GB2040681A

GB2040681A - The use in the treatment of hypertension and intestinal disorders of certain N-aryl-N'-(2-imidazolidinylidene)ureas

Info

Publication number: GB2040681A
Application number: GB7944114A
Authority: GB
Original assignee: McNeilab Inc
Current assignee: Ortho McNeil Pharmaceutical Inc
Priority date: 1978-12-22
Filing date: 1979-12-21
Publication date: 1980-09-03
Also published as: NO794249L; CA1127651A; GR68018B; SE7910612L; CH647236A5; GB2040681B; HU183013B; AU532332B2; FI66354C; GB2113204B; FR2445321A1; NL7909265A; DK548179A; IT7951164A0; ATA808979A; IL59019A0; ZW25379A1; AU5378079A; AT373878B; SU971098A3

Abstract

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

Description

SPECIFICATION The use in the treatment of hypertension and intestinal disorders of certain N-aryl-N'-(2imidazolidinylidene)-urea derivatives This invention relates to the use in the treatment of hypertension and intestinal disorders of certain N-aryl-N'-(2-imidazolidinylidene)-urea derivatives and compositions intended for such use.

Irritable bowel syndrome is a functional disorder characterised primarily by abdominal pain, but also by diarrhea and constipation and like symptoms. It is believed that the pain associated with this syndrome is due to excessive sensitivity to distention of the bowel caused either by intestinal gas and/or fecal material.

Treatments which would provide relief from the discomforts associated with such symptoms and/or the disorder which produce such symptoms are highly desirable.

Certain imidazolidine ureas are known in the art. Thus, U.S. Patent No.3,168,520 discloses certain imidazolidine ureas and hexahydropyrimidine ureas. These compounds are taught to be useful as dye stabilizers. The patent specifically teaches 2-phenylcarbiliminoimidazolidine which is N-(2imidazoiidinylidene)-N'-phenylurea. There is no teaching or suggestion in the patent however for the use of imidazolidineureas and hexahydropyrimidine-ureas as active ingredients in pharmaceutical compositions.

Some urea compounds have been disclosed to have certain pharmacological properties. Thus, U.S. Patent No. 4,060,635 discloses amidinoureas. These compounds have an aryl group on one urea nitrogen and a substituted amidino group on the other urea nitrogen. U.S. Patents Nos. 3,539,616 and 3,784,582 teach amidinoureas in which 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, also directed to amidinoureas but more remote, teaches compounds in which one of the amidino nitrogens necessarily is attached to an oxygen. None of the patents teach or suggest the substitution of an imidazolidino group on a urea nitrogen.

None of these patents teach or suggest anti-hypertensive activity.

A recent publication, G.H. Douglas et al., Arz.Forsch/Drug Res. 28(11), 1480(1978), discloses the results of many aryl substituted amidinoureas screened for antimotility and antisecretory activity. N-2,6 Dimethylphenyl)-N'-(2-imidazolidinylidene)urea and N-(2,6-dimethylphenyl)-N'-(1 -methyl-2imidazolidinylidene)urea are among the compounds tested. The article does not teach the compounds to have useful antimotility activity and no other pharmacological test is reported or use suggested for these compounds.

This invention is concerned with the use in the treatment of hypertension and functional intestinal disorders and for relieving pain discomfort and other symptoms associated with irritable bowel conditions of an N-aryl-N'-(2-imidazolidinylidene)urea compounds of the formula;

or a pharmaceutically acceptable acid addition salt thereof. It also embraces pharmaceutical compositions suitable for treating hypertension and for inhibiting diarrhea and treating intestinal disorders, wherein the foregoing urea compound is in admixture with a pharmaceutically acceptable carrier or diluent.

In the foregoing and subsequent formulae, Ar is phenyl group substituted with from 0 to 3 substituents which are each independently selected from a group in which a halogen atom is present or a carbon-containing group have from 1 to 2 carbon atoms which is optionally attached to the phenyl through a non-basic hetero atom, with the proviso that when the compound is for use in controlling intestinal disorders, then Ar is restricted to phenyl substituted at least in the 2 and 6 positions with the halogen or carbon containing groups. 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; methylthio; methylsulfonyl; methylsulfinyl; and cyano. In the most preferred compounds intended for controlling hypertension, Ar may be represented by

wherein r is methyl, ethyl, chloro, bromo, or methoxy and n isO or an integer of from 1 to 3. In the most preferred compounds intended for controlling intestinal disorders, Ar may be represented by

wherein X and Y are each selected from methyl, ethyl, chloro and bromo.

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

Certain of the compounds of Formula I are novel perse namely compounds of the formula

wherein R1 and R2 are each independently halo, loweralkoxy, or loweralkyl, with the proviso that R1 and R2 cannot both be loweralkyl.

The pharmacologically useful N-aryl-N'-(2-imidazolidinylidene)urea compounds are prepared by substantially two methods. The most generally useful method is by the reaction of an appropriate 2-iminoimidazoline (11) with an aryl isocyanate (III) according to the following equation:

The 2-iminoimidazoline starting materials conveniently may be prepared (according to art methods and as subsequently described) and stored as an acid addition salt

Thus, the initial step is usually the conversion of the acid addition salt to the free base. This may be carried out 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 thus obtained biphasic mixture is contacted with an appropriate aryl isocyanate to produce the desired N-aryl-N'-imidazolidinylideneurea compound.

In a preferred method for carrying out the reaction between the aryl isocyanate and the 2-imidazolidine, a solution of aryl isocyanate in tetrahydrofuran is added portionwise with stirring to the biphasic mixture at temperatures in the range of about 20 to 300C and the mixture stirred for from a few hours to overnight. The N-aryl-N'-imidazolidinylideneurea compound thus obtained is recovered, converted to an acid addition salt form, if desired, and purified employing conventional procedures.

