DE2951213A1 - USE OF N-ARYL-N '- (2-IMIDAZOLIDINYLIDES) UREAS FOR THE TREATMENT OF HYPERTONIA AND INTESTINAL DISORDERS - Google Patents

Description

"Use of N-aryl-N '- (2-imidazolidinylidene) ureas for the treatment of hypertension and intestinal disorders "

The invention relates to the use of certain N-aryl-N '- (2-imidazolidinylidene) ureas for the treatment of hypertension and intestinal disorders.

Intestinal irritation (irritable bowel syndrome) is a functional disorder that is mainly noticeable through abdominal pain, but also through diarrhea, constipation and similar symptoms. It is believed that the pain associated with this syndrome is due to hypersensitivity against intestinal flatulence caused by intestinal gas and / or fecal material, are due. There is a need for treatment methods that alleviate the associated discomfort can be alleviated.

Furthermore, there is still a need for high potency drugs with antihypertensive effect.

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From US-PS 3,168,520 certain imidazolidine and Hexahydropyrimidine ureas are known as stabilizers for dyes. In particular, in this document 2-Phenylcarbiliminoimidazolidin described. In this Ver bond is N- (2-imidazolidinylidene) -N »- phenylurea. In this publication, however, there is no reference to the use of this imidazolidine and hexahydropyrimidine urea as pharmacological agents. 10

Certain urea compounds with a certain pharmacological activity are known from US Pat. No. 4,060,635. These compounds have an aryl group on one urea nitrogen atom and a substituted amidine residue on the other urea nitrogen atom. From the US PSs 3,539,616 and 3,784,582 amidine ureas are known in which a urea nitrogen atom with an aryl group and the other is substituted with an unsubstituted amidine group. U.S. Patent 4,058,557 also relates (albeit further away from the subject of the application) amidine ureas in which an amidine nitrogen atom is attached to one Oxygen atom must be bound. There is no imidazolidine substituent in any of the aforementioned publications

on a urea nitrogen atom. Further finds 25th

in none of these publications is a reference to a

ant! hypertensive effect.

G.H. Douglas et al, report in Arz. Research / Drug

Res., Vol. 28 (II) (1978), p. 1480 on investigation 30

from many aryl-substituted amidine ureas to one

Antimotility and antisecretory activity. The compounds examined also include N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea and N- (2,6-dimethylphenyl)

nyl) -N ^l - (1-methyl-2-imidazolidinylidene) urea. From the-35

However, this publication does not indicate that the

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both of the aforementioned compounds have antimotility activity. There is also no indication any other pharmacological activity of these

Links.
5

The invention relates to the use of N-aryl-N ¹ - (2-imidazolidinylidene) ureas of the general formula I below and of pharmacologically acceptable ones

Salts thereof for the treatment of hypertension and functional 10

intestinal disorders and to relieve pain and other symptoms associated with intestinal irritation. The invention also relates to medicinal preparations for the treatment of hypertension, diarrhea and intestinal disorders, the active ingredient is a urea compound of the general formula I below or a pharmacologically acceptable one Contain salt thereof together with a pharmacologically acceptable carrier.

In the general formula I.
20th

Q-

M-C-NH-Ar (Σ)

Ajc means a phenyl radical with 0 to 3 identical or different Substituents. Halogen atoms or radicals containing 1 or 2 carbon atoms are used as substituents, which are optionally bound to the phenyl radical via a non-basic heteroatom, with the proviso, that with active ingredients for the treatment of intestinal disorders Ar to at least one in the 2- and 6-position by halogen atoms or phenyl radical substituted by the carbon-containing radicals mentioned.

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Examples of halogen atoms are fluorine, chlorine and bromine atoms. Examples of carbonaceous radicals are lower ones Alkyl radicals, such as the methyl and ethyl groups, lower alkoxy radicals, such as the methoxy and ethoxy groups, the trifluoro methyl, methylthio, methylsulfonyl, methylsulfinyl and Cyano group.

For the treatment of hypertension, compounds are preferred in which Ar is a radical of the general formula

in which R is a methyl or ethyl group, a chlorine or Is a bromine atom or a methoxy group and η is a whole Is a number with a value from 0 to 3.

For the treatment of intestinal disorders, compounds are preferred in which Ar is a radical of the general formula means

in which X and Y are methyl or ethyl groups or chlorine or bromine atoms.

Pharmacologically acceptable salts of the aforementioned compounds are, for example, hydrochlorides, hydrobromides, Hydroiodides, phosphates, sulfates, p-toluenesulfonates, benzenesulfonates, malates, tartrates, fumarates, citrates, pamoates,

O ₅ maleates, malonates, succinates, oxalates, methosulfates, methanesulfonates and 2-napsilates (2-naphthalene sulfonates).

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- "- 2351213

Some of the compounds used according to the invention are new, namely the compounds of the general formula

N » II * Vs N ~ C - NH -

Ν '

HR ₂

in which R ₁ and R ~ each denote halogen atoms, lower alkoxy or lower alkyl radicals, with the proviso that R ₁ and R _{2 are} not simultaneously lower alkyl radicals. These new compounds are also a subject of the invention.

The pharmacologically valuable N-aryl-N '- (2-imidazolidinylidene) ureas can essentially be prepared by two processes. It is most convenient to react 2-iminoimidazoline of the formula II with an aryl isocyanate of the general formula III according to the following reaction equation:
20th

NH + O-C-N-Ar

U 25

(II) (HD

The 2-iminoimidazoline is, as explained below,

produced according to the usual methods and as a salt with ei-30

acid of the general formula Ha

¹ acid 35

Ο "·

stored.

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^Γ 12

~ ¹² '295-213

To carry out the process according to the invention, the salt of 2-iminoimidazoline is generally first converted into the free base. For this purpose, for example, a solution or suspension of this salt in tetrahydrofuran is stirred thoroughly with 2 molar equivalents of 50 percent aqueous sodium hydroxide solution. Anhydrous sodium sulfate is then added to remove excess water. The biphasic mixture obtained in this way is brought into contact with a corresponding aryl isocyanate, whereby the desired N-aryl-N ¹ -imidazolidinylideneurea is formed.

Preferably the implementation of the aryl isocyanate with the 2-imidazolidine is added a solution of the aryl isocyanate in tetrahydrofuran in portions, with stirring, to the biphasic mixture at temperatures of about 20 to 30 ⁰ C. The mixture is then stirred for a few hours and, if necessary, overnight. The N-aryl-N'-imidazolidinylideneurea obtained in this way is obtained,

^ O if necessary converted into a salt with an acid and cleaned according to standard procedures.

