NL7909265A - N-ARYL-N '- (2-IMIDAZOLIDINYLIDEES) -UREA DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

1. N.O. 28,561 N-Aryl-N-imidazolidinylidene urea derivatives and pharmaceutical preparations containing these derivatives.

The present invention relates to methods and compounds for the control of hypertension and for the relief of intestinal ailments using N-aryl-Nf (2-imidazolidinylidene) urea preparations.

Irritable bowel syndrome is a functional ailment, characterized primarily by abdominal pain, but also by diarrhea and constipation and the like. It is believed that the pain associated with this syndrome is due to an over-sensitivity to swelling of the gut 10 caused by intestinal gas and / or faecal material. Treatments that would provide relief from the discomfort associated with such symptoms and / or the ailment producing such symptoms are highly desirable.

Background Art Certain iraidazolidine ureas are known in the art. For example, U.S. Patent 3,168,520 discloses imidazolidine urea and hexahydropyrimidine urea. These compounds are taught to be suitable as color stabilizers. In particular, the patent teaches 2-phenylcarbiliminoimidazololidine, which is N- (2-imidazolidinylidene) -N'-phenylurea. However, there is no teaching or suggestion in this patent about the use of imidazolidine ureas and hexahydropyrimidine ureas as active ingredients in pharmaceutical preparations.

Some urea compounds have been reported to have certain pharmacological properties. For example, U.S. Patent 4,060,635 describes amidinourea. These compounds have an aryl group on one urea nitrogen and a substituted amidino group on the other urea nitrogen. U.S. Pat. Nos. 3,539,686 and 3,784,582 teach amidinourea, in which one urea nitrogen is substituted with an aryl group and the other urea nitrogen is substituted with an unsubstituted amidino group. US Pat. No. 4,058,557, also directed to amidinourea, although further removed, teaches compounds wherein one of the amidino nitrogen atoms is necessarily bonded to an oxygen. None of the patents teach or suggest the substitution of an imidazolidino group with a urea nitrogen. None of these patents teach or suggest 7909265 * 2 an anti-hypertensive activity.

A recent publication, Q.H. Douglas et al., Arz. Forsch / Drug Res. 28 (II), (1978) 1 ^ 80 describes the results of many aryl substituted amidinourea tested for antimotility and anti-secretory activity. N- (2,6-dimethylphenyl) -N '- (2-imidazolydinylidene) urea and N- (2,6-dimethylphenyl) -N, - (1-methyl-2-imidazolydinylidene) urea are among the examined compounds. The article does not teach that the compounds have a suitable antimotility activity and no other pharmacological test has been reported or use suggested for these compounds.

The present invention relates to a method of treating hypertension and to a method of treating functional intestinal ailments and to relieve pain discomfort and other symptoms associated with an irritable bowel by administration to an individual, which requires therapy of a composition containing an N-aryl-N- (2-imidazolidinylidene) urea compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof. The invention also relates to compositions suitable for the treatment of hypertension and for the prevention of diarrhea and the treatment of intestinal ailments, wherein the aforementioned urea compound is mixed with a pharmaceutically acceptable carrier.

In the foregoing and subsequent formulas, Ar phenyl is substituted with 0 to 3 substituents independently selected from groups characterized by the presence of halogen or a carbon-containing group of one or two carbon atoms, optionally bonded to phenyl by a non-basic heteroatom, with the proviso that when the compound is for use in combating intestinal ailments, Ar is limited to phenyl substituted at least in the 2 and 6 positions with halogen or carbon-containing groups. Representative substituents are halogen such as fluorine, chlorine and bromine, alkyl with a small number of carbon atoms such as methyl and ethyl, alkoxy with a small number of carbon atoms such as methoxy and ethoxy, trifluoromethyl, methylthio, methylsulfonyl, methylsulfinyl and cyano. In the most preferred compounds intended to combat hypertension, Ar can be represented by formula 7 wherein R represents methyl, ethyl, chlorine, bromine or methoxy and n are an integer from 0 to 3.

kO In the most preferred compounds, 7-9 0 9 2 6 5 0 3 intended for combating intestinal ailments, Ar can be represented by the formula 8 wherein X and T are selected from methyl, ethyl, chlorine and bromine.

The activities of the above compounds are in the urea base, so that suitable acid addition salts can be prepared from various acids, with the proviso that the acids are pharmaceutically acceptable. Representative acid salts include hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, p-toluenesulfonate, benzenesulfonate, malate, tartrate, fumarate, citrate, pamoate, maleate, malonate, succinate, oxalate, methosulfate, methanesulfonate, 2-napsylate and such.

Certain of these compounds are new as such, namely a compound of the formula wherein in which and 2 ^ each represents halogen, alkoxy or alkyl with a small number of carbon atoms, it being understood that 2 ^ and 2 ^ are not both alkyl with can be a small number of carbon atoms.

The pharmacologically useful N-aryl-N '- imidazolidinylidene urea compounds are prepared essentially by two methods. The most commonly used method is by the reaction of a suitable 2-iminoimidazoline (2) with an aryl isocyanate (3) according to the reaction equation with Figure 1.

The 2-iminoiraidazoline starting materials can be conveniently prepared (according to prior art methods and as described below) and stored as an acid addition salt of the formula 2a.

Therefore, the initial stage is usually the conversion of the acid addition salt to the free base. This can be done by thoroughly stirring a solution or suspension in tetrahydrofuran of the acid addition salt with 2 mole equivalents of a 50 percent solution of sodium hydroxide in water, followed by the addition of anhydrous sodium sulfate to remove excess water. The biphase mixture thus obtained is contacted with a suitable aryl isocyanate to prepare the desired N-aryl-N'-imidazolidinylide compound.

