HU183013B - Process for producing pharmaceutical compositions containing n-phenyl-n-comma above-bracket-2-imidazolidinilidene-bracket closed-urea derivatives as active agents for treating high blood-pressure and irregular intestinal activity - Google Patents

Abstract

The use in the treatment of hypertension and intestinal disorders of certain N-aryl-N-N'-(2-imidazolidinylidene)ureas. Compounds of formula I:- <IMAGE> wherein Ar is optionally substituted phenyl, are prepared by known methods.

Description

FIELD OF THE INVENTION The present invention relates to novel pharmaceutical compositions for the treatment of hypotensive and intestinal disorders which contain N-phenyl-N '- (2-imidazolidinylidene) urea as an active ingredient.

Intestinal tenderness syndrome is a functional disorder characterized primarily by abdominal pain but also accompanied by other symptoms such as diarrhea or constipation. The pain associated with the syndrome is explained by the fact that the intestinal tract is highly sensitive to bloating caused by gases and / or faeces. Thus, there is a great need for medications to relieve the discomfort associated with these and similar symptoms and / or disorders leading to the syphilis.

Certain imidazolidine urea derivatives are known in the literature. Thus, U.S. Pat. No. 3,168,520 discloses imidazolidinecarbamide and hexahydropyrimidine urea derivatives. The compounds have been described as dye stabilizers. The cited patent designates a 2-phenylcarbyliminoimidazolidine, also known as N- (2-imidazolidinylidene) -N'-phenyl [urea], which is also included in the compounds of formula I of the present invention prepared by the reaction of -imidido-imidazoline and carbanyl acryl ester. However, there is no mention in the patent that imidazodine urea derivatives and hexahydropyrimidine urea derivatives are useful for medicinal purposes.

Certain curative effects have also been reported for some urea derivatives but are not within the scope of the invention. Thus, U.S. Patent 4,060,635 discloses smidino-urea derivatives. These compounds contain an aryl group on one nitrogen atom of urea and a substituted amidino group on another nitrogen atom of urea. U.S. Patent Nos. 3,539,616 and 3,784,582 disclose amldinocarbamide derivatives in which one nitrogen atom of the urea moiety is replaced by an aryl group and the other nitrogen atom is replaced by an unsubstituted amido group. U.S. Patent 4,058,557 also discloses amidino-urea derivatives, but the compounds are structurally farther away because they are characterized in that one nitrogen atom of the amidino moiety is always attached to an oxygen atom. None of the patents mentions compounds in which an imidazolidino group is attached to the nitrogen atom of the urea moiety. In addition, none of the patents cited mentions the antihypertensive effect.

The Arz. Forsch / Drug Slit. 28 (11), 1480 (1978) disclose immobilized and anti-secretory activity data for a number of aryl-substituted amidino-urea derivatives. Among others, N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea and N- (2,6-dimethylphenyl) -N' - (1-methyl-2- imidazolidinylidene) urea. These compounds are said to have no such effect, and the article does not provide any data suggesting that the compounds may be used for therapeutic purposes.

FIELD OF THE INVENTION The present invention relates to a novel pharmaceutical composition for the treatment of hypertensive and intestinal disorders which comprises as an active ingredient a N-phenyl-N ^, - (2-imidazolidinylidene) urea derivative of the formula (I) wherein A is optionally 1- With 3 halogens, 1 or 2 C 1 -C 2 alkyl groups, 1 or 2 C 1 -C 2 alkoxy groups, or 1 halogen and 1 or 2 C 1-2 alkyl groups, with the proviso that if the compound is to be used for the treatment of intestinal disorders, the phenyl group is substituted at least in the 2- and 6-positions - or a pharmaceutically acceptable acid addition salt thereof.

The pharmaceutical compositions of the present invention are useful in the treatment of hypertension, the prevention of diarrhea and other intestinal disorders, and include the compounds of formula (I) or acid addition salts together with pharmaceutically acceptable carriers.

Representative substituents for the phenyl group in formula (I) include fluorine, chlorine or bromine; methyl or ethyl; methoxy cut ethoxy group. In the compounds having the best antihypertensive activity, A represents a group of the general formula (a) wherein

R is methyl, ethyl, chloro, bromo or methoxy; ή is an integer from 0 to 3.

In the most effective compounds for treating intestinal disorders, A is a group of formula (b) wherein

X and Y are independently methyl, ethyl, chlorine or bromine.

The urea base is responsible for the activity of the chemical compounds, so that suitable acid addition salts can be prepared using any pharmaceutically acceptable acid. examples of such salts are hydrochloride, hydrobromide, hydrogen iodide, phosphate, sulfate, p-toluenesulfonate, benzenesulfonate, maleate, tartrate, fumarate, citrate, pamoate, melate, malonate, succinate, oxalate, methosulfate, methanesulfonate salts.

Certain compounds of formula I are novel. These may be summarized by the formula (1/3) wherein R 1 and R 1 are halogen, C 1 -C 2 alkoxy or C 1 -C 2 alkyl, with the proviso that R 1 and R 1 cannot simultaneously be C 1 -C 2 alkyl.

The pharmaceutically active N-phenyl-N '- (2-imidazolidinylidene) urea derivatives can be prepared by essentially two methods. According to the most commonly used method, the 2-imino-imidazoline derivative of formula II is reacted with a phenyl isocyanate of formula III according to the reaction equation shown in Scheme A. In the general formula (III), A has the meaning given above.