The free base can also according to another method obtained by mixing a solution of the acid salt of 2-iminoimidazolidine with a suspension of lithium hydride, preferably in the same solvent, under an inert atmosphere. Examples of corresponding Solvents are anhydrous dimethylformamide, dimethyl

sulfoxide and tetrahydrofuran. The temperature at the

30 o

there would generally be 0 to 30 C. To form the inert Atmosphere, nitrogen or argon are expediently used.

A solution is preferably used for the aforementioned reaction

of the salt of 2-iminoimidazolidine drop by drop while stirring

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to a cooled solution of lithium hydride in an anhydrous solvent under a nitrogen atmosphere while maintaining the temperature in the range of 0-5 ° C. When the addition is complete, stirring is continued, while 5. the mixture is allowed to gradually warm to room temperature. In this way the free base is obtained. The reaction between the 2-iminoimidazolidine and the aryl isocyanate can be carried out by adding a solution of the aryl isocyanate dropwise with stirring and with cooling to the mixture containing the free base under an inert atmosphere. The mixture is allowed to gradually warm to room temperature with stirring. The temperature is then increased to about 30 to 110 ^° C. and, in order to achieve optimal yields, preferably to 65 to 110 ^° C. The desired N-aryl-N '- (2-imidazolidinylidene) urea is obtained. When the reaction is carried out at ambient temperature, the mixture is generally stirred for several hours or overnight. When carrying out the reaction at elevated temperatures, a reaction time of about 2 hours is sufficient.

The following reaction scheme illustrates a second, less preferred process for the preparation of the N-aryl

N '- (2-imidazolidinylidene) ureas. 25th

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- 11 »-

Ar-NCO + H ₂ NC-NH ₂ Lo ^ g ₃ ,; ?

medium (IZI)

H ₂ NJ-NH-C-NH-Ar

(IV)

/ NH ₂

CH

CH,

I ²

₂ ^, (J · HJi ^0H

alcohol

In a first stage, by reacting the aryl isocyanate of the general formula III with thiourea, an N-arylthioimidodicarboxylic acid diamide of the general formula IV is obtained, which is then reacted with methyl iodide to form a methyl N ¹ - ^ (arylamino) carbonyl _ / - earbamidothioate of the general formula V. will. The latter Pro-25

Then, with an appropriately substituted xthylenediamine of the general formula VI, the product becomes N-aryl-N '- (2-imidazolidinylidene) urea hydroiodide of the general formula I implemented. This salt can be converted to the free base in a conventional manner. The aforementioned 30th

However, the reaction sequence is not suitable for the production of ureas in which the aryl radical is a 2,6-disubstituted Phenyl radical is present.

The first stage of the aforementioned procedure can be carried out under 35

Modification of the procedure of Lakra et al., (J. Am. Chem. Soc, 51, 2220 (1929)).

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A corresponding aryl isocyanate of the general formula III is reacted with thiourea to form an N-arylthioimidodicarboxylic acid diamide of the general formula IV, hereinafter referred to as "thiobiuret compound" for short. Essentially equimolar amounts of the reactants and preferably a slight excess of the thiourea are used for this reaction. The reaction temperature may range from about 80 to 120 ⁰ C. Preferably the reaction

carried out in a solvent. Examples of suitable solvents are dimethylformamide and dimethyl sulfoxide.

Preferably the reaction takes about 2 to 12 hours The isocyanate and the thiourea were heated to steam bath temperature. The Thiobiuret compound of the general formula IV in the reaction mixture. To facilitate the crystallization of the

Thiobiuret compound is then mixed with water 20

diluted and cooled. The product is separated off from the reaction mixture and purified by customary methods.

In the second reaction stage, the N-aryl-thiobiuret compound is reacted with an S-methylating agent. A methyl N ¹ - ^ (arylamino) carbonyl _ / - carbamidothioate of the general formula V is obtained. The latter compound is hereinafter referred to for short as the “thioate compound”. There are essentially equimolar amounts of the reactants and preferably a slight excess

shot of methylating agent used. Although other methylating agents such as dimethyl sulfate and the like can be used, methyl iodide is preferred. A solvent is preferably used. Examples of suitable solvents are acetone. Methanol, ethanol and isopropanol. The reaction temperature ..... n ., "Range

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BATH ORIGINAL

γ ~ ι

from ambient temperature to reflux temperature, with operation at ambient temperature preferred will.

The reaction is expediently carried out by the thiobiuret compound and the methyl iodide are mixed in methanol and at room temperature for several hours implements. The hydroiodide formed in the reaction mixture is obtained and, if necessary, purified by conventional methods.

In the third stage, the thioate hydroiodide of the general formula V is reacted with xthylenediamine of the formula VI,

whereby the desired N-aryl-N'-imidazolidinylidene-

urea hydroiodide. This is essentially done

equimolar amounts of the reactants are used. The reaction is preferably carried out in methanol or other lower alkanols, with methanol being particularly preferred.
20th

The reaction is expediently carried out by refluxing the hydroiodide of the general formula V and the xthylenediamine in methanol for 1 to several hours and then evaporating the solvent. The residue obtained is the desired N-aryl-N ^f -imidazolidinylidene urea hydroiodide. The product can then be recovered and purified using conventional methods.

The salt can be converted into the free base. is

If the preparation of another salt is intended, the free base is mixed with another acid to form the desired salt implemented. Conventional methods can be used for this purpose. For example, the Her-35

position of the free base a salt in as

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^Γ -π-

wrestle amount of a lower alkanol, such as methanol or
Xthanol, dissolved. The solution is heated with an organic base such as triethylamine and then cooled. Man
receives the free base as a crystalline solid. To the

Conversion of the free base into a salt with an acid
the base is heated in a corresponding manner with an alcoholic solution of an acid. After cooling, the desired salt is obtained.

The pharmacological activity of the present invention will be described below used compounds explained in more detail.

Treatment of hypertension

The N-aryl-N '- (2-imidazolidinylidene) ureas cause
relief from hypertension without an increase in heart rate. Such active ingredients with an antihypertensive effect that do not increase the heart rate, but leave it unchanged or decrease it, are used to treat

Particularly suitable for patients with hypertension. The aforementioned 20

Properties can be determined on rodents in the antihypertensive test and on dogs by means of a hemodynamic assessment determine.

