CH647236A5 - N-ARYL-N '- (2-IMIDAZOLIDINYLIDES) UREAS AND MEDICINES FOR THE TREATMENT OF HYPERTONIA AND INTESTINAL DISORDERS. - Google Patents

Description

The invention relates to new N-aryl-N '- (2-imidazolidinyli-den) ureas and medicaments which are suitable for the treatment of hypertension and intestinal disorders and, in addition to the new compounds, also known N-aryl-N' - (2- 30 -imidazolidinylidene) ureas contain.

Irritable bowel syndrome is a functional disorder that mainly manifests itself 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 to intestinal gas caused by intestinal gas and / or fecal matter. There is a need for treatment methods that can alleviate the 40 associated complaints.

Furthermore, there is still a need for highly effective drugs with an antihypertensive effect.

Certain imidazolidine and hexahydropyrimidine ureas are known from US Pat. No. 3,168,520 as stabilizers for 45 dyes. In particular, 2-phenylcarbiliminoimidazolidine is described in this publication. This compound is N- (2-imidazolidinylidene) -N'-phe-nylurea. In this publication, however, there is no reference to the use of these imidazolidine and hexa-50 hydropyrimidine ureas as pharmacologically active substances.

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. Amidine ureas are known from US Pat. Nos. 3,539,616 and 3,784,582, in which one urea nitrogen atom is substituted with an aryl group and the other with an unsubstituted amidine group. US Pat. No. 4,058,557 also relates to 60 (albeit further from the subject of the application) amidine ureas in which an amidine nitrogen atom must be bound to an oxygen atom. None of the above-mentioned documents shows an imidazolidine substituent on a urea nitrogen atom. Furthermore, there is no indication of an antihypertensive effect in any of these publications.

G.H. Douglas and co-workers. report in Arz. Forsch./ Drag Res., Vol. 28 (II) (1978), p. 1480 on the study

3rd

647236

of many aryl-substituted amidine ureas for anti-motility and anti-secretion activity. The compounds examined also include N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea and N- (2,6-dimethylphenyl) -N' - (l-methyl-2 -imidazolidinylidene) urea. However, it is not apparent from this publication that the two aforementioned compounds have anti-toxicity activity. Furthermore, there is no obstacle to any other pharmacological activity of these compounds.

The new compounds have the following formula

H

R,

(> "-

II

C.

NK

i -? o>

N H

* 2

wherein and R;, each represent halogen atoms, alkoxy or alkyl radicals having 1 or 2 carbon atoms, with the proviso that Ri and R2 are not simultaneously alkyl radicals.

The new compounds can also be present as pharmacologically acceptable salts thereof. N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea is a preferred compound according to the invention.

The drugs for the treatment of hypertension and intestinal disorders are characterized in that they contain at least one compound of the following general formula as active ingredient

H

Q>

N-Ü-NH-Ar

H

in which Ar is a phenyl radical which may have up to 3 identical or different substituents, where halogen atoms and radicals containing 1 or 2 carbon atoms, which are optionally bonded to the phenyl radical via a non-basic heteroatom, are suitable, with the proviso that for the treatment of intestinal disorders Ar is limited to a phenyl radical substituted at least in the 2 and 6 positions by halogen atoms or by the carbon-containing radicals mentioned, or a pharmacologically acceptable salt thereof.

Preferred substituents of the phenyl ring are the methyl and ethyl group, the methoxy and ethoxy group, the trifluoromethyl, methylthio, methylsulfonyl, methylsulfonyl and cyano group.

Preferred drugs are suitable for the treatment of hypertension and they are characterized by a content of 5 to 500 mg of a urea of the formula given below or a pharmacologically acceptable salt thereof as an active ingredient together with a pharmacologically acceptable carrier

H

Q. n-LH- ^ T1

n

(i ')

in which the radicals R independently of one another are chlorine or bromine atoms or methyl, ethyl or methoxy groups and n is 0 or an integer with a value from 1 to 3.

Further preferred medicaments for the treatment of intestinal disorders are characterized by a content of 5 to 500 mg per dose unit of a urea of the formula below or a pharmacologically acceptable salt thereof

(Ia)

(I ")

in which X and Y are methyl or ethyl groups or chlorine or 2o bromine atoms.

Pharmacologically acceptable salts of the abovementioned compounds are, for example, hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, p-toluenesulfonates, benzenesulfonates, malates, tartrates, fumarates, citrates, 25 pamoates, maleates, malonates, succinates, oxalates, methosulfates , Methanesulfonates and 2-napsilates (2-naphthalenesulfonates).

The pharmacologically valuable N-aryl-N '- (2-imidazolodinylidene) ureas can be prepared essentially after 2 processes. The most expedient is the reaction of 2-iminoimidazoline of the formula II with an aryl isocyanate of the general formula III according to the following reaction equation.

(I)

H

O

40

(Ii)

NH + OON-Ar

(Iii)

The 2-iminoimidazoline can, as explained below, be prepared 45 by conventional methods and is usually used as a salt with an acid of the general formula IIa

K -N

O

I NH * acid

(Ha)

• N 'H

55 stored.

