FI66354C - FORM OF THERAPEUTIC PREPARATION OF NUTRITIONAL N-2,6-DISUBSTITUERAD-PHENYL) -N '- (2-IMIDAZOLIDINYLIDES) -UREAD ERVAT - Google Patents

Description

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Patent- och Ieglrttfityrdwn AiwBfc— nrtfl aeh «LakrMa · patieind 29.06.84 (32) (33) (31) * n *« ty woMww UjHtrtoctet December 22, 2007 ., Camp Hill Road, Fort Washington, Pennsylvania, USA (72) Chris Royce Rasmussen, Ambler, Pennsylvania, USA (74) Oy Kolster Ab (54) Method for the treatment of therapeutically useful N- (2,6-disubstituted -phenyl) -N '- (2-imidazolidinylidene) -urea derivatives -For the preparation of therapeutic derivatives of N- (2,6-disubstituted-phenyl) -N1- (2-imidazolidinylidene) -urea derivatives

The invention relates to a process for the preparation of novel N- (2,6-disubstituted-phenyl) -N '- (2-imidazolidinylidene) -urea derivatives of the formula I and their pharmaceutically acceptable acid additions.

for the preparation of salts; D

R1 H Q ^ \ N Π / _ \ N - C - NH_ (Q)

B

wherein R 2 and R 2 represent halogen, lower alkoxy or lower alkyl, provided that R 1 and R 2 are not both lower alkyl groups.

These compounds are useful for controlling hypertension and relieving intestinal diseases.

2 66354 'Irritable bowel symptoms are a functional disorder characterized mainly by abdominal pain but also diarrhea and constipation and similar symptoms. The pain associated with these symptoms is believed to be due to hypersensitivity to intestinal elongation caused by either intestinal gases and / or fecal material. Therapeutic measures that would provide relief from the ailments associated with these symptoms and / or the disease that causes these symptoms are highly desirable.

Certain imidazolidineurea compounds are known in the art. Accordingly, U.S. Patent 3,168,520 describes imidazolidineurea and hexahydropyrimidine urea compounds. These compounds are reported to be useful as stabilizers. In particular, the patent describes 2-phenylcarbamyliminoimidazolidine, which is N- (2-imidazolidinylidene) -N1-phenylurea. However, the patent does not mention anything about the possible use of imidazolidineurea and hexahydropyrimidine urea compounds as active ingredients in the pharmaceutical preparations of the ingredient.

Certain urea compounds have been reported to have certain pharmacological properties. Accordingly, U.S. Patent 4,060,635 describes amidinourea compounds. These compounds have an aryl group in the second urea nitrogen and a substituted amidino group in the second urea nitrogen. U.S. Patents 3,539,616 and 3,784,582 describe amidinourea compounds in which one urea nitrogen is substituted with an aryl group and the other urea nitrogen is substituted with an unsubstituted amidine group. U.S. Patent 4,058,557, which also relates to amidine ureas, describes compounds in which one of the amidine nitrogen atoms is attached to an oxygen atom. However, these patents do not describe or suggest the substitution of urea nitrogen with an imidazolidino group, nor do they mention any possible antihypertensive effect of the compounds.

In G.H. Douglas et al., Arz, Forsch / Drug Res. 28 (II), 1480 (1978) describes aryl-substituted amidinourea compounds that have been studied for mobility and secretion inhibitory activity. N- (2,6-dimethylphenyl) -N '- (2-imidazolidinylidene) urea and N- (2,6-dimethylphenyl) -N1- (1-methyl-2-imidazolidinylidene) urea are some of the compounds tested. However, Article 3 66354 does not disclose the compounds having beneficial inhibitory activity, and no other pharmacological test has been reported or suggested for use with these compounds.

It has now been found that the compounds of formula I and their acid addition salts are useful in the treatment of hypertension and functional bowel disorders, as well as in the relief of pain and other symptoms associated with irritable bowel syndrome. Suitable pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, p-toluenesulfonate, benzenesulfonate, malate, tartrate, fumarate, citrate, pamoate, maleate, malonate, methosulfate, succinate, oxalate, oxalate, oxalate, napsylate etc.