The starting material of the 2-imino-imidazole (according to methods known in the art and described below) is preferably prepared and stored in the form of its acid addition salt. The acid addition salt is represented by the general formula (11a). Thus, the first step in the synthesis is generally the conversion of the acid addition salt to the free base. This can be accomplished by thoroughly mixing the solution or suspension of the acid addition salt in tetrahydrofuran with 2 molar equivalents of 50% aqueous sodium hydroxide solution, followed by

-2183,013 leaks ^: - ore anhydrous sodium sulfate is added. The resulting biphasic reaction mixture is contacted with the appropriate phenyl isocyanate to obtain the desired N-phenylN-indazolidinylidene urea.

In a preferred embodiment of the process, a solution of phenyl isocyanate in tetrahydrofuran is added portionwise to the biphasic reaction mixture with stirring at 20-30 ° C, and the mixture is stirred for a few hours to overnight. The resulting N-phenyl-N'-imidazoquinylideneurea derivative is isolated, optionally converted to its acid addition salt and purified by conventional techniques.

The free base may also be prepared by contacting a solution of the acid addition salt of 2-iminotmidazolidine with a suspension of lithium hydride, preferably in the same solvent, under inert atmosphere. Suitable solvents are, for example, dimethylformamide, dimethylsulfoxide, tetrahydrofuran. The addition temperature is usually 0-30 ° C. The inert atmosphere is usually provided using nitrogen or argon.

The reaction is preferably carried out by reacting the 2-imino-tmldazoiidin acid addition salt hozzáesepegtetjük stirring solution of lithium aluminum hydride in dry solvent, chilled suspension nitrogénatrooszféfában while maintaining the temperature at 0-5 ^P Cofton. Stirring is continued after the addition is complete while allowing the reaction mixture to gradually warm to room temperature. We get a free base.

Alternatively, the reaction of 2-thiomolphiolazolidine with the aryl isocyanate can be carried out by adding the solution of the aryl isocyanate to the free base reaction mixture under stirring and cooling, stirring until it is warmed to room temperature. 110 ° C was continued at 65-110 ° C to optimize yield. The desired N-phenyl-N '- (2-imidazolidinylidene) carbamide derivative is obtained. If the reaction is carried out at room temperature, stirring is usually carried out for a few hours to overnight, while at elevated temperatures it is sufficient to obtain two hours.

In another, less preferred method, the desired N-phenyl-N'-p-imidazolidinylidene / urea derivatives are prepared according to Scheme B. In the general formulas shown in the Scheme, A has the meaning given above. it can be seen that the initial step is the reaction of a suitable phenyl isocyanate of formula (III) with thiourea, which leads to the formation of an N-phenylthioimodicarboxylic acid diamide of formula (IV). This compound is then treated with methyl iodide to give an N '(phenylamino) carbonylurea thioate of formula (V). The resulting compound is reacted with a suitably substituted ethylenediamine of formula (VI) to give the desired N-phenyl-N '- (2-imidazolidinylidene) urea derivative of formula (1), in the form of its hydrogen iodide, from which the free base can be prepared . However, the process described is not suitable for the preparation of urea compounds containing 2,6-disubstituted phenyl.

The first step of Lakra et al., J. Med. Am. Chem. Soc. 57, 2220 (1929)] may be carried out by reacting a suitably substituted phenyl isocyanate of formula (III) with thiourea to form N-phenylthioimidodicarboxylic acid amide. hereafter referred to as &quot; thio biuret compound &quot; for simplicity. Reagents are used in substantially equimolar amounts, but a small excess of thiourea is preferred. The reaction temperature is 80-120 ° C. The reaction is preferably carried out in a solvent. Suitable solvents include dimethylformamide, dimethylsulfoxide.

In practical embodiments, the isocyanate and thiourea are preferably held in a steam bath for 2 to 12 hours. The resulting mixture was then diluted with water and cooled, and the precipitated thiobureth compound was isolated from the reaction mixture and purified by conventional means.

In a second reaction step, the N-phenylurea derivative is reacted with an S-methylating agent to give methyl N '- [(phenylamino) carbonyl) carbaminidothioate of formula (V), which for convenience will hereinafter be referred to as a "tloate compound" . The reagents are generally used in equimolar amounts, but it is preferred that a small excess of the methylating agent be present. Methyl iodide is preferably used as the methylating agent, although other methylating agents such as dimethyl sulfate are also possible. The reaction is preferably carried out in the presence of a solvent. Examples of the solvent include acetone, methanol, ethanol, isopropanol. The reaction temperature may range from room temperature to the reflux temperature, but is preferably carried out at room temperature.

In practice, it is common practice to stir the thiobiuret compound and the methyl iodide in methanol at room temperature for several hours. The compound formed as the hydroiodide addition salt in the reaction mixture is recovered and, if desired, purified by conventional techniques.

In a third step, the resulting thioate compound (V) is reacted with ethylenediamine (VI) as its hydroiodide salt. The desired N-phenyl-N'-imidazolidinylideneurea is obtained in the form of its hydroiodide salt. The reagents have to do! equimolar amounts. The reaction is preferably carried out in methanol or other lower alcohols, but methanol is most preferred.

The resulting salt can be converted into the free base in a known manner. If another salt is to be prepared, the free base is reacted with another acid to produce the desired acid addition salt.

The conversion is carried out in a known manner. For example, the free base can be prepared from the resulting salt by dissolving the acid addition salt in a minimal amount of lower alkanol such as methanol or ethanol, heating the solution with an organic base such as triethylamine, and cooling the desired free base as a crystalline solid. is obtained. Similarly, the free base can be converted, for example, to a desired acid addition salt by reacting the base with an acid corresponding to the desired acid addition salt and crystallizing the resulting salt by cooling the mixture.