Antihypertension test , 'in rodents

25th

This test provides information about the effects on arterial pressure and heart rate. The arterial pressure of spontaneously hypertensive rats or of
Rats made hypertensive by injection of deoxycorticosterone acetate and administration of drinking water containing 2 percent sodium chloride were determined directly by means of an aortic cannula. The rats
are numbed by inhaling an anesthetic (methoxyflurane or ether). The left carotid artery becomes iso-

lated and cannulated. The cannula tip goes into the aorta
advanced. The cannula itself is behind to the outside

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the neck placed at the level of the shoulder blade. Make recovery from the anesthesia they will be without restrictions held. The arterial cannula is connected to a pressure transducer connected to a recording device. The heart rate is determined from the recording of the arterial pressure. Animals with a pressure greater than 149 mmHg are sufficiently hypertensive to test for antihypertensive effects. The compounds to be examined are administered either orally (p.o.) or intraperitoneally (i.p.). The arterial pressure and heart rate will be observed for at least 4 hours. A test compound is considered an antihypertensive agent when the average arterial pressure (MAP ^ falls by more than 19 mmHg. Each animal serves as a control animal. 15th

Two rats are used for each compound. The results for various N-aryl-N '- (2-imidazolidinylidene) ureas are compiled in Table I.

Hemodynamic Assessment in Dogs

This experiment is carried out to determine the effects of the compounds on the cardiovascular and autonomic nervous systems to be determined in normal anesthetized animals.

Hybrid dogs are given 20 mg / kg body weight of thiopental sodium and 60 mg / kg oc-chlorolose anesthetized. Possibly are used to maintain anesthesia an additional 60 mg / kg (X-Chlorolose. One with an inflatable Cuffed endotracheal tube is inserted to maintain an unobstructed airway. The animal is ventilated with a ventilation pump. A femoral artery and vein are catheterized around the arterial one Record pressure or give intravenous injections. For performing bilateral carotid occlusion both carotid arteries are isolated. Of the

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Γ "1

Vagus nerve is at the peripheral ends for 10 seconds with 5 V at 20 pulses per second of 2 milliseconds each Duration stimulated in order to obtain a cardiac arrest - The electrocardiogram is recorded via the limb lead II recorded.

Cardiovascular control reactions are obtained according to the following pharmacological measures: 1.0 ig / kg body weight i.v. 1-epinephrine, carotid occlusion, 10 µg / kg i.v. Dimethylphenylpiperazinium iodide (DMPP), peripheral vagal stimulation, 10 ^ g / kg i.v. Acetylcholine and 2 ^ g / kg i.v. Angiotensin. These control reactions are produced twice. Then the connection to be examined at a dose of 5 rag / kg body weight i.v. using bolus injections within a period injected for about 1 minute. If there is no change in terms of arterial pressure, heart rate or ECG (limb lead II) a further 5 mg / kg of the compound to be tested are administered i.v. administered. The influence of too 20th

investigating connection on the electrocardiogram, the arterial pressure and the heart rate is determined. Another series of hemodynamic responses is performed 10 minutes after administration of the test compound.
25th

A dog is assigned to each compound to be examined. The influence of the N-aryl-N '- (2-imidazolidinylidene) ureas is given in Table I.

The results of Table I show that the N-aryl-N ¹ - (2-imidazolidinylidene) ureas and their salts not only have a beneficial antihypertensive effect, but also prove beneficial in that the heart rate is maintained or decreased will. These properties are when using the inventive

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1 connections used.

To treat hypertension or to relieve high blood pressure, a therapeutically effective amount of one will be used N-Aryl-N '- (2-imidazolidinylidene) urea of the general formula I or a pharmacologically acceptable one Salt thereof administered as an active ingredient. The active ingredients can be used with or without a carrier in those specified below Quantities are administered. Preferably they are in the form of medicaments in the form of unit doses, such as explained below, administered.

For oral or parenteral administration, about 5 to about 500 mg of the active ingredients are in the form of dose units administered. Treatment in humans or other mammals is possible. In general, they are Doses about 0.5 to 50 mg / kg body weight.

030028/0/3 0

antinvmrfcensiven wiriciwn and of influence

on aim

link S-MH-Ar • HX
KX sDontaneously hypertensive (SH) rats) Maximum departure
near the
KM> (nntfci) Effect on the
Heart rate
(Beats / min) httnodynamic
Dog test Ψ-
Ar - dose
(mg / kej i.p.) 72 +78 maximum decrease in
Heartbeats on doses
of 10 mg / kg i.v.
(Beats / min) 0 - 30th 39 -108 no change (kV) . 0 - 10 p.o. 30th ♦ 30 - 0 HI 100 p.o. 63 -42 - ο 3-α0 . · · Ha 30th 39-96 -39 to -108 -30 UJ
O
O 2,6-α / Ha 20-200 (p.o.) •> 19 4 · -54 *
to
ta * ro
00 Ha 30th > 19 I. -60 ι "Ν,
O 2-Cl, 6-CH / Ha 30th > 19 -42 U)
O 2,6-Br / 2/3 Fumarate 30th > 19 Φ -54 2-C ₂ H ₅ ^ e-CH ₃ Ji Ha 30th > 19 * kv -42 4-CH / Ha 30th 95 -108 * kV (5 mg / kg i.V.) 2-OCH / n / A 30th 23 -84 ♦ 30 ··· 2-CCH / Ha 10 p.O. 90 -84 - N) 2-CCH / κα 100 p.o. > 19 -108 "" cn 2-α0 30th kv κ: ■ ftL ^ aBtBBmBBBh IBBlAm tm bB.bb & bbbb> Y BKBBBUBBBBBBtBBBBBBBBt. *!

considered more meaningful

_Γ -22-

1 Treatment of intestinal disorders

The N-aryl-H ^f - (2-imidazolidinylidene) ureas of the invention bring about an alleviation of the symptoms associated with functional intestinal disorders, which are referred to as irritable bowel syndrome. These disorders manifest themselves through abdominal pain, diarrhea, constipation and similar symptoms and are due to an over-sensitivity to intestinal gas

intestinal gas and / or fecal material. 10

The effectiveness of the compounds of the invention against these complaints is determined by means of a test in which one Glass bead is inserted into the rectum. The time between the insertion and the ejection of the pearl will be-IS

it's correct. Compounds that increase sensitivity to flatulence decrease the colonic wall, delay the expulsion of the pearl.

