US3729463A

US3729463A - P-aminoalkylbenzenesulfonamide derivatives

Info

Publication number: US3729463A
Application number: US00068796A
Authority: US
Inventors: H Dietrich; C Lehmann
Original assignee: Ciba Geigy Corp
Current assignee: Novartis Corp
Priority date: 1969-09-04
Filing date: 1970-09-01
Publication date: 1973-04-24
Anticipated expiration: 1990-04-24
Also published as: GB1305650A; FI52463C; IE34502B1; YU34125B; SU382285A3; IE34502L; FR2070668B1; IL35222A0; YU220270A; CH523254A; DE2043801C3; FR2070668A1; ES383341A1; DK131566B; FI52463B; SE367410B; CA920137A; DE2043801A1; BG17542A3; BG17541A3

Abstract

COMPOUNDS OF THE CLASS OF 1-(P-THIOCARBOXAMIDOALKYL)PHENYLSULFONYL)-2-IMINO-IMIDAZOLIDINES AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE HYPOGYLCEMIC ACTIVITY, THEY ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS AND ARE USEFUL FOR THE TREATMENT OF DIABETES MELLITUS, A TYPICAL EMBODIMENT IS 1-(P-(2-THIOACETAMIDOETHYL)-PHENYLSULFONYL) - 2 - IMINO-3-ISOBUTYLIMIDAZOLIDINE.

Description

United States Patent 3,729,463 p-AMINOALKYL BENZENESULFONAMIDE DERIVATIVES Henri Dietrich, Arlesheim, Basel-Land, and Claude Lehmann, Basel, Switzerland, assignors to Ciba-Geigy Corporation No Drawing. Filed Sept. 1, 1970, Ser. No. 68,796 Claims priority, application Switzerland, Sept. 4, 1969, 13,397/69 Int. Cl. C07d 49/30 U.S. Cl. 260309.7 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class of l-[p-thiocarboxamidoalkyl)- phenylsulfonyl]-2-imino-imidazolidines and pharmaceutically acceptable acid addition salts thereof have hypoglycemic activity; they are active ingredients of pharmaceutical compositions and are useful for the treatment of diabetes mellitus; a typical embodiment is l-[p-(Z-thioacetamidoethyl)-phenylsulfonyl] 2 imino-3-isobutylimidazolidine.

The present invention relates to derivatives of l-[paminoalkyl benzenesulfonyl]-2-imidazolidines, to pharmaceutical compositions containing these compounds and to the use thereof.

More particularly, the present invention relates to compounds of formula R is alkyl having at most six carbon atoms, allyl, cycloalkyl or cycloalkenyl having from five to nine carbon atoms, or phenylalkyl having at most nine carbon atoms;

R is hydrogen, methyl or ethyl;

R is alkyl having at most seven carbon atoms, alkenyl having from three to five carbon atoms, cycloalkyl having at most eight carbon atoms, phenyl or tolyl; and

m is the integer 2 or 3;

and the pharmaceuically acceptable acid addition salts thereof.

These compounds have been found to have a hypoglycemic effect in warm-blooded animals upon oral or parenteral administration. This activity, incombination with a favorable therapeutic index, characterizes the compounds of the present invention as being suitable for the treatment of diabetes mellitus.

The hypoglycemic action can be demonstrated in the standard tests on experimental animals.

In the compounds of Formula I, alkyl can be, eg the methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, 1- methylbutyl, l-ethylpropyl, 1,2-dimethylpropyl, or the hexyl group; as cycloalkyl, R can be, eg.. the cyclopropyl, cyclobutyl, cyclopentyl, 2- and 4-methylcyclohexyl, cyclohexyl or the cycloheptyl group; as cycloalkenyl, R can be, e.g. the Z-cyclopenten-l-yl, 2-cyclohexen-1-yl, 3-cyclohexen-l-yl, 2-methyl-2-cyclohexen-l-yl or the 3-cycl0heptenl-yl group; as phenylalkyl, R can be, e.g. the benzyl, phenethyl or the a-methylphenethyl group. The substiuent R, can be, as alkyl, anyone of the alkyl groups listed under R having at most seven carbon atoms; as alkenyl, R can be the allyl, l-methylallyl, Z-methylallyl, butenyl or pentenyl group; as cycloalkyl, R can be the cyclopropyl,

F CC

cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, 'cyclopentylmethyl, cyclohexyl, methylcyclohexyl, 4-methylcyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cycloheptylmethyl or the cycl-ooctyl group.

Compounds of Formula I are produced by reacting a dithiocarboxylic acid ester, especially a benzyl ester, of formula wherein R has the meaning given under Formula I, and R represents a hydrocarbon radical having at most seven carbon atoms, with a compound of formula bl H (III) wherein m, R and R have the meaning given under Formula I;

and, optionally, converting the reaction product with an inorganic or organic acid into an addition salt.

