° (from ether) , [the starting material is produced analogously to Example 1 c) from 21.1 g of 1- (p-tolylsulphonyl) -2-methyl-aziridine and 150 ml of cyclohexylamine].

Example 15 Analogously to Example 1 a), starting from 10.6 g of cyanogen bromide, the following end products are obtained: a) with 27.0 g of N- ( 2-n-putyl a mino-ethyl) -p-toluene-sulphonamide , 1- (p-tolylsulphonyl) -2-imino-3-n-butyl-imidazolidine m.p. 91-92° (from methanol); b) with 28.6 g of N- ( 2-n-butylamino-ethyl) -p-methoxy-pheiiyl-sulphonamide , 1- (p-methoxyphenylsulphonyl) -2-imino-3-n-butyl-imidazolidine, m.p . 85-86° (from ether); c) with 28.5 g of N- (l-ethyl-2-propylamino-ethyl) -p-toluene-sulphonamide , 1- (p-tolylsulphonyl) -2-imino-3-n-propyl-5-ethyl-imidazolidine , m.p. 61-63° (from ether); d) with 28.2 g of N- ( 2-allyl a mino-ethyl) -p-acetyl-phenyl-sulphonamide 5 1- (p-acetylphenylsulphonyl) -2-imino-3-allyl-imidazolidine , m.p. 104-105° (from benzene). a) 36.0 g · cf N-( 1 -benzyl- 2-butylamino-ethyi ) -p-tolusne- sulphonamide are. dissolved in 5C0 ml of benzene. 10.6 g cf cyanogen bromide are added to the solution, the reaction rr.ixture is stirred for 3 hours at room temperature and then concentrated The residue is rendered alkaline with 2 ίί sodium hydroxide solution. Crystals precipitate, which are washed with water and recrystallized from methanol/ether. The resulting, pure l-(p-tolyl sulphonyl ) -2-imi o-3-butyl-imidazolidine melts at 91-92° (from ether) .

The starting material is produced as follows: b) 24.0 g of l-(p-tolylsulphonyl) -aziridine are dissolved in 100 ml of dioxane and 20 ml of water, and refl xed" for 5 hours with stirring. The reaction mixture is then concentrated. The residue , -(N' -benzyl-2-butylamino-ethyl) -p-toluenesulphon-amide, is used as crude product.

Example '17 Analogously to Example la starting from 10.6 g of cyanogen bromide, the following end .products are obtained: a) with 37.9 g of. N- (N*-benzyl~2-n-butylamino-ethyl) -p-methoxyphenyl sulphonamide , l-(p-methoxyphenylsulphonyl) - 2-imino- 3-n-butyl-imidazolidine , m.p. 85-86°; b) with 38.2 g of N- (N'-benzyl-2-n-butylamino-ethyl)— p-chlorophenylsulphonamide , l-(p-chloro-phenylsulphonyl) -2-imino- 3-n-butyl-imidazolidine , m.p. 74-75°; c) with 39.0 g of N-(N'-benzyl-2-butylamino-ethyl)-p-acetylphenylsulphonamide , 1- (p-acetylphenyl sulphonyl) -2-imino- 3-n-butyl-imidazolidine, m.p. 120-122°; d) with 42.0 g of ' - (Ν' -benzyl-2-cyclohexylamino- ethyl) p-methylthiophenyl sulphonamide , l-(p-methylthio-phenyl sulphonyl) - 2-imino-3-cyclohexyl-imidazolidine , m.p. 129-130°; e) with 37.4 g of N-.(N * -benzyl-2-allylamino-ethyl) -p-acetylphenylsulphonamide , 1- (p-acetylphenylsulphonyl) -2-imino- 3-allyl-imidazolidine j m.p. 104-105°; f) with 37.7 g of N-[ (1-ethyl-N1 -benzyl-2-propylamino) -ethyl] -p-tolylsulphonamide , 1- (p-tolylsulphonyl) -2-imino- 3-n-propyl-5-ethyl-imidazolidine , m.p. 61-63°.