The free base may be generated by another procedure in which 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 addition is generally in the range of 0 to 30"C. An inert atmosphere is conveniently provided by use of 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 nitrogen atmosphere while maintaining temperatures in the 0-5"C range. Stirring is continued after the completion of the addition while the mixture is gradually allowed to warm to room temperature to obtain the free base.

The reaction between 2-iminoimidazolidine and aryl isocyanate may be carried out by adding a solution of an aryl isocyanate, dropwise with stirring and cooling, to the reaction mixture containing the free base in an inert atmosphere, stirring the resulting mixture while gradually warming to ambient temperature and thereafter in the temperature range of from about 30 to 11 00C, preferably in the range of 65" to 11 00C for optimizing yields, to obtain the desired N-aryl-N'-(2-imidazolidinylidene)urea product. When the reaction is carried out at ambient temperatures, stirring is usually continued for several hours or overnight; when it is carried out at the elevated temperatures, about two hours is satisfactory.

A second general but less preferred method for the preparation of N-aryl-N'-(2-imidazolidinylidene)-urea compounds proceeds through the following sequence of reactions.

s H20-C-002 + o1',ent (110) S 0 CO CH3I SCO3 a 20 H2N-c-NH-c-NH-Ar > H2N-C - N - C - NH-Ar (IV) (V) ,rNH2 CN2 (VI) C12 &num;-2o2oi (I HI) OH A It is seen that the initial step is a reaction between an appropriate aryl isocyanate (III) and thiourea to produce a N-arylthioimidodicarbonicdiamide (IV) which is then reacted with methyl iodide to produce a methyl N'-[(arylamino)-carbonyl]carbamimdothioate (V). The latter when reacted with an appropriately substituted ethylenediamine (VI) produces the N-aryl-N'-(2-imidazolidinylidene)urea (I) as a hydroiodide addition salt and which may be converted to the free base by conventional means. The foregoing reaction sequence however is not applicable for the preparation of urea compounds in which the aryl group is a 2,6-disubstituted phenyl group.

The first step may be carried out employing a modification of a procedure reported by Lakra et al., (J. Am.

Chem. Soc. 51,2220 (1929)) in which an appropriate aryl isocyanate (III) and thiourea are reacted to produce a N-arylthioimidodicarbonic diamide compound (IV), hereinafter referred to for convenience as a "thiobiuret compound." For the reaction, substantially equimolar amounts of the reactants, preferably a slight excess of the thiourea, are employed. The temperature for the reaction may be in the range of from about 800 to 1200C.

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 at steam bath temperature for from about two to twelve hours whereupon the thiobiuret compound (IV) is formed in the reaction mixture.

The mixture is then diluted with water and cooled to induce crystallization of the thiobiuret compound which is then separated from the reaction mixture and purified employing conventional procedures.

In the second step of the reaction, the N-aryl thiobiuret compound and an S-methylating agent are reacted to produce a methyl N'-[(arylamino)carbonylicarbamimidothioate compound (V), hereinafter referred to for convenience as the "thioate compound." Substantially equimolar amounts of the reactants, preferably a slight excess of methylating agent, are employed. Although other methylating agents such as dimethyl sulfate and the like also may be used, methyl iodide is preferred. A solvent is preferably employed. Suitable solvents include acetone, methanol, ethanol, isopropanol, and the like. The temperature of the reaction may range from ambient to reflux temperatures, ambient temperatures being preferred.

The reaction is conveniently carried out by mixing together the thiobiuret compound and methyl iodide in methanol at ambient temperature for several hours. The product which forms in the reaction mixture as its hydroiodide addition salt is recovered and purified, if desired, employing conventional procedures.

In the third step, the thioate compound (V) as the hydroiodide salt and an appropriate ethylenediamine compound (Vl) are reacted to produce the desired N-aryl-N'-imidazolidinylideneurea product as a hydroiodide salt. Substantially equimolar amounts of the reactants are employed. The reaction is preferably carried out in methanol and other lower alkanols, methanol being preferred.

The reaction is conveniently carried out by refluxing together the hydroiodide salt of V and the ethylenediamine compound in methanol for from about one to several hours and thereafter vaporizing the solvent to obtain as residue the desired N-aryl-N'-imidazolidinylideneurea product as a hydroiodide salt. The product may then be recovered and purified employing conventional procedures.

The salt may be converted to the free-base. If another salt is desired, the free base is caused to react with another acid to form a desired acid addition salt. Conventional procedures may be employed for these conversions. Thus, for example, a representative convenient procedure for obtaining the free base from the salt is dissolving the acid addition salt in a minimal amount of lower alkanol solvent such as methanol or ethanol, warming with an organic base such as triethylamine and the like, and cooling to obtain the free-base product as a crystalline solid. Similarly, a representative convenient procedure for converting the free base to an acid addition salt is mixing the base with an alcoholic solution of an acid corresponding to the addition salt desired and cooling to obtain the acid addition salt.

METHOD FOR CONTROLLING HYPERTENSION The N-aryl-N'-(2-imidazolidinylidene)urea compounds have been found to alleviate hypertension and further, to generally accomplish this without an accompanying increase in heart rate. An agent which has an antihypertensive effect without increasing but rather maintaining or decreasing heart rate, is the one considered most useful for beneficially treating a hypertensive subject. The extent to which a compound possesses these properties may be determined in the anti hypertensive test on rodents and in the hemodynamic evaluation in dog hereinafter described.