In a preferred method for carrying out the reaction between the aryl isocyanate and the 2-imidazolidine, a solution of an aryl isocyanate in tetrahydrofuran is added portionwise with stirring to the biphase mixture at temperatures ranging from about 20 ° to 50 ° C and the mixture is stirred overnight for several hours. The N-aryl-N'-imidazo-7909265i + lidinylidene urea thus obtained is recovered, optionally converted to the form of an acid addition salt and purified by conventional methods.

The free base can be developed by another method, wherein a solution of 2-iminoimidazolidine acid addition salt is contacted with a suspension of lithium hydride, preferably in the same solvent, in an inert atmosphere. Suitable solvents include dry dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran and the like. The temperature for addition generally ranges from 0 ° to 30 ° C. An inert atmosphere is efficiently provided by using nitrogen or argon.

In a preferred method of carrying out the reaction, a solution of 2-iminoimidazolidinic acid addition salt is added dropwise with stirring to a cooled suspension of lithium hydride in a dry solvent under a nitrogen atmosphere, while the temperature is in the range of 0 to 5 ° C enforced. Stirring is continued after the addition is complete, while the mixture gradually reaches room temperature to obtain the free base.

The reaction between 2-iminoimidazolidine and aryl isocyanate can be carried out by adding a solution of an aryl isocyanate, dropwise with stirring and cooling, to the reaction mixture, which contains the free base in an inert atmosphere, while stirring the resulting mixture gradually until ambient temperature is heated and then in the temperature range of about 30 ° C to 110 ° C, preferably in the range of 63 ° to 110 ° C to optimize yields, to obtain the desired N-aryl-N, - (2-imidazolidinylidene) urem product.

When the reaction is carried out at ambient temperatures, the stirring treatment is usually continued for several hours or overnight; when the reaction is carried out at elevated temperatures, about 2 hours is sufficient.

A second general, but less preferred, method for the preparation of N-aryl-N'-t-imidazolidinylidene urea compounds proceeds according to the reaction scheme of Figure 2.

It appears that the initial stage is a reaction between a suitable aryl isocyanate (3) and thiourea to prepare an N-arylthioimido-dicarbamide (k) which is then reacted with methyl iodide to prepare a methyl N '- [(arylamino) - carbonyl] carbamidothioate [7909265] (5) The latter, when reacted with an appropriately substituted ethylenediamine (6), gives the N-aryl-N'-t-imidazolidinylidene) urea (1) as a hydroiodide addition salt and that can be converted to the free base by conventional methods. However, the foregoing reaction sequence is not applicable to the preparation of urea compounds in which the aryl group is a 2,6-disubstituted phenyl group.

The first step can be performed using a modification of the methods reported by Lakra et al., 10 (J · Am. Chem. Soc. 51 (1929) 2220), in which a suitable aryl isocyanate (3) and thiourea are converted to preparation of an N-arylthioimidodicarbondiamide compound (4), hereinafter referred to for convenience as a "thiobouret compound". For the reaction, substantially equimolar amounts of the reactants, preferably a slight excess of the thiourea, are used. range from about 80 to 120 ° C. The reaction is preferably carried out in a solvent Suitable solvents include dimethylformamide, dimethyl sulfoxide and the like.

The reaction is preferably carried out by heating the isocyanate and thiourea to steam bath temperature for about 2 to 12 hours, after which the thioburet compound (k) is formed in the reaction mixture. The mixture is then diluted with water and cooled to induce crystallization of the thiobiuret-25 compound, which is then separated from the reaction mixture and purified by conventional methods.

In the second step of the reaction, the N-arylthio-biuret compound and an S-methylating agent are reacted to prepare a methyl N '- [(arylamino) carbonyl] carbamimidothioate compound 30 (5) hereinafter referred to as the "thioate compound" for convenience. Nearly equimolar amounts of the reactants, preferably a slight excess of the methylating agent are used. Although other methylating agents such as dimethyl sulfate and the like may also be used, methyl iodide is preferred. A solvent is preferably used. Suitable solvents include acetone, methanol, ethanol, isopropanol and the like. The temperature of the reaction may vary from ambient temperature to reflux temperatures, with ambient temperatures being preferred.

* f0 The reaction is effectively carried out by the biuret 7909265. 6 bond and methyl iodide in methanol at ambient temperature for several hours. The product which arises in the reaction mixture when the hydroiodide addition salt is recovered and, if desired, purified using conventional methods.

In the third step, the thioate compound (5) as the hydroiodide salt and a suitable ethylenediamine compound (6) are reacted to prepare the desired N-aryl-N'-imidazolidinylidene urea product as a hydroiodide salt. Substantially equimolar amounts of the reactants are used. The reaction is preferably conducted in methanol and other low molecular weight alkanols, with methanol being preferred.

The reaction is expediently carried out by refluxing the hydroiodide salt of 5 and the ethylenediamine compound in methanol for about 1 to a few hours and then evaporating the solvent to give the residue of the desired N-aryl-N'-imidazolidinylidene urea product as hydroiodide salt. The product can then be recovered and purified using conventional methods.

The salt can be converted to the free base. When a different salt is desired, the free base is reacted with another acid to form a desired acid addition salt. Conventional methods can be used for these conversions. For example, a representative effective method of obtaining the free base from the salt is the solution of the acid addition salt in a minimal amount of an alkanol with a small number of carbon atoms as the solvent, such as methanol or ethanol, heating with e. and organic base such as triethylamine and the like and cooling to obtain the free base product as a crystalline solid. Similarly, a representative effective method of converting the free base to an acid addition salt is to mix the base with an alcoholic solution of an acid corresponding to the desired addition salt and cool it to obtain the acid addition salt.

The N-aryl-N- (2-imidazolidinylidene) urea compounds have been shown to alleviate hypertension and furthermore generally accomplish this without an accompanying increase in heart rate. One agent that has an antihypertensive activity without increasing but substantially maintaining or lowering the heart rate is the agent considered most suitable for the beneficial treatment of an individual with hypertension. The extent to which a compound has these properties can be determined in the rodent antihypertensive test and in the hemodynamic evaluation in the dog, as described below.

