NO794249L - PROCEDURE FOR THE CONTROL OF HYPERTENSION AND INTESTINAL DEFECTS, AND PREPARATIONS THEREOF - Google Patents

Description

Procedure for control of hypertension

and intestinal deficiencies, as well as preparations therefore.

The present invention relates to methods and compounds for controlling hypertension and for alleviating intestinal deficiencies using N-aryl-N'-(2-imidazolidinylidene)-urea preparations.

Irritable bowel syndrome is a functional deficiency characterized primarily by pain in the lower abdomen, but also by diarrhea and constipation and similar symptoms. It is assumed that the pain associated with this syndrome is due to increased sensitivity and expansion of the intestine which is either caused by intestinal gas and/or faecal material. Treatment that will provide relief for the inconveniences associated with such symptoms and/or the diseases that cause such symptoms is highly desirable.

Certain imidazolidine ureas are known per se. Thus, the U.S. describes Patent No. 3,168,520 imidazolidine ureas and hexahydropyrimidine ureas. These compounds are described as useful as dye stabilizers. The patent specifically describes 2-phenylcarbiliminoimidazolidine which is N-(2-imidazolidinylidine)-N<*->phenylurea. However, there is no description or suggestion in the patent for the use of imidazolidine ureas and hexahydropyrimidine ureas as active ingredients in pharmaceutical preparations.

Some urea compounds that have been described have certain pharmacological properties. Thus, the U.S. describes Patent No. 4,060,635 amidinourea. These compounds have an aryl group on the urea nitrogen and a substituted amidino group on the other urea nitrogen. U.S. patent nos. 3,539,616 and 3,784,582 describe amidinoureas and ureas where one urea nitrogen is substituted with an aryl group and the other urea nitrogen is substituted with an unsubstituted amidino group. U.S. patent no. 4,058,557, which is also more distantly related to amidinoureas, describes compounds where one of the amidino nitrogens is necessarily linked to an ok-sygen. None of these patents describe or suggest the substitution of an imidazolidino group on a urea nitrogen. None of these patents describe or suggest anti-hypertensive activity.

A recent publication, G.H. Douglas et al., Arz. Forsch/Drug Res. 28(11), 1480 (1978), describes the results of many aryl substituted amidinoureas tested for antimotility and antisecretory activity. N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene)urea and N-(2,6-dimethylphenyl)-N'-(1-methyl-2-imidazolidinylidene)urea are among the compounds described . The article does not describe that these compounds have useful antimotivation activity and no other pharmacological tests are reproduced or use suggested for these compounds. The present invention relates to a method for treating hypertension and a method for treating functional, intestinal deficiencies and diseases and for alleviating pain and other symptoms associated with an irritable bowel, by supplying the person who requires therapy with a preparation comprising N-aryl-N'-(2-imidazolidinylidene)urea compound with the formula

or a pharmaceutically acceptable acid addition salt thereof. The invention also includes preparations suitable for treating hypertension and for preventing diarrhea and treating intestinal deficiencies and diseases where the aforementioned urea compound is mixed with a pharmaceutically acceptable carrier.

In the preceding and following formula, Ar is phenyl-substituted with 0 to 3 substituents independently selected from groups characterized by the presence of halogen or by a group containing carbon with from 1 to 2 carbon atoms optionally linked to phenyl through a non-basic heteroatom, with the proviso that when the said compound is to be used to control intestinal deficiencies and diseases, Ar is limited to phenyl substituted in at least the 2 and 6 position by said halogen or carbon-containing groups. The representative substituents are halogen such as fluorine, chlorine and bromine; lower alkyl, such as methyl and ethyl; lower alkoxy, such as methoxy and ethoxy; trifluoromethyl; methylthioj methylsulfonylj methylsulfinylj and cyano. In the most preferred compounds to control hypertension, Ar may be represented by

where R is methyl, ethyl, chlorine, bromine or methoxy and n is an integer from 0 to 3. In the most preferred compounds to control intestinal deficiencies and diseases, Ar may be represented by the formula

where X and Y are selected from methyl, ethyl, chlorine or bromine.

The activities of the above compounds lie in the urea base, so that useful acid addition salts can be prepared from various acids provided the acids are pharmaceutically acceptable. Representative acid salts include hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, p-toluene sulfonate, benzene sulfonate, maleate, tartrate, fumarate, citrate, pamoate, maleate, malonate, succinate, oxalate, methosulfate, methanesulfonate, 2-napsylate and the like .

Certain of the present compounds are new in and of themselves, namely a compound of formula

where FL and R 2 are each halogen, lower alkoxy or lower alkyl, with the proviso that R 1 and R ? not both can be lower alkyl.

The pharmacologically useful N-aryl-N' (2-imidazolidinylidene)urea compounds are prepared by basically two methods. The most commonly used method is the reaction of a suitable 2-imino-imidazoline (II) with an aryl isocyanate (III) according to the following equation: following) and is stored as an acid addition salt

Thus, usually the first step is the conversion of acid addition salts to the free base. This can be accomplished by thoroughly stirring a solution or suspension in tetrahydrofuran of the acid addition salt with two molar equivalents of 50 percent aqueous sodium hydroxide, followed by the addition of anhydrous sodium sulfate to remove excess water. The biphasic mixture is contacted with an appropriate aryl isocyanate to produce the desired N-aryl-N'-imidazolidinylideneurea compound.