Rodentantihypertensive screen. This test evaluates compounds for effects on arterial pressure and heart rate. In this test, the arterial pressure of spontaneously hypertensive rats or rats made hypertensive with injections of desoxycorticosterone acetate and 2 percent sodium chloride for drinking water, is monitored directly via an aortic cannula. Rats are anesthetized with an inhalation anesthetic (methoxyflurane or ether).

The left carotid artery is isolated and cannulated. The tip of the cannula is advanced to the aorta and the cannula is exteriorized behind the neck at the level of the scapula. Animals are placed in individual cases and allowed to recover from the anesthetic and are kept unrestrained. The arterial cannula is connected to the pressure transducer which is attached to the recorder. Heart rate is determined from the arterial pressure recording. Animals with pressures greater than 149 millimeters of mercury are considered sufficiently hypertensive to be employed in the test for antihypertensive effects. The test compounds are administered either orally (p.o.) by gavage or by intraperitoneal (i.p.) injection. The arterial pressure and heart rate are monitored for a minimum of 4 hours. A test compound is considered to be active as an anti hypertensive agent if the mean arterial pressure (MAP) indicates a fall of > 19 mm of Hg. Each animal serves as his own control.

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

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

In this test, mongrel dogs are anesthetized with 20 mg/kg (milligrams per kilogram of body weight) of thiopental sodium and 60 mg/kg of alpha-chlorolose. Supplemental alpha-chlorolose (60 mg/kg) is used for maintenance of anesthesia, if necessary. A cuffed endotracheal tube is inserted to maintain an unobstructed airway, and the animal is respired with a ventilation pump. A femoral artery and vein are catheritized for recording of arterial pressure and for intravenous injections, respectively. Both common carotid arteries are isolated for performance of bilateral carotid occlusion. The vagus nerve is stimulated electrically at the peripheral end for ten seconds with five volts at 20 pulses per second each with a two milli-second duration to obtain cardiac arrest. The electrocardiogram is monitored through Limb Lead II.

Control cardiovascular responses are obtained to the following pharmacological procedures: 1.0 mcg/kg I.V. (microgram per kilogram of body weight, intravenous) of 4epinephrine, carotid occlusion, 10 mcg/kg IV. of dimethylphenylpiperazinium iodide (DMPP), peripheral vagal stimulation, 10 mcg/kg I.V. of acetylcholine and 2 mcglkg l.V. MDB 12-20-CRR12/20 of angiotensin. These control responses are produced twice, then the test compound is injected at 5 mg/kg (milligram per kilogram) I.V. employing bolus injections over approximately a one minute period. If no change in arterial pressure, heart rate, or ECG (Limb Lead II) occurs, an additional 5mg.kg l.V. of the test compound is administered. The effects of the test compound are noted on the electrocardiogram, arterial pressure, and heart rate. Ten minutes after administration of the test compound, another series of hemodynamic responses is obtained.

Employing a dog for each test compound, heart rate data are obtained for N-aryl-N'-(2imidazolidinylidene)urea compounds. The results from this test are also shown in Table I.

The results seen in Table I show that N-aryl-N'-(2-imidazolidinylidene)urea compounds and their salts possess not only the beneficial antihypertensive property but also the desirable property of maintaining or lowering normal heart rate. The properties are utilized in the methods and compositions of the present invention.

One process of the present invention, namely, a method for treating hypertension or alleviating high blood pressure comprises administering to subjects in need of treatment, a therapeutically effective hypertension or arterial pressure reducing amount of a N-aryl-N'(2.imidazolinylidene) urea compound of Formula I or its pharmaceutically acceptable salt as active agent. The active agents may be administered with or without carrier in the amounts hereinafter set forth. A preferred method of administration is by the use of pharmaceutical compositions in unit dosage form as described below.

The operable ranges for carrying out the process is the administration, orally or parenterally, of from about 5 milligrams to about 500 milligrams of a N-aryl-N'-(2-imidazolidinylidene) urea compound in dosage unit form. While the therapeutic method is most useful for human subjects, it may also be employed for other mammals. Operable amounts are generally within the range of from about 0.5 to 50 mg/kg of body weight.

TABLE I Antihypertensive and cardiac rate determinations Compound Spontaneously hypertensive (SH) Rat Hemodynamic dog

Maximum decrease ,C?IAr. (5 Maximum Effect on in Heart Beat Dose Decrease Heart Rate at Dosage 10 mg/kg I.V.

&commat; CD O E E m c, E X oz x O O, I D O a: 1 I E ,u D 0O E (D x 0O o 0=S i Ar HX (mg/kg i.p.) in MAP (mmHg) (beats/minute) (beats/min) # - 30 72 +78 No change (NC) # - 10 p.o. 39 -108 # - 100 p.o. 30 +30 3-Cl# Hl 30 63 -42 -30 2,6-Cl2# HCl 20-200 (p.o.) 39-96 -39 to -108 -54 2,6-(CH3)2# HCl . 1/2 H2O 30 > 19 #* -60 2-Cl,6-CH3# HCl 30 > 19 # -42 2,6-Br2# HCl 30 > 19 # -54 2-C2H5,6-CH3# 2/3 fumarate 30 > 19 # -42 4-CH3# HCl 30 > 19** NC NC (5 mg/kg I.V.) 2-OCH3# HCl 30 95 -108*** +30*** 2-OCH3# HCl 10 p.o. 23 -84 2-OCH3# HCl 100 p.o. 90 -84 2-Cl# HCl 30 > 19 -108 No change *Decrease **One-half the number of rats ***Large slowing effect on spontaneously hypertensive rat regarded to be more meaningful METHOD FOR CONTROLLING INTESTINAL DISORDERS The N-aryl-N'-(2-imidazolidinylidene)urea compounds have been found to provide relief from the discomfort associated with functional intestinal disorders spoken of as the irritable bowel syndrome. The disorder is characterized by abdominal pain, diarrhea, constipation and like symptoms caused by excessive sensitivity to distension of the bowel by the presence of intestinal gas and/or fecal material.