Rodent antihypertensive test. This trial 5 evaluates compounds for effects on arterial pressure and heart rate. In this test, the arterial pressure of spontaneously hypertensive rats or rats rendered hypertensive with injections of deoxycorticosterone acetate and 2% sodium chloride for drinking water is directly recorded through an aortic cannula. Cats are anesthetized with an inhalation of an aesthetic agent (methoxyfluran or ether). The left carotid artery is isolated and cannulated. The tip of the cannula is advanced to the aorta and the cannula is advanced behind the neck at the level of the scapula. Animals are placed in separate cages and given the opportunity to recover from the anesthetic and are kept casual. The arterial cannula is connected to the pressure transducer, which is connected to the recording device. The heart rate is determined from the recording of arterial pressure. Animals with pressures greater than 1 ^ 9 mm of mercury are considered sufficiently hypertensive to be used in the test for antihypertensive effects. The test compounds are administered orally (p.o.) by administration or by intraperitoneal (i.p.) injection. Arterial pressure and heart rate are recorded for a minimum of ^ hours. A test compound is considered active as an antihypertensive agent when mean arterial pressure (MAP) indicates a drop of> 19 mm of mercury. Each animal serves as its own control.

The results of this test using two rats for each compound and performed with N-aryl-N'- (2-imidazoli-50 dinylidene) urea compounds are listed in Table A.

Hemodynamic appreciation in the dog. This assay is used to evaluate the effects of a given compound on both cardiovascular and autonomic nervous systems in normally anesthetized animals.

In this test, hybrid dogs are anesthetized with 20 mg / kg (milligrams per kilogram body weight) thiopental sodium and 60 mg / kg α-chlorolose. Supplemental α-chlorolose (60 mg / kg) is used to maintain anesthesia if necessary. A cuffed endotracheal tube is included to maintain an unobstructed KO airway and the animal is ventilated with a ventilation pump 7909265% δ. A femoral artery and vein are cath / rised to record arterial pressure for intravenous injections, respectively. Both common carotid arteries are isolated to perform bilateral carotid occlusion.

The vagus nerve is electrically stimulated at the peripheral end for 10 seconds at 5 volts at 20 pulsations per second each of 2 milliseconds duration to obtain cardiac arrest. The electrocardiogram is recorded by r, Limb Lead II ".

Control cardiovascular reactions are obtained according to the following pharmacological methods: 1.0 mcg / kg I.V. (micrograms per kilogram body weight, intravenously) of 1-epinephrine, carotid occlusion, 10 mcgj / kg I.V. of dimethylphenylpiperazinium iodide (DMPP), peripheral vagal stimulation, 15 mcg / kg I, V. of acetylquinoline and 2 mcg / kg I.V. of angiotensin.

These control reactions are generated twice, then the test compound is injected with 5 ntg / kg (milligrams per kilogram) I.V. using pill injections over a period of about 1 minute. When there is no change in arterial pressure, heart rate or ECG (Limb Lead II), an additional 5 mg / kg I.V. of the compound to be tested. The effects of the test compound are recorded on the electrode cardiogram, arterial pressure and heart rate. Another series of heraodynamic reactions are obtained ten minutes after administration of the test compound.

Using a dog for each compound to be tested, heart rate data is obtained for N-aryl-N (2-imidazolidinylidene) urea compounds. The results of this test are also included in Table A.

The results from Table A show that N-aryl-N * - (2-imidazilidinylidene) urea compounds and their salts have not only the beneficial antihypertensive property, but also the desired ability to maintain or maintain a normal heart rate to lower. The properties are used in the methods and compositions of the present invention.

A method of the present invention, namely, a method of treating hypertension or alleviating high blood pressure, consists of administering to individuals in need of treatment a therapeutically effective amount of hypertension or arterial pressure reducing amount of a 7909255 9 N-aryl-N - (2-imidazolidinylidene) urea compound of formula 1 or a pharmaceutically acceptable salt thereof as active agent.

The active agents can be administered with or without a carrier in the amounts set forth below. A preferred method of administration is through the use of unit dosage pharmaceutical preparations, as described below.

The effective ranges for carrying out the method are the oral or parenteral administration of about 5 mg to about 500 mg of a K-aryl-N- (2-imidazolidinylidene) urea compound in unit dosage form. While the therapeutic method is most suitable for human individuals, it can also be used in other mammals. Active amounts are generally in the range of about 0.5 to 50 mg / kg body weight.

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Method for controlling intestinal ailments

The N-aryl-N- (2-imidazolidinylidene) ureas have been found to provide relief from the discomfort associated with functional intestinal ailments, referred to as irritable bowel syndrome. The ailment is characterized by abdominal pain, diarrhea, constipation and the like, caused by excessive sensitivity to bowel swelling due to the presence of visceral gas and / or faecal material

The extent to which a compound is effective in providing illumination can be determined by an experiment in which a glass ball is inserted into the rectum and the time course between the inclusion and expulsion of the ball is determined. Compounds effective in reducing the susceptibility to expansion of the intestinal wall delay expulsion of the bullet.

The test is performed on male albino mice with a body weight of 18-25 g used in groups of five mice for each dose of compound tested. The initial trial dose selected for all compounds carries 20 50 mg / kg body weight (mg / kg) administered orally in a volume of 0.1 ml per 10 g body weight. The control groups receive the vehicle, 0.5% methocel, used for both oral and intraperitoneal administration. The mice are fasted for 1 hour before the experiment and the drugs to be tested are administered 1 hour before the recording of the glass ball.