To carry out this process, 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 thoroughly stirred with 2 molar equivalents of 60 percent 50 percent aqueous sodium hydroxide solution. Anhydrous sodium sulfate can then be added to remove excess water. The biphasic mixture obtained in this way is preferably brought into contact with a corresponding aryl isocyanate 65, whereby the desired N-aryl-N '- imidazolidinylidene urea is formed.

A solution of the aryl isocyanate in tetra is preferably used for the reaction of the aryl isocyanate with the 2-imidazolidine

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Hydrofuran added in portions to the biphasic mixture with stirring at temperatures of about 20 to 30 ° C. The mixture is then usually stirred for a few hours and, if appropriate, overnight. The N-aryl-N'-imidazolidinylidene urea obtained in this way can be obtained and is optionally converted into a salt with an acid. It can be cleaned using standard procedures.

The free base can also be obtained by another method by contacting 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 during the addition is generally 0 to 30 ° C. Nitrogen or argon are expediently used to form the inert atmosphere.

For the aforesaid reaction, a solution of the salt of 2-iminoimidazolidine is preferably added dropwise with stirring to a cooled solution of lithium hydride in an anhydrous solvent under a nitrogen atmosphere, the temperature being kept in the range from 0 to 5 ° C. After the addition has ended, stirring is preferably continued, the mixture being allowed to gradually warm to room temperature. In this way you get the free base. The reaction between the 2-iminoimide azolidine and the aryl isocyanate can be carried out by adding a solution of the aryl isocyanate dropwise with stirring and cooling to the mixture containing the free base under an inert atmosphere. The mixture is generally allowed to warm gradually to room temperature with stirring. The temperature can then be raised to about 30 to 110 ° C and preferably to 65 to 110 ° C to achieve optimum yields. 15 gives the desired N-aryl-N '- (2-imidazolidinylidene) urea. When the reaction is carried out at ambient temperature, the mixture is generally stirred for several hours or overnight. When the reaction is carried out at elevated temperatures, a reaction time of about 2 hours is usually sufficient.

The reaction scheme below illustrates a second, less preferred process for the preparation of the N-aryl - N '- (2-imidazolidinylidene) ureas.

s

Ar-N-c-o ♦ b2h-c-nh2 lsV;>

medium

(iii)

s I

0

II

H2N-C-NH-C-NH-Ar ch j 3

sh

, n-i

U-

NH-Ar

(iv)

(v)

ym2

ch, (vi)

I 2

ch-

Alcohol> »->, 1,

A

55 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 can be obtained, which is then conveniently combined with methyl iodide to form a methyl N '- [(arylamino) -60-carbonyl ] carbamidothioate of the general formula V is implemented. The latter product can then be reacted with an appropriately substituted ethylenediamine of the general formula VI to give N-aryl-N '- (2-imidazolidinylidene!) Urea hydroiodide of the general formula I. 65 This salt can be converted to the free base in a conventional manner. However, the above-mentioned reaction sequence is not suitable for the production of ureas in which a 2,6-disubstituted phenyl radical is present as the aryl radical.

5

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The first step of the aforementioned method can be carried out by modifying the method of Lakra et al., (J. Am. Chem. Soc., Vol. 51 (1929), p. 2220).

A corresponding aryl isocyanate of the general formula III is preferably reacted with thiourea to form an N-arylthioimidocarboxylic acid diamide of the general formula IV, hereinafter referred to briefly as the “thiobiuret compound”. Essentially equimolar amounts of the reactants and preferably a small excess of the thio-urea can be used for this reaction. The reaction temperature can range from about 80 to 120 ° C. The reaction is preferably carried out in a solvent. Examples of corresponding solvents are dimethylformamide and dimethyl sulfoxide.

The reaction is preferably carried out by heating the isocyanate and the thiourea to the steam bath temperature for about 2 to 12 hours. The thiobiuret compound of the general formula IV is formed in the reaction mixture. The mixture can then be diluted with water and cooled to facilitate crystallization of the thiobiuret compound. The product is generally separated from the reaction mixture and purified by customary methods.

In the second reaction stage, the N-aryl-thio-biuret compound can be reacted with an S-methylating agent. A methyl N '- [(arylamino) -carbonyl] carbamidothioate of the general formula V is obtained. The latter compound is referred to below as the “thioate compound”. Substantially equimolar amounts of the reactants and in particular a small excess of methylating agent are preferably 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 corresponding solvents are acetone, methanol, ethanol and isopropanol. The reaction temperature can be in the range from ambient temperature to the reflux temperature, with an implementation at ambient temperature being preferred.

The reaction is expediently carried out by mixing the thiobiuret compound and the methyl iodide in methanol and reacting for several hours at room temperature. The hydroiodide formed in the reaction mixture can be obtained and, if necessary, purified by customary processes.

In the third stage, the thioate hydroiodide of the general formula V can be reacted with ethylenediamine of the formula VI, which gives the desired N-aryl-N '- imidazolidinylidene-urea hydroiodide. Essentially equimolar amounts of the reactants are usually used for this. The reaction is preferably carried out in methanol or other lower alkanols, methanol being particularly preferred.