The extent to which a compound is effective in providing relief may be determined by a test in which a glass bead is inserted into the rectum and the lapse of time between insertion and expulsion of the bead determined. Compounds which are effective in decreasing the sensitivity to distension of the colonic wall delays the expulsion of the bead.

The test is carried out with male albino mice of 18-25 grams body weight using groups of five mice for each compound dose tested. The initial screen dose selected for all compounds is 50 milligrams per kilogram of body weight (mg/kg) administered orally in a volume of 0.1 milliliter per 10 grams of body weight. The control groups receive the vehicle, 0.5 percent methocel, used for both oral and intraperitoneal administration. The mice are fasted one hour before testing and the test drugs are given one hour prior to glass bead insertion.

At the end of the pretreatment time, the mouse is picked up and held firmly in one hand with his abdomen facing the technician. The glass bead of 3 millimeters in diameter is positioned at the rectum and using a pinching action with a thumb and forefinger, the bead is pushed into the rectum. Then using a glass rod of 3 millimeters in diameter which has been lubricated with 0.5 percent methocel to facilitate insertion, the glass bead is pushed up into the rectum a distance of 2 centimeters using a slow gentle turning motion. The mice are timed as a group using the last mouse inserted as zero time and the number of beads expelled in a group at different timed intervals are recorded. The groups are based on timed intervalsofOto 5 minutes, 5 to 10 minutes, 10 to 20 minutes, 20 to 40 minutes and greater than 40 minutes. They are given the activity index values of 0, 1,2,3 and 4, respectively. Mice who have not expelled their beads by the 40-minute cutoff time are examined for perforations. Those mice whose colons are perforated are eliminated from the group. The -sum of the values divided by the number of mice or beads is termed the activity index for the drug tested.

The ED50 is determined by regression lines using the method of least squares. The ED50 is arbitrarily assigned as that dose causing an activity index of 2.

The results of this test employing intraperitoneal and oral administration of N-aryl-N'-(2 imidazolidinylidene)urea compounds are shown in Table I.

TABLE i Compound

ED50 (mg/kg) Intraperi Ar HX toneal Per Os 2,6-diCI- HCI 7 13.7 2,6-di(CH3)-O HCl.1/2H2O 12 16 2-CI,6-CH3- HCI 8 35 2,6-diBr- HCI 9 38 2-C2H5, 6-CH3- 2/3fumarate 43 121 The foregoing results illustrate the beneficial effect of N-arylN'-(2-imidazolidinylidene)urea compounds in decreasing abnormal sensitivity to distention of bowel. These properties are utilized in the methods and compositions of the present invention.

One use of the compounds of Formula I, namely, their use for alleviating functional intestinal disorders and for treating the discomforts associated therewith comprises administering to subjects in need of treatment, a therapeutically effective amount of a N-aryl-N'-(2-imidazolidinylidene)urea compound of Formula I or its pharmaceutically acceptable salt as active agent. The active agents may be administered with or without carrier in the amounts hereinafter set forth. A preferred method of administration is by use of pharmaceutical compositions in unit dosage form as described below.

The operable range for the administration, orally or parenterally, is of from about 5 milligrams to about 500 milligrams of a N-aryl-N'-(2-imidazolidinylidene)urea compound in dosage unit form. While the therapeutic use is most useful for human subjects, it may also be employed for other mammals. Amounts used are generally within the range of from about 0.50 to 50 mg/kg, preferably at least 3 mg/kg of body weight.

The outstanding properties when intended for controlling hypertension or when intended for controlling intestinal disorders are most effectively utilized by use of the pharmaceutical compositions of the present invention. The pharmaceutical compositions comprising a N-aryl-N'-(2-imidazolidinylidene) urea compound or acid addition salt thereof, as the active ingredient, may be prepared by intimately mixing the urea compound with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques; which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents 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, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterais, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The term "dosage unit form" as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets, capsules, pills, powder packets, wafers, teaspoonsful, tablespoonsful and the like, and segregated multiples thereof. A dosage unit generally will contain from about Sto about 500 mg of the N-aryl-N'-(2-imidazolidinylidene)-urea compounds.

The following examples illustrate the preparation of the N-aryl-N'-(2-imidazolidinylidene)urea compounds and the novel pharmaceutical compositions suitable in the practice of the invention but are not to be construed as limiting: Starting Material The 2-imidazolidine starting material of Formula II may be prepared by literature described methods or by the following representative preparation of the hydroiodide addition salt: 213 grams (1.5 moles) of methyl iodide is added with stirring over one hour to a suspension of 153.24 grams (1.5 moles) of ethylenethiourea in 300 milliliters of methanol. Stirring is continued for about an additional hour to complete the formation of S-methyl-ethylenethiourea. Anhydrous ammonia then is added thereto whereupon a reaction takes place with the formation of 2-iminoimidazolidine hydroiodide and methylmercaptan by-product. The stirring and intermittent addition of ammonia is continued for a total of about 26 hours. The mixture is concentrated with concomitant addition of isopropanol to replace the vaporized methanol, and then cooled and ether added thereto to produce 2-iminoimidazoline hydroiodide as a crystalline solid which after recrystallization from methanol/tert.-butanol has a melting point of 152-154"C.