At the end of the pretreatment time, the mouse is taken up and held firmly in one hand with its abdomen facing the technician. The 5 mm diameter glass ball is placed at the rectum and, using a pinching action with a thumb and a forefinger, the ball is pushed into the rectum. Then, using a 3 mm diameter glass rod lubricated with 0.5% methocell to facilitate recording, the glass ball is pushed into the rectum over a distance of 2 cm using a slow gently spinning motion. The mice are monitored as a group using the last treated mouse as time zero and the number of bullets expelled in a group at different time intervals are recorded. The groups are based on time intervals of 0 to 5 minutes, 5 to 10 minutes, 10 to 20 minutes, 20 to 0 minutes, and more than * 0 minutes. They are given the activity index values of 0, 1, 2, 3 and kMice, respectively, which have expelled their bullets with the time limit of JfO minutes are examined for perforations. Those mice whose colon is perforated are removed from the group. The sum of the values divided by the number of mice or bullets is called the activity index for the investigated drug. The ED ^ q is determined by regression lines using the method of the smallest squares. The ED ^ q is arbitrarily referred to as that dose causing an activity index of 2.

The results of the trial using intraperitoneal and oral administration of N-aryl-N- (2-imidazolidinylidene) urea compounds are shown in Table B.

Table B.

Compound H 0 r ^ N \ I> = NC-NH-Ar __, »H intraperi-Ar HX tonal per os 2.6-diiCl-0 HCl 7 13.7 2.6-di (CH3) -0 HC1.1 / 2 H20 12 16 2-Cl, 6-CH3-0 HC1 8 35 2.6-diBr-0 HC1 9 3δ 2-C2H5, S-CE ^ -0 2/3 fumarate k3 121

The foregoing results illustrate the beneficial effect of N-aryl-β-CB-imidazolidinylidene urea compounds in reducing abnormal susceptibility to bowel swelling. These properties are used in the methods and compositions of the present invention.

A method of the present invention, namely, a method for alleviating functional intestinal ailments and for treating discomfort associated therewith, consists of administering to individuals in need of treatment a therapeutically effective amount of an N-aryl -N * - (2-imidazolidinylidene) urea compound of formula 1 or a pharmaceutically acceptable salt thereof as active agent. The active agents can be administered with or without carrier in amounts to be explained below. A preferred method of administration is through the use of pharmaceutical compositions in unit dosage form, as described below.

79 0.9 2 6 5 13 a

The effective ranges for carrying out the method are the oral or parenteral administration of about 5 mg to about 500 mg of an N-aryl-N- (2-imidazolidinylidene) urea compound in unit dosage form. While the therapeutic method is most suitable for human individuals, it can also be used in other mammals. Active amounts are generally in the range of 0.50 to 50 mg / kg, preferably at least 3 mg / kg of body weight.

The excellent properties, when intended for combating hypertension or when intended for combating intestinal ailments, are most effectively used when using the pharmaceutical compositions of the present invention. The pharmaceutical preparations containing an N-aryl-N '- (2-imidazolidinylidene) urea compound or acid addition salt thereof as the active ingredient, can be prepared by thoroughly mixing the urea compound with a pharmaceutical carrier according to the usual pharmaceutical mixing techniques which carrier can take a wide variety of forms, depending on the form of the formulation desired for administration, for example, oral or parenteral.

Any of the conventional pharmaceutical media can be used in the preparation of preparations in oral dosage form. Thus for liquid oral preparations such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavors, preservatives, colorants and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Because of their ease of administration, tablets and capsules are the most effective oral unit dosage form, in which case solid pharmaceutical carriers are used. If desired, tablets may be coated with sugar or a gastric acid resistant coating according to standard techniques. For parenteral preparations, the carrier will usually consist of sterile water, although terminal ingredients may be included, for example, for purposes such as solubility enhancement or preservation. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be used. The term "" unit dosage form "as used in the specification and claims refers to physically separate units, suitable as unit doses, each containing a unit / predetermined amount of active ingredient calculated to provide the desired to produce therapeutic effect together with the required pharmaceutical carrier Examples of such unit dosage forms are tablets, capsules, pills, powders, oblies, teaspoonful, tablespoonful and the like and isolated multiples thereof A dosage unit will generally be from about 5 to about 500 mg contain the N-aryl-N- (2-imidazolidinylidene) urea compounds.

The following examples illustrate the preparation of the N-aryl-N'-imidazolidinylidene urea compounds and the novel pharmaceutical preparations which are suitable for the practice of the invention, but are not limited thereto.

Starting product The starting 2-imidazolidine product of the formula II can be prepared according to methods described in the literature or according to the following representative preparation of the hydroiodide addition salt: 213 g (1.5 mol) of methyl iodide are added with stirring in 1 hour to a suspension of 153 * 24 g (1.5 mol) of ethylene thio-20 urea in 300 ml of methanol. Stirring is continued for an additional hour to complete the formation of S-methyl ethylene thiourea. Anhydrous ammonia is then added thereto and a reaction takes place to form 2-iminoimidazolidine hydroiodide and methyl mercaptan by-product. The stirring and intermittent addition of ammonia is continued for a total of about 26 hours. The mixture is concentrated with accompanying addition of isopropanol to replace the evaporated methanol and then cooled and ether is added thereto to prepare 2-iminoimidazolidine hydroiodide as a crystalline solid which, after recrystallization from methanol / tert-butanol, has a melting point of 152 - 154 ° C.

Analysis calculated for C 16.92; H, 3.79. Found: C, 16.85; H 3.82 ♦ 7909265 £ 15

Example I

H- (2,6-dichlorophenyl) -H, - (2-imidazolidinylidene) urea hydrochloride (Compound of formula 1θ) 5 To a stirred suspension of 2.13 g (0.01 mol) 2-iminoimidazolidine hydroiodide in 50 ml dry dimethylformamide under an atmosphere of nitrogen, 0.8 g (0.01 mol) of a 50 percent aqueous solution of sodium hydroxide is added to prepare the free 2-iminoimidazolidine base and sodium iodide. Thereafter, 1 g of anhydrous sodium sulfate is added and stirring is continued for an additional 30 minutes. To the mixture is then added dropwise over a period of 2.5 hours a solution of 0.94 g (0.005 mol) of 2,6-dichlorophenyl isocyanate in 20 ml of tetrahydrofuran and the mixture is stirred overnight at ambient temperature to obtain of H- (2,6-dichlorophenyl) -H'- (2-imidazolidinylidene) urea. The sodium salts are removed by filtration and the filtrate is concentrated on a water bath under reduced pressure to obtain a light yellow oil.