The test is carried out on male albino mice weighing 18 to 25 g 20

Body weight carried out. Groups of 5 mice are used for the individual doses of the compounds. The dose initially selected is 50 mg / kg body weight for all compounds. It is administered orally Ways in a volume of 0.1 ml per 10 g of body weight. The control groups only receive the vehicle, i.e. a 0.5 percent Methocell solution used for both oral and intraperitoneal administration. 1 hour the mice are no longer fed before the experiment. The drugs to be examined are 1 hour before Inserting the glass beads given. After the pretreatment is finished, the mice are taken out and held in one hand with the abdomen facing the examiner. A glass bead of 3 mm in diameter is made ge positioned at the rectura and with thumb and forefinger pressed into the rectum. Then the glass bead with a glass rod of 3 mm diameter, which is used for

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To facilitate the introduction, it has been lubricated with 0.5 percent methocel solution, introduced 2 cm deep into the rectum with a slight twisting motion. The treatment of the mice in a group is timed, with the introduction of the pearl in the last mouse being set as time 0. The period of time that elapses before the pearls are expelled is determined. The following evaluation is made: 0 = ejection time from 0 to 5 minutes; 1 = ejection time of 5 to 10 minutes; 2 = output time from 10 to 20 minutes, 3 = output time from 20 to 40 minutes; and 4 = ejection time of more than 40 minutes. Mice that have not expelled their pearl after 40 minutes are examined for the presence of a perforation. Mice with perforated colon are excluded. The activity index for the drug to be investigated results from the quotient of the sum of these values and the number of mice or pearls. The ED _cn values

YOU

are determined by regression lines using the least squares method. As an EDj-Q value ^ the dose is determined which produces an activity index of 2.

The results of these studies at intraperitoneal and oral administration of N-aryl-NU-2-imidazolidinylidene) ureas are compiled in Table II.

Table II compound

Γ ^ - N-C-NH-Ar H

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HX 2951213 13.7 HCl ED ₅₀ (mg / kg) 16 Ar HCl «1/2 H ₂ O intraperitoneally Per Os 35 2,6-diCl-? HCl 7th 38 2,6-di (CH ₃ ) -0 BCl 12th 121 2-Cl, 6-CH ₃ -Ji 2/2 fumarate 8th 2,6-diBr-P 9 2-C ₂ H ₅ , 6-CH ₃ -PT 43

₁₀ The above values show the beneficial effect of

Compounds of the invention for reducing abnormal susceptibility to intestinal gas. This Property is used when the compounds are used according to the invention.

To alleviate functional intestinal disorders and to treat the associated complaints, the patient is administered a therapeutically effective amount of the N-aryl-N '- (2-imidazolidinylidene) ureas of the general formula I or a pharmacologically acceptable salt thereof as the active ingredient. The active ingredients can be administered with or without a carrier in the amounts given below. Preferably, pharmaceutical compositions are in the form of unit doses, as discussed below, comparable

25 follows.

To treat the aforementioned complaints, about 5 to about 500 mg of an N-aryl-N ¹ - (2-imidazolidinylidene) urea are administered orally or parenterally in the form of a unit dose. This type of treatment can be used in particular for humans but also for other mammals. The amounts of active ingredient are in the range from about 0.50 to 50 mg / kg and preferably from at least 3 mg / kg of body weight.

Medicines can be manufactured by using the active

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Substance according to usual procedures with a pharaacological compatible carrier mixed - depending on the desired route of administration, for example orally or parenterally, a wide variety of carriers come in Question examples of carriers and additives for liquid orally administrable preparations, such as suspensions, elixirs and solutions are water, glycols, oils, alcohols, flavorings, Preservatives and colorants - Corresponding examples of solid, orally administrable preparations, such as powder, capsules and tablets, are starch, sugar, diluents, granulating agents, lubricants, Binders and disintegrants. Because of their ease of administration, tablets and capsules are used for oral dosage units preferred. Optionally, tablets can be made by conventional methods with sugar or an enteric Be provided with a coating. Medicines which can be administered parenterally contain sterile substances as the carrier Water, but also contain other constituents, for example solubilizers or preservatives

* ". Injectable suspensions can also be prepared containing appropriate liquid carriers, suspending agents and the like. The expression "Unit dose" refers to individual drug units, which serve as unit doses, the individual units containing a predetermined amount of active ingredient, the is calculated so that, in conjunction with the required pharmacological carrier, the desired therapeutic Effect. Examples of this are tablets, capsules, pills, powder packets, wafers, amounts of teaspoons

and tablespoon quantities as well as multipacks thereof. A unit dose generally contains about 5 to about 500 mg of active ingredient.

The examples illustrate the invention. 35

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Production of the starting material

The 2-imidazolidine of the formula used as the starting product II can be used for the preparation of the hydroiodide by the process described in the literature or by the following procedure getting produced.

213 g (1.5 mol) of methyl iodide are added within 1 hour with stirring to a suspension of 153.24 g (1.5 mol) of ethylene thiourea in 300 ml of methanol. In order to achieve complete formation of S-methylethylthiourea, the mixture is stirred for about another hour. Anhydrous ammonia is then added, after which a reaction occurs with the formation of 2-iminoimidazolidine hydroiodide and methyl mercaptan as a by-product. The mixture is stirred for a total of about 26 hours with the intermittent addition of ammonia. The mixture is then concentrated with the simultaneous addition of isopropanol to replace the evaporated methanol. It is then cooled and diethyl ether is added. This gives 2-iminoimidazolidin hydriodide as a crystalline solid, having a F. 152-15 ¹ J ⁰ C after recrystallization from methanol / t-butanol.

C ₃ H ₇ N ₃ . HJ 1 6th C. 3 H ber .: 1 6th , 92 3 , 79 found: , 85 , 82

example 1

N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride

• HCl

< _N / - v ^

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^Γ - 27 -

A suspension of 2.13 g (0.01 mol) of 2-iminoimidazolidine hydroiodide in 50 ml of anhydrous dimethylformamide is treated under nitrogen with 0.8 g (0.01 mol) of aqueous 50 percent sodium hydroxide solution, whereby 2-iminoiraidazolidine in the form of the free base and sodium iodide is formed. Then 1 g of anhydrous sodium sulfate is added and the mixture is stirred for a further 1/2 hour. A solution of 0.94 g (0.005 mol) of 2,6-dichlorophenyl isocyanate in 20 ml of tetrahydrofuran is then added dropwise over the course of 2 1/2 hours . The mixture is stirred at room temperature overnight. N- (2,6-dichlorophenyl) -N ¹ - (2-imidazolidinylidene) urea is obtained. The sodium salts are filtered off. The filtrate is evaporated on a water bath under reduced pressure.