Anal. Calcd. for C3H7N3.HI; C, 16.92; H, 3.79 Found: C 16.85; H, 3.82 EXAMPLE I N-62,6-DichlorophenylJ-N'-g2-imidazolidinylideneJurea hydrochloride

To a stirred suspension of 2.13 grams (0.01 mole) of 2-iminoimidazolidine hydroiodide in 50 milliliters of dry dimethylformamide under an atmosphere

EXAMPLE II N-t2-Chloro-6-methylphenylJ-N'-(2-ímidazolidinylideneJ-urea and Hydrochloride Asolution of 10.65 grams (0.05 mole) of 2-iminoimidazolidine hydroiodide in dimethylformamide is added dropwise with stirring over a 15 minute period to a cooled to 5"C suspension of 397.5 milligrams (0.05 mole) of lithium hydride in 50 milliliters of dry dimethylformamide under nitrogen whereupon hydrogen evolution is observed. While stirring is continued, the mixture is allowed to gradually warm to room temperature.

Thereafter, the reaction mixture is cooled to 0-5"C and a solution of 5.0 grams (0.03 mole) of 2-chloro-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period. After completion of the addition, the mixture is allowed to warm gradually to room temperature while the stirring under nitrogen atmosphere is continued overnight to obtain the desired N-(2-chloro-6methylphenyl)-N'-(2-imidazolidinylidene)urea product which remains in solution. The product is recovered from the reaction mixture by (a) adding the mixture to 300 milliliters of ice water with stirring, (b) lowering the pH below 2 with aqueous 10 percent hydrochloric acid to precipitate acid insoluble 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. The product after washing thoroughly with water has a melting point of 169"-171"C.

The product urea base is dissolved in 30 milliliters of methanol, and methanoiic hydrogen chloride added thereto to a pH below 3. Ether is then added whereupon a N-(2-chloro-6-methylphenyl)-N'-(2imidazolidinylidene)urea hydrochloride product precipitates. The latter is recovered and recrystallized successively from 2-propanol and methanol-ether to obtain a purified product, m.p.209-211 ,which decomposes to a solid melting at 270"C (dec.) Anal. Calcd. for C11H13ClN40.HCl: C, 45.69; H, 4.88; N, 19.37 Found: C, 45.59; H, 4.93; N, 19.35 EXAMPLE III N-62,6-DibromophenylJ-N'-r2-imidazolidinylideneJurea Hydrochloride In a manner similarto that described in Example II, a solution of 12.0 grams (0.0563 mole) of 2-iminoimidazolidine hydroiodide in 50 milliliters of dry dimethylformamide is added dropwise with cooling and under an atmosphere of nitrogen to a suspension of 447 milligrams (0.0563 mole) of lithium hydride in 50 milliliters of dry dimethylformamide. After completion of the addition the mixture is allowed to warm to room temperature over a period of about half an hour, then cooled to 0-5"C, and a solution of 7.8 grams (0.0282 mole) of 2,6-dibromophenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period while maintaining the cooled temperature range, The mixture is then allowed to warm to room temperature and stirred overnight under nitrogen to obtain the desired N-(2,6dibromophenyl)-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 percent hydrochloric acid to pH below 3, filtering to remove impurities, saturating the filtrate with solid sodium chloride and basifying with potassium carbonate to a pH of 8-9 to precipate the N-(2,6-dibromophenyl)-N'-(2imidazolidinylidene)urea product as a white solid, m.p. 185-190"C (dec.).

The thus obtained base urea product is suspended in 40 milliliters of methanol and methanolic hydrogen chloride added thereto to a pH below 2. Ether is then added to precipitate the N-(2,6-dibromophenyl)-N'-(2imidazolidinylidene)urea hydrochloride as a white solid, m.p. 200-202"C (dec.). After two recrystallizations from methanol/2-propanol/ether, there is obtained a purified product, m.p. 215-217"C decomposing to a solid, m.p. 255"C (dec.) Anal. Calcd. for C10H10N4Br20.HCI: C, 30.14; H, 2.78; N, 14.06 Found: C, 30.12; H, 2.81; N, 14.04 EXAMPLE IV In a similar manner the following compound is prepared: N-(2-lmidazolidinylidene)-N'-(2-methoxyphenyl)urea.hydrochloride, m,p. 197-199.5"C, by reacting 2iminoimidazolidine (prepared from 2-iminoimidazolidine hydroiodide and lithium hydride) and 2methoxyphenyl isocyanate at about 5 to 10 C to obtain a N-(2-imidazolidinylidene)-N'-(2methoxyphenyl)urea product, followed by reacting the urea base with methanolic hydrogen chloride and recrystallizing first from methanol/2-propanol, then twice from methanol ether.

Anal. Calcd. for CHl4N402.HCI: C, 48.80; H, 5.58; N, 20.70 Found: C, 48.75; H, 5.61; N, 20.71 EXAMPLE V N-62-Ethyl-6-methylphenyl)-N'-{2-imidazolidinylidene)urea.Fumarate {3:2) In a manner similar to that previously described, 15.55 grams (0.073 mole) of 2-iminoimidazoline hydroiodide is added dropwise to a dry cooled suspension of 596 milligrams (0.075 mole) of lithium hydride in 30 milliliters of dimethylformamide under an atmosphere of nitrogen. After completion of the addition, the mixture is allowed to warm to room temperature to complete the reaction. Thereafter the mixture is again cooled, a solution of 8.1 grams (0.05 mole) of 2-ethyl-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period and then after the resulting mixture is stirred overnight while the temperature is allowed to rise to ambient temperatures to obtain a N-(2-ethyl-6methylphenyl)-N'-(2-imidazolidinylidene)urea product. The base product is recovered by procedures similar to that previously described and after recrystallization from methanol-water, a purified base product, m.p.

185-187"C is obtained.