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

The salt can be converted into the free base. If a different salt is intended, the free base can be reacted with another acid to form the desired salt. Usual methods can be used for this. For example, to produce the free base, a salt is dissolved in the smallest possible amount of a lower alkanol, such as methanol or ethanol. The solution is preferably heated with an organic base such as triethylamine and then cooled. The free base 5 is obtained as a crystalline solid. To convert the free base into a salt with an acid, the base can be heated in a corresponding manner with an alcoholic solution of an acid. After cooling, the desired salt is obtained.

io The pharmacological activity of the compounds used as active ingredient is explained in more detail below.

Treatment of hypertension

The N-aryl-N '- (2-imidazolidinylidene) ureas provide relief at high pressure without increasing the heart rate. Such active substances with an antihypertensive effect, which do not increase the heart rate, but rather leave it unchanged or lower, are particularly suitable for the treatment of patients with hypertension. The above-mentioned properties can be determined on rodents in the anti-hypertension test and on dogs using a homeopathic assessment.

Anti-hypertension test in rodents 25 This test provides information about the effects on arterial pressure and heart rate. The arterial pressure of spontaneously hypertensive rats or of rats which have been made hypertensive by injection of deoxycorticosterome acetate and by administration of a drinking water with a Ge-30 content of 2 percent sodium chloride is determined directly by means of an aortic cannula. The rats are anesthetized by inhalation of an anesthetic (methoxyflurane or ether). The left carotid artery is isolated and cannulated. The tip of the cannula is advanced into the 35 aorta. The cannula itself is placed outwards behind the neck at the level of the shoulder blade. After recovery from the anesthetic, they are kept without restrictions. The arterial cannula is connected to a pressure transducer, which is connected to a recording device. The heart rate is determined from the recording of the arterial pressure. Animals with a pressure of more 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.). Arterial pressure and heart rate are observed for at least 4 hours. A test compound is considered an anti-hypertensive agent if the average arterial pressure (MAP) drops by more than 19 mmHg. Each animal serves as a control animal.

Two rats are used for each connection. The results for various N-aryl-N '- (2-imidazolidin-ylidene) haro substances are summarized in Table I.

55 Hemodynamic evaluation in dogs

This experiment is conducted to determine the effect of the compounds on the cardiovascular and autonomic nervous systems in normal anesthetized animals. Bastard dogs are anesthetized with 20 mg / kg body weight, 60 thiopental sodium and 60 mg / kg chlorolose. If necessary, an additional 60 mg / kg - chlorolose is used to maintain the anesthesia. An inflatable cuffed endotracheal tube is inserted to maintain an undisturbed airway. The animal is ventilated with a ventilation pump.

A femoral artery and vein are catheterized to record arterial pressure and intravenous injections. To carry out a bilateral car

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6

Both carotid arteries are isolated in isocclusion. The vagus nerve is stimulated at the peripheral ends for 10 seconds with 5 V at 20 pulses per second each with a duration of 2 milliseconds in order to achieve cardiac arrest. The electrocardiogram is recorded via limb lead II.

Cardiovascular control reactions are obtained according to the following pharmacological measures: 1.0 [ig / kg body weight i.v. 1-epinephrine, carotid occlusion, 10 | xg / kg IV Dimethylphenylpiperazinium iodide (DMPP), peripheral vagus stimulation, 10 [ig / kg i.v. Acetylcholine and 2 ng / kg IV Angiotensin. These control reactions are called twice. The compound to be examined is then administered in a dose of 5 mg / kg body weight i.v. injected using bolus injections within a period of about 1 minute. If there is no change with regard to arterial pressure, heart rate or ECG (limb lead II), a further 5 mg / kg of the compound to be examined i.v. administered. The influence of the compound to be examined on the electrocardiogram, arterial pressure and heart rate is determined. Another 10 series of hemodynamic reactions are performed 10 minutes after administration of the compound to be examined.

A dog is set up for each connection 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'-5 - (2-imidazolidinylidene) ureas and their salts not only have a beneficial antihypertensive effect, but also prove beneficial in the relationship that the heart rate is maintained or is lowered. These properties are used in the application of the described active compounds.

For the treatment of hypertension or for the relief of high blood pressure, a therapeutically effective amount of an N-aryl-N '- (2-imidazolidinylidene) urea of the general formula I or a pharmacologically acceptable salt thereof can be administered as an active ingredient. The active ingredients can be administered with or without a carrier in the amounts indicated below. They are preferably administered in the form of drugs in the form of unit doses, as explained below.

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

TABLE I

Determination of the antihypertensive effect and the influence on the heart rate

Connection of spontaneously hypertensive (SH) rats

H

O

> = N-O-WH-Ar. HX

Ar

HX

dose

(mg / kg i.p.)

Maximum decrease in MAP (mmHg)

Effect on the

Heart rate

(Beats / min)

hemodynamic dog test maximum decrease in heartbeat at doses of 10 mg / kg IV (Beats / min)

0

-

30th

72

+78

no change (kV)

0

-

10 p.o.

39

-108

-

0

-

100 p.o.

30th

+ '30

-

3-C10

HI

30th

63

-42

-30

2,6-ci2er

HCl

20-200 (p.o.)

39-96

-39 to -108

-54

2,6- (CH3) 20

HCl. H HaO

30th

> 19th

1*

-60

2-Cl, 6-CH30 '

HCl

30th

> 19th

1

-42

2,6-BrgS

HCl

30th

> 19th

1

-54

2C2H3.6-CH30 "

% Fumarate

30th

> 19th

1

-42

4-CH3J0r

HCl

30th

> 19 **

kV

kV (5 mg / kg I.V.)

2-OCH

HCl

30th

95

-108 ***

+30 ***

2-OCHjJ0f

HCl

10 p.o.

23

-84

-

2-OCHßf

HCl

100 p.o.

90

-84

-

2-C10

HCl

30th

> 19th

-108

kV

* Decrease!

** half the number of rats

*** The strongly slowing effect in spontaneously hypertensive rats is considered to be more meaningful

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Treatment of intestinal disorders

The active N-aryl-N '- (2-imidazolidinylidene) ureas relieve the symptoms that go hand in hand with functional intestinal disorders known as irritable bowel syndrome. These disorders are manifested by abdominal pain, diarrhea, constipation and similar symptoms and are due to hypersensitivity to intestinal gas caused by intestinal gas and / or fecal matter.

The effectiveness of the described compounds against these complaints is determined by means of a test in which a glass bead is inserted into the rectum. The time between insertion and ejection of the pearl is determined. Compounds that reduce sensitivity to bloating of the colon wall delay the pearl's expulsion.

The test is carried out on male albino mice weighing 18 to 25 g body weight. Groups of 5 mice are used for the individual doses of the compounds. The initially selected dose is 50 mg / kg body weight for all compounds. It is administered orally in a volume of 0.1 ml per 10 g body weight. The control groups receive only the carrier, i.e. a 0.5 percent methocell solution used for both oral and intraperitoneal administration. The mice were given no food 1 hour before the experiment. The drugs to be examined are given 1 hour before the glass beads are inserted. After the pretreatment has ended, the mice are removed and held in one hand, with the abdomen facing the examiner. A 3 mm diameter glass bead is placed on the rectum and pressed into the rectum with the thumb and index finger. Then the glass bead with a glass rod of 3 mm diameter, which has been lubricated with 0.5% methocell solution to facilitate the introduction, is inserted 2 cm deep into the rectum with a slight twisting motion. The treatment of the mice in a group is timed, with time 0 being the introduction of the pearl in the last mouse. The time that elapses before the pearls are ejected is determined. The following evaluation is carried out: 0 = ejection time from 0 to 5 minutes; 1 = ejection time of 5 to 10 minutes; 2 = ejection time from 10 to 20 minutes, 3 = ejection time from 20 to 40 minutes; and 4 = ejection time of more than 40 minutes. Mice that have not yet ejected their pearl after 40 minutes are examined for the presence of a perforation. Mice whose colon is perforated are excluded. The activity index for the drug to be examined is the quotient of the sum of these values and the number of mice or pearls. The ED50 values are determined by regression lines using the least squares method. The ED50 value is set as the dose that produces an activity index of 2.

The results of these investigations with intraperitoneal and oral administration of N-aryl-N '- (2-imidazolodinylidene) ureas are summarized in Table II.

TABLE II

connection

B

TN »N-1-NH-Ar

TJ ED50 (mg / kg)

H

mtrape-

Ar HX ritoneal Per Os

2,6-diCl-ef

HCl

7

13.7

2,6-di (CH3) -j0f

HCl. y% HjO

12

16

2-Cl, 6-CHs- £ T

HCl

8th

35

2,6-diBr- ^ r

HCl

9

38

2-C2H5, 6-CH3-j0f

Ys Fumarate

43

121

The above values show the beneficial effects of the active compounds in reducing the abnormal sensitivity to intestinal gas. This property is used when using the compounds in medicinal products.

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

For the treatment of the aforementioned complaints, about 5 to about 500 mg of an N-aryl - N '- (2-imidazolidinylidene) urea can be 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 substance are preferably in the range from about 0.50 to 50 mg / kg and preferably at least 3 mg / kg body weight.

Pharmaceuticals can be produced by mixing the active ingredient with a pharmacologically acceptable carrier by conventional methods. Depending on the desired route of administration, for example orally or parenterally, a wide variety of carriers are possible. Examples of carriers and additives for liquid orally administrable preparations, such as suspensions, elixirs and solutions, are water, glycols, oils, alcohols, flavors, preservatives and colorants. Corresponding examples of solid, orally administrable preparations, such as powders, capsules and tablets, are starch, sugar, diluents, granulating agents, lubricants, binders and disintegrants. Because of their ease of administration, tablets and capsules are preferred for oral dosage units. If necessary, tablets can be provided with sugar or an enteric coating by conventional methods. Parenterally administrable drugs usually contain sterile water as a carrier, but other constituents, for example solubilizers or preservatives, may also be present. Injectable suspensions containing appropriate liquid carriers, suspending agents and the like can also be made. The exit

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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“Dose unit” refers to individual pharmaceutical units that serve as unit doses, the individual units containing a predetermined amount of active ingredient, which is calculated in such a way that the desired therapeutic effect results in connection with the required pharmacological carrier. Examples include tablets, capsules, pills, powder packets, wafers, teaspoons and tablespoons, as well as multiple packs thereof. A unit dose generally contains from about 5 to about 500 mg of active ingredient.

The examples illustrate the invention.

Production of the starting material

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

213 g (1.5 mol) of methyl iodide are added with stirring to a suspension of 153.24 g (1.5 mol) of ethylene thiourea in 300 ml of methanol within 1 hour. In order to achieve complete formation of S-methyl-ethylene-thiourea, the mixture is stirred for another 1 hour. Anhydrous ammonia is then added, after which a reaction with the formation of 2-iminoimidazolino-din-hydroiodide and methyl mercaptan occurs as a by-product. The mixture is stirred for a total of about 26 hours with the batchwise addition of ammonia. The mixture is then concentrated with the simultaneous addition of isopropanol to replace the evaporated methanol. The mixture is then cooled and diethyl ether is added. This gives 2-imino-imidazolidine hydroiodide as a crystalline solid which, after recrystallization from methanol / tert-butanol, has a melting point of 152 ° to 154 ° C.

C3H, N3. HJ:

calculated: C 16.92 H 3.79 found: C 16.85 H 3.82

example 1

N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea - hydrochloride h ci r "\

H

0

II

N-C-NH-

hc1

A suspension of 2.13 g (0.01 mol) of 2-imidazolidine hydroiodide in 50 ml of anhydrous dimethylformamide is mixed with 0.8 g (0.01 mol) of aqueous, 50% sodium hydroxide solution under nitrogen, whereby 2-iminoimide azolidine is formed in the form of the free base and sodium iodide. Then 1 g of anhydrous sodium sulfate is added and the mixture is stirred for a further% hour. A solution of 0.94 g (0.005 mol) of 2,6-dichlorophenyl isocyanate in 20 ml of tetrahydrofuran is then added dropwise to the mixture within 2 hours. The mixture is stirred at room temperature overnight. N- (2,6-dichlorophenyl) -N '- (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 saline, then dried over anhydrous potassium carbonate and treated with hydrogen chloride until a pH <3 is reached. The solvent and excess hydrogen chloride are removed under reduced pressure. The residue is recrystallized from methanol / diethyl ether. This gives N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride with a melting point of 210 to 212 ° C., which is formed under the formation of a new solid with a melting point of 239 ° C. decomposes.

Example 2

N- (2-chloro-6-methylphenyl) -N '~ (2-imidazolidinylidene) urea and the corresponding hydrochloride

10th

A solution of 10.65 g (0.05 mol) of 2-iminoimidazolidine hydroiodide in dimethylformamide is added dropwise with stirring within 15 minutes to a suspension of 397.5 mg (0.05 mol) of lithium hydride in 15 which has been cooled to 5 ° C. 50 ml of anhydrous dimethylformamide were added under nitrogen, after which hydrogen evolution can be observed. While continuing to stir, the mixture is allowed to gradually warm to room temperature. The reaction mixture is then cooled to 0 to 5 ° C. and. 20 dropwise within 2 hours with a solution of 5.0 g (0.03 mol) of 2-chloro-6-methylphenyl isocyanate in 25 ml of anhydrous dimethylformamide. When the addition is complete, the mixture is allowed to gradually warm to room temperature, stirring being continued under nitrogen. 25 After stirring overnight, the desired N- (2-chloro-6-methy] phenyl) -N '- (2-imidazolidinylidene) urea is obtained, which remains in solution. The product is obtained from the reaction mixture in the following manner: (a) addition of 300 ml of ice water with stirring ^ (b) lowering the pH 30 below 2 by adding 10 percent aqueous hydrochloric acid with precipitation of an acid-insoluble material, (c) Filter, (d) make the filtrate alkaline by adding solid potassium carbonate to pH 8 to 9 and (e) saturate the solution with solid sodium chloride, the desired 35 N- (2-chloro-6-methylphenyl) - N '- (2-imidazolidin-ylidene) urea (free base) precipitates in the form of a white solid. After thorough washing with water, the product has a melting point of 169 to 171 ° C.

The above product is dissolved in 30 ml of methanol 40 and brought to a pH below 3 by adding hydrogen chloride in methanol. After the addition of diethyl ether, N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidin-ylidene) urea hydrochloride precipitates. This product is obtained and successively recrystallized from 2-propanol and methanol / 45 diethyl ether. A purified product of F. 209 to 211 ° C. is obtained, which decomposes to form a new solid of F. 270 ° C. (dec.).

CUH13C1N40. HCl:

calculated: C 45.69 H 4.88 N 19.37 thus found: C 45.59 H 4.93 N 19.35

Example 3

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

55

According to Example 2, a solution of 12.0 g (0.0563 mol) of 2-iminoimidazolidine hydroiodide in 50 ml of anhydrous dimethylformamide is added dropwise with cooling and under nitrogen to a suspension of 447 mg (0.0563 mol) of 60 lithium hydride in 50 ml given anhydrous dimethylformamide. After the addition has ended, the mixture is allowed to warm to room temperature within about% 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 65 anhydrous dimethylformamide is added dropwise over the course of 2 hours, the cooling being maintained at the temperature range indicated . The mixture is then allowed to warm to room temperature and stirred

9

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Night under nitrogen. The desired N- (2,6-dibromophenyl) -N '- (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 to a pH below 3 with 10% hydrochloric acid, filtering to remove impurities, saturating the filtrate with solid sodium chloride and adding potassium carbonate sets the pH value from 8 to 9. It precipitates N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea as a white solid of mp 185 to 190 ° C (dec.).

The above product is suspended in 40 ml of methanol and acidified to a pH below 2 with a solution of hydrogen chloride in methanol. Diethyl ether is then added. A precipitate of N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) -urea - hydrochloride is formed in the form of a white solid with a melting point of 200 to 202 ° C. (dec.). After recrystallization twice from methanol / 2-propanol / diethyl ether, a purified product of F. 215 to 217 ° C is obtained, which decomposes to a solid of F. 255 ° C (decomp.).

C10H10N4Br2O. HCl:

calculated: C 30.14 H 2.78 N 14.06 found: C 30.12 H 2.81 N 14.04

Example 4

Similarly, N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) urea hydrochloride, mp 197-199.5 ° C, is prepared by using 2-iminoimidazolidine (made from 2-iminoimidazolidine hydroiodide and lithium hydride) and 2-methoxyphenyl isocyanate at about 5 to 10 ° C to form N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) - urea. The latter product is reacted with a solution of hydrogen chloride in methanol. After recrystallization from methanol / 2-propanol once and subsequent recrystallization from methanol / diethyl ether twice, the compound mentioned at the outset is obtained. CuH14NA • HCl:

calculated: C 48.80 H 5.58 N 20.70 found: C 48.75 H 5.61 N 20.71

Example 5

N- (2-ethyl-6-methylphenyl) -N '- (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 mg (0.075 mol) of lithium hydride in 30 ml of dimethylformamide. When the addition is complete, the mixture is allowed to warm to room temperature to complete the reaction. The mixture is then cooled again and a solution of 8.1 g (0.05 mol) of 2-ethyl-6-methylphenyl isocyanate in 25 ml of anhydrous dimethylformamide is added dropwise over the course of 2 hours. The resulting mixture is then stirred overnight, allowing the temperature to rise to ambient. N- (2-ethyl-6-methylphenyl) -N '- (2-imidazolidinylidene) urea is obtained. The base is obtained in the manner described in the examples described above and recrystallized from methanol / water. A purified base of 185 ° to 187 ° C. is obtained.

A solution of 4.32 g (0.0175 mol) of the above base in 35 ml of hot isopropanol is mixed with a solution of 2.04 g (0.0175 mol) of fumaric acid in 35 ml of hot isopropanol. The solution obtained is allowed to cool, N- (2-ethyl-6-methylphenyl) -N '- (2-imidazolidinylidene) urea fumarate crystallizing. After washing with isopropanol and then with diethyl ether, this salt has an F. of 180 ° C. (dec.). Subsequent recrystallization processes from methanol / isopropanol, methanol / diethyl ether and methanol give no salt with a repro-5 producible sharp melting point. From the Elementarana; lysis shows that the salt formed contains 3 moles of base per 2 moles of fumaric acid.

(C13H18N40) 3. (C4H404) 2:

Calculated: C 58.13 H 6.44 N 17.31, found: C 58.03 H 6.57 N 17.59

Example 6

Similarly, N- (2-chlorophenyl) -N '- (2-imide-azolidinylidene) urea hydrochloride of mp 187 to 189 ° C i5 is prepared by using 2-iminoimidazoline (made from 2-iminoimidazoline hydroiodide and lithium hydride in dimethylformamide at about 20 ° C) and 2-chlorophenyl isocyanate overnight at about 20 to 30 ° C. After 15 minutes of heating to 100 ° C. on a steam bath, 20 N- (2-chlorophenyl) -N '- (2-imidazolidinylidene) urea is obtained as a crystalline solid. This product is converted into the hydrochloride with a solution of hydrogen chloride in methanol.

C10HUN4OC1. HCl:

25 calculated: C 43.66 H 4.40 N 20.36

found: C 43.69 H 4.43 N 20.36

Example 7

The following compounds can be produced according to Examples 2 to 6:

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

N- (2-chloro-5-trifluoromethylphenyl) -N '- (2-imidazolidin-35 ylidene) 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 of mp 210 to 212 ° C; «N- (2,4-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride from mp 217 to 219 ° C;

N- (2,3-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride from mp 218 to 220 ° C;

N- (3,5-dichlorophenyl) -N '- (2-imidazolidinylidene) urea 45 and its hydrochloride of mp 200 to 202 ° C .;

N- (3,4-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride from mp 217 to 219 ° C;

N- (2,5-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride from mp 213 to 215 ° C; so N- (2-imidazolidinylidene) -N '- (2,4,6-trichlorophenyl) urea and its hydrochloride of F. 232 ° C, which forms a solid of F. 260 ° C (dec. ) decomposes;

N- (2-fluoro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride; 55 N- (2-imidazolidinylidene) -N '- (2-methyl-6-trifluoromethylphenyl) urea and its hydrochloride;

N- (2-imidazolidinylidene) -N '- (2-methyl-6-methylsulfonylphenyl) urea and its hydrochloride;

N- (2-cyano-6-methylphenyl) -N '- (2-imidazolidinylidene) -60-urea and its hydrochloride;

N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride;

N- (2-bromo-6-methylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride; 65 N- (2-bromo-6-ethylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride;

N- (2-chloro-6-ethylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride;

647236

10th

N- (2-bromo-6-chlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride;

N- (2-methoxy-6-methylphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride;

N- (2-methyl-6-trifhiormethylphenyl) -N '- (2-imidazolidin-ylidene) urea and its hydrochloride; and

N- (2-chloro-6-fluorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride.

Example 8

Calculated N- (2-imidazolidinylidene) -N'-phenylurea and its hydroiodide: C 58.81 H 5.92 N 27.43 found: C 58.79 H 5.92 N 27.48 After recrystallization from acetone, the hydroiodide shows an F. of 223 to 225 ° C (dec.). When used to determine the melting point at a temperature of 225 ° C, the F. is 230 ° C (dec.).

HJ:

calculated: C 36.16 H 3.94 N 16.87 J 38.21 found: C 36.22 H 3.96 N 6.88 J 38.21

CioHJ2N; jC)

H

V

H

N -

O

t -

NH -

(and HJ)

In a first reaction step, 119 g (1 mol) of phenyl isocyanate are added in one portion with stirring to a bath solution of 83.73 g (1.1 mol) of thiourea in 120 ml of anhydrous dimethylformamide. The solution obtained is heated for 3 hours. The solution is then cooled and a mixture of ice and ice water is carefully added. The vessel wall is rubbed in to initiate the crystallization of the desired intermediate N-phenylthioimidodicarboxylic acid diamide. After crystallization has started, more ice water (up to about 1 liter) is added. The crystals formed are collected, washed with water and recrystallized from methanol. 127 g of N-phenylthioimidodicarboxylic acid diamide of mp 176 ° to 180 ° C. are obtained.

In a second stage, 45.5 g (0.32 mol) of methyl iodide are added to a solution of 59.5 g (0.305 mol) of N-phenylthioimidodicarboxylic acid diamide in 300 ml of acetone. The resulting mixture is stirred at room temperature for about 2 hours. Crystals form in the reaction mixture, which are then filtered and dried. This gives methyl N '- [(phenylamino) carbonyl] carbamimido thioate hydroiodide of mp 195 to 200 ° C. An analytical sample obtained after recrystallization from methanol has the F. (190 ° C) 200 to 202 ° C (Hoover).

C4HnNaOS. HJ: calculated: found:

C 32.06 C 32.11

H 3.59 H 3.62

N 12.46 N 12.48

A methanol solution of 33.72 g (0.1 mol) of the methyl N '- [(phenylamino) carbonyl] carbamimidothioate hydroiodide obtained in this way and a methanol solution of 6.01 g (0.1 Mol) mixed ethylenediamine (about a total of 50 ml of methanol) and heated under reflux for about V / i hours. The mixture is then cooled to -20 ° C. Crystalline N- (2-imidazo-lidinylidene) -N'-phenylurea hydroiodide is obtained. Several yields are obtained. These yields are combined, purified by dissolving in methanol, filtered and evaporated. The desired hydroiodide is obtained as a residue.

The hydroiodide is converted into the free base and purified by 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 with ethanol and then cooling. N- (2-imidazolidinylidene) -N'-phenylurea of F. (181 ° C.) 182 to 183 ° C. is obtained after recrystallization from methanol.

Example 9

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

15 According to Example 8, 153.57 g (1.0 mol) of m-chlorophenyl isocyanate are added to a warm solution of 95.15 g (1.25 mol) of thiourea in 100 ml of dimethylformamide. The resulting mixture is heated on a steam bath overnight. N- (3-Chlorophenyl) -thioimidodicar-20 bonsäurediamid is obtained as an intermediate in the reaction mixture. The mixture is then cooled to complete precipitation of the desired intermediate. After filtration and washing with diethyl ether, a product of F. 187 to 189 ° C (dec.) Is obtained. Additional yields are obtained and combined with the first yield. After 2 times recrystallization from methanol / water and another 2 times recrystallization from acetonitrile, a purified product of mp 205 to 207 ° C. (dec.) Is obtained.

A clear acetone solution of 80.3 g (0.35 mol) of N- (3-30-chlorophenyl) thioimidodicarboxylic acid diamide (prepared according to the above instructions) is mixed with 75.0 g (0.525 mol) of methyl iodide. The reaction mixture is stirred overnight. The desired methyl N '- {{(3-chlorophenyl) amino] carbonyl} carbamimidothioate hydroiodide is obtained as a 35 crystalline solid of mp 182 ° to 183 ° C. (dec.).

37.1 g (0.1 mol) of the methyl N '- {[(3-chlorophenyl) amino] carbonyl} carbamimidothioate hydroiodide prepared in this way are mixed with 6.0 g (0.05 1 mol) of ethylenediamine in 100 ml of methanol. The mixture obtained is heated under reflux for 40 hours. The reaction mixture is then evaporated to dryness under reduced pressure and diluted with tert-butanol. N- (3-Chlorophenyl) -N '- (2-imidazolidinylidene) urea hydroiodide is obtained as a crystalline solid. The crystals are recrystallized more than 45 times from tert-butanol. A purified product of F. 192 to 194 ° C (dec.) Is obtained.

C10HnClN4O. HJ:

calculated: C 32.76 H 3.29 found: C 32.82 H 3.33 see below The examples below illustrate the preparation of medicaments for the treatment of hypertension.

Example 10

■ 1000 hard gelatin 55 capsules, each containing 200 mg of N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea, are produced from the following constituents:

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

-urea 200 g

60 starch 250 g

Lactose 750 g

Talcum 250 g

Calcium stearate 10 g

65 A uniform mixture of the components mentioned is produced and filled into two-part hard gelatin capsules. When administered orally, the capsules reduce blood pressure in hypertensive patients.

11

647236

Example 11

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

Example 12

1000 compressed tablets, each containing 500 mg of N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) -urea, were prepared from the ingredients listed below.

N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) -

-urea

500

G

Strength

750

g dibasic calcium phosphate (water-containing)

5000

G

Calcium stearate

2.5

G

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

Example 13

According to Example 12, tablets are produced using N- (2,6-dibromophenyl) -N '- (2-imidazolidinyIiden) urea as the active ingredient.

Example 14

According to Example 10, gelatin capsules are prepared using N- (3-chlorophenyl) -N '- (2-imidazolidinylidene) urea as the active ingredient.

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

Example 15

1000 hard gelatin capsules, each containing 200 mg of N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urine, were prepared from the ingredients listed below:

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

-urea 200 g

Starch 250 g

Lactose 750 g

Talcum 250 g

Calcium stearate 10 g

The ingredients are processed into a uniform mixture and filled into two-part hard gelatin capsules. The capsules are suitable for oral administration to patients with functional bowel disorders.

Example 16

According to Example 15, gelatin capsules containing 400 mg of N- (2,6-dibromophenyl) -N '- (2-imide-azolidinylidene) urea as active ingredient are produced.

Example 17

According to Example 16, gelatin capsules containing N- (2-ethyl-6-methyl) -N '- (2-imidazolidinylidene) urea as the active ingredient are produced.

Example 18

According to Example 16, gelatin capsules containing N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea as the active ingredient are produced.

Example 19

1000 compressed tablets, each containing 500 mg of N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea, were prepared from the ingredients listed below:

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

nylidene) urea 500 g

Starch 750 g dibasic calcium phosphate (water-containing) 5000 g

Calcium stearate 2.5 g

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

5

10th

15

20th

25th

30th

35

40

45

Claims (7)

647 236 2. N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea as a compound according to claim 1. - ^ 2) (Ia) 8. Medicament according to claim 3, characterized by a content of N- (2-chlorophenyl-N '- (2-imidazolidinyIiden) - urea. 9. Medicament according to claim 3 for the treatment of intestinal disorders, characterized by a content of 5 to 500 mg per dose unit of a urea of the formula below or a pharmacologically acceptable salt thereof H wherein R 1 and R 2 each represent halogen atoms, alkoxy or alkyl radicals having 1 or 2 carbon atoms, with the proviso that Rt and R 2 are not alkyl radicals at the same time and pharmacologically acceptable salts thereof. 2nd PATENT CLAIMS 1. Compounds of the general formula H o Rls. 3. Medicament for the treatment of hypertension and intestinal disorders, characterized in that it contains at least one compound of the following general formula as active ingredient H (I ") in which X and Y are methyl or ethyl groups or chlorine or bromine atoms. 20 10. Medicament according to claim 9, characterized by a content of N- (2-chloro-6-methylphenyl) -N '- (2-imide-azolidinylidene) urea. Q O II - N-d-NH- Ar (i) H in which Ar is a phenyl radical which may have up to 3 identical or different substituents, where halogen atoms and radicals containing 1 or 2 carbon atoms, which are optionally bonded to the phenyl radical via a non-basic heteroatom, are suitable, with the proviso that for the treatment of intestinal disorders Ar is restricted to a phenyl radical substituted at least in the 2- and 6-positions by halogen atoms or by the carbon-containing radicals mentioned, or a pharmacologically acceptable salt thereof. 4. Medicament according to claim 3 for the treatment of hypertension, characterized by a content of 5 to 500 mg of a urea of the formula given below or a pharmacologically acceptable salt thereof as an active ingredient together with a pharmacologically acceptable carrier H O II N-C-NK - ^^ n (T) H in which the radicals R independently of one another are chlorine or bromine atoms or methyl, ethyl or methoxy groups and n is 0 or an integer with a value from 1 to 3. 5. Medicament according to claim 4, characterized by a content of N- (2,6-dichlorophenyl) -N '- (2-imidazolidinyli-den) urea. 6. Medicament according to claim 4, characterized by a content of N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea. 7. Medicament according to claim 3, characterized by a content of N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) urea.