It has been found that N-phenyl-N '- (2-imidazolidinyltylidene) urea derivatives reduce hypertension without generally increasing heart rate. For the treatment of hypertension, agents which lower blood pressure while maintaining or even lowering the heart rate are ideally suited for the antihypertensive effect. The antihypertensive effect of a compound in rodents 3

-3183,013 can be tested by hemodynamic experiments in dogs. A summary of the experiments and the results obtained with the compounds of the invention is given below.

Study of the antihypertensive effect in rodents

The effect of arterial blood pressure and heart rate was investigated. Specifically, rats hypertensive with spontaneous hypertension or deoxy corticosterone acetate and 2% sodium chloride in drinking water were tested for arterial blood pressure directly through an aortic cannula. Rats were anesthetized by instillation of anesthetic such as methoxyl fluoride or ether. The left carotid artery was isolated and the cannula was attached. The tip of the cannula was inserted into the aorta and the cannula was advanced behind the neck at the level of the shoulder blade. The animals were placed in individual crates, waited for them to return to magide from anesthesia and left free. The arterial cannula was connected to a pressure transducer coupled to the writing device. Heart rate was determined by recording arterial pressure. Animals with a blood pressure of 149 Hgmtn were higher. hypertension, and experiments were conducted on these. Test compounds were administered either orally or intraperitoneally by injection. Arterial pressure and heart rate were recorded for at least 4 hours. The test compound was considered to be an effective antihypertensive if it lowered mean arterial blood pressure (MAE) by more than 19 mmHg. Individual animals also acted as controls.

The results of the experiment are summarized in Table I together with the test compounds.

Hemodynamic examination in dogs

Ez.ta attempt to examine the performed to exert the effects of the compounds to be tested on the cardiovascular system and the autonomic nervous system ^5.

The experiment was carried out by anesthetizing dogs of mixed species with 20 mg / kg body weight thiophthalate sodium and 60 mg / kg body weight o-chlorol. If necessary, θ additional (50 mg / kg body weight) α-chlorol was used to maintain the anesthetized state. An end-tracheal tube with a collar was used to ensure a smooth air passage and the animals were ventilated with a ventilator. The conical bone artery and vein were fitted with a catheter for recording arterial blood pressure and intravenous injection. Both carotid arteries were separated to perform bilateral occlusion of the carotid arteries. The planetary nerve was electrically stimulated at its peripheral end for 10 seconds using 20 V pulses per second for 2 msec. The etchocardiogram was recorded on a Limb Lead 11 instrument and used as a control to induce cardiovascular reactions as follows: 1.0 pg / kg body weight 1-epinephrine intravenously, carotid artery obstruction; 10 pg / kg body weight ^b dimethylphenyl piperaziniutn iodide (DMPP) intravenously, peripheral nerve stimulation planet; 10 pg / kg body weight acetylcholine and 2 pg / kg body weight angtotensin intravenously. Control experiments were performed twice influenced, trug the test compounds 5 mg / kg body weight ^u dose was applied intravenously to the animals, in nearly one-minute period. If no change in arterial blood pressure, heart rate, or electrocardiogram (Limb Lead 11) was observed during this time, an additional dose of mg / kg intravenously was used. We tested the

Table I

Examination of hypotension and heart rate

compound (L) 'HX Spontaneous hypertensive (SH) rats hemodynamic dogs the medium art heart rate is maximal THE HX Dose of diabetic blood pressure (mg / kg i.p.) max. decrease (MmHg) heart rate (Beats / min) decrease 10 mg / kg i.v. dose phenyl 30 72 +78 no change upper - 10 p.o. 39 -108 - phenyl - 100 p.o. 30 + 30 - 3-Ct phenyl hl 30 63 -42 -30 2,6-Cli phenyl HCI 20-200 p.o. 39-96 From -39 to-108 -54 2,6- (CH ₃ ) ₂ phenyl HCl · 1/2 HjO 30> 19 ) * -60 2-C1.6-CH, phenyl HCI 30> 19 1 -42 2,6-Br ₂ pheny, HCI 30> 19 1 -54 2-C ₂ H _s , 6-CH ₃ phenyl 2/3 fumarate 30> 19 -42 4-CH 3 above HCI 30> 19 ** no change no change (5 mg / kg i.v3 2-OCH3 phenyl HCI 30 95 -108 *** + 30 * * 2-OCH3 phenyl HCI 10 p.o. 23 -84 2-OCH ₃ phenyl HCI 100 p.o. 90 -84 - 2-C 1 phenyl HCI 30> 19 -108 no change

* Decrease ** Half the number of rats *** The major slowing effect in spontaneous hypertensive rats is more significant 4

The effect of Compound 183,013 on electrocardiogram, arterial pressure and heart rate. 10 minutes after the administration of the test compound, a new series of hemodynamic properties was started.

Each compound was assayed in other dogs for heart rate values characteristic of N-phenyl-N '- (2-imidazolidinylidene) urea. The results obtained are summarized in Table I below.

It is clear from the data in Table I that the N-phenyl-1 '- (2-imidazolidinylidene) urea compounds and their salts not only have antihypertensive properties but also maintain or decrease heart rate. These properties are very favorable for tough vascular use.

The compounds of the present invention are used to treat hypertensive diseases and reduce hypertension by administering to a subject a therapeutically effective amount of an N-phenyl-N '- (2-imidazolidinitidine) urea compound or a pharmaceutically acceptable salt thereof. The active ingredient may be administered alone or in combination with a vehicle, in the form of a pharmaceutical composition. Use of pharmaceutical compositions in unit dosage forms is preferred.