The reaction of the dithio esters of Formula II with an amine of Formula III is performed, e.g. in an inert organic solvent. Suitable inert organic solvents are, e.g. hydrocarbons such as benzene, toluene or xylene; chlorinated hydrocarbons such as methylene chloride; ethereal liquids such as diethyl ether, dioxane or tetrahydrofuran; and lower ketones such as acetone or methyl ethyl ketone. The reaction can, however, also be carried out without any solvent being present. The required reaction temperatures are between 0 and 150, preferably, however, at ca. r

The dithiocarboxylic acid esters required as starting materials are, in some cases, described in the literature [Marvel et al.: J. Am. Chem. Soc. 77 (1955), 5997 599 9]; others are produced analogously by reacting the corresponding cyanides with the corresponding merca'ptans in the presence of hydrogen chlorideto give iminothiocarboxylic acid ester. The obtained iminothiocarboxylic' acid esters react with hydrogen sulfide to give the corresponding dithiocarboxylic acid esters. 'Schematically, the" described reactions can be depicted as follows:

NIELHCI The substituents R and R given in the formulaehave;

the meanings given under Formula I.

The hitherto unknown starting materials of the Formula III are obtained, e.g. by reacting substituted p-(aminoalkyl)benzenesulfonamides of Formula 1V.

The compounds of Formula I obtained by the process according to the invention are optionally subsequently converted into their salts with inorganic as well as organic acids. These salts are produced, e.g. by reaction of the compounds of Formula I with the equivalent amount of an acid in a suitable aqueous-organic or organic solvent such as, e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.

For use as medicaments it is possible to use, instead of the free compounds of Formula I, pharmaceutically acceptable salts thereof With acids. Suitable addition salts are, e.g. salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, fl-hydroxyethanesulfonic 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 with hypoglycemic sulfonyl ureas such as, e.g. p-toluenesulfonylbutyl urea, p-chlorobenzenesulfonylpropyl urea, and p-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-phenylsulfonyl-cyclohexyl urea.

For their intended use, the compounds of the invention are administered preferably orally, in amounts depending on the species, the age, weight and the particular condi-.

tion of the individual being treated and the mode of administration. In general, the daily dosage varies between about 0.1 and 100 mg./kg. of body weight for warm-blooded animals. Advantageously, the compounds of the invention are administered in dosage units. Suitable dosage units such as drages and tablets, preferably contain 30-300 mg. of an active substance according to the invention, i.e. 20 to 80% of a compound of Formula I.

They are produced by combining the active substance, e.g. with 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 gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or drage cores. The latter are coated, e.g. with concentrated sugar solutions which may also contain, e.g. gum arabic, talcum and/ or titanium dioxide; or they are coated with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. for identification of the various dosage amounts.

Further dosage units suitable for oral administration are hard gelatine capsules as well as soft closed capsules made from gelatine and a softener, such as glycerin. The hard capsules contain the active substance preferable as a granulate, e.g. in admixture with filters such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulfite (Na S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as polyethylene glycols, whereby likewise stabilizers can be added.

The following prescriptions serve to further illustrate the preparation of tablets and drages:

(a) 1000 g. of 1-[-p-(2-thioacetamidoethyl)-phenylsulphonyl] 2 imino-3-(2-methylcyclohexyl)-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 is then granulated through a sieve. After the granulate has dried, 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; the mixture is then 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 to facilitate a more precise adjustment of the dosage amount.

(b) A granulate is produced from 1000 g. of 1-[p-(2- thioacetamidoethyl)-phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, 345.0 g. of lactose, and the aquecits s u o of at gof g atine are: dry g, h gran:

ulate 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 drage 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 dyestufi; and then dried. The obtained drages each weigh 240 mg. and each contain 100 mg. of active substance.

The following examples further illustrate production of the new compounds of Formula I and of intermediate products not hitherto described; the examples, however, in no way constitute the only embodiments thereof. The temperatures are given in degrees centigrade.

EXAMPLE 1 (a) An amount of 41.5 g. of 1-[p-(2-aminoethyl)- phenylsulfonyl] -2-imino-3-isobutylimidazolidine dihydrochloride monohydrate is dissolved in 200 ml. of water; to this solution are then added 300 m1. of 2-n sodium hydroxide solution. The liberated base is taken up in methylene chloride. The methylene chloride solution, dried over sodium sulphate, is concentrated by evaporation to dryness; to the oily base remaining as residue are then added at 30 40, in a nitrogen atmosphere, 18.2 g. of dithioacetic acid benzyl ester. The reaction mixture, well mixed by being shaken, is heated for /2 hour on the water bath (temperature ca. 80), whereby the colouration of the dithioester gradually disappears, and the obtained product crystallises. The thereby forming benzyl mercaptan is removed by the crystals being washed with four portions of petroleum ether each of 100 ml. The 1-[p-(2 thioacetamidoethyl)-phenylsulfonyl]-2-imino-3- isobutyl imidazolidine is recrystallised from acetone, and melts at 180-182.