E ample 18 · ' A solution of 10.6 g of cyanogen bromide in 50 ml of absolute ether is added with stirring at -10° to -5° within 30 minutes to a solution of 14.6 g of butylamine in 100 ml of absolute ether. The reaction mixture is stirred for 30 minutes more and the precipitated butylamine-hydrobromide is removed by filtration. While cooling is continued, a suspension of 2.8 g of sodium hydride in 40 ml of absolute ether is added to the filtrate which contains the resultant butyl cyanamide in solution. While cooling at this temperature is continued, the suspension is stirred for another 30 minutes and then 19.7 g o 1- (p-tolylsulphonyl) -aziridine are added to the suspended sodium derivative of butyl cyanamide which has formed. The mixture is warmed to room temperature and stirred for 15 hours at this temperature. 2 N hydrochloric acid is then slowly added to the reaction mixture and the two phases which form are separated. The acidic aqueous phase is washed twice with ether, purified with active charcoal, filtered and rendered alkaline v/ith concentrated sodium hydroxide solution at 0°. The precipitated l-(p-tolylsulphonyl) -2-imino- 3-butyl-imidazolidine is separated by filtration ad ecrystallized from methanol-, it then melts at 91-92°. ' ' E ample -19 Analogously to Exa ple S , the following end products are obtained: a) from 14.6 g of tert. butylamine in 100 ml of ether' with 10.6 g of cyanogen bromide, tert. butyl-cyana ide , which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this yields with 21.1 g of l-(p-tolyl- sulphonyl ) -2-methyl-azi idine , 1- ( -tolyl sulphonyl) -2-imino- 3- tert .butyl-5-methyl-imidazolidine , m.p. 92-94°; b) from 14.6 g of butylamine in 100 ml of ether with 10.6 g of cyanogen bromide, butyl-cyanamide, which with 2.8 g of. sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 21.3 g of 1- (p-methoxy-phenyl sulphonyl) - aziridine yields l-(p-methoxy-phenylsulphonyl) -2-imino-3-butyl-imidazolidine , m.p. 85-86°; c) from 19.8 g of cyclchexylamine in 100 ml of ether with 10.6 g of cyanogen bromide, cyclohexyl-cyanamide , which with 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 21.75 g of l-(p-chloro-phenyl sulphonyl) -aziridine yields l-(p-chloro-phenylsulphonyl) - —imi o— 3—c cloyiexy1—i idazolidine , m.p. 108-110°, and d) from 11.8g of isopropyla ine in 100 ml of ether with 10.6 g of cyanogen bromide, i sopropyl-cyanamide , which v/ith 2.8 g of sodium hydride in 40 ml of ether is converted to the sodium derivative; this with 18.4 g of 1-phenylsulphonyl-aziri-dine yields 1-phenyl sulphonyl-2-imino- 3-iospropyl-imidazolidine , m.p. 71-72°.

Example 20 Analogously to Example 18, starting from 10.6 g of cyanogen bromide, the following end products are obtained: a) with 21.0 g of 1- (p-acetyl p henylsulphonyl) -aziridine end 14.6 g of n-butylamine, 1 - (p-acetylphenylsulphonyl) -2-imino- 3-n-butyl-imidazolidine , m.p. 120-122° (from ether) ; b) with 20.2 g of 1- (p-chlorophenylsulphonyl) -aziridine and 14.6 g of n-butylamine, 1- (p-chlorophenylsulphonyl) -2-imino-3-n-butyl-imidazolidine , m.p. 74-75° (from ether); c) with 21.1 g of l-(p-tolylsulphonyl)-2-ethyl-aziridine and 11.8 g of n-propylamine , 1- (p-tolylsulphonyl) -2-imino-3-n-propyl-5-ethyl-imidazolidine , m.p. 61-63° (from ether); d) with 21.0 g of 1- (p-acetylphenylsulphonyl) -aziridine and 11.4 g of allylamine, l-(p-acetylphenylsulphonyl) -2-imino-3-allyl-imidazolidine , m.p. 104-105° (from benzene) ; e) with 21.4 g of l-(p-methylthiophenylsulphonyl) -aziridine and 19.8 g of cyclohexylamine ,1-Cp-methylthio-phenyl-sulphonyl) -2-imino-3-cyclohexyl-imidazolidine , m.p. 129-130° (from ether) .

Example 21 9.9 g of 1-butyl-aziridine [cf. A. Wei ssberger , Heterocyclic Compounds with Three and Four-Membered Rings, Joh .Wiley & Sens Inc., London (1964) , page 530] are dissolved in 50 ml of dioxane, and 10.6 g of cyanogen bromide in 50 ml of dioxane are added thereto. In an exothermic reaction a solution of N- ( 2-bromc-ethyl ) -N-butyl-cyanamide is obtained, which is poured with stirring into a solution of 17.1 g of toluene-sulphonamide in 60 ml of 2 N sodium hydroxide solution. The reaction mixture is refluxed for one hour, then concentrated to half its volume under vacuum, nd the solution is cooled to 0C. The precipitated crystals are separated by filtration, washed with water, dried under vacuum at 60° and recrystallized from ether. The resulting l-(p-tolylsulphonyl) -2-imino- 3-butyl -imidazolidine melts at 91-92°.

'Examnl e 22.