Administration is by the oral or parenteral route of about

It may be presented in unit dosage form containing from 5 to 500 mg of the N-phenyl-N '- (2-imidazolinylidene) urea compound. Although therapeutic use has proven to be most advantageous in human medicine, the compounds may also be used to treat other mammals. Usable amounts are generally between 0.5 and 50 mg / kg body weight.

Treatment of intestinal disorders

We have found that ^N-phenyl-N, used in the present invention - (2-imidazotidinilidén) urea derivatives useful in the functional gastrointestinal disorder is derived, and thus eliminate unpleasant condition from bélérzékenységböl. Intestinal tenderness-related abnormalities are characterized by abdominal pain, diarrhea, constipation, and the like, which are triggered by increased intestinal sensitivity to bloating caused by intestinal gases and / or faeces.

The efficacy of the compounds in eliminating gastrointestinal discomfort can be determined by placing a glass bead in the rectum and determining the time between insertion and withdrawal. Compounds that are capable of reducing susceptibility to gastrointestinal bloating delay the pearl excretion.

The assay was performed on male albino mice weighing 18-25 g and tested the effects of each chemical in groups of 5 to 5 mice. In the first step, the effect of each compound was tested at an oral dose of 50 mg / kg body weight in a volume of 0.1 ml per 10 g of body weight. Control groups were treated with vehicle alone, i.e., 0.5% methocell, for both oral and intraperitoneal administration. The mice were fasted for one hour prior to the start of the experiment and the test compounds were administered one hour prior to insertion of the glass bead.

At the end of the pretreatment time, the mouse under examination was lifted and held firmly in the hands with the abdomen facing the observer. A glass bead of 3 mm diameter was inserted into the rectum, facilitated by the movement of the entry and thumb. A 3 mm diameter glass rod moistened with 0.5% methocell was then slowly inserted into the rectum to a depth of 2 cm. The mice were observed in groups and the time at which the bead was introduced into the rectum of the last mouse was selected as the zero time point. The number of glass beads discharged within a given time interval was recorded. The time intervals were 0-5 minutes, 5-10 minutes, 10-20 minutes, 20-40 minutes and longer than 43 minutes. Activity index values of 0, 1, 2, 3 and 4 corresponded to each time interval. In mice where no bead was evacuated within 40 minutes, we tested for perforation. Perforated fin animals were excluded from the evaluation. The sum of the values is divided by sr. mice or beads to determine the activity index of the test drug. The ED50 value was determined by regression lines using the least squares method. ED _{S0 is} approximately the dose corresponding to 2 activity indices.

The results obtained by intraperitoneal and oral administration are shown in Table II. are summarized in Table.

II. Table I: Compounds of Formula I

THE HX EDse mgtkg intraperi- intraperitoneal po 2,6-phenyl-dicle HCI 7 13.7 2,6-di (CH ₃ ) -phenyl HCl 1/2 H ₂ O 12 16 2-Cl, 6-CH-phenyl HCI 8 35 2,6-dibromophenyl HCI 9 38 2-C ₂ H _s , -O-CH 3 -phenyl 2/3 fumarate 43 121

The experimental results presented in the table illustrate the beneficial effect of the tested N-phenyl-N '- (2-imidazolidinyl) urea derivatives in reducing abnormal bowel sensitivity.

For the treatment of intestinal disorders, a therapeutically effective amount of a N-phenyl-N '- (2-imidazolidinylidene) carbamate derivative or a pharmaceutically acceptable salt thereof is administered to the patient. The active ingredient may be used alone or in combination with excipients in the form of a pharmaceutical composition. Preferably, unit dosage forms are used.

For oral and parenteral administration, the dosage of the active ingredient may range from 5 to 500 mg per unit dose. Although therapeutic use has proven to be most advantageous in human medicine, the compounds may also be used to treat other mammals. Usually, the amount to be used is 0.50 to 50 mg / kg body weight, preferably at least 3 mg / kg body weight.

In accordance with the present invention, pharmaceutical compositions for treating the above-mentioned conditions are prepared by thoroughly mixing the N-phenyl-N '- (2-imidazolidinitdene) urea or an acid addition salt thereof with a pharmaceutical carrier using any of the known methods well known in the pharmaceutical art. The quality of the carrier may vary greatly, depending on the form of the product to be manufactured and on the

-5183 013 whether the administration is to be effected, for example, orally or parenterally. Oral formulations may be prepared using conventional pharmaceutical excipients. Thus, for example, water, glycols, oils, alcohols, colorants, preservatives, and flavoring agents may be used as carriers and excipients for liquid oral preparations such as suspensions, elixirs, solutions. Carriers and excipients for solid oral preparations such as powders, capsules and tablets may include, for example, starches, sugars, diluents, granulating agents, wetting agents, binders, disintegrating agents. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage forms. Solid carriers are used. The tablets may be sugar coated or enteric coated, if desired. For parenteral administration, the vehicle will usually contain sterile water, although other ingredients, for example, auxiliaries and preservatives, may be present. Injectable suspensions are also available. Suitable liquid carriers, suspending agents and the like may be used. The term "unit dose" is used throughout the specification to denote physically discrete units, each containing a predetermined amount of the active ingredient, which is capable of producing the desired pharmaceutical effect, with appropriate pharmaceutical carriers. Such unit dosage forms are, for example, tablets, capsules, pills, powder packets, wafers, teaspoons and tablespoons, and integers multiples thereof. Such a unit generally contains from 5 to 50 mg of N-phenyl-N '- (2-imidazolidinylidene) urea.

Further details of the present invention are illustrated by the following examples, but are not intended to be limiting.