In an analogous manner is obtained from:

43.8 g. of 1-[p-(Z-aminoethyl)-phenylsulfonyl]-2-imino-3-(2-methylcyclohexyl)-imidazolidine dihydrochloride and 18.2 g. of dithioacetic acid benzyl ester: 1-[p-(2-thioacetamidoethyl)-phenylsulfonyl-2-imino-3-(2 methylcyclohexyl)-imidazolidine, M.P. 175 -177.

The applied starting products are produced as follows:

(b) An amount of 3.8 g. of hydrogen chloride gas is passed at -10 into a mixture of 4.1 g. of acetonitrile and 13.3 g. of benzylmercaptan; the solution is then allowed to stand for several days in a refrigerator at -5 to 10 until crystallisation occurs. The formed acetoimino-thiobenzyl ester hydrochloride is triturated with petroleum ether, washed, and dried in vacuo. The unpurified substance melts, with decomposition, at 160-- 164.

(c) An amount of 20.1 g. of acetoimino-thiobenzyl ester hydrochloride is suspended in 60 ml. of abs. pyridine, and the suspension saturated, with stirring and cooling (Dry Ice-l-acetone), with hydrogen sulfide for two hours. The temperature is then allowed to rise to 0 and the reaction mixture is allowed to stand, with stirring, for a further hour at this temperature. Whilst cooling with ice is applied, 120 ml. of water are then added dropwise within 10 minutes. The obtained emulsion is poured on to a mixture of 270 ml. of concentrated hydrochloric acid and 430 ml. of water, and the precipitated red-yellow oil extracted three times with ether. The combined ethereal phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The dithioacetic acid benzyl ester obtained as residue is distilled in high vacuum, M.P.=111-113/0.02 torr.

(d) A mixture of ml. of dimethylsulfoxide, 11.2 g. of powdered potassium hydroxide, 23.65 g. of p-(2- aminoethyl)-benzenesulfonamide hydrochloride [Lit.: E. Miller et al., I. Am. 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 Aftercooling, the mixture is poured on to water. The obta n d 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 then dried over sodium sulfate 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)-phenylsulfonyl]-2-imino-3-isobutylimidazolidine dihydrochloride monohydrate precipitates, M.P. 151152.

In an analogous manner are obtained from 23.65 g. of p-(Z-aminoethyl)-benzenesulfonamide hydrochloride and:

11.8 g. of N-(2-chloroethyl)-N-methylcyanamide: 1- [p-(2 aminoethyl)-phenylsulfonyl]-2-imino-3-methylimidazolidine dihydrochloride, M.P. 230235;

13.0 g. of N-(2-chloroethy1)-N-ethylcyanamide: l-[p- (Z-aminoethyl)-phenylsulfonyl] 2 imino-3-ethylimidazolidine dihydrochloride, M.P. 242-244;

14.4 g. of N-(2-chloroethyl)-N-allylcyanamide: l-[p- (2 aminoethyl)-phenylsulfonyl]-2-imino-3-allylimidazolidine dihydrochloride, M.P. 232233;

16.0 g. of N-(2-ch1oroethyl)-N-butylcyanamide: l-[p- (Z-aminoethyl)-phenylsulfonyl] 2 irnino-3-butylimidazolidine dihydrochloride, M.P. 231-233";

20.5 g. of N-(2-bromoethyl)-N-sec-butylcyanamide: l-[p-(Z aminoethyl)phenylsulfonyl] 2 imino-3-sec. butylimidazolidine dihydrochloride, M.P. 250 (decomposition);

16.0 g. of N-(2-chloroethyl)-N-tert.butylcyanamide: 1-[p-(2-aminoethyl) phenylsulfonyl1-2-imino 3 tert. butylimidazolidine dihydrochloride monohydrate, M.P. 232234;

17.2 g. of N-(2-chloroethyl)-N-cyclopentylcyanamide: I-[p-(Z-aminoethyl)-phenylsulfonyl] 2 imino-3-cyclopentylimidazolidine dihydrochloride, M.P. 270 (decomposition);

23.1 g. of N-(2-bromoethyl)-N-cyclohexylcyanamide: 1-[p-(Z-aminoethyl)-phenylsulfonyl] 2 imino-3-cyclohexylimidazolidine dihydrochloride, M.P. 247250;

20.1 g. of N-(Z-chloroethyl)-N-(4-methylcyclohexyl)- cyanamide: 1 [p (2 aminoethyl)-phenylsulfonyl]-2 imino-3-(4-methylcyclohexyl)-imidazolidine dihydrochloride, M.P. 260 (decomposition);

20.1 g. of N-(Z-chloroethyl)-N-(2-methylcyclohexyl)- cyanamide: 1 [p-(Z-aminoethyl)-phenylsulfonyl]-2-imino-3-(Z-methylcyclohexyl)-imidazo1idine, as oil;

22.9 g. of N-(2-chloroethyl)-N-(3,3,5-trimethylcyclohexyl -cyanamide: 1- [p- Z-aminoethyl -phenylsulfonyl] 2-imino-3-(3,3,5-trimethylcyclohexyl) imidazolidine dihydrochloride, as foam.

