DE1445505A1 - Process for the preparation of new substituted phenyl-amino-1,3-diazacyclopentene- (2) - Google Patents

Description

Case 1/173 -

New complete registration documents

C. H. BOEHRINGER SOHN, Ingelheim am Rhein

Process for the preparation of new substituted phenylamino-l, 3-diazacyclopentene- (2)

It has been found that substituted phenylamino-l ^ -diazacyclopentene- (2) the general formula

Z-NH-C

- OH ₂

N - CH
H

worm Z the 2,6-dichlorophenyl, a-chloro-ö-methylphenyl, 2-methyl-4-chlorophenyl, 2-chloro-4-methylphenyl-, 2-chloro-4-ethylphenyl-, 2-chloro-6-ethylphenyl-, 2-Chlo2? 4-tert-butylphenyl-, 2,6-dichloro-4-methylphenyl-, 2 , 4-dichloro-6-methy! Phenyl-, 2,4-dimethyl-6-chlorophenyl, 2,6-dimethyl-4-chlorophenyl or 2-iri fluorine thy / phenyl group Dedeutet and their salts have valuable pharmaceutical properties.

According to the invention, the new compounds can also be various Because of being made.

a) So you can use an isothiuronium salt of the general formula II

Z-NH-C .HX II

SR

wherein Z has the meaning given above, R ^{1 is} a lower alkyl radical and Ϊ is an acid radical, react diamine with ethylene.

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The reaction is preferably carried out without using a solvent by simply heating the reaction components at about 100 - 200 ⁰ C performed. This method leads to satisfactory yields of the desired end product in a short time. In principle, the reaction can also take place at lower temperatures (60 ° 140 ° C.) with the addition of a suitable solvent, which preferably contains polar groups, such as water or lower alcohols; however, it has been found that long reaction times have to be accepted if a good yield is to be achieved. When using 2,6-disubstituted phenyl derivatives, even prolonged heating in the solvent in question only leads to a slight yield of the reaction product. Even a variant of the process mentioned last, the course of the reaction under pressure, possibly using an internal gas, does not bring about an increase in the yield.

The isothiuronium salt of the formula II required as starting material is obtained, for example, by heating in a known manner from an appropriately substituted aniline and ammonium thiocyanate produced thioureas (see. Houben Weyl, Volume 9, page 887) with an alkyl compound such as an alkyl halide or dialkyl sulfate in a suitable solvent, e.g. B. a lower alcohol.

b) Another method for the preparation of the new phenylamino-1,3-diazacyclopentene- (2) consists in the ring closure of an appropriately substituted N-phenyl-NKβ-aminoethyl) - (thio) -ureas the formula

H ₉ C - NH ₉
ι

H ₉ C -HC-BH-.Z. ■ ^ά Η Il
Y

where Z has the meaning given and T = S or = 0, by pyrolysis.

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The required starting compounds can by reacting a substituted Hienyliso (thiο) cyanate with ethylenediamine according to the Information in Journal Organic Chemistry, Vol. 24, p. 818 (1959) can be obtained.

The compounds of general formula I can be converted into the corresponding physiologically harmless acid addition salts by customary methods be transferred, e.g. B. by treatment with an inorganic or organic acid such as mineral acids, e.g. B. Hydrochloric acid or hydrobromic acid, nitric acid, Acetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, citric acid, Ascorbic acid or propionic acid.

The preparation of acid addition salts is particularly advantageous when they are water-soluble and suitable for injection purposes Connections should be made.