A solution of 4.32 grams (0.0175 mole) of the base product thus obtained in 35 milliliters of hot isopropanol is mixed with a solution of 2.04 grams (0.0175 mole) offumaric acid in 35 milliliters of hot isopropanol and the resulting solution is allowed to cool whereupon a N-(2-ethyl-6-methylphenyl)-N'-(2- imidazolidinylidene)urea fumarate addition salt product crystallizes. The salt product after washing first with isopropanol and thereafter with ether melts at 1800C (dec.). Successive recrystailizations from methanol isopropanol, methanol/ether, and methanol does not produce a salt of reproducibly sharp melting point.

Elemental analysis indicates the salt to be formed from three moles of base and two moles of fumaric acid.

Anal. Calcd. for (C13H18N40)3(C4H404)2: C, 58.13; H, 6.44; N, 17.31 Found: C, 58.03; H, 6.57; N, 17.59 EXAMPLE VI In a similar operation there is prepared N-(2-Chlorophenyl)-N'-(2-imidazolidinylidene)urea.hydrochloride, m.p. 187-1895C by reacting 2-iminoimidazoline (prepared from 2-iminoimidazoline hydroiodide and lithium hydride in dimethylformamide at about 20"C) and 2-chlorophenyl isocyanate at about 20"-30"C overnight, then heating for 15 minutes to 1000C on a steam bath to obtain a N-(2-chlorophenyl)-N'-(2imidazolidinylidene)urea product as a crystalline solid, and thereafter reacting the urea base with methanolic hydrogen chloride.

Anal. Calcd. for CloH11N40CI.HCI: C, 43.66; H, 4.40; N, 20.36 Found: C, 43.69; H, 4.43; N, 20.36 EXAMPLE VII In operations carried out in a manner similar to that described in Examples II - VI, the following compounds may be prepared: N-2-lmidazolidinylidene-N'-(4-methoxyphenyl)-urea and its hydrobromide.

N-(2-Chloro-5-trifluoromethylphenyl)-N'-(2-imidazoiidinylidene)urea and its tartrate.

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

N-(2-lmidazolidinylidene)-N'-(4-methyl-phenyl)urea and its hydrochloride, m.p. 210-212"C.

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

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

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

N-(3,4-Dichlorophenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride, m.p. 217-2190C.

N-(2,5-Dichlorophenyl)-N'-(2-imida2olidinylidene)urea and its hydrochloride, m.p. 213-215"C.

N-(2-lmidazolidinylidene)-N'-(2,4,6-trichlorophenyl)urea and its hydrochloride, m.p. 232"C decomposes to solid, m.p. 260"C (dec.).

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

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

N-(2-lmidazolidinylidene)-N'-(2-methyl-6-methylsulfonylphenyl)urea and its hydrochloride.

N-(2-Cyano-6-methylphenyl)-N'-(2-imidazolidinylidene)u rea 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-imidazolidinylidene)urea and its hydrochloride.

N-(2-Chloro-64luorophenyl)-N'-(2-imidazolidinylidene)urea and its hydrochloride.

EXAMPLE VIII N-(2-imidazolidinylidene)-N'-phenylurea and its Hydroiodide

As the first step in the reaction, phenyl isocyanate, 119 grams (1 mole) is added in one portion with swirling to a warm solution of 83.73 grams (1.1 mole) of thiourea in 120 milliliters of dry dimethylformamide and the resulting solution heated for three hours. Thereafter, the solution is cooled, a mixture of ice and ice water cautiously added and the vessel scratched to induce crystallization of the desired intermediate N-phenylthioimidodicarbonic diamide. After crystallization starts, additional ice water (to about 1 liter) is added. The crystals which form are then recovered, washed with water and recrystallized from methanol to obtain 127 grams of a N-phenylthioimidodicarbonic diamide intermediate product, m.p. 176"-1 80"C.

As a second step, 45.5 grams (0.32 mole) of methyl iodide is added to a solution of 59.5 grams (0.305 mole) of N-phenylthioimidodicarbonic diamide in 300 milliliters of acetone and stirring the resulting mixture for about two hours at room temperature. As a result of these operations crystals form in the reaction mixture which then are filtered and dried to obtain a methyl N'-[(phenylamino)carbonyl]-carbamimidothioate hydroiodide product, m.p.195-200 C. analytical sample, m.p. (190 ) 200-202"C (Hoover) is obtained by recrystallization from methanol.

Anal. Calcd. for C4H11N3OS.HI: C, 32.06; H, 3.59; N, 12.46 Found: C, 32.11; H, 3.62; N, 12.48 Next, a methanol solution of 33.72 grams (0.1 mole) of the thus prepared methyl N'-[(phenylamino)carbonyl]carbamimidothioate hydroiodide and a methanol solution of 6.01 grams (0.1 mole) of ethylenediamine (about 50 milliliters total of methanol) are mixed together and heated under reflux for about 1.5 hours. The mixture is then cooled to -20 C to crystallize N-(2-imidazolidinylidene)-N'-phenylurea product as its hydroiodide. Several crops are recovered, combined and the combined crops purified by dissolving in methanol, filtering, and evaporating the filtrate to isolate the hydroiodide product as residue.

The hydroiodide product residue is converted to the urea base product and purified by a series of steps including dissolving the residue in a minimal amount of methanol, mixing and warming with 8.0 grams (0.079 mole) of triethylamine, replacing the methanol with ethanol, and then cooling to obtain crystals of N-(2-imidazolidinylidene)-N'-phenylurea base m.p. (181 ) 182-183"C after recrystallization from methanol.

Anal. Calcd. for C10H12N40: C, 58.81; H, 5.92; N, 27.43 Found: C, 58.79; H, 5.92; N, 27.48 The hydroiodide addition salt after recrystallization from acetone had a melting point of 223-225"C. (dec.) when immersed at 225"C., m.p. 230"C (dec.).