EXAMPLE 2 (a) An amount of 42.3 g. of 1-[p-(2-aminoethyl)- phenylsulfonyl] 2 imino-3-cyclohexyl-imidazolidine dihydrochloride is dissolved in 200 ml. of water; to this solution are then added 300 ml. of 2-n sodium hydroxide solution. The liberated base is taken up in methylene chloride. The methylene chloride solution, dried over sodium sulphate, is concentrated by evaporation to dryness; to the oily base remaining as residue are then added at 3040, in a nitrogen atmosphere, 21.0 g. of dithiobutyric acid benzyl ester. The reaction mixture, well mixed by being shaken, is heated for half an hour on a waterbath (temperature ca. 80), whereby the colouration of the dithio ester disappears, and the obtained product crystallises. The thereby formed benzylmercaptan is removed by the crystals being washed with four portions of petroleum ether each of 100 ml. The 1-[p-(2-thiobutyramidoethyl)-phenylsulfonyl]-2-irnino 3 cyclohexyl-imidazolidine is recrystallised from ethyl acetate, and melts at 134-135.

In an analogous manner are obtained from:

39.7 g. of 1-[p-(2-aminoethyl)-pheny1sulfonyl]-2-imino- 3-butyl-imidazolidine dihydrochloride and 21.0 g. of dithiobutyric acid benzyl ester: 1-[p-(2-thiobutyramido- 6 ethyl)-phenylsulfonyl]-2-irnino 3 butyl-imidazolidine, M.P. l 6l-l62;

41.5 g. of 1-[p-(Z-aminoethyl)-pheny1sulfonyl]-2-imino- 3-tert.butyl-imidazolidine dihydrochloride monohydrate and 21.0 g. of dithiobutyric acid benzyl ester: 1-[p-(2- thiobutyrarnidoethyl)-phenylsulfonyl] 2 imino-B-tert. butyl-imidazolidine, M.P. 165166;

40.9 g. of 1- p- 2-aminoethyl -phenylsulfonyl] -2-imino- 3-cyclopentyl-imidazolidine dihydrochloride and 21.0 g. of dithiobutyric acid benzyl ester: 1-[p-(2-thiobutyramidoethyl)-phenylsulfonyl]-2-imino 3 cyclopentyl-imidazolidine, M.P. -151;

43.7 g. of 1- [p- (2-aminoethyl)-phenylsulfonyl]-2-imino 3 (2 methylcyclohexyl)-imidazolidine dihydrochloride and 21.0 g. of dithiobutyric acid benzyl ester: 1-[p-(2- thiobutyramidoethyl)-phenylsulfonyl] 2 imino-3-(2- methylcyclohexyl)-imidazolidine, M.P. 152153;

43 .7 g. of l- [p- Z-aminoethyl -phenylsulfonyl] -2-imino- 3 (4 methylcyclohexyl)-imidazolidine dihydrochloride and 21.0 g. of dithiobutyric acid benzyl ester: l-[p-(2- thiobutyramidoethyl) phenylsulfonyl] 2 imino-3-(4- methylcyclohexyl)-imidazolidine, M.P. 152.5 -154.5

(b) The dithiobutyric acid benzyl ester used as starting product is produced as follows:

An amount of 3.8 g. of hydrogen chloride is passed at -l0 into a mixture of 6.9 g. of butyro nitrile and 13.3 g. of benzylmercaptan; the mixture is then allowed to stand for several days in a refrigerator at -5 to 10 until crystallisation occurs. The formed butyriminothiobenzyl ester hydrochloride is triturated with petroleum ether, washed, and dried in vacuo. The obtained crude product melts at -168.

(c) An amount of 23 g. of butyrimino-thiobenzyl ester hydrochloride is suspended in 60 ml. of abs. pyridine; the suspension is then saturated, with stirring and cooling (Dry Ice and acetone), with hydrogen sulfide for 2 hours. The temperature is then allowed to rise to 0, and the reaction mixture allowed to stand whilst stirring is maintained. To the mixture are then added dropwise within 10 minutes, with ice cooling, 120 ml. of water. The obtained emulsion is poured into a mixture of 270 ml. of concentrated hydrochloric acid and 430 ml. of water, and the precipitated red-yellow oil extracted three times with ether. The combined ethereal phases are washed with water, dried over sodium sulfate, and concentrated by evaporation. The dithiobutyric acid benzyl ester obtained as residue is distilled under high-vacuum, B.P. 112- 1l4/0.05 torr.

EXAMPLE 3 a) An amount of 43.7 g. of l-[p-(2-aminoethyl)- phenylsulfonyl] Z-imino-(4-methylcyclohexyl)-imidazolidine dihydrochloride is dissolved in 200 ml. of water; to this solution are then added 300 ml. of 2-n sodium hydroxide solution. The hereby liberated base is taken up in methylene chloride, the methylene chloride solution dried over sodium sulfate concentrated by evaporation to dryness; and to the oily base, remaining as residue, are added at 3040, in a nitrogen atmosphere, 21.0 g. of diethioisobutyric acid benzyl ester. The reaction mixture is well mixed by shaking, and heated for one hour on a waterbath (temperature ca. 80), whereby the colouration of the dithio ester disappears, and the product crystallises. The obtained benzylmercaptan is removed by washing of the crystals with four portions of petroleum ether each of 100 ml. The 1-[p-(2-thioisobutyramido-ethyl)phenylsulfonyl] 2-imino-3-(4-methylcyclohexyl)-imidazolidine is recrystallised from acetone, and melts at -177.