According to the invention, the following end products or their Acid addition salts are obtained:

2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopentene- (2) 2- (2-chloro-4-methylpheny]} - amino-1,3-diazacyclopentene- (2) 2- (2-chloro-6-methylphenyl) -amino-1,3-diazacyclopentene- (2) 2- (2-Methy1-4-chlorophenyl) -amino-1,3-diazacyclopentene- (2) 2- (2-chloro-4-ath.ylph.enyl) -amino-1,3-diazacyclopentene- (2) 2- (2-chloro-6-ethylphenyl) -amino-1,3-diazacyclopentene- (2) 2- (2-chloro-4-tert-butylphenyl) -amino-1,3-diazacyclopentene- (2)

2- (2,6-dichloro-4-meth.ylph.enyl) -amino-1,3-diazacyclopentene- (2) 2- (2,4-dichloro-6-methylphenyl) amino-1,3-diazacyclopentene- (2) 2- (2,4-dimethyl-6-chlorophenyl) amino-1,3-diazacyclopentene- (2 ) 2- (2,6-Dimethy1-4-chlorophenyl) -amino-1,3-diazacyclopentene- (2) 2- (2-trifluoromethylphenyl) -amino-1,3-diazacyclopentene- (2)

A number of the compounds preparable by the methods of the invention became similar to various known substances Direction of action with regard to the antihypertensive effect tested. The test animals were rabbits under urethane anesthesia, the The substances were administered intravenously.

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The following table provides an overview of the antihypertensive effects, toxicity and therapeutic index of some of the new Compounds as well as three known reference substances.

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H H ti
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ti r «Q n Il * ri fi
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9 09840 / 17U

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BATH ORIGINAL

-J -

The new compounds claimed with the present application were tested on test subjects for their antihypertensive effect. In healthy test subjects, for example, a dose of 0.3 mg 2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopenten- (2) a systolic blood pressure decrease Ms to 35 mm Hg, which had not completely subsided after 24 hours. About the same Blood pressure reductions over the same period were 0.6 mg 2- (2-chloro-4-methylphenyl) -amino-1,3-diazacyclopentene- (2) and 0.6 mg 2- (2-chloro-6-methylphenyl) -amino-1,3-diazacyclopentene- (2) achieved. It should be particularly emphasized that the compounds obtained according to the invention also reduce the blood pressure can be achieved in healthy test persons with normal blood pressure,

This is especially important because most of them are used therapeutically Antihypertensive agents in healthy people with normal blood pressure values either have no effect at all or reduce blood pressure only lower in case of extreme overdose. Experience has shown that the therapeutic application for the treatment of hypertensive patients significantly more Heinere doses required. For example, the 2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopenten- (2) has an orienting effect In clinical trials, a dose of 0.15 mg already reduces systolic blood pressure by an average of 45 mm Hg.

The low toxicity of the new compounds offers a further advantage. The I ^ 5Q for mice is e.g. B. per os and subcutaneously for 2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopenten- (2) 390 or 127.5 mg / kg, for 2- (2-chloro-6-methylphenyl) -amino-1,3-diazacyclopenten- (2) 280 or 102 mg / kg and for 2- (2-0hlor-4-methylphenyl) -amino-1,3-diazaoyclopenten- (2) 320 and 42.5 mg / kg, respectively. An extraordinarily favorable therapeutic result results from these values Width that allows individually dosed, safe use of the new compounds.

In addition, the substances that can be prepared according to the invention have a good sedative effect, which is already detectable at the above-mentioned blood pressure-lowering doses, but only becomes evident in higher doses. Thus, with 0.2-0.4 mg 2- (2,6-diohlorophenyl) -amino-1,3-aazacyclopenten- (2) a sedation lasting 6 hours was achieved, while with doses of 1-2 mg this effect and the like . Lasted 30 hours. With the 2- (2-chloro-4-methylphenyl) -aaino-1,3-diazaoyolopenten- (2) could be in doses of _£

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0.6 - 1 mg observe a 5-8 hour sedation; at 2.4 mg, the test subjects slept for about 19 hours. A similar one The course of action also shows, for example, 2- (2-chloro-6-methylphenyl) -amino-1,3-diazacyclopenten- (2).