Anal. Calcd. for COH12N4OsHI C, 36.16; H, 3.94; N, 16.87; I, 38.21 Found: C, 36.22; H, 3.96; N, 16.88; 1, 38.21 EXAMPLE IX N-(3-Ch,orophenyl)-N'-(24midazolldin ylidene)urea In operations carried out in a manner similar to that described in Example VIII, 153.57 grams (1.0 mole) of m-chlorophenyl isocyanate is added to a warm solution of 95.15 grams (1.25 mole) of thiourea in 100 milliliters of dimethylformamide and the resultant mixture warmed overnight on the steam bath to obtain a N-(3-chlorophenyl)thioim idodicarbonicdiam ide intermediate product in the reaction mixture. The mixture is then cooled to completely precipitate the desired intermediate product which after recovery by filtration and washing with ether has a melting point of 187-189C (dec.). Additional crops are obtained, combined and recrystallized twice from methanol-water and twice from acetonitrile to obtain a purified product, m.p.

205-1070C. (dec.) To a clear acetone solution of 80.3 grams (0.35 mole) of N-(3-chlorophenyl)thioimidiodicarbonic diamide (prepared as above-described) is added 75.0 grams (0.525 mole) of methyl iodide and the reaction mixture stirred overnight to obtain the desired methyl N'-{[(3-chlorophenyl)amino]-carbonyl}-carbamimidothioate hydroiodide product as a crystalline solid, m.p. 182"-183"C (dec.).

To 37.1 grams (0.1 mole) of methyl N'-([(3-chlorophenyl )amino[carbonyl)-carbamimidothioate hyd roiodidethus prepared is added 6.0 grams (0.1 mole) of ethylenediamine in 100 milliliters of methanol and the resulting mixture allowed to heat under reflux for five hours. The resulting reaction mixture is evaporated to dryness in vacuo and diluted with tertiary-butyl alcohol to obtain crystals of N-(3chlorophenyl)-N'-(2-imidazolidinylidene)urea hydroiodide product as a crystalline solid. The crystals are recrystallized from tertiary butyl alcohol several times to obtain a purified product, m.p. 192-194"C. (dec.).

Anal. Calcd. for C10H1 1Cl N40.Hl: C, 32.76, H, 3.29 Found: C, 32.82, H, 3.33 The following examples illustrate the novel pharmaceutical compositions intended for controlling hypertension, but are not to be construed as limiting: Example X 1,000 hard gelatin capsules, each containing 200 milligrams of N-(2,6-dichlorophenyl)-N'-(2imidazolidinylidene)urea are prepared from the following formulation: Grams N-(2,6-Dichlorophenyl) N'-(2-imidazolidinylidene)urea 200 Starch 250 Lactose 750 Talc 250 Calcium stearate 10 A uniform mixture of the ingredients is prepared by blending and employed to fill two-piece hard gelatin capsules. The capsules are suitable to be orally administered to hypertensive subjects to reduce blood pressure.

Example Xl Gelatin capsules are prepared as described in Example X except that in the formulation, 325 grams of N-(2,6-dimethylphenyl-N'-(2-imidazolidinylidene)urea is employed as active agent providing capsules containing 325 milligrams of N-(2,6-dimethylphenyl)-N'-(2-imidazolidinylidene)urea.

Example XII 1,000 compressed tablets, each containing 500 milligrams of N-(2-imidazolidinylidene)-N'-(2methoxyphenyl) urea are prepared from the following formulation.

Grams N-(2-imidazolidinylidene) N'-(2-methoxyphenyl)urea 500 Starch 750 Dibasic calcium phosphate hydrous 5,000 Calcium stearate 2.5 The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets using starch as a disintegrant and calcium stearate as a lubricant.

Example Xlil Tablets are prepared as described in Example XII except that N-(2,6-dibromophenyl)-N'-(2imidazolidinylidene)urea is employed as active agent.

Example XIV Gelatin capsules are prepared as described in Example X except that N-(3-chlorophenyl)-N'-(2imidazolidinylidene)urea is employed as active agent.

The following examples illustrate the novel pharmaceutical compositions intended for controlling intestinal disorders, but are not to be construed as limiting: Example XV 1,000 hard gelatin capsules, each containing 200 milligrams of N-(2,6-dichlorophenyl)-N'-(2imidazolidinylidene)urea are prepared from the following formulation: Grams N-(2,6-Dichlorophenyl) N'-(2-imidazolidinylidene)urea 200 Starch 250 Lactose 750 Talc 250 Calcium stearate 10 A uniform mixture of the ingredients is prepared by blending and employed to fill two-piece hard gelatin capsules. The capsules are suitable to be orally administered to subjects with functional novel disorders.

Example XVI Gelatin capsules are prepared as described in Example VI except that in the formulation, 400 grams of N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea is employed as active agent providing capsules containing 400 milligrams of N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea.

Example XVII Gelatin capsules are prepared as described in Example VII except that N-(2-ethyl-6-methyl)-N'-(2imidazolidinylidene)urea is employed as the active agent.

Example XVIII Gelatin capsules are prepared as described in Example VII except that N-(2,6-dimethylphenyl)-N'-(2imidazolidinylidene)urea is employed as the active agent.

Example XIX 1,000 compressed tablets, each containing 500 milligrams of N-(2-Chloro-6-methylphenyl)-N'-(2imidazolidinylidene)urea are prepared from the following formulation: Grams N-(2-Chloro-6-methylphenyl) N'-(2-imidazolidinylidene)urea 500 Starch 750 Dibasic calcium phosphate hydrous 5,000 Calcium stearate 2.5 The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets using starch as a disintegrant and calcium stearate as a lubricant.