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be prepared by reacting 2-iminoimidazolidine with a phenyl isocyanate of formula

0 = C = N ~ \ 0) H

R 2 · and wherein are as defined above, in a suitable solvent and if desired, the compound of formula I obtained is converted into a pharmaceutically acceptable acid addition salt. The 2-iminoimazole starting material can be prepared in a manner known per se and suitably stored as an acid addition salt.

B

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I y? = NH * acid H

The acid addition salt of 2-iminoimidazoline is converted to the free base by thoroughly mixing two molar equivalents of a 50% aqueous solution of sodium hydroxide in a solution or suspension of the acid addition salt and then adding anhydrous sodium sulfate to remove excess water. The biphasic mixture thus obtained is contacted with a suitable phenyl isocyanate of formula II to give the desired compound of formula I.

The reaction between the phenyl isocyanate and 2-iminolxidazolidine is preferably carried out by adding a solution of the phenyl isocyanate in tetrahydrofuran portionwise with stirring to a biphasic mixture at a temperature of about 20-30 ° C and stirring for a few hours overnight. The N-phenyl-N'-imidazolinylidene urea compound thus obtained is recovered, if desired converted into the acid addition salt form and purified using conventional procedures.

The free base of 2-iminoimidazolidine can also be obtained by contacting a solution of the acid addition salt of 2-iminoimidazolidine with a suspension of lithium hydride, preferably in the same solvent, under an inert atmosphere. Suitable solvents include dry dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and the like. The liquefaction temperature is generally between 0 and 30 ° C. An inert atmosphere is suitably provided using nitrogen or argon.

The reaction is preferably carried out by adding a solution of the acid addition salt of 2-iminoimidazolidine dropwise with stirring to a cooled suspension of lithium hydride in a dry solvent under a nitrogen atmosphere while maintaining temperatures between 0 and 5 ° C. Stirring is continued after the addition is complete while allowing the mixture to gradually warm to room temperature to give the free base.

The reaction between 2-iminoimidazolidine and phenyl isocyanate can be carried out by adding the aryl isocyanate solution dropwise with stirring and cooling to the reaction mixture containing the free base under stirring under an inert atmosphere while gradually warming to ambient temperature and then at about 30-110 ° C. C, preferably 65-110 ° C to optimize the yield to give the desired N-phenyl-N '- (2-imidazolidinylidene) urea compound. When the reaction is carried out at ambient temperature, stirring is usually continued for several hours or overnight; when performed at elevated temperature, about two hours is sufficient. The acid addition salts of the compounds of formula I can be prepared in a manner known per se. For example, the free base can be mixed with an alcoholic solution of an acid corresponding to the desired addition salt and cooled to obtain an acid addition salt.

5 66354

Antihypertensive Effect The N-phenyl-N '- (2-imidazolidinylidene) urea compounds have been found to alleviate hypertension and still generally cause this without an associated increase in heart rate. An agent that has an antihypertensive effect without raising, but rather maintaining or decreasing the heart rate, is one that is considered more useful for the beneficial treatment of a patient suffering from hypertension. The amount to which a compound has these properties can be determined in an antihypertensive test in rodents and in a hemodynamic evaluation in dogs as described below.

Antihypertensive effect in rodents This experiment evaluates compounds based on their effects on arterial pressure and heart rate. In this experiment, arterial pressure in spontaneously hypertensive or hypertensive rats with deoxycorticosterone acetate injection and administration of 2% sodium chloride as drinking water is monitored directly via an aortic cannula. Rats are anesthetized with a vapor respiratory anesthetic (methoxyflurane or ether). The left carotid artery is isolated and cannulated. The tip of the cannula is inserted into the aorta and the cannula is brought out from behind the neck at the level of the scapula. The animals are placed in separate cages and allowed to recover from anesthesia and kept untethered. The arterial cannula is connected to a pressure transfer system connected to the plotter. Heart rate is determined by recording arterial pressure. Animals with pressures above 149 mmHg are considered to be sufficiently overpressured for use in an experiment measuring antihypertensive effects. Test compounds are administered either orally (p.o.) by gavage or intraperitoneally (i.p.) by injection. Arterial pressure and heart rate are monitored for at least four hours. The test compound is considered to be active as an antihypertensive agent if the mean arterial pressure (MAP) shows a decrease of> 19 mmHg. Each animal serves as its own comparison.