A preferred method for carrying out the reaction between the aryl isocyanate and 2-imidazolidine, a solution of aryl isocyanate in tetrahydrofuran is added portionwise with stirring to the two-phase mixture at temperatures in the range of 20° to 30°C and the mixture is stirred from some few more hours overnight. The N-aryl-N'-imidazolidinylideneurea compound thus obtained is recovered, converted into an acid addition salt if desired, and purified using known methods.

The free base can be produced by another method and a solution of 2-iminoimidazolidine acid addition salt is brought into contact with a suspension of lithium hydride, preferably in the same solvent, in an inert atmosphere. Suitable solvents include dry dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. The temperature for the addition is in the range 0° to 30°C. An inert atmosphere is obtained by using nitrogen or argon.

In a preferred method for carrying out the reaction, a solution of 2-iminoimidazolidine acid addition salt is added dropwise with stirring to a cooled suspension of lithium hydride in a dry solvent under a nitrogen atmosphere, while maintaining a temperature in the range between:.0-5° C. The stirring is continued after the addition has ended, while the mixture is gradually heated to room temperature to obtain a free base.

The reaction between 2-iminoimidazolidine and aryl isocyanate can be carried out by adding a solution of aryl isocyanate, dropwise with stirring and cooling, to the reaction mixture containing

wherein the free base in an inert atmosphere, stirring the resulting mixture while gradually heating it to room temperature and then in the temperature range of from 30° to 110°C, preferably in the range of from 65° to 110°C to optimize the yield, to provide the desired N-aryl-N'-(2-imidazolidinylidene)urea product. When the reaction is carried out at room temperature, stirring is usually continued for several hours or overnight; when the reaction is carried out under heating, two hours is usually satisfactory.

Another general, but less preferred method for preparing the N-aryl-N'-(2-imidazolidinylidene)-urea compound goes through the following reaction sequence:

It is seen that the first step is a reaction between an appropriate aryl isocyanate (III) and thiourea to produce an N-arylthio-imidodicarbonicdiamide (IV) which is then reacted with methyl iodide to produce a methyl N,-[(arylamino)- carbonyl]carbamimidothioate (V). The latter produces when reacted with a suitably substituted ethylenediamine (VI) N-aryl-N'-(2-imidazolidinylidene)urea (I) as a hydroiodide addition salt which can then be converted to the free base in a manner known per se. However, the aforementioned reaction sequence is not applicable for the preparation of urea compounds where the aryl group is a 2,6-disubstituted phenyl group.

The first step can be performed by applying a modification

of the method reproduced by Lakra et al., (J.Am.Chem.

Soc. 5_lj 2220 (1929)) where a suitable aryl isocyanate (III) and thiourea are reacted to produce an N-arylthioimidodicarboxylic acid diamide compound (IV), hereinafter for convenient reasons referred to as "thiobiuret compound". For this reaction, mostly equimolar amounts of the reactants are used, preferably with a small excess of thiourea. The temperature for the reaction can be in the range of 80° to 120°C. The reaction is preferably carried out in a solvent. Suitable solvents include dimethylformamide, dimethylsulfoxide and the like.

The reaction is preferably carried out by heating isocyanate

and thiourea at steam bath temperature for from two to twelve hours, after which the thiobiuret compound (IV) is formed in the reaction mixture. The mixture is then diluted with water and cooled to produce a crystallization of the thiobiuret compound, which is then rinsed from the reaction mixture and purified using known methods.

In the second reaction step, the N-aryl thiobiuret compound and an S-methylating agent are reacted to produce a methyl N.'-[(arylamino)carbonyl]carbamimidothioate compound (V), which is hereafter referred to as "the thioate compound" for expedient reasons. Largely equimolecular amounts of the reactants, preferably a small excess of methylating agent are used. Although other methylating agents, such as dimethyl sulfate and the like can be used, methyl iodide is preferred. A solvent is preferably used. Suitable solvents include acetone, methanol, ethanol, isopropanol and the like. The temperature in the reaction can go from room temperature to reflux temperature,

and room temperatures are preferred.

The reaction is suitably carried out by mixing together the thiobiuret compound and methyl iodide in methanol at room temperature for several hours. The product formed in the reaction mixture as its hydroiodide addition salt is recovered and purified, if desired, using conventional methods.

In the third step, the thioate compound (V) is reacted as the hydroiodide salt and a suitable ethylenediamine compound (VI)

to produce the desired N-aryl-N'imidazolidinylideneurea product as the hydroiodide salt. Largely equimolecular amounts of the reactants are used. The reaction is preferably carried out in methanol and other lower alkanols, and methanol is preferred.

The reaction is conveniently carried out by boiling the hydroiodide salt from V and the ethylenediamine compound in methanol under reflux for from one to several hours, and then evaporating the solvent to provide as a residue the desired N-aryl-N'-imidazolidinylideneurea- product as hydroiodide salt. The product can then be recovered and purified using known methods.

The salt can be converted into the free base. If another salt is desired, the free base is reacted with another acid to form the desired acid addition salt. Usual methods can be used for these transformations. Thus, e.g. a representative convenient method for producing the free base from the salt is to dissolve the acid addition salt in a minimal amount of a lower alkanol solvent such as methanol or ethanol, heat together with an organic base such as triethylamine and the like, and then cool the mixture to providing the free base product as a crystalline solid. Similarly, a representative convenient method is to convert the free base to an acid addition salt, and mix the base with an alcoholic solution of an acid corresponding to the desired addition salt and cool to provide the acid addition salt.

Procedure for controlling hypertension.