The latter is dissolved in dichloromethane and the dichloromethane solution is first washed with a saturated brine, dried over anhydrous potassium carbonate and treated with hydrogen chloride until a pi of less 3 is reached. The solvent and excess hydrogen chloride are removed under reduced pressure and the residue is recrystallized from methanol / ether to obtain purified H- (2,6-dichlorophenyl) -IT1 - (2-imidazolinylidene) urea hydrochloride, mp 210-212 ° C. decomposes to a new solid which melts at 239 ° C.

Example II

H- (2-chloro- (6-methylphenyl) -H1- (2-imidazololidinylidene urea and hydrochloride)

A solution of 10.65 g (0.05 mol) of 2-iminoimidazolidine hydroiodide in dimethylformamide is added dropwise with stirring over 15 minutes to a suspension of 397.5 mg (0.05 mol) of lithium hydride in 50 cooled to 5 ° C. ml of dry dimethylformamide 35 under nitrogen, after which hydrogen evolution is observed. While the stirring treatment is continued, the mixture gradually warms to ambient temperature. The reaction mixture is then cooled to 0-5 ° C and a solution of 5.0 g (0.03 mol) of 2-chloro-6-methyl-phenyl isocyanate in 25 ml of dry dimethylformamide is added dropwise over a period of two hours. . After completion of the addition, the mixture gradually warms to ambient temperature while stirring under nitrogen atmosphere overnight to obtain the desired N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene). ) urea product, which remains in solution. The product is recovered from the reaction mixture by (a) adding the mixture to 300 ml of ice water with stirring, (b) lowering the pH to below 2 with 10% aqueous hydrochloric acid to precipitating the acidic insoluble product, (c) filtration, (d) alkalizing the filtrate to a pH of 8-9 with solid potassium 10 carbonate and (e) saturating the solution with solid sodium chloride to achieve the desired N- (2-chloro-6-methylphenyl) -N '- (2-imidazolinylidene) urea free base to precipitate as a white solid The product, after thorough washing with water, has a melting point of 169-171 ° C .

The urea base product is dissolved in 30 ml of methanol and methanolic hydrogen chloride is added thereto to a pH of less than 3. Then ether is added, after which an N- (2-chloro-6-methylphenyl) -IP - (2-imidazolidinylidene) urea hydrochloride product is added. precipitates. The latter is recovered and recrystallized successively from 2-propanol and methanol-ether to yield a purified product, mp 209-211 ° C, which decomposes to a solid which melts at 270 ° C with decomposition.

Analysis calculated for O 2 H 1 ClN 2 O.HCl: C 45> 69; Η 4> 88; H 19.37. Found: C 45> 59; Η 4.93; N 19> 55

Example III

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

In a manner similar to that described in Example II, 30, a solution of 12.0 g (0.0563 mol) of 2-iminoimidazolidine hydroiodide in 50 ml of dry dimethylformamide is added dropwise under cooling and under a nitrogen atmosphere to a suspension of 447 mg (0.0563 mol) of lithium hydride in 50 ml of dry dimethylformamide. After completion of the addition, the mixture reaches ambient temperature in a period of about half an hour, is cooled to 0-5 ° C and a solution of 7> 8 g (0.082 mol) of 2,6-dibromo-phenyl isocyanate in 25 ml of dry dimethylformamide is added dropwise over a period of two hours, while maintaining the cooled temperature range. The mixture then warms to ambient temperature and is stirred overnight under nitrogen to obtain the desired N- (2,6-dihromophenyl) -1- (2-imidazolidinylidene) urea product in the reaction mixture. The product is recovered from the reaction mixture by pouring the mixture into 400 ml of ice water, bringing it to pH 5 below 10% hydrogen chloride, filtering to remove impurities, saturating the filtrate with solid sodium chloride and making it alkaline with potassium carbonate to a pH of 8-9 to precipitate the N- (2.β-dibromophenyl) -1- (2-imidazolinylidene) urea product as a white solid, mp 185-190 ° C (decomposition).

The urea base product thus obtained is suspended in 40 µl of methanol and methanolic hydrogen chloride is added thereto to a pH below 2. Thereafter, ether is added to give the H- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride as a white solid with a melting point of 200-202 ° C (decomposition). After two recrystallizations from methanol / 2-propanol / ether, a purified product with a melting point of 215-217 ° C is obtained, which decomposes to a solid at 255 ° C (decomposition).

20 Analysis calculated for Ο ^ φΞ ^ φϊΓ ^ Β ^ Ο.ΞΟΙ: 0 30.14; H 2.78; U, 14.06 Found: C, 30.12; Ξ 2.81; N 14.04.

Example 17

In a similar manner, the following compound is prepared: H- (2-Imidazolidinylidene) -H '- (2-methoxyphenyl) urea, hydrochloric acid, melting point 197-199.5 ° G, by reaction of 2-iminoimidazolidine ( prepared from 2-iminoimidazolidine hydroiodide and lithium hydride) and 2-methoxyphenyl isocyanate at about 5 to 10 ° C to obtain an H- (2-imidazolidinylidene) -N1- (2-methoxyphenyl) urea product, followed by reaction of the urea base with methanolic hydrogen -30 chloride and recrystallization first from methanol / 2-propanol and then twice from methanol-ether.

Analysis calculated for C 21 H 21 H 2 OHCl: C 48.80; Η 5.58; N 20.70

Found: C 48.75; H 5.61; ,7 20.71.