The pale yellow oil obtained is dissolved in methylene chloride. This solution is first washed with saturated sodium chloride solution, then dried over anhydrous potassium carbonate and treated with hydrogen chloride until a pH value <3 is reached. The solvent and excess hydrogen chloride are removed under reduced pressure. The residue is recrystallized from methanol / diethyl ether. N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride with a melting point of 210 to 212 ° C is obtained _. which decomposes to form a new solid with a temperature of 239 ° C.

²⁵ places.

Example 2 N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) -urine-

substance and the corresponding hydrochloride 30

A solution of 10.65 grams (0.05 moles) of 2-iminoimidazolidine hydroiodide in dimethylformamide is added dropwise with stirring within 15 minutes to a cooled to 5 ° C Suspension of 397.5 mg (0.05 mol) of lithium hydride in 50 ml of anhydrous dimethylformamide under nitrogen, whereupon hydrogen evolution can be observed.

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With continued stirring, the mixture is allowed to gradually warm to room temperature. The reaction mixture is then cooled to 0 to 5 ° C. and a solution of 5.0 g (0.03 mol) of 2-chloro-6-methylphenyl isocyanate in 25 ml of anhydrous dimethylformamide is added dropwise over the course of 2 hours. When the addition is complete, the mixture is allowed to gradually warm to room temperature while continuing to stir under nitrogen. After stirring overnight, the desired N- (2-chloro-6-methylphenyl) -N ^t - (2-imidazolidinylidene) urea is obtained, which remains in solution. The product is obtained from the reaction mixture in the following way: (a) addition of 300 ml of ice water with stirring, (b) lowering the pH value below 2 by adding 10 percent aqueous hydrochloric acid with precipitation of an acid-insoluble material, (c) filtering , (d) making the filtrate alkaline by adding solid potassium carbonate to a pH of 8 to 9 and (e) saturating the solution with solid sodium chloride, the desired N- (2-chloro-6-methylphenyl) -N ' - (2-imidazolidinylidene) urea (free base) precipitates in the form of a white solid. After thorough washing with water, the product has a temperature of 169 to 171 ° C.

The above product is dissolved in 30 ml of methanol and by adding hydrogen chloride in methanol to a brought pH below 3. After addition of diethyl ether, N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea hydrochloride precipitates the end. This product is obtained and successively from 2-propanol and methanol / diethyl ether

recrystallized. A purified product is obtained from

F. 209 to 211 ° C, which decomposes under formation of a new solid, mp 270 ⁰ C (dec.).

C ₁₁ H ₁₃ ClN ₄ O. HCl CH N

HCl C. 69 H ber .: 45, 59 4.88 found : 45, 4.93

calc .: 45.69 4.88 19.37

■ n 35

030028 / ü7 ^on

Γ

1 example3

N- ( ^{2,6-Dibromophenyl) -N t} - (2-imidazolidinylidene) urine hydrochloride

According to Example 2, a solution of 12.0 g (0.0563 Mol) 2-iminoimidazolidine hydroiodide in 50 ml of anhydrous Dimethylformamide dropwise with cooling and under nitrogen to a suspension of 447 mg (0.0563 mol) lithium hydride given in 50 ml of anhydrous dimethylformamide. To

When the addition is complete, the mixture is left within about 10%

Warm up to room temperature for 1/2 hour. The mixture is then cooled to 0 to 5 ° C. and a solution of 7.8 g (0.0282 mol) of 2,6-dibromophenyl isocyanate in 25 ml of anhydrous dimethylformamide is added dropwise over the course of 2 hours, the cooling being maintained at the specified temperature range. The mixture is then allowed to warm to room temperature and stirred under nitrogen overnight. The desired N- (2,6-dibromopheny]) - N ^l - (2-imidazolidinylidene) urea is obtained in the reaction mixture. The product is obtained from the reaction mixture by pouring the mixture into 400 ml of ice water, acidifying with 10 percent hydrochloric acid to a pH value below 3, filtering to remove impurities, saturating the filtrate with solid sodium chloride and adding potassium carbonate Adjusts pH value from 8 to 9. It falls N- (2,6-dibromophenyl) -N · - (2-imidazolidinylidene) urea as a white solid, mp 185-190 ⁰ C (dec.) Made.

The above product is suspended in 40 ml of methanol and with a solution of hydrogen chloride in methanol

acidified to a pH below 2. Diethyl ether is then added. ) (2-imidazolidinyl idene) -urea hydrochloride as a white solid, mp 200 to 202 g_ ⁰ C (dec After two recrystallizations - there is formed a precipitate of N- (2,6-DibromphenyD-N. ^1. from methanol / 2-propanol / diethyl ether a purified

030028/0730

Nigt product with a melting point of 215 to 217 ° C, which decomposes to a solid with a melting point of 255 ° C (decomp.).

C. 10 « 10 ^N 4 ^Br 2 ° . HCl 30th C. 2 H 14th N ber .: 30th , 14 2 , 78 14th , 06 found: , 12 , 81 , 04

Example 4 N- (2-imidazolidinylidene) -N '- (2-methoxyphenyD-urea hydrochloride with a melting point of 197 ° to 199.5 ° C. is prepared in a similar manner by adding 2-iminoimidazolidine (prepared from 2-iminoimidazolidine-hyd ;. ojodid and lithium hydride) and 2-methoxyphenyl isocyanate at about 5 to 10 ⁰ C to give N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) urea converts The latter product is washed with a solution of hydrogen chloride in methanol After one recrystallization from methanol / 2-propanol and subsequent two recrystallization from methanol / diethyl ether, the compound mentioned at the outset is obtained.

C * HM
Til 1 »1 * O ₂ . KCl C. 5 H 20th N ber .: 48.80 5 , 58 20th , 70 found : 48.75 , 61 , 71

Example5

N- (2-Xthyl-6-methylphenyl) -N ¹ - (2-imidazolidinylidene) urea fumarate (3: 2)

Similar to the procedure described above, 15.55 g (0.073 mol) of 2-iminoimidazoline hydroiodide are added dropwise under nitrogen to an anhydrous, cooled suspension of 596 rag (0.075 mol) of lithium hydride in 30 ml Given dimethylformamide. When the addition is complete, the mixture is allowed to come to room temperature to complete the reaction heat. The mixture is then cooled again and added dropwise over the course of 2 hours a solution of 8.1 g (0.05 mol) of 2-ethyl-6-methylphenyl-

030028/0730

Γ Π

isocyanate in 25 ml of anhydrous dimethylformamide. The resulting mixture is then stirred overnight while allowing the temperature to rise to ambient temperature. N- (2-ethyl-6-methylphenyl) -N ^l - (2-imidazolidinylidene) urea is obtained. The base is obtained in the manner explained in the examples described above and recrystallized from methanol / water. A purified base with a melting point of 185 to 187 ° C. is obtained.