N-aryl-N'-(2-imidazolidinylidene)urea compound has been shown to relieve hypertension and further, to largely provide this without increasing the heart rate. An agent which has an antihypertensive effect without increasing, but rather maintaining and/or reducing the heart rate, is considered most useful for the beneficial treatment of hypertensive individuals. The degree to which the compound possesses these properties can be determined in antihypertensive tests on rodents and in hemodynamic assessment in skins which is described below.

Antihypertensive study in rodents.

This test evaluates the compounds with regard to their effect on arterial pressure and heart rate. In this test, arterial pressure is monitored in hypertensive rats or rats made hypertensive by injection of desoxycorticosterone acetate and 2 percent sodium chloride for drinking water, directly through a cannula into the aorta. The end of the cannula is passed into the aorta and the cannula is passed out behind the neck at the level of the scapula. The animals are placed in individual cages and are allowed to recover from the anesthesia and are kept without obstacles. The arterial cannula is connected to a pressure transducer which is connected to a gauge. The heart rate is determined from the measurements of arterial pressure. Animals with a pressure greater than 149 mm of mercury are considered sufficiently hypertensive to be used in the tests with regard to antihypertensive effects. The test compound is administered either orally (p.o.) or intraperitoneally by injection. The arterial pressure and heart rate are monitored for a minimum of four hours. A test compound is considered active as an antihypertensive agent if mean arterial pressure (MAP) suggests a drop of greater than 19 mm Hg. Each animal serves as its own control.

Results of this test using two rats for each compound and performed with N-aryl-N'-(2-imidazolidinylidene)-urea compounds are shown in Table I.

Hemodynamic assessment in dogs.

This test is used to assess the effect of a given compound on both the cardiovascular and autonomic nervous systems in normal, anesthetized animals.

In this test, bastard dogs are anesthetized with 20 mg/kg (milligrams per kilogram of body weight) sodium thiopental and 60 mg/kg alpha-chlorolose. Additional chlorolose (60 mg/kg) is used to maintain anesthesia if necessary. A cuffed endotracheal tube is inserted to maintain a clear airway and the animal is allowed to breathe through a ventilation pump. A femoral artery and vein are catheterized for measurement of arterial pressure and for intra-venous injection, respectively. Both common cartoid arteries are isolated to achieve a bilateral cartoid occlusion. The Vargus nerve is electrically stimulated peripherally and for ten seconds with five volts and 20 pulses per second each with two milli-second duration to

have cardiac arrest. The electrocardiograms are monitored through the Limb Lead II.

Control cardiovascular responses are provided to the following pharmacological methods: 1.0 mcg/kg I.V. (micrograms per kilogram of body weight intravenously) /^-epinephrine, carotid occlusion, 10 mcg/kg I.V. dimethylphenyl-piperazinium iodide (DMPP), peripheral vagal stimulation, 10 mcg/kg I.V. acetylcholine and 2 mcg/kg I.V. MDB 12-20-CRR 12/20 angio-tensin. These control responses are produced twice, after which the test compound is injected at 5 mg/kg (milligrams per kilogram) I.V. using bolus injections during approx. one minute. If no change in arterial pressure, heart rate or ECG (Limb Lead II) is obtained, a further 5 mg/kg I.V. of the sample compound. The effects of the test compound are recorded on the electrocardiogram, arterial pressure and heart rate. Ten minutes after the administration of the test compound, another series of hemodynamic responses is obtained.

Using one dog for each test compound, heart rate data are obtained for N-aryl-N(2-imidazolidinylidene)-urea compounds. The results of these tests are also shown in Table I.

The results in Table I show that the N-aryl-N'-(2-imidazolidinylidene)urea compounds and their salts not only have a beneficial antihypertensive effect but also the property of maintaining or lowering heart rate. The properties are used in the methods and preparations according to the invention.

A method according to the invention, namely a method for treating hypertension or for reducing high blood pressure, consists in supplying people who require such treatment, is therapeutically effective hypertension or arterial pressure reducing amount of N-aryl-N(2-imidazolinylidene)urea compound with formula I or its pharmaceutically acceptable salt as active agent. The active agent can be added with or without a carrier in the amounts given below. A preferred method of administration is by using the pharmaceutical preparations in unit doses which are described below.

The operative areas for carrying out the method are supply, orally or parenterally, or from approx. 5 to 500 milligrams of N-aryl-N'-(2-imidazolidinylidene)urea compound' in dosage unit form. Although the therapeutic method is most useful for humans, it can also be used for all mammals. Operative amounts are usually in the range from 0.5 to 50 mg/kg body weight.

Procedure for controlling intestinal deficiencies or diseases.

N-aryl-N'-(2-imidazolidinylidene)urea compound has been shown to provide relief from discomfort associated with functional intestinal deficiencies or diseases referred to as irritable bowel syndrome. The disease is characterized by abdominal pain, diarrhoea, constipation and similar symptoms caused by excessive sensitivity to the expansion of the intestine in the presence of intestinal gas and/or faecal material.

The degree to which a compound is effective in terms of

provide relief, can be determined by a test where a glass ball is inserted into the rectum and the time difference between insertion and expulsion of the ball is determined. Compounds effective in reducing sensitivity to distension of the intestinal wall delay expulsion of the pellet.

The test is performed with a male albino mouse of 18-25 g body weight, using a group of five mice for each compound tested. The first dose chosen for all compounds is 50 milligrams per kilogram of body weight (mg/kg) given by mouth in a volume of 0.1 milliliters per 10 grams of body weight. The control group receives the vehicle, 0.5 percent methocel, used for both oral and intraperitoneal administration. The mice are fasted one hour before testing and the test drug is given one hour before the introduction of the glass ball.