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

66354

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

In this experiment, mixed breed dogs are anesthetized with 20 mg / kg (milligrams per kilogram body weight) of thiopental sodium and 60 mg / kg of alpha-chlorolose. Complementary alpha-chlorolose (60 mg / kg) is used as needed to maintain anesthesia. The folded intratracheal tube is inserted to maintain an unobstructed airway and the animal is artificially ventilated by a ventilation pump. The femoral artery and vein are catheterized to record arterial pressure and for intravenous injections, respectively. Both common main arteries are isolated to perform bilateral main artery occlusion. The circulatory nerve is electrically excited at the peripheral end for 10 seconds at five volts using 20 pulses per second each for a duration of two milliseconds to cause cardiac arrest. The electrocardiogram is monitored via limb coupling II.

Comparative cardiovascular reactions are obtained for the following pharmacological procedures: 1.0 mcg / kg I.V. (micrograms per kilogram body weight, intravenously) 1-epinephrine, main artery occlusion, 10 mcg / kg I.V. dimethylphenylpiperazinium iodide (DMPP), peripheral nerve excitation, 10 mcg / kg I.V. acetylcholine and 2 mcg / kg I.V. angiotensin. These control reactions are performed twice, after which the test compound is injected at 5 mg / kg (milligrams per kilogram) I.V. using vial injections in approximately one minute. If no change in arterial pressure, heart rate, or ECG (limb coupling II) occurs, an additional 5 mg / kg I.V. test compound. The effects of the test compound on the electrocardiogram, arterial pressure and heart rate are observed. 10 minutes after administration of the test compound, a second series of hemodynamic reactions is obtained.

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

The results seen in Table I show that the N-phenyl-N '- (2-imidazolidinylidene) urea compounds and their salts not only have the advantageous antihypertensive property, but also the desired property of maintaining or lowering the normal heart rate.

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8 66354

Intestinal Disorder Effect N-phenyl-N '- (2-imidazolidinylidene) urea compounds have been found to alleviate functional intestinal disorders called irritable bowel disorders. A disorder characterized by abdominal pain, diarrhea, constipation, and the like symptoms, bowel hypersensitivity caused by stretching of intestinal gas and / or fecal material effect.

The amount by which a compound is effective to provide relief can be determined by an experiment in which a glass balloon is inserted into the rectum and the time elapsed between insertion and removal of the balloon is determined. Compounds which are effective in reducing the sensitivity j s colon wall stretching, delaying the sphere exiting from i.

j The test is performed on a male albino with a body weight of 18-25 g; mice using five mice for each dose of compound tested. The first screening dose selected for each compound is 50 mg / kg body weight (mg / kg) administered orally in a volume of 0.1 ml per 10 g body weight. The control groups receive a carrier (S) of 0.5% Methocelia® (methylcellulose)

S

both oral and intraperitoneal. Mouse j is allowed to fast for one hour before testing and test drugs are administered one hour before insertion of the glass bead.

At the end of the pretreatment period, the mouse is lifted up and held firmly in one hand with its abdomen facing the experimenter. A 3 ml diameter glass balloon is placed in the anus and, using a pinching grip with the thumb and forefinger, the balloon is inserted into the rectum. Thereafter, using a 3 ml diameter glass rod lubricated with 0.5% Methocel® to facilitate insertion, the glass balloon is inserted into the rectum at a distance of 2 cm using a slow, gentle rotation. The mice are divided into groups and in the group at different time intervals calculated from the last mouse treatment, the number of defecated spheres is recorded. Groups are based on time intervals of 0.5 minutes, 5-10 minutes, 10-20 minutes, 20-40 minutes, and more than 40 minutes. They are assigned activity index values of 0, 1, 2, 3, and 4, respectively. Mice that have not defecated after 40 minutes are examined for outbreaks. Those mice whose colon has erupted are removed from the group. The sum of the values divided by the number of mice or beads is called the activity index of the drug tested. The ED_ value is determined by regression curves using the least squares method. The ED 2 value is defined as the dose that causes an activity index of 2.

The results of the test for intraperitoneal and oral administration of the compounds of formula I are shown in Table II.

Table II

Compound H Ri N 0 Γ ^> = n - !!: - nh- ^ q \. hx H R2 ^ ED50 (mg / kg)

Intraperitoneal Oral- R 1, R 2 HX internally ti 2.6- Cl HCl 7 13.7 2-Cl, 6-CH 3 HCl 8 35 2.6- Br HCl 9 38

The above results indicate that N-phenyl-N '- (2-imidazolidinylidene) urea compounds reduce the sensitivity of the abnormal bowel movement with respect to elongation. Pharmaceutical compositions containing compounds of formula I or pharmaceutically acceptable acid addition salts thereof may be prepared by intimately admixing the urea compound with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, the carrier being able to take a wide variety of forms depending on, e.g., oral or parenteral administration. In preparing the compositions into oral dosage form, any of the usual pharmaceutical media may be employed. Thus, suitable carriers and excipients for liquid oral preparations such as suspensions, medicated beverages and solutions include water, glycols, oils, alcohols, spices, preservatives, colorants and the like; Suitable carriers and excipients for solid oral preparations such as powders, capsules and tablets are starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Due to their ease of administration, tablets and capsules carriers. If desired, tablets may be sugar or enteric coated by standard techniques. For parenteral preparations, the carrier will usually comprise sterile water, though other ingredients, for example, to aid 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" 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 connection with. Examples of such dosage unit forms are tablets, capsules, pills, etc. The dosage unit will generally contain about 5 to 500 mg of a compound of formula I.

The following examples illustrate the invention.

Example I Preparation of the starting material 213 g (1.5 mol) of methyl iodide are added with stirring over 1 hour to a suspension of 153.24 g (1.5 mol) of ethylenethiourea. In 300 ml of ethanol. Stirring is continued for about another hour to complete the formation of S-methylethylenethiourea. Anhydrous ammonia is then added to the reaction to form 2-iminoimidazolidine hydroiodide and a methyl mercaptan by-product. Stirring and intermittent addition of ammonia are continued for a total of about 26 hours. The mixture is concentrated with the simultaneous addition of isopropanol to replace the evaporated methanol and then cooled and ether is added to give 2-iminoimidazolidine hydroiodide as a crystalline solid having a melting point of 152-154 ° C after recrystallization from methanol / tert-butanol.

Analysis calculated for C 16 H 25 N 2 O 3 H 3: C 16.95 H, 3.79 Found: C 16.85 H, 3.82

Preparation of final products Example 1 N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride 11 66354 "P C1 C>" -! -NH_ (E)) 'HCl H Cl

To a stirred suspension of 2.13 g (0.01 mol) of 2-iminoimidazolidine hydroiodide in 50 ml of dry dimethylformamide under a nitrogen atmosphere is added 0.8 g (0.01 mol) of a 50% aqueous solution of sodium hydroxide, whereby free 2-iminoimidazolidine base and sodium iodide are obtained. 1 g of anhydrous sodium sulphate is then added and stirring is continued for a further half hour.

A solution of 0.94 g (0.005 mol) of 2,6-dichlorophenyl isocyanate in 20 ml of tetrahydrofuran is then added dropwise over 2.5 hours and the mixture is allowed to stir overnight at room temperature to give N- (2.6 -dichlorophenyl) -N '- (2-imidate-solidinylidene) urea product. The sodium salts are removed by filtration and the filtrate is concentrated in a water bath under reduced pressure to give a pale yellow oil. The latter is dissolved in methylene chloride and the methylene chloride solution is first washed with saturated brine, dried over anhydrous potassium carbonate and treated with hydrogen chloride until a pH of less than 3 is reached.

The solvent and excess hydrogen chloride are removed in vacuo and the residue is recrystallized from methanol / ether to give purified N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride, m.p. 210-212 ° C, which decomposes to a solid, melting at 239 ° C.

Example 2 N- (2-Chloro-6-methyl-phenyl) -N1- (2-imidazolidinylidene) -urea and its hydrochloride

A solution of 10.65 g (0.05 mol) of 2-iminoimidazolidine hydrochloride in dimethylformamide is added dropwise with stirring over 15 minutes to a suspension cooled to 5 ° C of 397.5 mg (0.05 mol) of lithium hydride in 50 ml. in dry dimethyl formad under nitrogen, after which the evolution of hydrogen is observed. While stirring is continued, 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 (0.03 mol) of 2-chloro-6-methylphenyl isocyanate in 25 ml of dry dimethylformamide is added dropwise over two hours. At the end of the addition, the mixture is allowed to gradually warm to room temperature while stirring under nitrogen overnight to give the desired N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea product which remains in solution. The product is recovered from the reaction mixture (a) by adding the mixture to 300 ml of ice water with stirring, (b) lowering the pH to below 2 with 10% aqueous hydrochloric acid to precipitate the acid insoluble material, (c) by filtration, (d) basifying the filtrate to pH to 8-9 with solid potassium carbonate and (e) saturating the solution with solid sodium chloride to purify the desired N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea free base as a white solid. After thorough washing with water, the melting point of the product is 169-171 ° C.