Analogously to Example 21 the following end products are obtained: a) from 9.9 g of 1-tert . bntyi-aziridine with 10.6 g of. cyanogen bromide in dioxane ,. the solution of N-( 2-bron-o-ethyl) N-tert . butyl-cyanarr.ide , which v/ith 17.1 g of p-toluenesulphon- amide in 60 ml of 2 sodium hydroxide solution yields l-(p- tolyl sulphonyl) -2-i ino-3-tert . butyl-i idazolidine , m.p. 131- 132° (from ethyl acetate); b) from 13.5 g of 1-cyclohexyl th 10.6 g of cyanogen bromide in dioxane, the solution of N-(2-bromo-ethyl) K-cyclohexyl-cyanamide j which with 17.1 g of p-toluenesulphcn- amide in 60 ml of 2 N sodium hydroxide solution yields l-(p- tolylsulphonyl) -2-imino-3-cyclohexyl-imidazolidine , m.p. 118-120° (from methanol) ; c) from 9.9 g of 1-butyl-aziridine v/ith 10.6 g of cyanogen bromide in dioxane, the solution of N-( 2-bromo-ethyl) N-butyl-cyanamide , which with 18.7 g of p-methcxy-benzene-sulphonamide in 60 ml of 2 N sodium hydroxide solution yields l-(p-methoxy-phenyl sulphonyl) -2-imino-3-butyl-imidazolidine , m.p. 85-86° (from methanol); d) from 9.5 g of 1-tert . butyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the solution of N-( 2-bromo-ethyi) N-tert.butyl-cyanamide , which with 18.7 g of p-methoxy-benzene sulphonamide in 60 ml of 2 N sodium hydroxide solution yields l-(p-methoxy-phenyl sulphonyl) -2-imino- 3-tert . butyl-imidazol i-dine, m.p. 107-108° (from methanol); e) from 9.9 g of 1-butyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the solution of- - ( 2-bromo-ethyl ) - N-butyl-cyanamide , which with 20.3 g of p-methylthio-benzene- sulphonamide in 60 ml of 2 N sodium hydroxide solution yields l-(p-methylthio-phenylsulphenyl) -2-imi o- 3-butyl-icidazolidine , m.p. 87-88° (from ether); f) from '9.9 g of 1-tert . butyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the. solution of N-( 2-bromo-ethyl) - N-tert . butyl cyanamide , which with 20.3 g of p-methylthio- benzenesulphonamide in 60 ml of 2 N sodium hydroxide solution yields 1- (p-methylthio-phenylsulphonyl) -2-imino-3-tert . butyl- imidazolidine , m.p. 138-139° (from ethyl acetate); g) from 12.5 g of 1-cyclohexyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the solution of N- ( 2-bromo-ethyl) - N-cyclohexyl-cyanamide ,, which with 20.3 g of p-methylthio- benzenesulphonamide in 60 ml of 2 N sodium hydroxide solution yields 1- (p-methylthio-phenylsulphonyl) -2-imino-3-cyclohexyl-imidazolidine , m.p. 129-130° (from ethyl acetate); h) from 8.5 g of 1-propyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the solution of N-( 2-bromo-ethyl) -N-propyl-cyanamide , which with 19.1 g of p-chloro-benzenesulphon-amide in 60 ml of 2 N sodium hydroxide solution yields l-(p-chloro-phenylsulphonyl) -2-imino-3-propyl-imidazolidine } m.p . .68-69°; i) from 9.9 g of l-butyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the solution of N-( 2-bromo-ethyl) -N-butyl-cyanamide, which with 19.1 g of p-chloro-benzene-sulphonamide in 60 ml of 2 sodium hydroxide solution yields l-(p-chloro-phenyl sulphonyl) -2-imino- 3-butyl-imidazolidine , m.p. 74-75° (from ether); -Ύ-' j) from 12.5 g of l-cyclohexyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the solution of !;-( 2-bromo-ethyl ) - N-cyclohexyl-cyanamide , which with 19.1 g of p-chloro-benzene- sulphonamide in 60 ml of 2. N sodium hydroxide solution yields l-Cp-chloro-phenylsulphonyl) -2-inino-3-cyclche yl-imidazolidine , m.p. 108-110 (from ethyl acetate/ether); k) from 8.5 g of 1-isopropyl-aziridine v/ith 10.6 g of cyanogen bromide in dioxane, the solution of H- ( 2-bromo-ethyl) -N-isopropyl-cyanamide j. which with 1.5.7 g of benzenesulphona ide in 60 ml of 2 sodium hydroxide solution yields 1-phenyl-sulphonyl-2-imi.no-3-isopropyl-imidazclidine , m.p. 71-72° (from ethyl acetate/ether) and 1) from 12.5 g of 1-cyclohexyl-aziridine with 10.6 g of cyanogen bromide in dioxane, the sdution of - ( 2-bromo-ethyl) -N-cyclohexyl-cyanamide , which with 15.7 g of benzenesulphonamide in 60 ml of 2 N sodium hydroxide solution yields 1-phenyl-sulphonyl-2-imino-3-cyclohexyl-imidazoiidine j m.p. 94-95° (from ethyl acetate) .