Towards the end of the pretreatment time, the mice are picked up and held firmly in one hand with the abdomen facing the technician. The glass ball of 3 mm is placed in the rectum (, J>. mm = diameter) and using a pinching movement with the thumb and forefinger, the ball is introduced into the rectum. A glass rod (3 mm diameter) is then used which is lubricated with 0.5 per cent methocel to facilitate insertion, and the glass ball is introduced 2 cm into the rectum using a slow and careful rotating movement. The mice are timed as a group and the last mouse that received the ball is used as the zero time and the number of glass balls ejected in a group at different time intervals is determined. The group is based on timed intervals of 0 to 5 minutes, 5 to 10 minutes, 10 to 20 minutes, 20 to 40 minutes and more than 40 minutes. They are given an activity index value of 0,1,2,3 and 4 respectively. Mice that have not ejected their balls after the 40 minute period are examined with regard to perforation. The mice that have perforated are eliminated from the group. The sum of the values divided by the number of mice or balls is called the activity index for the drug being tested. ED^q is determined by regression lines using the least squares method. ED^og^"s a random designation of the dose that causes an activity index of 2.

The results of this trial using intraperitoneal and oral administration of N-aryl-N'-(2-imidazolidinylidene)-urea compound are shown in Table I.

The aforementioned results demonstrate a beneficial effect of N-aryl-N'-(2-imidazolidinylidene)urea compound in reducing normal susceptibility to distension of the intestine. These properties are used in the method and preparation according to the invention.

A method according to the invention, namely a method for

to alleviate functional intestinal deficiencies or diseases and to treat discomfort associated therewith, comprises administering to individuals requiring such treatment a therapeutically effective amount of N-aryl-N'-(2-imidazolidinylidene)urea compound of formula I or its pharmaceutically acceptable salt as active agent

The active agent can be added with or without a carrier in amounts given below. A preferred method for administering the preparation is to use pharmaceutical preparations in unit dose form as described below.

The operative areas for carrying out the process are the administration, orally or parenterally, of from 5 to 500 milligrams of N-aryl-N'-(2-imidazolidinylidene)urea compound in unit dose form.

Although the therapeutic method is most appropriate for humans, it can also be used for all mammals. Operative amounts are usually in the range from 0.50 to 50 mg/kg, and preferably at least 3 mg/kg body weight.

The outstanding properties when it comes to controlling hypertension or controlling intestinal deficiencies, most effectively used when using pharmaceutical preparations according to the invention. The pharmaceutical preparations comprise the N-aryl-N'-(2-imidazolidinylidene)urea compound or its acid addition salt as an active ingredient, and it can be prepared by thoroughly mixing the urea compound with a pharmaceutical carrier in a manner known per se, and the carrier can take a number of forms depending on the preparation desired for delivery, e.g. oral or parenteral. When preparing the preparations in oral dosage form, any of the known pharmaceutical media can be used. Thus for liquid oral preparations, such as e.g. suspensions, elixirs and solutions, are suitable carriers and additives such as water, glycols, oils, alcohols, flavourings, preservatives, dyes and the like, and for solid, oral preparations such as e.g. powders, capsules and tablets are suitable carriers and additives starch, sugar, diluents, granulating agents, lubricants, binding agents, disintegrating agents and the like. Due to the ease of administration, tablets and capsules are the most favorable unit dose form for oral administration, and here solid, pharmaceutical carriers are used. If desired, the tablets can be sugar-coated or enteric-coated using standard methods. For parenteral administration, the carrier usually comprises sterile water,

and other constituents, e.g. to increase solubility or for preservation purposes can be used. Injectable suspensions can also be prepared and in that case suitable liquid carriers can

substance, suspending agents etc. used. The term "unit dose form" used under the specifications and claims means physically separate units suitable for unit doses, and where a unit contains a specific amount of active ingredients calculated to produce the desired therapeutic effect together with the pharmaceutical carrier. Examples of such dosage units are capsules, pills, tablets, powder packs, plates, teaspoons, tablespoons etc. and separated whole numbers from this. A dosage unit will usually contain from 5 to 500 mg of N-aryl-N'-(2-imidazolidinylidene) urea compounds.

The following examples illustrate the production of N-aryl-N'-(2-imidazolidinylidene)urea compounds and the new pharmaceutical preparations which are suitable according to the invention, but the examples do not limit the invention.

Source material

2-imidazolidine starting material with formula II can be prepared by methods described in the literature or by the following representative preparation of hydroiodide addition salt: 213 grams (1.5 mol) of methyl iodide are added with stirring over the course of an hour to a suspension of 153.24 grams (1.5 mol ) ethylenethiourea in 300 milliliters of methanol. Stirring is continued for an additional hour to terminate the formation of S-methyl-ethylenethiourea. Anhydrous ammonia is then added after which a reaction takes place with the formation of 2-iminoimidazolidine hydroiodide and methylmercaptan by-product. The stirring and interrupted addition of ammonia continues for a total of 26 hours. The mixture is concentrated by simultaneous addition of isopropanol to replace evaporated methanol, then cooled and ether added to produce . 2-iminoimidazoline hydroiodide as a crystalline solid which, after recrystallization from methanol/tert.-butanol, has a melting point of 152<0->154°C.