Preparation of starting material

The 2-imidazolidine derivatives of the formula (II) used as starting materials can be prepared by methods known in the art or by the following hydroiodide salt:

Methyl iodide (213 g, 1.5 moles) was added under stirring over a period of one hour to a slurry of ethylene thiourea (153.24 g, 1.5 moles) in methanol (300 mL). Stirring was continued for about an additional hour to After completion of the reaction, anhydrous ammonia is added to the reaction mixture to give the 2-imino-indazolide-t-hydroiodide and the methyl mercaptan by-product. Stirring and addition of ammonia were continued for a total of 26 hours. The mixture is concentrated with simultaneous addition of isopropanol. The isopropanol is used to replace the evaporated methanol. The mixture is cooled and 2-iminimidazoline hydroiodide is precipitated as an crystalline solid by addition of ether. The product was recrystallized from a mixture of methanol and tert-butanol to give a solid, m.p. 152-154 ° C.

~ Analysis results based on CjH ₇ N ₃ · Hl:

Calculated: C, 16.92; H = 3.79%; Found: C, 16.85; H, 3.82%.

Example 1

Preparation of N- (2,6-Dichlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride

To a suspension of 2.13 g (0.01 mol) of 2-iminimidazolidine hydroiodide in 50 ml of anhydrous dimethylformamide was added 0.8 g (0.01 mol) of 50% aqueous sodium hydroxide solution under nitrogen. Thus, 2-iminimidazolidine base and sodium iodide are prepared. Anhydrous sodium sulfate (1 g) was added and stirring was continued for an additional 1.5 hours. The mixture was then treated with 0.94 g (0.005 mol) of 2,6-dichlorophenyl isocyanate (20 ml) over 2.5 hours. tetrahydrofuran solution was added dropwise and the mixture was stirred overnight at room temperature. N- (2,6-dichlorophenyl) -N ^, - (2-imidazolidinylidene) urea is obtained. The sodium salts were collected by filtration and the filtrate was concentrated in a water bath under reduced pressure. A light yellow oil is obtained which is dissolved in methylene chloride and the methylene chloride solution is washed with a saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate and treated with hydrogen chloride until the pH is lower than 3, and the aq. Solvent and excess hydrogen chloride are obtained. it was removed in vacuo and the residue was recrystallized from methanol / ether. Purified N- (2,6-dichlorophenyl) -N ^, - (2-imidazolidinylphenyl) urea hydrochloride, m.p. 210-212 ° C. The product decomposes to form a new compound, m.p. 239 ° C.

Example 2

Feeding of N- (2-Chloro-6-methylphenyl) -N '- (2-methyldimethylbenzyl) carbamide and hydrochloride

Of a solution of 10.65 g (0.05 mL) of 2-iminimidazolidin hydrochloride in dimethylformamide under stirring over a period of 15 minutes, 397.5 mg (0.05 mol) of lithium hydroxide in 50 ml of anhydrous dimethylformamide, ^{of this} slurry, cooled to C, under a nitrogen atmosphere. Hydrogen evolution was observed. The mixture was allowed to gradually warm to room temperature with constant stirring. The reaction mixture was then cooled to 0-5 ° C and a solution of 5.0 g (0.03 mol) of 2-chloro-6-methylphenylisoleyanate in 25 ml of anhydrous dimethylformamide was slowly added dropwise over 2 hours. After the addition was complete, the mixture was allowed to gradually warm to room temperature while stirring under nitrogen overnight. The desired N- (2-chloro-6-methyl-phenyl) -N '- (2-imidazolidinitidene) -carbafnide is obtained which remains in solution. The product is isolated from the reaction mixture by (a) dissolving the mixture in 300 ml of ice water with stirring. (b) lowering the pH to less than 2 with 10% aqueous hydrochloric acid to precipitate the acid insoluble material, (c) filtering, (d) adjusting the filtrate to pH 8-9 with solid potassium carbonate. and (e) saturating the solution with sodium chloride, whereupon the free base of N 2 -chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) carbatamide is precipitated as a white solid. Wash product thoroughly with water. Melting point: 169-171 ° C.

The base obtained was dissolved in methanol (30 ml) and the pH was adjusted by addition of hydrogen chloride in methanol.

Less than -6183,013. Subsequently, N (2-chloro-octylphenyl) -N '- (2-imidazolidinylidene) carbarate hydrochloride is precipitated by addition of ether. The salt was separated and recrystallized sequentially from 2-propanol and methanol-ether. Clear, ^209,211, melting product which decomposes mp (dec) 270 ° solid

Analytical results for C11H13CIN4O HC! according to the formula:

Calculated: C, 45.69; H = 4.88%; N = 19.37%; Found: C, 45.59; H, 4.93%; N, 19.35%.

Example 3

Preparation of N- (2,6-dibromophenyl) -N- (2-imidazolidinylidene) cerhamide hydrochloride

A solution of 12.0 g (0.0563 mol) of 2-iminimidazolidine hydroiodide in 50 ml of anhydrous dimethylformamide in a nitrogen atmosphere was treated with lithium hydride (447 mg, 0.0563 mol) in 50 ml of anhydrous dimethylformamide. of the suspension. After the addition was complete, the mixture was allowed to warm to room temperature over about half an hour, then cooled to 0-5 ° C and added dropwise over two hours.

A solution of 7.8 g (0.0282 mole) of 2,6-dibromophenyl isocyanate in 25 ml of anhydrous dimethylformamide was maintained at 0-5 ° C. The mixture was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The desired N- (2, 6-dibromophenyl) -N '- (2-imidazobdmylidene) urea is obtained, which remains in the reaction mixture. The product was isolated by pouring the mixture into ice water (400 mL), acidifying it to pH 3 with 10% aqueous hydrochloric acid, removing the impurities by filtration, saturating the filtrate with solid sodium chloride and adjusting to pH 8-9 with sodium carbonate. to alkaline. N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea precipitates as a white solid. The product melts at 185-190 ° C with decomposition.