Analogously to Example 21 , starting from 10.6 g of cyanogen bromide, the following end products are obtained: a) with 19.9 g of p-acetylphenyl sulphonamide and 9.9 g of l-n-butyl-aziridine , l-(p-acetylphenylsulphonyl) - 2-imino-3-n-butyl-imidazolidine , m.p. 120-122° (from ether); b) with 19.9 g of p-acetylphenylsulphonamide and 8.3 g of 1-allyl-aziridine , l-(p-acetylphenylsulphonyl) -2-imino-3-allyl-imidazolidine , m.p. 104-105° (from benzene); c) with 17.1 g of 1-toluenesulphonamide and 11.3 j of l-propyl-2-ethyl-aziridine , 1- (p-tolylsulphonyl) -2-imino- 3-n-propyl-5-ethyl-imidazolidine , m.p. 61-63°.

Example 24 a) 30.3 g of N- ( 2-bromo-ethyl) - -cyano-p-toluenesulphon- amlde are dissolved in 500 ml of ethanol and 7.3 g of tert. butylamine . and refluxed for 17 hours. The reaction mixture is concentrated and the residue is taken up in chloroform and 2 hydrochloric acid. The acidic aqueous extract is rendered alkaline v/ith concentrated sodium hydroxide solution. The crude product precipitates; it is filtered and purified by recrystal- lization from ethyl acetate. The' resulting 1- (p-tolylsulphon- yl) -2-imino-3-tert . butyl-i idazolidine melts at 130-131°.

The starting material is produced as follows: b) During 30 minutes a solution of 4.3 g of aziridine in 20 ml of ether is added dropvise at 0° to a solution of .6 g of cyanogen bromide in 30 ml of ether.- The resulting suspension is concentrated under vacuum at a bath temperature of 40°. The residue is slurried in 60 ml of water and a solution of 19.9 g of p-toluenesulphonyl chloride in 190 ml of acetone is added to the suspension. 4.5 g of sodium hydroxide in 10 ml of water are then added dropwise during 10 minutes and the resulting mixture is refluxed for 30 minutes. After cooling, the crude product crystallizes. It' is filtered. Upon dilution with water, the filtrate yields another batch of crude product, which is separated and combined with the first fraction. The two fractions are recrystallized from methanol to yield N-(2-bromo-ethyl) -iN'-cyano-p-toluenesulphonamide melting at 67-69°.

Analogously to Example .24,, starting from 30.3 g of - ( 2-bromo-ethy .) - -cyan.o-p-toluenesulphor.amide in 5GC ml of ethancl , the following are obtained: a) with 5.9 g of propylamine, l-(p-tolylsulphcnyl) -2-imino-3-rpropyl-irnidazolidine , m.p. 95-96°, b) with 9.9 g of cyclohexylamine , l-(p-tolylsulphonyl) -2-imino- 3-cycichexyl-imidazolidine , ■ si. . 118-120° (from methanol) , . and c) with 7.3 g of n-butylamine j 1 (p-t.olyl sulphonyl) -2-imino-3-n-butyl-imidazolidine , m.p. 91-92° (from methanol).

Example ■ 26 Analogously to Example - 24, the following are obtained: a) starting from 31.9 g of N- ( 2-bromo-ethyl ) -N-cyano- p-methoxyphenylsulphonamide with 7.3 g of n-butylamine, l-(p-methoxy-phenyl sulphonyl) -2-imino- 3-n-butyl-imi azolidine , m.p. 85-86°;' b) starting from 32.2 g of N- ( 2-bromo-ethyl) -N- cyano - p-chlorophenylsulphonamide with 7.3 g of n-butylamine, 1- (p-chlorophenyl sulphonyl) -2-imino- 3-n-butyl-imidazolidine , m.p.. 74-75°; c) starting from 33.0 g of N- ( 2-bromoethyl) -N-cyano-p-acetylphenyl sulphonamide with 7.3 g of n-butylamine, 1- (p-acetyl-phenylsulphonyl).-2-imino-3-n-butyl-imidazolidine , m.p. 120-122°; d) starting from 33.0 g of N-( 2-bromoethyl) -N-cyano-p-acetylphenylsulphonamide with 5.7 g of allylamine, l-(p-acetylphenylsulphonyl) -2-imino-3-allyl-imidazolidine , m.p. 104-105°; e) starting from 33.1 g of N-[ (l-ethyl-2-bromo) -ethyl] -N-cyano-p-toluenesulphonamide with 5.9 g of propylamine, 1- (p-tolyl sulphonyl) -2-imino-3-n-propyl-5-ethyl-imidazolidine , m.p. 61-63°; f) starting from 33.4 g of N-( 2-bromoethyl) -N-cyano-p-methylthiophenyl sulphonamide with 9.9 g of cyclohexylamine , 1- (p-methylthio-phenylsulphonyl) -2-imino- 3-cyclohexyl-imidazolidine, m.p. 129-130°.

E ample 27. a) 33.15 g of the addition salt of p-tolylsulphonyl cyana,;ide and N- ( 2-chloro-ethyl) -tert . butylamine are heated for one hour at a bath temperature of 145°. The melt is cooled and' triturated v/ith 2 N hydrochloric acid. The solution is decanted to remove insoluble resin and rendered alkaline with concentrated sodium hydroxide solution. The precipitated 1- (p-tolylsulphonyl) -2-imino- 3-tert .butyl-imidazolidine is filtered, rinsed with water and recrystallized from ethyl acetate* it then melts at 130-131°.

The starting material is produced as follows: b) 19.0 g of p-toluenesulphonyl chloride and 50 ml of dioxane are added with stirring to a solution of 8.6 g of disodium cyanamide in 100 ml of water. An exotherjiic reaction takes place and the p-toluenesulphonyl chloride dissolves. The solution is stirred for 15 minutes and then a solution of 17.2 g of N-( 2-chloro-ethyl) -tert .butylamine-hydrochloride in 40 ml of water is added. The reaction mixture is allowed to stand at room temperature for 2 hours* it is then concentrated to half its volume. The oil which precipitates is extracted with methylene chloride, the organic phase is separated, dried over sodium sulphate and concentrated. The residue, the addition salt of p-toluenesulphonyl cyanamide and N-( 2-chloro-ethyl) -tert .butylamine , is recrystallized from isopropanol ; it then melts at 103-1040.

Example 28 Analogously to Example 27, the following are obtained: a) starting from 33.1 g of an addition salt from (p-tolysulphonyl) -cyanamide and N- ( 2-chloro-ethyl) -ii-but lamine , 1- (p-tolyl sulphonyl) -2-imino-.3-n-butyl-imidazolidine , m. p . 91-92 b) starting from 34.7 g of. an addition salt from (p-methoxyphenyl sulphonyl) -cyanamide and N- ( 2-chloro-ethyl) -n- butylamine , 1- (p-methoxyphenyl- sulphonyl ) -2-imino- 3-n-butyl- imidazolidine , · m.p . 85-86°; c) starting from 35.2 g of an addition salt from (p-chlorophenylsulphonyl) -cyanamide and N-( 2-chloro-ethyl) -n-butylamine , l-( p-chlorophenylsulphonyl) - 2-imino- 3-n-butyl-imidazolidine , m.p. 74-75°; d) starting from 35.9 g of an addition salt from (p-acetylphenylsulphonyl) -cyanamide and N- ( 2-chloro-ethyl) -n-butylamine , l-( p-acetylphenylsulphonyl) -2-imino-3-n-butyl-imidazolidine j m.p. 120-122°; e) starting from 36.3 g of an addition salt from (p-methylthiophenylsulphonyl) -cyanamide and N-( 2-chloro-ethyl) -cyclohexylamine , l-(p-methylthiophenyl sulphonyl) - 2-imino- 3-cyclohexyl-imidazolidine , m.p. 129-130°; f) starting from 34.3 g of an addition salt from (p-acetylphenylsulphonyl) -cyanamide and - ( 2-chloro-ethyl) -allylamine , l-(p-acetylphenylsulphonyl) ^-imino-S-allyl-imidazolidine , m.p. 104-105°; g) starting from 34.6 g of an addition salt from (p-tolylsulphonyl) -cyanamide and N-( 2-chloro-butyl) -propylamine , 1- (p-tolyl sulphonyl)-2-imino- 3-n-propyl-5-(b tyl-imid,azolidine, m. . 61-63° . · ' Example 29 butyl 17.8 g of l-^^ t-2-irTiino-in;iQazolidine-hydrochloride are dissolved in 100 ml of water and .6.0 g of sodium hydroxide are added thereto. Then a solution of 15.0 g of p-toluenesulphon-yl chloride in 100 ml of acetone is added with stirring. The reaction mixture is refluxed for one hour and then concentrated under vacuum to half its volume. The oily residue crystallizes during cooling. The crystals are filtered, dried under vacuum at room temperature and recrystallized several times from hexane. The pure l-(p-tolylsulphonyl) -2-imino-3-butyl-imidazoli-dine melts at 91-92°.

Analogously to. Example 29, the following end products are obtained: • a) from 17.8 g of 1-ter .butyi-2-i:¾ino-imicazolidine- hydrcchloride in sodium hydroxide solution and 19.0 g of p- tolUenesulphonyl chloride, .1 -( -tclyl sulphonyl') - 2-imino- 3-ter . butyl-imidazolidine j m.p. 130-131° (from ethyl acetate); b) from 20.4 g of l-cyclohexyl-2-imino-imidazolidine- hydrochloride in sodium hydroxide solution and 19.0 g of p-toluenesulphonyl chloride , l-(p-t'olylsulphcnyl) -2-imino- 3^-cyclohexyl-imidazolidine j m.p. 118-120° (from methanol); c) from 22.6 g of l-phenethyl-2-imino-imidazolid.ine- hydrochloride in sodium hydroxide solution and 19.0 g of p-toluenesulphonyl chloride, l-(p-tolylsulphonyl) -2-imino- 3-phenethyl-imidazolidine ¾ d) from 17.8- g of l-butyl-2-imino-irnidazolidine- hydrochloride in sodium hydroxide solution and 20.6 g of p-methoxy-benzenesulphonyl chloride , l-(p-methoxy-phenylsulphonyl) -2-imino-3-butyl-imidazolidine , m.p. 85-87° (from methanol); e) from 17.8 g of 1-tert . butyl-2-iminc-imidazoiidine-hydrochloride in sodium hydroxide solution and 20.6 g of p-methoxy-benzenesulphonyl chloride, l-(p-methoxy-phenyl-sulphonyl ) -2-imino-3-tert . butyl-imidazolidine , m.p. 107 -108° (from methanol); f) from 17.8 g of l-butyl-2-imino-imidazolidine-hydro-chloride in sodium hydroxide solution and 22.2 g of p-methyl-thio-benzenesulphonyl chloride , l-(p-methylthio-phenyl sulphonyl) 2-imino-3-butyl-irr:idazolidine , m.p. 87-SS0 (from ether); g) from 17.8 g of 1-tert . butyl- 2-imino-imidazolidine- hydrochloride in sodium hydroxide solution and 22.2 g of p-methylthio-benzenesulphonyl chloride , l-(p-methylthio-phenyl~ sulphonyl ) - 2-imino- 3-tert . butyl-imidazolidine , m.p. 138.139° (from ethyl acetate); h) from 20.4 g of l-cyclohexyl-2-imino-imidazolidine- hydrochloride in sodium hydroxide solution and 22^2 g of p-methylthio-benzenesulfonyl chloride, l-(p-methylthio-phenyl sulphonyl) -2-imino-3-cyclchexyl-imidazolidine , m.p. 129- 130° (from ethyl acetate); i) from 16.4 g of l-propyl-2-imino-imidazolidine-hydro-chloride in sodium hydroxide solution and 21.0 g of p-chloro-benzenesulphonyl chloride, l-(p-chloro-phenylsulphonyl) -2-imino-3-propyl-imidazolidine j m.p. 68-69°; j) from 17.8 g of l-butyl-2-imino-imidazolidine-hydro-chloride in sodium hydroxide solution and 21.0 g of p-chloro-benzenesulphonyl chloride, l-(p-chloro-phenylsulphonyl) -2-imino-3-butyl-imidazolidine , m.p. 74-75° (from ether); k) from 20.4 g of. l-cyclohexyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide solution and 21.0 g of p-chloro-bensenesulphonyl chloride,- 1- (p-chloro-phenyl-sulphony1) —2—i ino—3—cyclchexyl—imidazolidine , m.p. 108-110° (from ethyl acetate/ether) ; 1) from 16.4 g of l-propyl-2-imino-imidazolidine-hydro-chloride in sodium hydroxide solution and- 17.6 g of benzene- sulphonyl chloride, 1-phenyl sulphcrrl-2-imino-3-propyl- irnidazolidine , m.p. 69-70° (from ether) ¾ . in) from 17. S g of l-butyl-2-irr.ino-i:rddazolidi2ie-hydro- chloride in sodium hydroxide solution and 17.6 g of benzene-' sulphonyl chloride, l-phenylsulphcnyl-2-imino-3-butyl-imidazol dine, m.p. 84-85° (from ether); n) from 17.8 g of 1-tert . butyl-2-imino-imidazolidine- hydrochlorid'e in sodium hydroxide solution and 17.6 g of benzene sulphonyl chloride , 1-phenyl sulphonyl-2-imino- 3-tert . butyl-imidazolidine , m.p. 98-100° (from ethyl acetate/ether); o) from 20.4 g of l-cyclohexyl-2-imino-i idazolidine-hydrochloride in sodium hydroxide solution and 17.6 g of benzenesulphonyl chloride, l-phenylsulphonyl-2-imino-3-cyclohexyl-imidazolidine , m.p. 94-95° (from ethyl acetate/ ether) ; p) from 16.2 g of l-allyl-2-imino-imidazolidine-hydro-chloride in sodium hydroxide solution and 21.8 g of p-acetyl-benzene sulphonyl chloride , l-(p-acetyl-phenylsulphonyl) -2-imino 3-allyl-imidazolidine , m.p. 104-105° (from benzene); q) from 17.8 g of 1-tert . butyl-2-imino-imidazolidine-hydrochloride in sodiUm hydroxide solution and 21.8 g of p-acetyl-benzenesulphonyl chloride , 1- (p-acetyl-phenyl sulphonyl) -2-imino-3-tert .butyl-imidazolidine , m.p. 144-147° (from isopropanol) ; r) from 17.8 g of l-butyl-2-imino-imidazolidine-hydro-chloride in sodium hydroxide solution and 21.8 g of p-acetyl- imino-3-butyl-imidazolidin.e , m.p. 120-122° (from isopropanol); s)' from 20.4 g of l-cyclchexyl-2-i:riinc-imidazolidirie- hydrochloride in sodium hydroxide solution and 21.8 g of p-acetyl-benzenesulphonyl chloride , 1- (p-acetyl -phenyl sulphonyl) -2-imino-3-cyclchexyl-imidazolidine , m.p. 164-166° (from isopropanol) ; t) from 17.8 g of 1 -butyl-2-imidazolidine-hydrochloride in sodium hydroxide solution and 19.4 g of p-fluoro-benzene- sulphonyl chloride , l-(p-fluoro-phenylsulphonyl) -2-imino-3-butyl-imidazolidine j m.p. 74-76° (from benzene); u) from 23.7 g of l-butyl-2-imino-4-methyl-imidazolidine-hydrobromide in sodium hydroxide solution and 19.0 g of p-toluene sulphonyl chloride, l-(p-tolylsulphonyl) -2-imino-3-butyl-5-methyl-imidazolidine, b.p. 173-17 °/0.01 Torr; v) from 23.7 g of 1-tert .butyl-2~imino-4-methyl-imidazoli dine-hydrobro ide in sodium hydroxide solution and 19.0 g of p-toluene sulphonyl chloride, l-(p-tolylsulphonyl) -2-imino-3-tert .butyl-5-methyl-imidazolidine , m.p. 92-94° (from ether) ; w) from 23.7 g of 1-tert . butyl-2-imino-4-methyl-imidazoli dine-hydrobromide in sodium hydroxide solution and 21.0 g of p-chloro-benzenesulphonyl chloride } 1- (p-chlorc-phenylsulphon-yl) -2-imino-3-tert .but l-5-methyl-imidazo idine; and x) from 23.5 g of l-n-propyl-2-imino-4-ethyl-imidazoli- dine-hydrobromide in sodium hydroxide solution and 19.0 g of p-methyl-benzenesulphonyl chloride, l-(p-tolylsulphonyl) -2- imino-3-n-propyl-5-ethyl-imidazolidine , m.p. 61-63° f x¾;r.o e - · .7 g of l-(p-tolylsulphcnyl) -2-imino-3-ailyl-5-ethyl-in-idazoiidins are hyarcgen ted at room temperature and under normal pressure in.350 ml of dioxane with 5.0. g of 5% palladium charcoal. 'When no more hydrogen is taken up, the catalyst is removed by filtration,' washed again vith dioxane and the. filtrate is concentrated to yield l-(p-tolylsulphonyl) -2-imino-3-propyl-5-ethyl-imida'zolidine , m.p. 61-63° (.from ether/petroleum ether).