Analysis? calculated for C^H^N^«HI;

C, 16.92; H, 3.79

found C, 16.85; H, 3.82

Example 1

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

To a stirred suspension of 2.13 grams (0.01 mol) of 2-iminoimidazolidine hydroiodide in 50 milliliters of dry dimethylformamide under a nitrogen atmosphere, 0.8 grams (0.01 mol) of aqueous 50-$ sodium hydroxide is added to produce 2-iminoimidazolidine free base and sodium iodide. Then 1 gram of anhydrous sodium sulphate is added and the stirring is continued for a further half an hour. A solution of 0.94 grams (0.005 mol) of 2,6-dichlorophenyl isocyanate in 20 ml of tetrahydrofuran is then added dropwise over 2.5 hours to the mixture and the mixture is stirred overnight at room temperature to obtain N-(2,6-dichlorophenyl) )-N'-(2-imidazolidinylidene)urea product. The sodium salt is removed by filtration and the filtrate is concentrated over a water bath under reduced pressure and gives a pale yellow oil. The latter is dissolved in methylene chloride and the methylene chloride solution is first washed with saturated salt water, dried over anhydrous potassium carbonate and treated with hydrogen chloride until pH < 3 is reached. The solvent and excess hydrogen chloride are removed in vacuo and the residue recrystallized from methanol/ether to provide purified N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea hydrochloride, mp 210°-212°C which decomp. to a new solid which melts at 239°C.

Example II

N-(2-Chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea

and hydrochloride

A solution of 10.65 grams (0.05 mol) of 2-iminoimidazolidine hydroiodide in dimethylformamide is added dropwise with stirring over the course of 15 minutes to a suspension of 397-5 milligrams (0.05 mol) of lithium hydride. cooled to 5°C, in 50 milliliters of dry dimethylformamide under a nitrogen atmosphere, so that hydrogen is evolved. While stirring rapidly, the mixture is gradually allowed to warm to room temperature. The reaction mixture is then cooled to 0-5°C and a solution of 5.0 grams (0.03 mol) of 2-chloro-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over the course of two hours. After the addition is complete, the mixture is gradually allowed to reach room temperature while stirring under nitrogen is continued overnight to obtain the desired N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea product which is kept in solution . The product is recovered from the reaction mixture by (a) adding 300 milliliters of ice water to the mixture with stirring, (b) lowering the pH below 2 with aqueous 10% hydrochloric acid to precipitate acid-dissolved material, (c) filtering, (d) basifying the filtrate to pH 8-9 with solid potassium carbonate, and (e) saturating the solution with solid sodium chloride to precipitate the desired N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea free base as a white solid -fabric. After thorough washing, the product has a melting point of 169° - 171°C.

The urea base product is dissolved in 30 milliliters of methanol, and methanolic hydrogen chloride is added to a pH less than 3. Ether is then added, after which the N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea hydrochloride product is precipitated. The latter is recovered and crystallized successively from 2-prop-anol and methanol-ether to obtain a purified product, mp 209° - 211°C, which decomposes to a solid melting at 270°C (decomposes).

Analysis calcd for C 2 H 2 Cl 2 O • HC 1 : C, 45.69; H, 4.88;

N, 19-37

found: C, 45-59; H, 4.93; N, 19-35

Example III

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

In a similar way as described in example II, is added

a solution of 12.0 grams (0.0563 mol) of 2-iminoimidazolidine hydroiodide in 50 milliliters of dry dimethylformamide dropwise under cooling under a nitrogen atmosphere to a suspension of 447 milli<g>ram (6.0563 mol) of lithium hydride in 50 milliliters of dry dimethylformamide. After the addition has ended, the mixture is brought to room temperature within approx. half an hour, after which it is cooled to 0-5°C, and a solution of 7-8 grams (0.0282 mol) of 2,6-dibromophenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over the course of two hours while the cooling is maintained des in the same area. The mixture is then brought to room temperature and stirred overnight under nitrogen to provide the desired N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea product in the reaction mixture. The product is recovered from the reaction mixture by pouring the mixture into 400 milliliters of ice water, acidifying with 10% hydrochloric acid to pH less than 3, filtering to remove impurities, saturating the filtrate with solid sodium chloride and basifying with potassium carbonate to pH 8-9 to precipitate N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea product as a white solid with a melting point of 185° - 190°C (decomposition).

The basic urea product provided is suspended in 40 milliliters of methanol and methanolic hydrogen chloride is added to pH less than 2. Ether is then added to precipitate N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea hydrochloride as a white , solid with melting point 200°-202°C (decomposition). After two recrystallizations from methanol/2-propanol/ether, a purified product with melting point 215°-217°C is provided which decomposes to a solid with melting point 255°C (decomposition).

Analysis calculated for C10H10N4Br2O-HCl: C, 30.14; H, 2.78;

N, 14.06

found: C, 30.12; H, 2.8i; N, 14.04

Example IV

In a similar manner, the following is prepared: N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl)urea hydrochloride, melting point 197°-199°C, by reacting 2-iminoimidazolidine

(prepared from 2-iminoimidazolidine hydroiodide and lithium hydride)

and 2 methoxyphenyl isocyanate at about 5° to 10°C to provide the N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl)urea product, followed by the reaction of the urea base with methanolic hydrogen chloride and recrystallization first from methanol/2 -propanol, and then twice from methanol ether.

Analysis calculated for C^^ H-^N^C^ -HCl:

C, 48.80; H, 5-58; N, 20.70

found: C, 48.75; H, 5-6i; N, 20.71

Example V

N-(2-ethyl-6-methylphenyl)-N'-(2-imidazolidinylidene)urea

fumarate (3:2)

In a similar manner as described above, 15-55 grams (0.073 mol) of 2-iminoimidazoline hydroiodide are added dropwise to a dry, cooled suspension of 596 milligrams (0.075 mol) of lithium hydride in 30 milliliters of dimethylformamide under a nitrogen atmosphere. After the addition is complete, the mixture is allowed to warm to room temperature to terminate the reaction. The mixture is then cooled again, a solution of 8.1 grams (0.05 mol) of 2-ethyl-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over two hours after which the resulting mixture is stirred overnight while the temperature is allowed to rise to room temperature to provide N -(2-ethyl-6-methylphenyl)-N'-(2-imidazolidinylidene)urea product. The basic product is recovered by a similar method as described above and after recrystallization from methanol-water, a purified, basic product with a melting point of 185°-187°C is obtained.

A solution of 4.32 grams (0.0175 mol) of the basic product provided, in 35 milliliters of warm isopropanol, is mixed with a solution of 2.04 grams (0.0175 mol) of fumaric acid in 35 milliliters of warm isopropanol and the resulting solution is allowed to cool, after which The N-(2-ethyl-6-methyl-phenyl)-N'-(2-imidazolidinylidene)urea fumarate addition salt product is crystallized. The salt product melts after first washing with isopropanol then with ether at 180°C (decomposition). Successive recrystallizations from methanol isopropanol, methanol/ether and methanol do not produce a salt with a reproducibly sharp melting point. Elemental analysis indicates that the salt consists of three moles of base and two moles of fumaric acid.

Analysis calculated for (C-^H^gN^O) ^ • (C^H^O^^ :

C, 58.13; H, 6.44; N, 17.31

found: C, 58.03; H, 6.57; N, 17-59

Example VI

In a similar way, N-(2-chlorophenyl)-N'-(2-imidazolidinylidene)urea hydrochloride with melting point 187<0->189°C is produced by reacting 2-iminoimidazoline (prepared from 2-iminoimidazoline hydroiodide and lithium hydride in dimethylformamide at approx. 20°C) and 2-chlorophenyl isocyanate at approx. 20°-30°C overnight, followed by heating for 15 minutes at 100°C on a steam bath to provide the N-(2-chlorophenyl)-N'-(2-imidazolidinylidene)urea product as a crystalline solid after which the urea base is reacted with a methanolic hydrogen chloride.

Analysis calculated for C-^H-^N^OCl • HC1:

C, 43.66; H, 4.40; N, 20.36

found: C, 43.69; H, 4.43; N, 20.36

Example VII

In a similar way as described in examples II - VI, the following compounds can be prepared: N-2-imidazolidinylidene-N'-(4-methoxyphenyl)-urea and its hydrobromide.

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

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

N-(2-imidazolidinylidene)-N'-(4-methylphenyl)urea and its hydrochloride, melting point 210°-212°C.

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

N-(2,3-dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride, melting point 2l8°-220°C.

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

N-(3j4-dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride, m.p. 217°-219°C.

N-(2,5-dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride, melting point 213°-215°C.

N-(2-imidazolidinylidene)-N'-(2,4,6-trichlorophenyl)urea and its hydrochloride, melting point 232°C

decomposes to a solid, melting point 260°C (decomposition)

N-(2-fluoro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride.

N-(2-imidazolidinylidene)-N'-(2-methyl-6-trifluoromethylphenyl)urea and its hydrochloride.

N-(2-imidazolidinylidene)-N'-(2-methyl-6-methylsulfonyl-phenyl)urea and its hydrochloride.

N-(2-cyano-6-methylphenyl)-N'-(2,imidazolidinidene)urea

and its hydrochloride.

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

N-(2-bromo-6-methylphenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride.

N-(2-bromo-6-ethylphenyl)-N!<->(2-imidazolidinylidene)urea and its hydrochloride.

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

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

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

N-(2-methyl-6-trifluoromethylphenyl)-N'-(2-imidazolidinyl-idene)urea and its hydrochloride.

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

Example VIII

N-(2-imidazolidinylidene)-N1-phenyl urea and its hydroiodide.

As in the first step of the reaction, 119 grams (1 mol) of phenyl isocyanate are added in one portion while rotating the container to a hot solution of 83.73 grams (1.1 mol) of thiourea in 120 milliliters of dry dimethylformamide and the resulting solution is heated for three hours. The solution is then cooled, a mixture of ice and water is carefully added and the reaction vessel is scraped to produce crystallization of the desired intermediate which is N-phenylthioimidodicarboxylic acid diamide. After the crystallization starts, further ice water is added (to about 1 litre). The crystals that form are recovered, washed with water and recrystallized from methanol to give 127 grams of N-phenylthioimidodicarboxylic acid diamide intermediate with a melting point of 176°-180°C.

As a second step, 45.5 grams (0.32 mol) of methyl iodide is added to a solution of 59-5 grams (0.305 mol) of N-phenylthioimidodicarboxylic acid diamide in 300 milliliters of acetone, and the resulting mixture...stirred for approx. two hours at room temperature.

As a result of these operations, crystals are formed in the reaction vessel which are then filtered off to provide methyl N'-[(phenylamino)carbonyl]-carbamimidothioate hydrochloride product with a melting point of 195°-200°C. An analytical sample, mp (190°C) 200°-202°C (Hoover) is provided by recrystallization from methanol.