The resulting base was suspended in methanol (40 mL) and enough methanolic hydrogen chloride was added to bring the suspension to below pH 2. The N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) carb3mid hydrochloride is precipitated as a white solid by addition of ether. The product melts at 200-202 ° C with decomposition. Recrystallization from a mixture of methanol, 2-propanol and ether gave a pure product, m.p. 215-217 ° C. The product decomposes to give a solid which melts at 255 ° C with decomposition.

Analysis for C _{1 (} ) I {> oN ,, Br ₂ O · HCl:

Calculated: C, 30.15; H = 2.78%; N, 14.06. Found: C, 30.12; H = 2.81%; N, 14.04%.

Example 4

Preparation of N- (2-Imidazo lidinylidine) -N- (2-methoxyphenyl) urea hydrochloride

Analogously to Example 3, using 2-imino-lmidazolidin (produced in a 2-imino-imidazolidine, hydroiodide and the reaction of lithium hydride) and 2-isocyanate reaction of about 5-10 ⁰ C, N- (2- m.p. , 5 (

Analysis results for ChHmNiOj HCi Compound · 1:

Calculated: C, 48.80; 11 5.58%; N, 20.70 '; Found: C, 48.75; H '^ 5.61%; Ν '- 20.71 /:

Example 5

Preparation of N- (2-Ethyl-6-methylphenyl) -N '- (2-imidazolidenylidene) urea fumarate (3: 2)

As described above, 15.55 g (0.073 mol) of 2-imidazolidine hydroiodide was added dropwise to a cooled suspension of lithium hydride (596 mg, 0.075 mol) in dimethylformamide (30 ml) under nitrogen, and the mixture was allowed to warm at The reaction mixture was cooled again, and a solution of 8.1 g (0.05 mol) of 2-ethyl-6-methylphenylisocyanate in 25 ml of anhydrous dimethylformamide was added dropwise over a period of 2 hours. stir overnight while allowing the temperature to warm to room temperature. N- (2-ethyl-6-methylphenyl) -N '- (2-imidazolidinylidene) 4'aryl) amide is obtained. The basic product was isolated by the method described in the previous examples and recrystallized from a mixture of methanol and water. The purified product has a melting point of 185-187'C.

A solution of the obtained base (4.32 g, 0.0175 mole) in 35 ml of hot zopropanoyl was stirred with a solution of 2.04 g (0.0175 mole) of fumaric acid in 35 ml of hot isopropanol, and the resulting solution was allowed to cool. The addition salt of N- (2-ethyl6-methylphenyl) -N '- (2-imidazolidinylidene) urea fumarate crystallized. The salt is washed first with isopropyl ether and then with ether. Melting point: 180 ° C (dec.). Serial recrystallization from methanolic isopropanol and a mixture of methanol and ether did not yield a product with a sharply melting point. The salt analysis showed 3 moles of base and 2 moles of fumaric acid.

Analysis results for (C | ₃ H »N ₄ O) s (€ 4 ^ () 4) 2:

Calculated: C, 58.13; 11 = 6.44%; N, 17.31. Found; C = 58.03%; H, 6.57%; N, 17.59%.

Example 6

Preparation of N- (2-Chlorophenyl) -N2-imidazolidinylidene) urea hydrochloride

In analogy to Example 5, 2-iminimidazolidine (prepared by reacting 2-iminimidazolidine hydroiodide and lithium hydride in dimethylformamide at a temperature in the region of 20 ° C) and 2-chlorophenylisocyanate at 20-30 ° C. by heating the mixture in a steam bath at 100 ° C for 15 minutes to give N- (2-chlorophenyl) -N '- (2-imidazolidinylidene) urea as a crystalline solid, and the resulting base is reacted with methanolic hydrogen chloride. M.p. 187-189 ° C.

Analysis for C | oHuN ₄ O € basis l HCl Calc'd:

Calculated: C, 43.66; 11 = 4.40%; N = 20.36%; Found: C, 43.69; H = 4.43%; N, 20.36%.

-7183013

Example 7

In analogy to the procedures described in Examples 2-6, the following compounds were prepared:

M- (4-Fluoro-2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) carbanide and its hydrochloride. mp 215-217 ° C (dec., HCl).

N- (2-imidazolidinylidene) -N ^, - (4-methylphenyl) urea and its hydrochloride, m.p. 210-212 ° C (hydrochloride),

N- (2,4-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride, m.p. 217-219 ° C (hydrochloride),

N- (2,3-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride, m.p. 218-220 ° C (hydrochloride),

N- (3,5-dichlorophenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride, m.p. 200-202 ° C (hydrochloride),

N- (3,4-dichlorophenyl) -N '- (2-imidazolidinylidene) carbamate and its hydrochloride, m.p. 217-219 ° C (hydrochloride).

N <2,5-dichlorophenyl) -N '- (2-imidazolidinylidene) carbamate and its hydrochloride.p. 213-215 ° C (hydrochloride),

N- (2-imidazolidinylidene) -N '- (2,4,6-trichlorophenyl) urea and its hydrochloride, m.p. 232 ° C (hydrochloride), decomposition product, m.p. 260 ° C (dec.).

N- (2,6-dimethoxyphenyl) -N'-f2-imidazolidinylidene) urea and its hydrochloride, m.p. 204-205 ° C (dec., Hydrochloride),

N- (4,5-Dimethoxyphenyl) -N '- (2-imidazolidinylidene) urea and its hydrochloride, m.p. 203-205 ° C (dec., Hydrochloride).