The following are obtained in an analogous manner:

From 35.8 g. of l-[p-(Z-aminoethyl)-phenylsulfonyl]- 2-imino-3-methyl-imidazolidine dihydrochloride and 21.0 g. of dithioisobutyric acid benzyl ester is obtained: l-[p- (2 thioisobutyramido-ethyl)-phenylsulfonyl]-2-imino-3- methyl-imidazolidine, M.P. 159161;

From 39.7 g. of 1-[p-(2-aminoethyl)-phenylsulfonyl]-2- imino-3-sec.butyl-imidazolidine dihydrochloride and 21.0

g. of dithioisobutyric acid benzyl ester is obtained: l-[p- (2 thioisobutyramido-ethyl)phenylsulfonyl]2-imino-3- sec.butyl-imidazolidine, M.P. 154-155;

From 40.9 g. of 1-[p-(2-amin0ethyl)phenylsulfonyl]2- imino 3-cyclopentyl-imidazolidine dihydrochloride and 21.0 g. of dithioisobutyric acid benzyl ester is obtained: 1- [p (2 thioisobutyramido ethyl) phenylsulfonyU-Z- imino-Z-cyclopentyl-imidazolidine, M.P. 182183;

From 43.7 g. of l-[p-(Z-aminoethyl)phenylsulfonyl]2- imino 3 cycloheptyl-imidazolidine-dihydrochloride and 21.0 g. of dithioisobutyric acid benzyl ester is obtained: 1 [p (2-thioisobutyroamidoethyl)phenylsulfonyl]2- imino3-cycloheptyl-imidazolidine, M.P. 169 170 (b) The dithioisobutyric acid benzyl ester used as starting product is produced in the following manner:

3.8 g. of hydrogen chloride are fed at -l into a mixture of 6.9 g. of isobutyronitrile and 13.3 g. of benzylmercaptan; the solution is then allowed to stand for several days in a refrigerator at 5 to until crystallisation occurs. The formed hydrochloride of isobutyrimino-thiobenzyl ester is triturated with petroleum ether, washed, and dried in vacuo. The obtained crude product melts at 165 168.

(c) 22.6 g. of isobutyrimino-benzyl ester hydrochloride are suspended in 60 ml. of abs. pyridine; and the suspension, whilst being stirred and cooled (Dry Ice acetone), is saturated for 2 hours with hydrogen sulfide. The temperature is then allowed to rise to 0, and the reaction mixture allowed to stand, whilst being stirred, for a further hour at this temperature. To the mixture are then added dropwise Within 10 minutes, whilst ice cooling is applied, 120 ml. of water. The obtained emulsion is poured on to a mixture of 270 ml. of cone. hydrochloric acid and 430 ml. of water; the precipitated red-yellow oil is then extracted three times with ether. The combined ethereal phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The dithioisobutyric acid benzyl ester obtained as residue is distilled under highvacuum, M.P. 103 -107/ 0.02 torr.

EXAMPLE 4 (a) An amount of 42.3 g. of l-[p-(Z-aminoethyD- phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is dissolved in 200 ml. of water, and to the base are added 300 ml. of 2-n sodium hydroxide solution. The liberated base is taken up in methylene chloride. The methylene chloride solution, after being dried over sodium sulfate is concentrated by evaporation to dryness; and to the oily base, remaining as residue, are added at 30- 40, in a nitrogen atmosphere, 22.4 g. of dithiovaleric acid benzyl ester. The reaction mixture, well mixed by shaking, is heated for half an hour on a water-bath (temperature ca. 80 whereby the colouration of the dithio ester disappears, and the product crystallises. The benzylmercaptan thereby obtained is removed by washing of the crystals with four portions, each of 100 ml. of petroleum ether. The 1- [p- (thiovaleraminoethyl phenylsulfonyl] 2-imino- 3-cyclohexyl-imidazolidine is recrystallised from acetone, and melts at l51152.

The following are obtained in an analogous manner:

From 41.5 g. of 1-[p-(Z-aminoethyl)phenylsulfonyl]- 2 imino-3isobutyl-imidazolidine-dihydrochloride-monohydrate and 22.4 g. of dithiovaleric acid benzyl ester is obtained: 1- [p- 2-thiovaleramidoethyl) phenylsulfonyl] 2-imino-3isobutyl-imidazolidine, M.P. 166-168.