Analysis calculated for C^H^N^OS • HI:

C,' 32.06; H, 3.59; N,12.46 found: C, 32.11; H, 3-62; N, 12.48

A methanol solution of 33.72 grams is then mixed

(0.1 mol) of the supplied methyl N'-[(phenylamino)-carbonyl] carbamimidothioate hydroiodide and a methanol solution of 6.01 grams (0.1 mol) of ethylenediamine (approx. 50 milliliters in total of methanol) together bg are heated under reflux for approx. one and a half hour. The mixture is then cooled to -20°C to crystallize the N-(2-imidazolidinylidene)-N'-phenylurea product as its hydroiodide. Several charges are obtained and the combined yield is purified in methanol, filtered and the filtrate is evaporated to isolate the hydroiodide product as a residue.

The hydroiodide product residue is converted to the urea base product and purified by a series of steps comprising dissolving the residue in a minimal amount of methanol, mixing and heating with 8.0 grams (0.079 mol) of triethylamine, replacing the methanol with ethanol, and then cooling to provide crystals of N- (2-imidazolidine ylidene)-N'-phenylurea base with melting point (181°) 182°-183°C after recrystallization from methanol.

Analysis calculated for <-'io<H1>2^4°<:>

C, 58.8i; H, 5.92; N, 27.43

found: C, 58.79"H, 5-92; N, 27.48

The hydroiodide addition salt has, after recrystallization from acetone, a melting point of 223-225°C (decomposition), when immersion occurred at 225°C the melting point was 230°C (decomposition).

Analysis calculated for cioHl2N4°'HI:

C, 36.16; H, 3-94; N, I6.87; I, 38.21 found: C, 36.22; H, 3-96; N, 16.88; I, 38.21

Example IX

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

In operations similar to those described in Example ¥111, 153557 grams (1.0 mol) of m-chlorophenyl isocyanate is added to a hot solution of 95-15 grams (1.25 mol) of thiourea in 100 milliliters of dimethylformamide and the resulting mixture is heated overnight on a steam bath to provide the N-(3-chlorophenyl)thio-imidodicarboxylic acid diamide intermediate in the reaction mixture. The mixture is cooled until complete precipitation of the desired intermediate product which, after recovery by filtration and washing with ether, has a melting point of 187°-189°C (decomposition). Additional quantities are obtained which combine and are recrystallized twice from methanol-water and twice from acetonitrile to provide a purified product mp 205°-207°C (decomposition).

To a clear acetone solution of 80.3 grams (0.35 mol) of N-(3-chlorophenyl)thiomidodicaponic acid diamide (prepared as described above) is added 75-0 grams (0.525 mol) of methyl iodide and the reaction mixture is stirred overnight to provide the desired N'- ^\ (3-Chlorophenyl)amino]-carbonyl]- -carbamimidothioate hydroiodide product as a crystalline solid, mp 182°-183°C (decomposition).

To 37.1 grams (0.1 mol) of methyl N'-£j(3-chlorophenyl)amino]carbonylj--carbamimidothioate hydroiodide, 6.0 grams (0.1 mol) of ethylenediamine in 100 milliliters of methanol are added and the resulting mixture is refluxed for five hours. The resulting reaction mixture is evaporated to dryness in vacuo and diluted with tert-butyl alcohol to provide crystals of the N-(3-chloro£enyl)-N'-(2-imidazolidinylidene)urea hydroiodide product as a crystalline solid. The crystals are recrystallized from tertiary butyl alcohol several times to provide a purified product, mp 192°-194°C (decomposition).

Analysis calculated for C^qH^<C>INjjO«HI:

C, 32.76, H, 3.29

found C, 32.82, H, 3-33

The following examples illustrate the novel pharmaceutical composition that can control hypertension, but are not limiting.

Example X

1,000 hard gelatin capsules each containing 200 milligrams of N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea are prepared from the following recipe:

A uniform mixture of the ingredients is produced by mixing and used to fill hard gelatin capsules that are in two pieces. The capsules are suitable for oral administration to hypertensive patients to reduce blood pressure.

Example XI

The gelatin capsules are prepared as described in example X, except that the preparation uses 325 grams of N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene) urea as the active ingredient, which gives capsules containing 325 milligrams of N-(2 ,6-dimethylphenyl)-N'-(2-imidazolidinylidene)urea.

Example XII

1,000 compressed tablets each containing 500 milli~

gram. N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl)urea is prepared from the following recipe:

The finely divided ingredients are mixed well and granulated with 10 percent starch paste. The granulate is dried and pressed into tablets using starch as a disintegrating agent and calcium stearate as a lubricant.

Example XIII

Tablets are prepared as in example XII except that N-(2j6-dibromophenyl)-N'-(2-imidazolidinylidene)urea is used as active ingredient.

Example XIV

Gelatin capsules are prepared as described in example X except that N-(3-chlorophenyl)-N'-(2-imidazolidinylidene)urea is used as active ingredient.

The following examples illustrate the new pharmaceutical preparations that can control intestinal deficiencies and diseases, but should not be considered limiting.

Example XV

1,000 hard gelatin capsules each containing 200 milligrams of N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea are prepared from the following recipe:

A uniform mixture of the ingredients is provided and used to fill hard gelatin capsules in two pieces. The capsules are suitable for oral administration to patients with functional intestinal diseases.