Example 32.

Analogously to Example 31, the following are obtained: a) starting from 32.1 g. of l-(p-tolylsulphonyl) -2-imino-3-( 2-butenyl) -imidazolidine , l-(p-tolylsulphonyl) -2-imino- 3-n-butyl-imidazolidine , m. ..91-92°; b) starting from 33.7 g of 1- (p-methoxyphenyl sulphon-yi)-2-imino-3-( 2-butenyl) -imidazolidine, 1- (p-methoxyphenyl-sulphonyl) -2-imino-3-n-butyl-imidazolidine , m.p. 85-86° ; c) . starting from 34.1 g of l-(p-chlorophenylsulphonyl) 2-imino-3- ( 2-butenyl) -imidazolidine , 1- (p-chlorophenylsulphonyl) 2-imino-3-n-butyl-imidazolidine , m.p. 74-75°; d) starting from 34.9 g of l-(p-acetylphenylsulphonyl) 2-imino-3- ( 2-butenyl) -imidazolidine , 1- (p-acetylphenyl sulphonyl) 2-imino-3-n-butyl-imidazolidine , m.p. 120-122°.

Claims (1)

1. A compound of the formula I wherein represents an alkyl group with 1-4 carbon atoms, an alkenyl group with 3-4 carbon atoms or a cycloalkyl group with 5-7 carbon atoms, represents hydrogen, the methyl or ethyl group, and X represents hydrogen, a halogen atom with an atomic number of at most 35, the methyl, methoxy or methylthio group, or the acetyl group, or a pharmaceutically acceptable saj&t thereof. 2. 1- (p-Tolylsulphonyl)-2-imino-3-n-butyl-imidazolidine . 3. 1- (p-Acetylphenylsulphonyl)-2-imino-3-n-butyl-imida2olidine . 1- (p-!Methylthiophenylsulphonyl)-2-imino-3-cyclohexyl-imidazolidine . 5. 1- (p-Acetylphenylsulphonyl)-2-irnino-3-allyl-imidazolidine . 6. 1- (p-Methoxyphenylsulphonyl) -2-imino-3-n-butyl-imidazo-lidine . 7. 1- (p0-Tolylsulphonyl-2-imino-3-n-propyl-5-ethyl-imida-zolidine. - - - - - - - - 318.00/2. - 57 - 9. Process for the production of a compound of the formula I as defined in claim 1 -or a pharmaceutically acceptable salt thereof comprising condensing a compound of general formula II wherein · X, ^ and ftave meanings given under Formula I, and R^ represents hydrogen, an arylmethyl , diar lmethyl or a triar-ylmethyl group, the methyl or the allyl group, with a reactive cyanogen halide or cyanic acid ester, whereby ring closure takes place and, depending on the starting material, R^-halide splits off, and optionally converting the compound obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid. 31800/2 0 . Process for the production of a compound of the formula I as defined in claim 1 wherein is in 5-position or a pharmaceutically acceptable salt thereof comprising condensiig and cyclising a compound of the general formula III H wherein X and have the meanings given in claim 1 under formula I, with a compound of general formula IV H - N - R, (IV) N wherein ^ has the meaning given injclaim 1 under formula I, or with an alkali metal or alkaline earth metal derivative thereof, and optionally converting the compound obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid. - 58 GB etc AA . Process for the production of a compound of the formula I as defined in claim.1 or a pharmaceutically acceptable salt thereof comprising condensing and cyclising a compound of general formula V wherein X has the meaning given in claim 1 under formula I, with a reactive ester of a hydroxy compound of general formula VI H ?2 HO -R 1 C s N wherein and have the meanings given in claim 1 under formula I, and optionally converting the compound obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid . i" · Process for the production of a compound of the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof comprising condensing and cyclising a reactive ester of a compound of general formula VII - _ QB etc . H R, H (VII) wherein X and R2 have the meanings given inclaim 1 under formula I, with an amine of general formula VIII R-, - H, (VIII) wherein R^ has the meaning given in claim 1 under formula I, and optionally converting the compound obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid. 13 /. Process for the production of a compound of the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof comprising cyclising by heating an addition salt of general formula IX 1 under formula I, and Y represents halogen, V · Process for the production of a compound of the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof comprising reacting a reactive functional derivative of a sulphonic acid of general formula Xf X -^"~^-S03H (X) wherein X has the meaning given in claim 1 under formula I, with a compound of general formula XI wherein and R2 have the meanings given in claim 1 under formula I, and optionally converting the compound obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid. $. Process for the production of a compound of the formula I as defined in claim 1 but wherein R^ represents specifically an alkyl group with 3 or 4. carbon atoms other than the tertiary butyl group or a pharmaceutically acceptable salt thereof comprising reducing a compound of general formula XII (XII) N - H wherein X and have the meanings given in claim 1 under formula I, and R-^1 represents a lower alkenyl group with 3 to 4 carbon atoms, and optionally converting the compound obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid. · ty . A compound of the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, whenever prepared by a process as claimed in claim 9. /% . A compound of the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, whenever 15 prepared by a process as claimed in any one of claims 10- t$ · Process for the production of a compound of the formula I as defined in claim 1, substantially as hereinbefore described with reference to any one of examples 1-32. 0. A compound of the formula I as defined in claim 1 or a pharmaceutically, acceptable salt thereof, whenever prepared by a process as claimed in claim ^8. 20 if. · A pharmaceutical composition comprising a compound 1 6 as claimed in claim V/ together with a pharmaceutically acceptable diluent or carrier therefor. fL . A pharmaceutical composition comprising a compound 1 7 1 9 as claimed in any one of claims 1 to 8 , and W together with a pharmaceutically acceptable diluent or carrier ther for . For the Applicants 28.2.69/ESC/dZ -63- - GB etc.