From 40.9 g. of l-[p-(Z-aminoethyl)-phenylsulfonyl]- 2 imino-3cyclopentyl-imidazolidine-dihydrochloride and 22.4 g. of dithiovaleric acid benzyl ester is obtained: l-[p- (2 thiovaleramidoethyl) phenylsulfonyl] 2-imino-3- cyclopentyl-imidazolidine, M.P. 152-154;

From 46.5 g. of 1-[p-(Z-aminoethyl)-phenylsulfonyl]- 2- imino-3-(3,3,S-trimethylcyclohexyl)imidazolidine-dihydrochloride, 22.4 g. of dithiovaleric acid benzyl ester is obtained: 1 [p (2-(Z-thiQVaIeIEmidOethyI)phenylsulfonyl] 2 imino-3-(3,3,5-trimethylcyclohexyl)imidazolidine, M.P. 113-1l5;

(b) The dithiovaleric acid benzyl ester used as starting product is produced as follows:

An amount of 3.8 g. of hydrogen chloride is passed at '10 into a mixture of 8.3 g. of valeronitrile and 13.3 g. of benzylmercaptan; the solution is then allowed to stand for several days in a refrigerator at -5 to 10 until crystallisation occurs. The formed hydrochloride of the valerimino-thiobenzyl ester is triturated with pertoleum ether, washed, and dried in vacuo. The obtained crude product melts at |132-139 with decomposition.

(c) An amount of 24.4 g. of valeriminothiobenzyl ester hydrochloride is suspended in 60 ml. of abs. pyridine; the suspension is then saturated, with stirring and cooling (Dry Ice acetone), with hydrogen sulfide for 2 hours. The temperature is then allowed to rise to 0, and the reaction mixture allowed to stand, whilst being stirred, for a further 1 hour at this temperature. Whilst cooling with ice, 120 ml. of water are then added within 10 minutes. The obtained emulsion is poured on to a mixture of 270 ml. of concentrated hydrochloric acid and 430 ml. of water, and the precipitated red-yellow oil extracted three times with ether. The combined ethereal phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The dithiovaleric acid benzyl ester, obtained as residue, is distilled in highvacuum, B.P. 120l25/0.02 torr.

EXAMPLE 5 (a) An amount of 42.3 g. of 1-[p-(2-aminoethy1)- phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidinedihydrochloride is dissolved in 200 ml. of Water; to this solution are then added 300 ml. of 2-n sodium hydroxide solution. The thereby liberated base is taken up in methylene chloride; and the methylene chloride solution, dried over sodium sulphate, is concentrated by evaporation to dryness. To the oily base, remaining as residue, are added at 30-40, in a nitrogen atmosphere, 24.4 g. of dithiobenzoic acid benzyl ester. The reaction mixture is well mixed by shaking, and then heated for half an hour on a water-bath (temperature ca. whereby the colouration of the dithio ether disappears, and the product crystallises. The formed benzylmercapban is removed by washing of the crystals with four portions, each of ml., of petroleum ether. The 1-[p-(2-thiobenzamidoethyl) phenylsulfonyl] 2 imino-3 cyclohexyl-imidazolidine is recrystallised from acetone, and melts at 194 /zCH COCH The following are obtained in an analogous manner:

From 37.2 g. of 1-[p-(Z-aminoethyl)-phenylsulfonyl]- 2imino-3-ethyl-imidazolidine and 24.4 g. of dithiobenzoic acid benzyl ester is obtained: 1-[p-(2-thi0benzamidoethyl) phenylsulfonyl] 2 imino-3-ethyl-imidazo1idine, M.P. 216-217;

From 39.7 g. of 1-[p-(Z-aminoethyD-phenylsulfonyl]- 2 imino 3 sec.butyl-imidazolidine-dihydrochloride and 24.4 g. of dithiobenzoic acid benzyl ester is obtained: .1 [p (2 thiobenzamidoethyD-phenylsulfonyl]2-imino- 3-sec.butyl-imidazolidine, M.P. 188189;

From 43.7 g. of l-[p-(Z-aminoethyl)-phenylsulfonyl]- 2 imino 3 (2-methylcyclohexyl)aimidazolidine-dihydrochloride and 24.4 g. of dithiobenzoic acid benzyl ester is obtained: 1 [p (2-thiobenzamidoethyl)phenylsulfonyl] 2 imino 3 (Z-methylcyclohexyl)dmidazolidine, M.P. 213-215;

(b) The dithiobenzoic acid benzyl ester used as starting product is produced as follows:

An amount of 3.8 g. of hydrogen chloride is fed at 10 into a mixture of 10.3 g. of benzonitrile and 13.3 g. of benzylmercaptan; the solution is then allowed to stand for several days in a refrigerator at 5 to 10 until crystallisation occurs. The formed hydrochloride of benziminothiobenzyl ester hydrochloride is triturated with petroleum ether, washed, and dried in vacuo. The obtained crude product melts at l74178 (decomposition).