A solution of 4.32 g (0.0175 mole) of the above base is in 35 ml of hot isopropanol with a solution of 2.04 g (0.0175 mol) of fumaric acid in 35 ml of hot isopropanol offset. The solution obtained is allowed to cool, whereby N- (2-ethyl-6-methylphenyl) -N '- (2-imidazolidinylidene) urine

^ substance fumarate crystallizes. This salt indicates washing with isopropanol and then with diethyl ether to a temperature of 180 ° C (decomp.). Subsequent recrystallization processes from methanol / isopropanol, methanol / diethyl ether and methanol do not result in a salt with a reproducible one sharp melting point. The elemental analysis shows that the salt formed is 3 moles of base per 2 moles Contains fumaric acid.

Example 6 In a similar manner, N- (2-chlorophenyl) -N '- (2-imidazolidinylidene) -urea hydrochloride prepared from the F. I87 to 189 ⁰ C by 2- iminoimidazolidin (one prepared from 2-iminoimidazolidin-hydroiodide and Lithium hydride in dimethylformamide at about 20 ^° C.) and 2-chlorophenyl isocyanate; .at converts at about 20 to 30 ^{° C. overnight.} After 15 minutes of heating to 100 ^° C. on a steam bath, N- (2-chlorophenvi) _N ^l - (2-imidazolidinylidene) -h-fr: * off as a critical

030028/0730

(C ₁₃ H ₁₈ N ₄ O) ₃ . (C ₁ ber .: 58 C. 6th H 17th N found : 58 , 13 6th , 44 17th , 31 , 03 , 57 , 59

stable solid. This product is converted into the hydrochloride with a solution of hydrogen chloride in methanol.

C. 10 ^H 1 , N ₁₁ OCl . HCl 43 C. 4th H 20th N ber .: 43 , 66 4th , 40 20th , 36 found : , 69 , 36

Example 7

According to Examples 2 to 6, the following compounds can be used produce:

N- (2-imidazolidinylidene) -N '- (4-raethoxy phenyl) urea and its hydrobromide;

N- (2-chloro-5-trifluoromethylphenyl) -N '- (2-imidazolidinylidene) urea and its tartrate;

N- (4-fluoro-2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea and its malonate;

N- (2-imidazolidinylidene) -N '- (4-methylphenyl) urea and its hydrochloride with a melting point of 210 to 212 ° C; N- (2,4-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride with a melting point of 217 to 219 C; N- (2,3-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride with a melting point of 218 to 220 ^° C .; N- (3,5-dichlorophenyl) -N '- (2-imidazoiidinylidene) urea

25 and its hydrochloride from mp 200 to 202 ⁰ C;

N- (3,4-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride / at a temperature of 217 to 219 ° C; N- (2,5-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride with a melting point of 213 to 215 ° C; N- (2-imidazolidinylidene) -N '- (2,4,6-trichlorophenyl) -urea and its ftydrochlorid mp 232 ⁰ C, which is to form a solid, mp 26O ⁰ C (dec.) Decomposed;
N - (? - Fluoro-6-methylphenyl) -N '- (2-imidazolidinylidene) -

35 urea and its hydrochloride

030028 / C /?

N- (2-imidazolidinylidene) -N ^l - (2-methyl-6-trifluoromethylphenyl) urea and its hydrochloride; N- (2-imidazolidinylidene) -N »- (2-methyl-6-methylsulfonylphenyD-urea and its hydrochloride; N- (2-cyano-6-methylphenyl) -N - (2-imidazolidinylidene) urea and its hydrochloride ; N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride; N- (2-bromo-6-methylphenyl) -N ¹ - (2-imidazolidinylidene) urea and its hydrochloride; N- (2-bromo-6-ethylphenyl) -N- (2-imidazolidinylidene) urea and its hydrochloride; N- (2-chloro-6-ethylphenyl) -N- (2-imidazolidinylidene ^ urea and its hydrochloride; N- (2-bromo-6-chlorophenyl) -N ^l - (2-imidazolidinylidene) urea and its hydrochloride; N- (2-methoxy-6-methylphenyl) -N • - (2-imidazolidinylidene ) urea and its hydrochloride; N- (2-methyl-6-trifluoromethylphenyl) -N ^f - (2-imidazolidinylidene) urea and its hydrochloride; and N- (2-chloro-6-fluorophenyl) -N '- ( 2-imidazolidinylidene) urea and its hydrochloride.

Example 8

N- ⁱ (2-imidazolidinylidene) -N ^t -phenylurea and its hydroiodide

CO
"" ^N " ^ _f

B (and HJ)

030028/0730

In a first reaction stage, 119 g (1 mol) of phenyl isocyanate are used in one portion with stirring to a warm solution of 83.73 g (1.1 mol) of thiourea in 120 ml of anhydrous Given dimethylformamide. The resulting solution is heated for 3 hours. The solution is then cooled and carefully mixed with a mixture of ice and ice water. To initiate the crystallization of the desired intermediate N-phenylthioimidodicarboxylic acid diamide the vessel wall is rubbed. After crystallization has started, more ice water (up to approx Liters) added. The crystals formed are collected, washed with water and recrystallized from methanol. 127 g of N-phenylthioimidodicarboxylic acid are obtained

diamid from m.p. 176 to 180 ° C. 15th

In a second stage, 45.5 g (0.32 mol) of methyl iodide are used to a solution of 59.5 g (0.305 mol) of N-phenylthioimidodicarboxylic acid diamide given in 300 ml of acetone. The mixture obtained is about 2 hours at room temperature

* "Stirred door. Crystals form in the reaction mixture, which are then filtered and dried. Methyl-N · - £" { phenylamino) carbonyl-7-carbamimidothioate hydroiodide with a melting point of 195 ° to 200 ° C. is obtained. An analytical sample obtained after recrystallization from methanol shows

^{25 to} the F. (190 ⁰ C) 200 to 202 ⁰ C (Hoover).