Example 7 H- (2-ethyl-6-methylphenyl) -H * - (2-imidazolidinylidene) urea. fumarate (3: 2)

In a similar manner as described above, 15.55 g (0.075 mol) of 2-iminoimidazolidine hydroiodide are added dropwise to a dry cooled suspension of 598 mg (0.075 mol) of 40 lithium hydride in 30 ml of dimethylformamide under a nitrogen atmosphere.

After completion of the addition, the mixture is allowed to warm to ambient temperature to complete the reaction. The mixture is then cooled again, a solution of 8.1 g (0.05 mol) of 2-ethyl-6-methylphenyl isocyanate in 25 ml of dry dimethylformamide is added dropwise over a period of two hours and then the resulting mixture is Stirred overnight, while the temperature rises to ambient temperatures, to obtain an N- (2-ethyl-6-methylphenyl) -N '- (2-imidazolidynylidene) urea product. The base product is recovered by similar methods as described above and after recrystallization from methanol-water, a purified base product with a melting point of 185-187 ° C is obtained.

A solution of 4.32 g (0.0175 mol) of the base product thus obtained in 35 ml of warm isopropanol is mixed with a solution of 2.04 S (0.0175 mol) of fumaric acid in 35 ml of warm isopropanol and the resulting solution is cooled, and an N- (2-ethyl-6-methylphenyl) -N '- (2-imidazololidinylidifeneum fumarate addition salt product crystallizes. The salt product melts after first washing with isopropanol and then with ether at 180 ° C (decomposition). Successive recrystallizations from methanol / isopropanol, methanol / ether and methanol 20 give no salt with a reproducible sharp melting point Elemental analysis indicates that the salt is formed from three moles of base and two moles of fumaric acid.

Analysis calculated for (C ^ H ^ gN ^ O) (C ^ H ^ O ^ Jgi c 58.13; Ξ 6.44; N 17.51; Found: C 58.03; Ξ 6.57; N 17. 59

Example VI

In a similar operation, N- (2-chlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride, mp 187-189 ° C is prepared by reaction of 2-iminoimidazoline (prepared from 2-imino-30 imidazoline hydroiodide and lithium hydride in dimethylformamide at about 20 ° C) and 2-chlorophenyl isocyanate at about 20 ° to 30 ° C overnight, then heating to -100 ° 0 on a steam bath for 15 minutes to obtain an N- (2-chlorophenyl) -N - (2-Imidazolidinylidene) urea product as a crystalline solid and then reaction of the urea base with methanolic hydrogen chloride.

Analysis calculated for C 14 H 14 N 3 OCI.HCl: C 43.66; Ξ 4.40; N 20.36 Found: G 43.69; H 4.43; ® 20.36 40 .7909 265 19

Example. YII

In operations performed in a similar manner as described in Examples II to 71, the following compounds can be prepared: 5 F-2-Imidazolidinylidene F '- (4-nonho: cyphenyl) urea and its hydrobromide F- ( 2-chloro-5-trifluoromethylphenyl) -F '- (2-imidazololidinylidene) urea and its tartrate.

F- (4-fluoro-2,6-dimethylphenyl) -Ff- (2-imidazolidinylidene) urea 10 and its malonate

H- (2-imidazolidinylidene) -N, - (4-methylphenyl) urea and its hydrochloride, mp 210-212 ° C

<tb> (2,4-dichlorophenyl) -1T, - (2-imidazolidinylidene) urea and its hydrochloride, m.p. 217-219 [deg.] C. 15- (2,3-dichlorophenyl) -IT '- (2-imidazolidinylidene) urea and the

hydrochloride thereof, mp 218-220 ° C

H, - (3 * 5 '<chchlorophenyl) -N' - (2-imidazolidinylidene) urea and its hydrochloride, mp 200-202 ° C

F- (3,4-dichlorophenyl) -H1 - (2-imidazolidinylidene) urea and its hydrochloride, mp 217-219 ° C

F- (2,5-dichlorophenyl) -F '- (2-imidazolidinylidene) urea and its hydrochloride, mp 213-215 ° C

F- (2-imidazolidinylidene) -N '- (2.4,6-trichlorophenyl) urea and its hydrochloride, mp 232 ° C decomposes to solid, mp 2 ° 0 (decomposition) F- (2-fluoro-é- methylphenyl) -F '- (2-imidazololidinylidene) urea and its hydrochloride F- (2-imidazololidinylidene) -F' - (2-methyl-trifluoromethylphenyl) urea and its hydrochloride F- (2- imidazololidinylidene) -F * - (2-methyl-6-methylsulfonylphenyl) -urea and its hydrochloride F- (2-cyano-6-methylphenyl) -F1 - (2-imidazololidinylidene) urea and its hydrochloride F- (2-chloro-6-methylphenyl) -F '- (2-imidazolidinylidene) urea and its hydrochloride F- (2-bromo-6-methylphenyl) -F, - (2-imidazolidinylidene) urea and its hydrochloride F- (2-bromo-6-ethylphenyl) -F1- (2-imidazolidynilidene) urea and its hydrochloride 40 F- (2-chloro-6-ethylphenyl) -F '- (2-imidazolidinylidene) urea and . . ; 2 6 5 ζ '20 its hydrochloride ET- (2-bromo-6-chlorophenyl) -ET' - (2-imidazolidinylidene) urea and its hydrochloride ΕΓ- (2-methoxy-6-methylphenyl) -ET'- (2-imidazololidinylidene) urea 5 and its hydrochloride ET- (2-methyl-6-tridluoromethylphenyl) -ET * - (2-imidazolidinylidene) • urea and its hydrochloride ET- (2-chloro-6-fluorophenyl) ) -ET'- (2-imidazolidinylidene) urea and its hydrochloride.