An amount of 26.4 g. of benziminothiobenzyl ester hydrochloride is suspended in 60 ml. of abs. pyridine; the suspension is then saturated, whilst being stirred and cooled (Dry Ice acetone), with hydrogen sulfide for 2 hours. The temperature is then allowed to rise to 0", and the reaction mixture is allowed to stand, with stirring, for a further hour at this temperature. To the mixture are then added dropwise, with ice cooling, 120 ml. of water within 10 minutes. The obtained emulsion is poured on to a mixtureof 270 ml. of cone. hydrochloric acid and 430 ml. of water, and the precipitated red-yellowoil extracted-three times with ether. The combined ethereal phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The dithiobenzenoi'c acid benzyl ester, obtained as residue, is distilled in high-vacuum, B.P. 174/0.05 torr.

EXAMPLE 6 (a) An amount of 41 g. of 1-[p-2-aminoethyl)-pheny1- sulfonyl] 2 imino 3 cyclopentyl-imidazolidine dihydrochloride is dissolved in 200 ml. of water, and to the solution are then added 300 ml. of 2-n sodium hydroxide solution. The thereby liberated base is taken up in methylene chloride, and the methylene chloride solution, dried over sodium sulfate is concentrated by evaporation to dryness. To the oily base, remaining as residue, are added at 3040, in a nitrogen atmosphere, 25.0 g. of dithiocyclohexanecarboxylic acid benzyl ester. The reaction mixture is well mixed by shaking, and then heated for /2 hour on the water-bath (temperature ca. 80), whereby the colouration due to the dithio ester gradually disappears, and the product crystallises. The formed benzylmercaptan is removed by washing of the crystals with four portions, each of 100 ml., of petroleum ether. The 1 [p-(2-thiocyclohexanecarboxamidoethyl)-phenylsru1fonyl]-2-imino-3-cyclopentylimidazolidine is recrystallised in acetone, and melts at 193 194.

The following are produced in a similar manner:

From 35.8 g. of 1-[p-(Z-aminoethyl)-phenylsu1fonyl]- 2-imino-3-methyl-imidazolidine dihydrochloride and 25.0 g. of dithiocyclohexanecarboxylic acid benzyl ester is obtained: l-[p-(2-thiocyclohexanecarboxamidoethyl)-phenylsulfonyl]-2-imino-3-methyl-imidazolidine, M.P. 195- 198";

From 37.2 g. of 1-[p-(2-aminoethyl)-phenylsulfonyl]- 2-imino-3-ethyl-imidazolidine dihydrochloride and 25.0 g. of dithiocyclohexanecarboxylic acid benzyl ester is obtained: l-[p-(2-thiocyclohexanecarboxamidoethyl)-phenylsulfonyl]2-imino 3 ethyl-imidazolidine, M.P. 191- 193;

From 38.2 g. of 1-[p-(Z-aminoethyl)-phenylsulfony1]- 2-imino-3-allyl-imidazolidine dihydrochloride and 25.0 g. of dithiocyclohexanecarboxylic acid benzyl ester is obtained: 1- [p- (2-thiocyclohexanecarboxamidoethyl )-phenylsulfonyl]-2-imino-3-allyl-imidazolidine, M.P. 162.5-- 164.5

(b) The dithiocyclohexanecarboxylic acid benzyl ester used as starting product is produced as follows:

An amount of 3.8 g. of hydrogen chloride is fed at 10 into a mixture of 10.9 g. of cyclohexanecarboxylic acid nitrile and 13.3 g. of benzylmercaptan; the solution is then allowed to stand for several days in a refrigerator at 5 to l0 until crystallisation occurs. The formed cyclohexanecarboximinothiobenzyl ester hydrochloride is triturated with petroleum ether, washed, and dried in vacuo. The obtained crude product melts at 163 -l67.

(c) 27.0 g. of cyclohexanecarboximinothiobenzyl ester hydrochloride are suspended in 60 ml. of abs. pyridine; and the suspension is then saturated, with stirring and cooling (Dry Ice and acetone), with hydrogen sulfide for 2 hours. The temperature is then allowed to rise to 10 0, and the reaction mixture is allowed to stand, whilst being stirred, for a further 1 hour at this temperature. To the mixture are then added dropwise within 10 minutes, with ice cooling, ml. of water. The formed emulsion is poured on to a mixture of 270 ml. of concentrated hydrochloric acid and 430 ml. of water, and the precipitated red-yellow oil extracted three times with ether. The combined ethereal phases are washed with water, dried over sodium sulfate concentrated by evaporation. The dithiocyclohexanecarboxylic acid benzyl ester obtained as residue is distilled in high-vacuum, B.P.= 156?/0.01 torr.