1 ^N 3 ^0S ' C. 06 3, H 12th N 32, 11 3, 59 12th , 46 32, 62 , 48 . HJ ber .: found :

A methanol solution of 33.72 g (0.1 mol) of the methyl-N · -_ / "(phenylamino ) -carbonyl_7-carbamimidothioat-hydr ο j od ids and a methanol solution of 6.01 g (0.1 mol) of ethylenediamine (about a total of 50 ml of methanol) mixed and heated under reflux for about 1 1/2 hours. Then the mixture

030028/0730

cooled to -20 ° C. Crystalline N- (2-imidazolidinylidene) -N'-phenylurea hydroiodide is obtained. Several crops are obtained. These yields are combined, purified by dissolving in methanol, filtered and evaporated. The desired hydroiodide is obtained as the residue.

The hydroiodide is converted to the free base and purified through a series of steps: Dissolving the residue in the smallest possible amount of methanol, mixing and heating with 8.0 g (0.079 mol) of triethylamine, replacing the Methanol by ethanol and then cooling. N- (2-ImidazoIidinyliden) -N'-phenylurea from F. (181 ° C) 182 to 183 ° C after recrystallization from methanol.

C ₁₀ H ₁₂ N ₄ O CH N

calc .: 58.81 5.92 27.43 found: 58.79 5.92 27.48

The hydroiodide has after recrystallization from acetone to a F. 223-225 ⁰ C fZers.). At the onset of melting point at a temperature of 225 · C of F. 230 ⁰ C (dec.) Weight.

C ₁₀ H NO. HJ

ber .:

found :

Example 9

N- (3-chlorophenyl) -N '- (2-imidazolidinylidene) urea 30

According to Example 8, 153.57 g (1.0 mol) of m-chlorophenyl isocyanate are obtained added to a warm solution of 95.15 g (1.25 mol) of thiourea in 100 ml of dimethylformamide. The received Mixture is heated on a steam bath overnight. N- (3-chlorophenyl) thioimidodicarboxylic acid diamide is obtained as an intermediate product in the reaction vessel. The mixture

C. 3 H 1 N J , 21 36 , 16 3 , 94 6th 6.87 38 , 21 36 , 22 , 96 , 88 38

030028/0730

ORIGINAL INSPECTED

Γ _

then becomes the complete precipitation of the desired Intermediate cooled. After filtration and washing with diethyl ether, a product with a mp of 187 bis is obtained 189 ° C (dec.). Additional crops are obtained and combined with the first crop. After recrystallization twice a purified one is obtained from methanol / water and further recrystallization from acetonitrile twice Product with a melting point of 205 to 207 ° C (decomp.).

75.0 g (0.525 mol) of methyl iodide are added to a clear acetone solution of 80.3 g (0.35 mol) of N- (I-chlorophenyD-thioimidodicarboxylic acid diamide (prepared according to the above procedure). The reaction mixture is stirred overnight the desired methyl-N'-W ~ (3-chlorophenyl) -amino_7-carbonylJ -carbamimidothioat hydriodide as a crystalline solid, melting at 182-183 ⁰ C (dec.).

37.1 g (0.1 mol) of the methyl-N'- / _ / (3-chlorophenyl) -amino _ / -carbonylj -carbamimidothioate hydroiodide prepared in this way will be 6.0 g (0.1 mol) of ethylenediamine in 100 ml of methanol were added. The resulting mixture becomes 5 Heated under reflux for hours. The reaction mixture is then evaporated to dryness under reduced pressure and diluted with tert-butanol. N- (3-chlorophe-

nyl) -N '- (i; -imidazolidinylidene) -urea-hydroiodide as crystalline solid. The crystals are recrystallized several times from tert-butanol. A purified one is obtained Product with a temperature of 192 to 194 ° C (decomp.).

^C 10 ^H 1 , ClN ₄ O . HJ C. 7b 3 H ber .: 32, 82 3 , 29 found : 32, , 33

The following examples illustrate the preparation of

Medicines to treat hypertension.

030028/0730

Γ - 37 -

2851213

Example 10

1000 hard gelatine capsules each containing 200 mg of N- (2,6-dichlorophenyl) -N- (2-imidazolidinylidene) urea are produced from the following ingredients: 5

N- (2, b-dichlorophenyl) -N'-

(2-imidazolidinylidene) urea 200 g Starch 250 g

Lactose 750 g

Talc 250 g

Calcium stearate 10 g

A uniform mixture of the above-mentioned ingredients is produced and filled into two-part hard gelatine capsules. * ^S the case of oral administration, the capsules at hyper-intensive patients cause a decrease in blood pressure.

Example 11

According to Example 10, using 325 g of N- (2,6-dimethylphenyl) -N ^f - (2-imidazolidinylidene) urea capsules with an active ingredient content of 325 eg each are produced.

Example 12

1000 compressed tablets each containing 500 mg of H- (2-imidazolidinylidene) -N - (2-methoxyphenyl) urea are produced from the ingredients listed below:

N- (2-imidazolidinylidene) -N -

(2-methoxyphenyl) urine peat strength

calcium dibasic phosphate. (containing water)
Calcium stearate

500 , 5 G 750 G 5000 G 2 G

030028/0730

- 3 »- 2851213

The finely powdered ingredients are mixed thoroughly and granulated with 10 percent starch paste. The granules are dried and made into tablets using starch as a disintegrant and calcium stearate as a lubricant.

5 tablets pressed.

Example 13

According to Example 12 tablets are made using N- (2,6-Dibromophenyl) -N- (2-imidazolidinylidene) urea manufactured as an active ingredient.

Example 14

According to Example 10, gelatin capsules are used of N- (3-chlorophenyl) -N'-C2-imidazolidinylidene) urea manufactured as an active ingredient.

The following examples illustrate the manufacture of medicaments for the treatment of intestinal disorders.

²⁰ Example 15

The ingredients listed below are used to make 1000 hard gelatin capsules, each containing 200 mg N- (2,6-dichlorophenyl) -N- (2-imidazolidinylidene) urea

manufactured:
25th

H- (2,6-dichlorophenyl) -N ¹ - (2-

imidazolidinyllden) urea 200 g

Starch 250 g

Lactose 750 g

Talc 250 g

Calcium stearate 10 g

The ingredients become an even mixture processed and put into two-part hard gelatine capsules

fills. The capsules are suitable for oral administration

030028/0730

-39-: ■ ""

to patients with functional bowel disorders -

fr

Example 16

According to Example 15, gelatin capsules are made with a content of MOO mg each of N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea manufactured as an active ingredient.