With the compounds obtainable according to the invention, a firm and long-lasting sleep is brought about, but from that the test subject can be awakened at any time. The new substances thus offer a significant advantage over the usual sleeping pills, especially the barbiturates, in which an overdose, the z. B. creates a sleep duration of 20 - 30 hours, always in the first few hours to an almost narcosis-like unconsciousness from which the patient can only be briefly awakened by strong stimuli and are then very dazed.

The new compounds are said to be used in medicine as hypotensives or Find sedatives use. They cater to all for pharmaceuticals Process the usual preparation forms for the purposes of this. E.g. pills, coated tablets,! Tablets, suppositories, emulsions, Prepare solutions and injection solutions.

The following examples are intended to explain the invention in more detail, without however, to limit them:

-1

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example 1

2- (2-chloro-4-methyl-aniline) -amino-1,3-diazstfrolopenten- (2) 43 g of the thiourea obtained in a known manner from 2-chloro-4-methyl-aniline and ammonium thiourea (pp. 124 ⁰ C) are heated with 20 ml of methyl iodide in 200 ml of methanol 2 levels under reflux. The solvent is then i. V. removed and the remaining residue as Isothiuroniumhydrojodid (73> 2 g) with 20.4 ml Ä'thylendiamin by stirring for about 1/2 hour at 150-160 ⁰ C is heated; mercaptan escapes in the process. The reaction mixture is then taken up in hot, dilute acetic acid and the resulting solution is made alkaline with 2N sodium hydroxide solution. The base precipitates, which suction filtered, washed with water and dried (yield. 10.2 g of PP 142-145 ⁰ C)

The base nitrate melts at 162-164 ° C and is in water and Methanol soluble.

The following compounds can be obtained analogously to Example 1:

2- (2-methyl-4-chlorophenyl) amino-l, 3-diazacyclopenten- (2) Pp of the base 133 ° C, Pp of the Hydrochloride 199 -.. 201 ⁰ C.

. 2- (2-chloro-4-ethylphenyl) amino-l, 3-diazacyclopenten- (2) Pp of the base 124-125 ⁰ C, Pp of the nitrate 126 -. 127 ⁰ C

Example 2

2- (2,6-Dichlorophenyl) -amino-1,3-diazacyclopenten- (2) 16 g of the in a known manner from 2,6-dichloroaniline (prepared according to the instructions in Org. Synth. III 262-63) and ammonium rhodanide obtained thiourea (boiling point 149 ° C.) are refluxed for 2 1/2 hours together with 16 g of methyl iodide in 150 ml of methanol. The solvent is removed in vacuo and the remaining residue as Isothiuroniumhydrojodid (22 g of Pp 170 ⁰ C.) With a slight excess of ethylene diamine ($> 120) with stirring for about 1 hour at 130 - 150 ⁰ C heated. Mercaptan escapes. The reaction mixture is then taken up in hot, dilute acetic acid and the resulting solution is made alkaline with 2N sodium hydroxide solution. The base which precipitates out is filtered off with suction, washed with water and dried. Yield 4.0 g of mp. 130 ^° C .; Hydrochloride: Pp 305 ° C

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The following compounds can be obtained analogously to the procedure described in Example 2:

2- (2-chloro-6-methylphenyl) amino-1,3-diazacyclopenten- (2), the base 143 Pp - 145 ^0C.; PP of the hydrochloride 217-220 ⁰ C.

2- (2-chloro-4-tert butylphenyl _e) amino-1,3-diazacyclopenten- (2), Pp of the base 156-158 ⁰ C. Pp of the nitrate 129 ° C

2- (2-chloro-6-ethylphenyl) amino-1,3-diazacyclopenten- (2), Pp. Of the hydrochloride 200 ⁰ C.