Example XVI

Gelatin capsules are prepared as described in example XV, except that 400 grams of N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene urea in the recipe is used as active ingredient, which gives capsules containing 400 milligrams of N-(2,6 -dibromophenyl)-N'-(2-imidazolidinylidene)urea.

Example XVII

Gelatin capsules are prepared as described in example XV, except that N-(2-ethyl-6-methyl)-N'-(2-imidazolidinylidene) urea is used as active ingredient.

Example XVIII

Gelatin capsules are prepared as described in example XV, except that N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene) urea is used as active ingredient.

Example XIX

1,000 compressed tablets each containing 500 milligrams of N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea are prepared from the following recipe:

The finely divided ingredients are mixed well and granulated with 10 percent starch paste. The granulate is dried and pressed into tablets using starch as a disintegrating agent and calcium stearate as a lubricant.

Claims (22)

1. Method for controlling hypertension and intestinal deficiencies and diseases in animals characterized in that the therapeutically effective amount of N-aryl-N'-(2-imidazolidinylidene)urea compound with the formula where Ar is phenyl substituted with from 0 to 3 substituents which are independently selected from groups characterized by the presence of halogen or by a group containing carbon with from 1 to 2 carbon atoms which are optionally attached to phenyl through a non-basic hetero atom with the proviso that when the said compound is to be used to control intestinal deficiencies or diseases, Ar is limited to phenyl substituted in at least the 2 and 6 positions with said halogen or carbon-containing groups, and pharmaceutically acceptable salts of this compound for the animal suffering from the said diseases . 2. Method for reducing arterial pressure in hypertensive subjects characterized in that the hypertensive subject is administered from 5 to 500 milligrams per unit dose of a urea compound with the formula wherein R is independently selected from the group consisting of chlorine, bromine, methyl, ethyl, methoxy, and n is an integer from 0 to 3, and pharmaceutically acceptable salts of this compound. 3. Process according to claim 1, characterized in that the urea compound is N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene) urea. 4. Method according to claim 1, characterized in that the urea compound is N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene) urea. 5. Method according to claim 2, characterized in that the urea compound is N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl) urea. 6. Method according to claim 1, characterized in that the urea compound is N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene) urea. 7. Method for alleviating discomfort associated with irritable bowel, characterized in that the subject who requires such treatment is administered from 5 to 500 milligrams per unit dose of a urea compound with the formula where X and Y are selected from methyl, ethyl, chlorine and bromine, and pharmaceutically acceptable salts of this compound. 8. Method for alleviating functional. bromine, and pharmaceutically acceptable salts of this compound. 9- Method according to claim 7, characterized in that the urea compound is N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene) urea. 10. Pharmaceutical preparation in unit dose form for the treatment of hypertension and intestinal deficiencies and diseases characterized in that it contains a therapeutically effective amount of a urea compound, where the said urea compound is selected from (a) compound with the formula where Ar is phenyl substituted with from 0 to 3 substituents independently selected from groups characterized by the presence of halogen or a group containing carbon, with from 1 to 2 carbon atoms optionally linked to phenyl through a non-basic, hetrocyclic atom, or ( b) pharmaceutically acceptable salts of this compound with the proviso that when said compound is to be used to control intestinal diseases or deficiencies, Ar is limited to phenyl substituted at least in the 2 and 6 positions with said halogen or carbon-containing groups, and in that said urea compound is in admixture with a pharmaceutically acceptable carrier. 11. Pharmaceutical preparation in unit dosage form for the treatment of hypertension characterized in that each dosage unit contains from 5 to 500 milligrams of a urea compound with the formula wherein R is independently selected from the group consisting of chlorine, bromine, methyl, ethyl and methoxy, n is an integer from 0 to 33 and pharmaceutically acceptable salts of this compound, wherein said urea compound is in admixture with a pharmaceutically acceptable carrier. 12. Preparation according to claim 10, characterized in that the urea compound is N-(2,6-dichlorophenyl)-N'-(2-imidazolinyl-idene) urea. 13. Preparation according to claim 10, characterized in that the urea compound is N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene) urea. 14. Preparation according to claim 8, characterized in that the urea compound is N-(2-imidazolidinylidene)-N'-(2-methoxyphenyl) urea. 15- Preparation according to claim 8, characterized in that the urea compound is N-(2-chlorophenyl)-N'-(2-imidazolidinylidene)urea. 16. Pharmaceutical preparation in unit dosage form suitable for alleviating discomfort associated with intestinal diseases or deficiencies, characterized in that each dosage unit contains from 5 to 500 milligrams of a urea compound of the formula where X and Y are selected from methyl, ethyl, chlorine and bromine and pharmaceutically acceptable salts of this compound. 17- Preparation according to claim 9 characterized in that the compound is N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene) urea. 18. Compound according to claim 1 characterized in that it is used to control hypertension or intestinal diseases or deficiencies. 19- Compound characterized in that it has the formula where and R^ are each halogen, lower alkoxy or lower alkyl, with the proviso that and R^ cannot both be lower alkyl. 20. Compound characterized in that it has the formula N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea. 21. Procedure for the preparation of a compound of the formula where R^ and R^ are each halogen, lower alkoxy, lower alkyl with the proviso that R^ and R^ cannot both be lower alkyl, characterized by reacting 2-iminoimidazolidine with a compound of the formula in a suitable solvent. 22. Process for the production of N-(2,6-dichlorophenyl)-N'-(2-imidazolidinylidene)urea characterized by reacting 2-iminoimidazolidine with 2,6-dichlorophenyl isocyanate.