Example 17

According to Example 16, gelatin capsules are made with a content made of N- (2-ethyl-6-methyl-N '- (2-imidazolidinylidene) urea as the active ingredient.

Example 18

Gelatin capsules containing N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea are made according to Example 16 manufactured as an active ingredient.

Example 19

The ingredients listed below are used to produce 1000 compressed tablets, each containing 500 mg N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea manufactured:

N- (2-chloro-6-methylphenyl) -N'-

(2-imidazolidinylidene) urea

strength

calcium dibasic phosphate

(containing water)

Calcium stearate
30th

The finely powdered ingredients are mixed thoroughly and granulated with 10 percent starch paste. That Granules are dried and pressed into tablets, with starch as a disintegrant and calcium stearate as a lubricant

medium can be used.

500 5 G 750 G 5000 G 2, G

030028/0730

Claims (12)

VOSSIUS · VOSSIUS TAUCHNER HEUNEMANN RAUH PATENT LAWYERS SIEBERTSTRASSE 4 SOOO MUNICH β PHONE: (Οββ) 47 4O7B CABLE) BtNZOlPATENT MÖNCHEN · TELEX B-Si 4 »ä VOPAT D 5 ET: p 444 19 December 1979 Case: MM 339/345 McNEILAB, INC. Fort Washington, PA, V.St.A. 10 "Use of N-Aryl-N '- (2-imidazolidinylidene) ureas. * Sur treatment of hypertension and intestinal Disturbances " Priority: "December 22, 1978, V.St.A., No. 972 579 December 22, 1978, V.St.A., No. 972 580 Claims 25 1 '· Use of N-aryl-N' - (2-imidazolidinylidene) ureas of the following general formula and their pharmacologically acceptable salts for the treatment of hypertension and intestinal disorders, 30 H ₀ >. N-C-NH-Ar 030028/0730 in which Ar is a phenyl radical, which optionally can have up to 3 identical or different substituents, with halogen atoms and 1 or Radicals containing 2 carbon atoms, which may be attached to the phenyl radical via a non-basic heteroatom are bound to come into question, with the proviso that for the treatment of intestinal disorders Ar on a at least in the 2- and 6-positions by halogen atoms or sub- 10 substituted phenyl is restricted. 2. Embodiment according to claim 1, characterized in that to lower the arterial pressure in patients with hypertension about 5 to 500 mg per unit dose a urea of the general formula below or a pharmacologically acceptable salt thereof administered 20th in which the radicals R independently of one another are chlorine or bromine atoms or methyl, xthyl or methoxy groups and η is an integer with a value from 0 to 3 is. 3. Embodiment according to claim 1, characterized in that N- (2,6-dichlorophenyl) -N ^l - (2-imidazolidinylidene) urea is used. 4. Embodiment according to claim 1, characterized in that N- (2,6-dimethylphenyl) -N »- (2-imidazolidinylidene) · urea used. 030028/0730 5. Embodiment according to claim 2, characterized in that N- (2-imidazolidinylidene) -N ^l - (2-methoxyphenyl) urea is used. 6. Embodiment according to claim 1, characterized in that N- (2,6-dibromophenyl) -N ^l - (2-imidazolidinylidene) urea is used. 7. Embodiment according to claim 1, characterized in that one for the treatment of complaints due to Then, for irritation and for the treatment of functional intestinal disorders, 5 to 500 mg per unit dose of a urea of the following general formula or a salt thereof are administered to a patient 15th Il
• NC-NH- * in which X and Y are methyl or ethyl groups or chlorine or bromine atoms. 8. Embodiment according to claim 7, characterized in that N- (2-chloro-6-methylphenyl) -N • - ^ - imidazolidinylidene) urea is used. 9. Medicaments for the treatment of hypertension and intestinal disorders, characterized by a content of a compound of the following general formula or a salt thereof as an active ingredient together with a pharmacologically acceptable carrier ^ K ϊ -Ar • N-C-HH-J 030028/0730 in which Ar is a phenyl group which may aufwei sen optionally up to 3 identical or different substituents, atoms as substituents halogen atoms and 1 or 2 carbon-containing residues that nylrest optionally via a non-basic heteroatom to the Phe are attached, come into question, with the proviso that for the treatment of intestinal disorders at least Ar a gene in the 2- and 6-position by halogen atoms or by the abovementioned kohlenstoffhalti-W substituted phenyl radicals is limited. 10. Medicament according to claim 9 for the treatment of hypertension, characterized by a content of about 5 up to 500 mg of a urea of the formula given below or a pharmacologically acceptable salt of which as an active ingredient together with a pharmacologically acceptable carrier 20th in which the radicals R independently of one another are chlorine or bromine atoms or methyl, ethyl or methoxy groups and η is an integer from 0 to 3. 30th 11. Medicament according to claim 9, characterized by a content of N- (2,6-dichlorophenyl) -N ^f - (2-imidazolidinylidene) urea. "G 12. Medicament according to claim 9, characterized by a content of N- ^ 2,) -Dibromphenyj ) N '- (2-imidazolidinylidene) urea. ü 3 0 0 2 3 / 13- Medicament according to claim 10, characterized by a content of N- (2-imidazolidinylidene) -N ^l - (2-methoxyphenyl) urea. 14. Medicament according to claim 10, characterized by a content of N- (2-chlorophenyl-N ^l - (2 ~ imidazolidinylidene) urea. 15. Medicaments for the treatment of intestinal disorders, characterized by a content of about 5 to 500 mg per unit dose of a urea of the formula below or a pharmacologically acceptable salt of that in which X and Y are methyl or ethyl groups or chlorine or bromine atoms. 16. Medicament according to claim 15, characterized by a content of N- (2-chloro-6-methylphenyl) -N ^l - (2-imidazolidinylidene) urea. Compounds of the general formula S ³⁰ HO 030028/0730 in which R ₁ and R ₂ each denote halogen atoms, lower alkoxy or lower alkyl radicals , with the proviso that R ₁ and Rp are not simultaneously lower alkyl radicals. 18. N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea. 19. Process for the preparation of the compounds according to claim 17, characterized in that 2-iminoimidazoli- din with a compound of the general formula reacted in an appropriate solvent. 20. The method according to claim 19, characterized in that for the preparation of N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea 2-iminoimidazolidine is reacted with 2,6-dichlorophenyl isocyanate. 030028/0730