CLAIMS 1. The use in the treatment of hypertension, intestinal disorders or irritable bowel disorders of an N-aryl-N'-(2-imidazolidinylidene)urea compound of the formula:

wherein Ar is phenyl group substituted with from 0 to 3 substituents which are each independently selected from a group in which halogen is present or a carbon containing group having 1 or 2 carbon atoms which is optionally attached to the phenyl group through a non-basic hetero atom, with the proviso that when the compound is for use in controlling intestinal disorders then Ar is a phenyl group substituted at least in the 2 and 6 positions with the halogen or carbon containing groups; or a pharmaceutically-acceptable salt thereof.

2. The use in the treatment of hypertension of a urea compound of the formula:

wherein each R is independently selected from chloro, bromo, methyl, ethyl and methoxy, n is O or an integer of from 1 to 3; or a pharmaceutically acceptable salt thereof.

3. The use in the treatment of irritable bowel conditions of a urea compound of the formula:

wherein X and Y are each independently selected from methyl, ethyl, chloro and bromo; or a pharmaceutically acceptable salt thereof.

4. The use in the treatment of a urea compound of the formula:

wherein X and U are each independently selected from methyl, ethyl, chioro and bromo; or a pharmaceutically acceptable salt thereof.

Claims

5. The use as claimed in claim 1 wherein the urea compound is N-(2,6-dichlorophenyl)-N'-(2- imidazolidinylidene)urea.

6. The use as claimed in claim 1 wherein the urea compound is N-(2,6-dimethylphenyl)-N'-(2imidazolidinylidene)urea.

7. The use as claimed in claim 1 wherein the urea compound is N-(2-imidazolidinylidene)-N'-(2methoxyphenyl)urea.

8. The use as claimed in claim 1 wherein the urea compound is N-(2,6-dibromophenyl)-N'-(2- imidazolidinylidene)urea.

9. The use as claimed in claim 1 wherein the urea compound is N-(2-chloro-6-methylphenyl)-N'-(2imidazolidinylidene)urea.

10. The use as claimed in claim 1 in the treatment of hypertension, intestinal disorders or irritable bowel conditions of a compound of Formula las hereinbefore described.

11. A pharmaceutical composition in dosage unit form for treating hypertension and intestinal disorders which comprises a therapeutically-effective amount of a urea compound, the urea compound being either (a) a compound of the general formula:

wherein Ar is a phenyl group substituted with from 0 to 3 substituents which are independently selected from a group in which halogen is present or a carbon containing group having 1 or 2 carbon atoms which is optionally attached to the phenyl group through a non-basic heterocyclic atom, or (b) a pharmaceuticallyacceptable salt thereof, with the proviso that when the compound is intended for use in controlling intestinal disorders, then Ar is restricted to phenyl substituted at least in the 2 and 6 positions with the halogen or carbon containing groups, the urea compound being in admixture with a pharmaceutically-acceptable carrier or diluent.

12. A pharmaceutical composition as claimed in claim 11 for treating hypertension comprising from 5 to 500 milligrams of the urea compound per unit dosage, the urea compound having the formula:

wherein each R is independently selected from chloro, bromo, methyl, ethyl and methoxy, n is O or an integer of from 1 to 3, or a pharmaceutically-acceptable salt thereof.

13. A pharmaceutical composition as claimed in claim 10 for relieving the discomforts associated with intestinal disorders comprising from 5 to 500 milligrams of the urea compound per unit dosage, the urea compound having the formula:

wherein X and Y are each independently selected from methyl, ethyl, chloro and bromo and pharmaceutically acceptable salts thereof.

14. A composition as claimed in claim 1 or claim 2 the urea compound is N-(2,6-dichlorophenyl)-N'-(2imidazolidinylidene)urea.

15. A composition as claimed in claim 1 or claim 2 wherein the urea compound is N-(2,6 dibromophenyl)-N'-(2-imidazolidinylidene)urea.

16. A composition as claimed in claim 1 or claim 2 wherein the urea compound is N-(2imidazolidinylidene)-N'-(2-methoxyphenyl)urea.

17. A composition as claimed in claim 1 or claim 2 wherein the urea compound is N-(2-chlorophenyl)-N' (2-imidazolidinylidene)urea.

18. A composition as claimed in claim 3 wherein the urea compound is N-(2-chloro-6-methylphenyl)-N' (2-imidazolidinylidene)urea.

19. A pharmaceutical composition as claimed in claim 11 substantially as hereinbefore described.

20. Acompound oftheformula:

wherein R1 and R2 are each independently a halogen atom, a loweralkoxy or loweralkyl group, with the proviso that R1 and R2 are both loweralkyl groups, or a pharmaceutically acceptable salt thereof.

21. N-(2,6-Dichlorphenyl)-N'-(2-imidazolidinylidene)urea.

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

23. N-(2,6-Dibromophenyl)-N'-(2-imidazolidinylidene)urea.

24. N-(2-Ethyl-6-methylphenyl)-N'-(2-imidazolidinylidene)urea.

25. A process for preparing a compound as claimed in claim 20, which process comprises reacting 2-iminoimidazolidine with a compound of the formula:

wherein R1 and R2 are as defined in claim 20, in a suitable solvent.

26. A process for preparing N-(2,6-dichlorophenyl)-N-(2-imidazolidinylidene)urea, which comprises reacting 2-iminoimidazolidene with 2,6-dichlorophenylisocyanate.

27. A process as claimed in claim 25 substantially as hereinbefore described.

28. A compound as claimed in claim 20 whenever prepared by a process as claimed in any one of claims 25 to 27.

29. A pharmaceutical composition as claimed in claim 11.