10 "Example · VIII

Egg - (2-imldazolidinylidene) -Eri-phenylurea and its hydroiodide (Compound of formula 11)

As the first step in the reaction, phenyl isocyanate, 119 g (1 mol), is added all at once while swirling in a warm solution of 83.73 S (1.1 mol) thiourea in 120 ml of dry dimethylformamide and the resulting solution is heated for three hours. The solution is then cooled, a mixture of ice and ice water carefully added and the reservoir scratched to induce crystallization of the desired intermediate ET-phenylthioimidodicarbondiamide. EAdditional ice water (about 1 L) is added after crystallization begins. The crystals formed are then collected, washed with water and recrystallized from methanol to give 127 g of an ET-phenylthioimidodicarbondiamide intermediate, melting point 17 DEG-180 DEG.

As a second step, 45.5 g (0.32 mol) of methyl iodide are added to a solution of 59.5 g (0.305 mol) of Ef-phenylthioimido-dicarbondiamide in 300 ml of acetone and the resulting mixture is stirred at ambient temperature for about two hours . As a result of these operations, crystals are formed in the reaction mixture, which are then filtered and dried to obtain a methyl N '- [(phenylamino) carbonyl] carbamimidothioate hydroiodide product, mp 195 DEG-200 DEG. An analytical sample, melting point (190 ° C) 200-202 ° C (Hoover) is obtained by recrystallization from methanol.

55 Analysis calculated for C 1 H 30 IT O OS HJ: C 32.06; H 3.59; N 12.46 Found; C, 32.11; H 3.62; ET 12.48

Then a methanol solution of 33.72 g (0.1 mol) of the methyl N '- [phenylamino) -carbonylcarbamimido-40 thioate hydroiodide thus prepared and a methanol solution of 6.01 g (0.1 mol) are added. 4, 1 92 6 5 21. Ethylenedylene diine (about 50 ml of total methanol) mixed together and refluxed for about 90 minutes. The mixture is then cooled to -20 ° C to crystallize N- (2-imidazolidinylidene) -1-phenylurea as its hydroiodide, 5 different yields are recovered, combined the combined yields purified by dissolving in methanol, filtering and evaporate the filtrate to isolate the hydroiodide product as a residue.

The hydroiodide product residue is converted to the urea base-10 product and purified by a series of steps, including dissolving the residue in a minimal amount of methanol, mixing and heating with 8.0 g (0.079 mol) of triethylamine, replacing the methanol with ethanol, and then cooling to obtain crystals of N- (2-imidazolidinylidene) -N-phenylurea base 15 mp (181 °) 182-183 ° C after recrystallization from methanol.

Analysis calculated for Ο ^ Η ^ Η ^ Ο: 0 58.81; Ξ 5.92; N 27.43 Found: C 58.79; H 5.92; H 27.48

The hydroiodide addition salt / recrystallization from acetone 20 melting point 223-225 ° C (decomposition) when immersed at 225 ° C, melting point 230 ° C (decomposition).

Analysis calculated for O ^ qE ^^ O.EJ

C, 36.16; H 3.94; N 16.87; J 38.21 Found: G 36.22; Ξ 3.96; H 16.88; 3 38.21

Example IX

ff- (3-chlorophenyl) -N1- (2-imidazolidinvlidene) urea

In operations carried out in a manner similar to that described in Example VIII, 153.57 g (1.0 mole) m-chlorophenyl isocyanate is added to a warm solution of 95.15 g 30 (1.25 mole) thiourea in 100 ml dimethylformamide and the resulting mixture is heated on the steam bath overnight to obtain an ff- (3-chlorophenyl) thioimidodicarbondiamide intermediate in the reaction mixture. Then, the reaction mixture is cooled to completely precipitate the desired intermediate, which, after recovery by filtration and washing with ether, has a melting point of 187-189 ° C (decomposition). Additional amounts are obtained, combined and recrystallized twice from methanol-water and twice from acetonitrile to obtain a purified product, mp 205-207 ° (decomposition).

40 On a transparent acetone solution of 80.3 g (0.35 mol) 70 0 0? £ 5 IJ V V «*« * '. 22 N- (3-chlorophenyl) thioimidodicarbondiamide (prepared as described above), 75.0 g (0.525 mol) of methyl iodide are added and the reaction mixture is stirred overnight to obtain the desired methyl Ν'- j * [3-chlorophenyl) amino] -carbonyl-carbamimidothioate hydroidoprodufct as a crystalline solid, mp 182-183 ° C (decomposition).

6.0 g (0.1 mol) of ethylenediamine in 100 ml of methanol are added to 57.1 g (0.1 mol) of methyl N * -j [(3-chlorophenyl) -amino] carbonyl] -carbamimidothioate hydroiodide thus prepared. the resulting mixture is refluxed for five hours. The resulting reaction mixture is evaporated to dryness under reduced pressure and diluted with tert.-butanol to obtain crystals of ΪΓ- (3-chlorophenyl) -1- (2-imidazolidinylidene) urea hydroiodide product as a crystalline solid. The crystals are recrystallized several times from tert-butanol to obtain a purified product, mp 192-194 ° C (decomposition).

Analysis calculated for C 16 H 14 C 16 H O.HJ; C, 32.76; H 3.29 Found: C 32.82; H 3.33.

7909265 23

The following examples illustrate, but are not limited to, the new pharmaceutical compositions intended to combat hypertension.

Example X.

5 1,000 hard gelatin capsules, each containing 200 mg of TT- (2,6-dichlorophenyl) -N, - (2-imidazolidinylidene) urea are prepared from the following formulation: g H- (2,6-dichlorophenyl) -N1 - (2-imida-10-zolidinylidene) urea 200 starch 250 lactose 750 talc 250 calcium stearate 10 15 An even mixture of the ingredients is prepared by mixing and used to fill two piece hard gelatin capsules. The capsules are suitable for oral administration to individuals with hypertension to lower blood pressure.

Example XI

Gelatin capsules are prepared as described in Example X, except that in the formulation 325 g of H- (2,6-dimethylphenyl) -N, - (2-imidazolidinylidene) urea is used as an active ingredient to provide capsules containing 325 mg of 11- (2.6-25 dime thy 1 f eny1) -N '- (2-imidazoin diny 1 i en) urea.