: EXAMPLE 7 Analogously to Example 6 are obtained the following: From 43.7 g. of 1-[p-(Z-amino-ethyl)-phenylsulfonyl]- Z-imino 3 cyclopentyl 4 ethyl-imidazolidine-dihydrochloride and 21.0 g. dithioisobutyric acid-benzylester, 1- [p-(2 thioisobutyramidoethyl)-phenylsulfony11-2-imino- 3-cyclopentyl-4-ethyl imidazolidine, M.P. 105107;

From 45.1 g. 1-[p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 cyclohexyl 4 methyl-imidazolidine-dihydrochloride and 25.0 g. dithiocyclohexanecarboxylic acidbenzylester, 1-[p-(2-thiocyclohexancarboxamido-ethyl)- phenylsulfonyl] 2 imino-3-cyclohexyl-4-methyl-imidazolidine, M.P. 173174;

From 42.5 g. 1-[p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 (1,2 dimethyl-butyl)-imidazolidine-dihydrochloride and 25.8 g. dithio p-toluic acid-benzylester, l-[p- (2 (thio-p-toluamido)-ethyl)-phenylsulfonyl]-2-imino-3- 1,2-dimethyl-butyl)-imidazolidine, M.P. 158 -160 From 40.9 g. 1-[p-(2-amino-ethyl)-pheny1sulfonyl]-2- imino 3 cyclopentyl-imidazolidine-dihydrochloride and 18.3 g. dithioacetic acid-benzylester, l-[p-(2-thioacetamido-ethyl) phenylsulfonyl] 2 imino cyclopentylirnidazolidine, M.P. 176177;

From 42.3 g. 1-[p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 cyclohexyl-imidazolidine-dihydrochloride and 18.3 g. dithioacetic acid-benzylester, 1-[p-(2-thioacetamide-ethyl)-phenylsulfonyl]-2imino 3 cyclohexyl-imidazolidine, M.P. 174 176";

From 43.1 g. 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2- imino-3-benzyl-imidazolidine-dihydrochloride and 18.3 g. dithioacetic acid-benzylester, 1 [p-(2 thioacetamidoethyl)-phenylsulfonyl]-2-imino 3 benzyl-imidazolidine, M.P. 182-183;

From 43.7 g. l-[p-(2-arnino-propyl)-phenylsulfonyl]- 2 imino-3-cyclohexyl-imidazolidine-dihydrochloride and 21.0 g. dithiobutyric acid-benzylester, I-[P-(Z-thiobutyramido-propyl)-phenylsu1fonyl]-2-imino 3 cyclohexylimidazolidine, as an oil.

From 43.7 g. l-[p-(2-amino-propyl)-phenylsulfony1]- 2 imino 3 cyclohexyl-imidazolidine-dihydrochloride and 18.3 g. dithioacetic acid-benzylester, 1-[p-(2-thioacetamido-propyl)-phenylsulfonyl] 2 imino 3 cyclofl hexyl-imidazolidine, M.P. -146.

From 42.3 g. l-[p-(2-amino-ethyl)-phenylsulfonyl]-2- imino 3 cyclohexyl-imidazolidine-dihydrochloride and 25.2 g. dithioheptanoic acid-benzylester, 1- [p- (Z-thioheptanamido-ethyl)-phenylsulfony1] 2 imino 3 cyclohexyl-imidazolidine, MJP. 141 143;

From 42.3 g. 1-[p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 cyclohexyl-imidazolidine-dihydrochloride and 20.8 g. dithiocyclopropane-carboxylic acid-benzyl ester, 1 [p (2 cyclopropanethiocarboxamido-ethyl)-phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidine, M.P. 197-199;

From 42.3 g. 1-[p-(2-amino-ethyl-phenylsulfonyl]-2- imino 3 cyclohexyl-imidazolidine-dihydrochloride and 23.6 g. dithiocyclopentane-carboxylic acid-benzyl ester, 1 [p (2 cyclopentanethiocarboxamido-ethyl)-phenylsulgonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. 207- 20 From 42.1 g. l-[p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 (3 cyclohexen-l-yl)-imidazolidine-dihydrochloride and 18.2 g. dithioacetic acid-benzyl ester, -1[p- (2-thio-acetamido-ethyl)-phenylsulfonyl] P 2 imino-3-.

(S-cyclohexen- 1-yl)-imidazolidine, M.P. 172-173 The starting materials can be prepared analogously to the methods described in Examples 1 t0 6.

What is claimed is:

1. A compound of formula Ill-I wherein R is alkyl of at most six carbon atoms, allyl, cycloalkyl, methyl substituted cycloalkyl, cycloalkenyl or methyl substituted cycloalkenyl of, in all, from five to nine carbon atoms, or phenylalkyl of at most three carbon atoms in the alkyl chain;

R is hydrogen, methyl or ethyl;

R is alkyl of at most seven carbon atoms, cycloalkyl or cycloalkylrnethyl of, in all, at most eight carbon atoms; and

m is the integer 2 or 3;

or the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, which is 1-[p- (Z-thioacetamidoethyl)-phenylsulfony1] 2 imin0-3-isobutyl-imidazolidine.

3.'A compound according to claim 1, which is l-[p-(Z- thiobutyramidoethyl)-phenylsulfonyl] 2 imino 3 cyclopentyl-imidazolidine.

4. A compound according to claim 1, which is I-[p- (2 thiocyclohexanecarboxamidoethyl) phenylsulfonyl] Z-imino-3-cyclopentylimidazolidine.

References Cited UNITED STATES PATENTS 3,538,085 11/1970 Dietrich 260-309] OTHER REFERENCES Dietrich et al.: Chem. Abst., vol.72, No. -12,725q (1970.)

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260--455 R, 556 AR, 566 R; 424273'