Example 3

2- (2-Tri fluorine thy phenyl) -amino-1,3-diazacyclopenten- (2) 20.3 g of the thiourea obtained in known manner from ο-Trifluorinethylanilin and ammonium thiocyanate from Pp 162 -. 163 ⁰ C with 10 ml of methyl iodide in 40 ml of absolute methanol heated under reflux for 2 1/2 hours. Thereafter, the solvent is removed in vacuo and 23 of the remaining residue as Isothiuroniumhydrojodids with 8 ml of ethylenediamine g for about 1/2 hour while stirring at 150-170 ⁰ C heated; mercaptan escapes in the process. After cooling, the reaction mixture is taken up in dilute hydrochloric acid and the solution is made alkaline with 2N sodium hydroxide solution. The precipitating base is taken up in chloroform and the chloroform solution is mixed with ethereal hydrochloric acid. The precipitation of the hydrochloride is completed by further addition of ether. Yield of 2- (2-Tri fluorine thy lphenyl) amino -l, 3-diazacyclopenten- (2)-hydro chloride: 6 g of Pp 196-198 ⁰ C..

Example 4

2- (2,4-dichloro-6-methylphenyl) -amino-1 _t 3-diazacyolopentene- (2) -oxalate 12.5 g 2,4-dichloro-6-methyl-aniline (produced by chlorinating o-toluidine in glacial acetic acid and perrichloride according to Adams: Journ. Am. Soc, Volume 72, page 2454), 170 ml of water, 37 ml of concentrated hydrochloric acid and 36.8 g of ammonium thiocyanate are refluxed for 7 hours, the yield of thiourea compound is from ether recrystallized from 18 g Pp.183 - 184 ⁰ C. 18 g of thiourea are heated for about 3 hours under reflux with 33 g of methyl iodide in 300 ml of methanol. Then the solvent is i. V. stripped off, 7 g of ethylenediamine were added to the residue and the mixture was heated to 180 ° C. for about 1 hour while stirring

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1U55Ü5

heated. Mercaptan escapes here. The reaction mixture thus obtained is taken up in 2N hydrochloric acid, the solution extracted with chloroform, filtered through charcoal and with the addition of Ammonia adjusted to be weakly alkaline. The base is then extracted with chloroform, the solution dried and filtered through charcoal and the solvent i. Y. distilled off.

The oxalate of 2- (2,4-dichloro-6-methylphenyl) -amino ~ 1,3-diazacyolopentene- (2) is obtained after adding an alcoholic oxalic acid solution by means of outer ether. 263 ⁰ C - After Umkristallisiation from isopropanol / lther 261, the yield is 9.5 g, mp.

The following compounds can be obtained analogously to Example 4:

2- (2,6-dichloro-4-methylphenyl) -amino-1,3-diazacyclopentene- (2) of bp 156 ° C.

2- (2,4-Dimethyl-6-chlorophenyl) amino-1,3-diazacyclopentene (2) oxalate from pp. 210 ° C.

2- (2,6-Dimethyl-4-chlorophenyl) -amino-1,3-diazacyclopentene- (2) oxalate from pp. 165 0.

Example 5

2- (2-Chloro-4-methy! Phenyl) -amino-1,3-diazaoyolopenten- (2) a) The solution of 41 g of the synthesized analogously to the procedure in Org. Synth., Volume I, p. 165 2-chloro-4-methylphenyl-isothiooyanate in 60 ml of absolute benzene is added dropwise to a solution of 15 g of ethylenediamine in 350 com of absolute benzene within half an hour while stirring. After two hours of stirring at room temperature, water is added to the above. 800 ml were made up and the reaction mixture was left to stand overnight. The suspension is then mixed with 21 ecm of concentrated hydrochloric acid and concentrated to dryness in vacuo. The residue is taken up in 250 ml of water, dissolved in a water bath at 50 ° C. while stirring, the insolubles are filtered off with suction and made alkaline with 2N sodium hydroxide solution while cooling with ice. The viscous excretion that occurs first becomes crystalline after a short time. It is filtered off with suction, washed with water and dried. Yield: 30 g of N- (2-chloro-4-methylphenyl) -N ^l - (ß-aminoethyl) thiourea (I), mp 123-125 ° 0.

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b) 10 g of I are heated in an oil bath at 155 ° C. for 1 1/2 hours. Here hydrogen sulfide escapes. The subject of cooling becomes the The contents of the flask were taken up in 2N hydrochloric acid and the solution was purified using charcoal. When alkalizing with 5N sodium hydroxide solution the imidazoline base separates out in an oily form and crystallizes when treated with petroleum ether. She is sucked off washed with water and petroleum ether and made from benzene / petroleum ether recrystallized. The yield is 1.15 g of Mp 148-150 ° C; Nitrate: I? P. 162 - 164 ° C.

Example 6

2- (2,6-Dichlorphen.Yl) -amino-1,3-diazac.yolopenten- (2) 36.3 g of N- (2,6-dichlorophenyl) -isothiuronium hydroiodide are mixed with 10 ml of ethylenediamine (150 fo) in 100 ml of isoamyl alcohol heated under reflux for 10 hours. The solvent and excess ethylenediamine are stripped off in vacuo, the residue is taken up in 1N hydrochloric acid, the insoluble fraction is filtered off and the piltrate is made alkaline with 5N sodium hydroxide solution. The deposited imidazoline base is filtered off with suction, washed with water and dried. Then it is dissolved in ether and the hydrochloride is precipitated from the ethereal solution - after cleaning with animal charcoal - with ethereal hydrochloric acid. After re-coding the hydrochloride from methanol / ether, 7.5 g of pure hydrochloride of I ¹ P. 311-315 ° C. are obtained.

Example A.
! Tablets:

2- ( ^2,6-1) chlorophenyl) -amino-1,3-diazacyclopentene- (2) 0.1 mg

Lactose 54.9 mg

Corn starch 30.0 mg

soluble starch 4.0 mg

Magnesium stearate 1.0 mg

90.0 mg

909840 / 17U

- - »-" 41 Tablets: 1 A A 550 O 2- (2,6-dichlorophenyl) -amino-1, Lactose 3-diazacyclopentene- (2) 0.4 mg Cornstarch 54.6 mg soluble starch 30.0 mg Magnesium stearate 4.0 mg 1.0 mg Example B. 90.0 mg Tablets:

0.2 mg 54.8 mg 30.0 mg 4.0 mg 1.0 mg

0.8 mg 54.2 mg 30.0 mg 4.0 mg 1.0 mg

2- (2-Chloro-4-methylphenyl) -amino-1,3-diazacyclopentene

Milk sugar -v ^;

Corn starch soluble starch magnesium stearate

90.0 mg

Tablets:

2- (2-chloro-4-methylphenyl) -amino-1,3-diazacyclopen-

Lactose- (2)

Corn starch soluble starch magnesium stearate

90.0 mg

Example 0 tablets:

2- (2-0hlor-6-methylphenyl) -amino-1,3-diazacyclopen-lactose ten- (2)

Corn starch soluble starch magnesium stearate

90.0 mg

- 1 *, - 909840/17 U

0.2 mg 54.8 mg 30.0 mg 4.0 mg 1.0 mg

Tablets:

2- (2-chloro-6-methylphynyl) -amino-1,3-diazacyclopen- 0.8 mg

Lactose. ten- (2) 54.2 mg

Corn starch 30.0 mg soluble starch - 4.0 mg

Magnesium stearate 1.0 mg

9OjO mg

Example D

Drops: (0.1 mg in 1 ml = 20 drops)

2- (2,6-dichlorophenyl) amino-1,3-diazacyclopentene- (2) 0.01 g

methyl p-benzoate 0.07 g

p-Benzoic acid propyl ester 0.03 g

demineralized water ad 100 ml

Example E.

Drops: (0.1 mg in 1 ml = 20 drops)

2- (2-chloro-4-methylphenyl) -amino-1,3-aiazacyclopen- 0.02 g

methyl p-benzoate ~ 0.07 g

p-Benzoic acid propyl ester 0.03 g

demineralized water ad 100 ml

Example ff
Ampoules:

2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopentene- (2) 0.025mg

Sodium chloride 18.0 mg

least. Water ad 2 ml

Example G
Ampoules:

2- (2-chloro-4-methylphenyl) -amino-1,3-diazacyclopen- 0.05 mg Sodium chloride ten- (2)

least. Water ad 2 ml

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Example H ampoules:

> ß 1U5505

2- (2-chloro-6-methylphenyl) -amino-1,3-diazaeyclopen- 0.05 mg

Sodium chloride ten- (2)

least. Water ad 2 ml

Example I suppositories:

2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopentene- (2) 0.4 mg Milk sugar 244.6 mg

Suppository mass ad 1.7 g

Example K

Suppositories:

2-X2-chloro-4-methylphenyl) amino-1,3-diazacyclopen- 0.8 mg

Milk sugar- (2) 244.2mg

Suppository mass ad 1.7 g

Example L suppositories:

2- (2-chloro-6-methylphenyl) -amino-1,3-diazacyclopen- 0.8 mg

Milk sugar- (2) 244.2 mg

Suppository mass ad 1.7 g

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Claims (8)

UAbbQb Claims 1. Compounds of the general formula Z- N CHp _N GH ₂ H ^ where Z is the remainder 2,6-dichlorophenyl, 2-chloro-6-methylphenyl, 2-methyl-4-chlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-4-ethylphenyl, 2-chloro-6-ethylphenyl, 2-chloro-4-tert.l3utylph.enyl, 2,6-di chloro-4-methylphenyl, 2,4-dichloro-6-methylphenyl, 2,4i-dimethyl-6-chlorophenyl, 2,6-dimethyl-4-chlorophenyl or 2-trifluoromethylphenyl means, as well as their acid addition salts. 2. 2- (2,6-dichlorophenyl) -amino-1,3-diazacyclopentene- (2) and its acid addition salts. 3. 2- (2-chloro-4-methylphenyl) -amino-1,3-diazacyclopentene- (2) and its acid addition salts. 4.2- (2-chloro-6-methylphenyl) -amino-1,3-diazacyolopentene- (2) and its acid addition salts. 5. 2- (2-Trifluoromethylphenyl) -amino-1,3-diazacyclopentene- (2) and its acid addition salts. 6. 2- (2-chloro-4-tert-butylphenyl) -amino-1,3-diazacyclopentene- (2) and its acid addition salts. 7. Process for the preparation of new substituted phenylamino-1,3-diazacyclopentene- (2) the general formula Z-NH-C ^ N GH 909840/171 U - 15 - ORiGIlMAL INSPECTED 1U5505 where Z is the remainder 2,6-dichlorophenyl, 2-chloro-6-methylphenyl, 2-methyl-4-chlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-4-ethylphenyl, 2-chloro-6-ethylphenyl, 4-tert-butyl-2-chlorophenyl, 2,6-dichloro-4-methylphenyl, 2,4-diclilor-6-methylphenyl, 2,4-dimethyl-6-chlorophenyl, 2,6-dimethyl-4-chlorophenyl or 2-irifluorinethylphenyl "mean, as well as their physiologically harmless acid addition salts, characterized in that one a) a leothiuronium salt of the formula NH
Z-NH-O · HX wherein Z has the meaning given, R ^{1 has} a lower one
Alkyl radical and X denotes an acid radical, if appropriate using a suitable solvent with ethylenediamine
implement or that one b) a compound of the formula H _n O NH N - C - HH - Z
H II
T 'where Z has the meaning given and Y = S or 0
means subjected to pyrolysis, and that one
optionally the end products of the specified ones obtained in this way
general formula converted in the usual way into their physiologically acceptable acid addition salts. - 16 - 909840 / 17U H45505 8. Pharmaceutical preparations containing one or more Compounds of the general formula I in a mixture with the customary auxiliaries and / or carriers. 9 “Pharmaceutical preparations containing the active ingredient (s) in a dosage of 0.05 - 10 mg / dose 909840/171 U