Example XII

1,000 beaten tablets, each containing 500 mg of U- (2-imidazolidinylidene) -if- (2-methoxyphenyl) urea are prepared from the following formulation: 30 g of N- (2-imidazolidinylidene) - N * - (2 -methoxyphenyl) urea 500 starch 750 hydrous dibasic calcium phosphate 5000 35 calcium stearate 2.5

The finely powdered ingredients are mixed well and granulated with 10% starch paste. The granulated product is dried and beaten into tablets using starch as a disintegrant and calcium stearate as a lubricant.

7909265 zb

Example XIII

Tablets are prepared as described in Example XII except that U- (2,6-dibromophenyl) -iP- (2-imidazolidinylidene) urea is used as the active ingredient,

Example XIV

Gelatin capsules are prepared as described in Example X, except that U- (3-chlorophenyl) -E '- (2-imidazolidinylidene) urea is used as the active ingredient.

The following examples illustrate new pharmaceutical compositions which are intended for, but are not limited to, combating internal ailments.

Example XV

1,000 hard gelatin capsules, which. each containing 200 mg of N- (2,6-dichloro-phenyl) -N, - (2-imidazolidinylidene) ureT3m are prepared from the following formulation:, g— H- (2,6-dichlorophenyl) -N1- ( 2-imidazolidinylidene) urea 200 starch 250 20 lactose 750 talc 250 calcium stearate 10

An even mixture of ingredients is prepared by mixing and used to fill two-piece hard gelatin capsules. The capsules are suitable for oral administration to individuals with functional bowel ailments.

Example XVI

Gelatin capsules are prepared as described in Example VI except that in the formulation 400 g of (- (2,6-dibromo-50-phenyl) -N, - (2-imidazolidinylidene) urea are used as active ingredient to provide capsules containing 400 mg of N- (2,6-dibromophenyl) -H '- (2-imidazolidinylidene) urea.

Example XVII

Gelatin capsules are prepared as described in Example VII except that N- (2-ethyl-6-methyl) -ur- (2-imidazolidinyl-idene) urea is used as the active ingredient.

Example XVIII

Gelatin capsules are prepared as described in Example VII, except that E- (2,6-dimethylphenyl) -N '- (2-imidazolidi-40-nylidene) urea is used as the active ingredient.

7 9 0 9 2 6 5.

. \ v 25

Example XIX

1,000 beaten tablets, each containing 500 mg of H- (2-chloro-methyl-phenyl) '- (2-imidazolidinylidene) urea are made from the following formulation: 5 g of N- (2-chloro-6-methylphenyl) -U'- (2-imidazolidinylidene) urea 500 starch 750 hydrous dibasic calcium phosphate 5000 10 calcium stearate 2.5

The finely powdered ingredients are mixed well and granulated with 10% starch paste. The granulated product is dried and beaten into tablets using starch as a disintegrant and calcium stearate as a lubricant.

"·) 0 9 2 8 5

Claims (12)

A pharmaceutical composition characterized by a therapeutically effective amount of a urea compound, which urea compound is selected from (a) a compound of formula 1, wherein Ar represents phenyl substituted with 0 to 3 substituents independently selected from groups characterized by the presence of halogen and of a carbon-containing group of 1 or 2 carbon atoms, which is optionally bound to the phenyl moiety by a non-basic heterocyclic atom or (b) a pharmaceutically acceptable salt thereof, provided that when the compound is intended to combat from intestinal ailments, Ar is limited to phenyl substituted in at least the 2 and 6 positions with. the halogen or carbon containing groups, wherein the urea compound is mixed with a pharmaceutically acceptable carrier. Pharmaceutical composition characterized by the presence per unit dosage form of 5 to 500 mg of a urea compound of formula 12, wherein each symbol E represents chlorine, bromine, methyl, ethyl and / or methoxy, n is an integer from 0 to 3 and pharmaceutically acceptable salts thereof, wherein the urea compound is mixed with a pharmaceutically acceptable carrier. 3. A composition according to claim 1, characterized in that the urea compound is ΕΓ- (2,6-dichlorophenyl) -15- (2-imidazolidinylidene) urea. 4. A composition according to claim 1, characterized in that the urea compound is U- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene) urea. 5. Preparation according to claim 1, characterized in that the urea compound is -T- (2-imidazoiidinylidene) -N, - (2-methoxyphenyl) urea. Preparation according to claim 1, characterized in that the urea compound is H- (2-chlorophenyl) -N, - (2-imidazoli dinylidene) urea. Pharmaceutical composition characterized by the presence per unit dosage form of about 5 to 500 mg of a urea compound of formula 9 wherein X and Y represent methyl, ethyl, chlorine and / or bromine, and pharmaceutically acceptable salts thereof. · Preparation according to claim 7, characterized in that the compound is N- (2-chloro-6-methylphenyl) -E, - (2-imidazolidinylidene) urum. 7909265 9. A compound of formula 9, wherein and Rg each represent halogen, low-carbon alkoxy or low-carbon alkyl, with the proviso that R 1 and R 2 are not both low-carbon alkyl. 10. 10.T- (2,6-diciiloorphenyl) -li, - (2-imidazolidinylidene) uretim. 11. A process for the preparation of a compound of formula 9, wherein R 1 and R 2 each represent halogen, alkoxy with a small number of carbon atoms or alkyl with a small number of carbon atoms, with the proviso that R 1 and R 2 are not both alkyl having a small number of carbon atoms, characterized in that 2-iminoimidazolidine with a compound of formula 13 is converted into a suitable solvent. 12. Process for the preparation of ΪΓ- (2,6-dichlorophenyl) -IT- (2-imidazolidinylidene) urea, characterized in that 2-iminoimidazolidine is reacted with 2,6-dichlorophenyl isocyanate. Process for the preparation of a pharmaceutical preparation, characterized in that one or more active compounds according to one or more of the preceding claims are brought into a form suitable for such use. J109265