Example 8

Preparation of N- (2- tnidazolidinitidene) -N'-phenylurea and htdro'iodide

To a warm solution of 83.73 g (1.1 mol) of thiourea in 120 ml of anhydrous dimethylformamide was added 119 g (1 mol) of phenyl isocyanate in one portion with stirring and the resulting solution was heated for three hours. The solution is then cooled, cautiously added with ice / ice water, and the vessel scraped to initiate crystallization of the desired N-phenylthio-thiournidodicarboxylic acid diamide. After crystallization started, additional ice water (about 1 liter) was added. The precipitated crystals are then separated, washed with water and recrystallized from methanol. 127 g of the N-phenylthioimidodicarboxylic acid diamide intermediate are obtained, m.p. 176-180 ° C.

In a second step, methyl iodide (45.5 g, 0.32 mol) was added to a solution of N-phenylthioimidodicarboxylic acid diamide (59.5 g, 0.305 mol) in acetone (300 ml) and the mixture was stirred at room temperature for about 2 hours. Meanwhile, crystals are formed in the reaction mixture which are filtered off and dried. Methyl N '- ((phenylamino) carbonyl) -carbamimidothioate hydro} odide is obtained, m.p. 195-200 ° C. An analytical sample of the product was obtained by recrystallization from methanol, m.p. 200-202 ° C. .

Analysis results for C ₄ HhN ₃ 0S Hl:

Calculated: C, 32.06; H = 3.59%; N, 12.46%; Found: C, 32.11; H, -3.62%; N, 12.48%.

Then, 33.72 g (0.1 mol) of the product thus obtained are dissolved in methanol and mixed with 6.01 g (0.1 mol) of ethylenediamine in methanol and the mixture is heated under reflux for about 1.5 hours. the mixture is then cooled to 20 ° C When the hydroiodide of the hydroiodide of N (2-imidazolidinylidene) -N-phenylurea crystallizes in the final phase, the precipitated crystals are collected in several portions, purified by dissolving in methanol, filtered, and the filtrate is evaporated to isolate the hydroiodide.

The hydroiodide is then converted to the corresponding urea base and purified in several steps. In particular, purification was accomplished by dissolving the products in a minimum amount of methanol, stirring and heating with 8.0 g (0.079 mol) of triethylamine, replacing the methanol with ethanol and cooling. The N- (2-imidazolidinylidene) -N'-phenylurea base was crystallized from m.p. 182-183 ° C after recrystallization from methanol.

Analysis results for C ₁₀ H ₁₂ N ₄ O;

Calculated: C, 58.81; H, 5.92%; N = 27.43%; Found: C, 58.79; == H, 5.92%; N, 27.48%.

The melting point of the hydroiodide addition salt after recrystallization from acetone is 223-225 T (dec.).

Analysis results for C _lo Hi ₂ N ₄ O Hl:

Calculated: C, 36.16; H = 3.94%; N = 16.87%; 1 = 38.21%;

Found: C, 36.22; H = 3.96%; N, 16.88%;

1 = 38.21%.

Example 9

Preparation of A- (3-Chlorophenyl) -N '- (2-imidazolidinylidene) urea

In a manner analogous to that described in Example 8, m-chlorophenyl isocyanate (153.57 g, 1.0 mole) was added to a warm solution of thiourea (95.15 g, 1.25 mole) in dimethylformamide (100 mL) and the resulting mixture was stirred at room temperature. overnight in a steam bath. N- (3-chlorophenyl) thioimidodicarboxylic acid diamide is obtained as an intermediate in the reaction mixture. The mixture was cooled to completely precipitate the intermediate, and the compound was collected by filtration and washed with ether. 187-189 ° C (dec.). Similar portions were prepared, combined and recrystallized twice from methanol / water and twice from acetonitrile. The resulting purified product melts at 205-207 ° C with decomposition.

Methyl iodide (75.0 g, 0.525 mol) was added to a clear acetone solution of 80.3 g (0.35 mol) of N- (3-chlorophenyl) thioimidodicarboxylic acid diamide prepared above, and the reaction mixture was stirred overnight. The desired N - [(3-dichlorophenyl) amino] carbonyl] carbamothiothioate hydroiodide is obtained in the form of a crystalline solid, m.p. 182-183 ° C with decomposition.

37.1 g (0.1 mol) of methyl N'- (3-chlorophenylamino-carbonyl) -carbamothiothioate hydroiodide (6.0 g, 0.1 mol) in 100 ml were thus prepared. methanol, and the resulting reaction mixture was refluxed for 5 hours, evaporated to dryness in vacuo and diluted with tert-butyl alcohol to give N- (3-chlorophenyl) -N '- (2-imidazolidinylidene) as a crystalline material. The crystals were recrystallized several times from tert-butyl alcohol to give a pure product, m.p. 192-194 ° C (dec.).

183,013

Analysis results for C _in HnClN4O · Hl:

Calculated: C, 32.76; H = 3.29%; Found: C, 32.82; H = 3.33%.

The following examples illustrate the preparation of pharmaceutical compositions for treating hypertension according to the invention, without limiting the invention to these examples.

Example 10

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

N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea 200 g starch 250 g lactose 750 g talc 250 g calcium stearate 10 g

The above components are thoroughly mixed and filled into two hard gelatin capsules. The capsules can be administered orally to lower the blood pressure in patients with high blood pressure.