The urea base product is dissolved in 30 ml of methanol and a methanolic hydrogen chloride solution is added to a pH below 3. Ether is then added to precipitate the hydrochloride product of N- (2-chloro-6-methylphenyl) -N '- (2-imidazolidinylidene) urea. The latter is recovered and recrystallized successively from 2-propanol and methanol ether to give the purified product, m.p. 209-211 ° C, which decomposes to a solid, melting at 270 ° C (decomposes).

Analysis for C 45 H 19 N 2 O 3 HCl: Calculated: C 45.69 H, 4.88 N 19.37 Found: C 45.59 H 4.93 N 19.35

Example 3 N- (2,6-Dibromophenyl) -N '- (2-imidazolidinylidene) urea hydrochloride

In the same manner as in Example 2, a solution of 12.0 g (0.0563 mol) of 2-iminoimidazolidine hydroiodide in 50 ml of dry dimethylformamide is added dropwise, under cooling and under a nitrogen atmosphere, to a suspension of 447 mg (0.0563 mol) of lithium hydride. In 50 ml of dry dimethylformamide. The decision of the addition, the mixture is allowed to warm to room temperature during about half an hour, then cooled to 0-5 ° C and a solution of 13 66354 of 7.8 g (0.0282 mol) of 2,6-dibromo phenyl isocyanate in 25 ml of dry dimethylformamide, is added dropwise over two hours while maintaining a cooled temperature range.

The mixture is then allowed to warm to room temperature and stirred overnight under nitrogen to give 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 ml of ice water, acids with 10% hydrochloric acid below 3, filtering to remove impurities, saturating the filtrate with solid sodium chloride and basifying with potassium carbonate to pH 8-9 N- (2.6 -dibromophenyl) -N1- (2-imidazolidinylidene) to precipitate the urea product as a white solid, m.p. 185-190 ° C (decomposes).

The urea base product thus obtained is suspended in 40 ml of methanol and a methanolic solution of hydrogen chloride is added to a pH below 2.

The ether is then added to precipitate N- (2,6-dibromophenyl) -N '- (2-imidazolidinylidene urea hydrochloride as a white solid, mp 200-202 ° C (decomposes).) After two recrystallizations from methanol / 2-propanol / ether, purified product, mp 215-217 ° C, which decomposes to a solid, mp 255 ° C (decomposes).

Analysis for C 10 H 10 N 4 Br 2 O * HCl: Calculated: C 30.14 H 2.78 N 14.06 Found: C 30.12 H 2.81 N 14.04.

Example 4

As described in Examples 2-3, N- (2,6-dimethoxyphenyl) -N '- (2-imidazolidinylidene) urea hydrochloride * 1/3 H 2 O, i.e. 204-205 ° C (dec.).

i

Claims (2)

14 66354 A process for the preparation of therapeutically useful N- (2,6-disubstituted-phenyl) -N '- (2-imidazolidinylidene) -urea derivatives of the formula I and their pharmaceutically acceptable acid addition salts, (^ y-n - ^ - nh-j5) ) H 2 in which R 1 and R 2 represent halogen, lower alkoxy or lower alkyl, provided that R 1 and R 2 are not both lower alkyl groups, characterized in that 2-iminoimidazolidine is reacted with a phenyl isocyanate of formula wherein R 1 and R 2 are as defined above, in a suitable solvent and if desired the compound of formula I obtained is converted into a pharmaceutically acceptable acid addition salt. Process for the preparation of N- (2,6-dichlorophenyl) -N '- (2-imidazolidinylidene) urea according to Claim 1, characterized in that the 2-iminoimidazolidine is reacted with 2,6-dichlorophenyl isocyanate.