Example 11

Gelatin capsules were prepared as described in Example 10. The only difference is that 325 g of the active ingredient N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea are prepared and each capsule contains 325 mg of N- (2,6-dimethyl) urea. -phenyl) -N ^, - (2-imidazolrdinylidene) urea.

Example 12

One thousand compressed tablets containing 500 mg of the active ingredient N- (2-imidazolidinylbene) -N '- (2-methoxyphenyl) urea are prepared from the following mixture:

N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) urea 500 g starch 750 g water-containing dibasic calcium phosphate 5000 g calcium stearate 2.5 g

The finely pulverized materials are mixed well and granulated with 10% starch paste. The granulate is dried and compressed into tablets using starch as a disintegrant and calcium stearate as a lubricant.

Example 13

Tablets were prepared as described in Example 12. The only difference is that the active ingredient is N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea.

Example 14

Gelatin capsules were prepared as described in Example 10, except that the active ingredient was N- (3-chlorophenyl) -N '- (2-imidazolidinylidene) urea.

The following examples illustrate the preparation of pharmaceutical compositions for use in the treatment of intestinal disorders, without limiting this part of the invention to the examples.

Example 75 1000 hard gelatin capsules containing 1000 mg each of N- (2,6-dichlorophenyl) -N- (2-imidazolidinylidene) urea were prepared from crushers of the following composition:

N- (2,6-dichlorophenyl) -N ^, - (2-imidazolidinylidene) urea 200 g starch 250 g lactose 750 g talc 250 g calcium stearate 10 g

The components are thoroughly mixed and the mixture is used to fill two pieces of hard gelatin capsules. The capsules may be administered orally to patients suffering from intestinal disorders.

Example 6

Gelatin capsules were prepared as described in Example 15. The only difference is that 400 g of N- (2, iodobromophenyl) -N '- (2-imidazolidinylidene) urea are used as the active ingredient, and thus 400 mg of N- (2,6-bromobromophenyl) -N' - (2) Capsules containing -imidazolidinylidene) urea are prepared.

Example 7

The procedure described in Example 15 was used to prepare gelatin capsules. The only difference is that the active ingredient is N- (2-ethyl-6-methyl) -N ^, - (2-imidazolidinylidene) kaxamide.

Example 18

The procedure described in Example 15 was used to prepare gelatin capsules. The only difference is that the active ingredient is N (2,6-dimethyl-phenyl) -N '- (2-imidazolidinylidene) urea.

Example 9

One thousand compressed tablets containing 500 mg each of N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea are prepared from the following mixture:

N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea 500 g starch 750 g water-containing dibasic calcium phosphate 5000 g dicalcium stearate 2.5 g

The finely powdered components are well mixed and then granulated with 10% starch paste. The granulate is dried and then compressed into tablets using starch as the disintegrant and calcium stearate as the lubricant.

Claims (6)

1. Procedure as active substance: a) by reacting 2-iminimidazolidine of formula II with phenyl isoclanate of formula III: A is phenyl optionally substituted with 3 halogens, 1 or 2 C 1-2 alkyl groups, 1 or 2 C 3-2 alkoxy groups, or 1 halogen and 1 or 2 C 1-2 alkyl groups, or b) The phenyl isocyanate A of formula III is reacted with the above ··· and thiourea, and the resulting N-ferrylthioimidodicarboxylic acid diamide of formula V is treated with the above methyl iodide to give (V). N'-1 (phenylanoyl) carbonyl] carbamothiothioate of formula A is as defined above; and N-phenyl-N- (2-imidazolidinylidene) -carboxylic acid compound of formula (I) obtained by reacting ethylene diamine of formula (VI) and liberating the base obtained in a known manner, wherein A has the meaning given above or a pharmaceutically acceptable acid addition salt thereof, for the treatment of hypertension and of intestinal disorders, provided that the compounds of formula I are used in the preparation of a composition for the treatment of intestinal disorders wherein A is at least 2- and 6-position substituted phenyl group, characterized in that the N-phenyl-N '- (2-imidazolidinylidene) urea derivative of the formula (I) obtained according to process a) or b), wherein A is a salt thereof, or an acid addition salt thereof. , pharmaceutical preparations e in the preparation of a medicament for constitution with a conventional vehicle or other excipient and formulated in the form of a tablet or capsule. 2. A process for the preparation of a medicament for the treatment of hypertension according to claim 1, characterized in that the active ingredient is a compound of the general formula (Ii), a compound of the general formula (I) R is independently selected from the group consisting of chlorine and bromine, or methyl, ethyl or methoxy; j 0 n is an integer from 0 to 3, or a pharmaceutically acceptable acid addition salt thereof, in a dosage of 5 to 500 mg per unit. 3. A process according to claim 2 wherein the active ingredient is N- (2,6-dichloro-15-phenyl) -N '- (2-imidazolinylidene) -urea. 4. A process according to claim 2 wherein the active ingredient is N- (2,6-dibromophenyl) -N ^, 42-imidazolidinylidene) urea. 5. The process of claim 2 wherein the active ingredient is N- (2-imidazolidinylidene) -N '- (2-methoxyphenyl) urea. 6. A process according to claim 2 wherein the active ingredient is N- (2-chlorophenyl) N- (2-imidazolidinylidene) urea. 7. The method of claim 1 for the manufacture of a medicament for the treatment of intestinal disorders wherein the active ingredient is a compound of formula (1/2), which is a narrower class of compounds of formula (I). 30 compounds of the formula X and Y are methyl, ethyl, chlorine or bromine, or a pharmaceutically acceptable acid addition salt thereof, at a dose of 5 to 500 mg per unit. 8. A process according to claim 7 wherein the active ingredient is N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea.