GB2094300A

GB2094300A - 4-(5)-alkylmercaptoimidazole derivatives, a process for their production and medicaments containing these compounds

Info

Publication number: GB2094300A
Application number: GB8205433A
Authority: GB
Original assignee: Heumann Ludwig and Co GmbH
Current assignee: Heumann Ludwig and Co GmbH
Priority date: 1981-02-27
Filing date: 1982-02-24
Publication date: 1982-09-15
Also published as: ES509853A0; GR75901B; IT1150160B; DE3107599C2; IT8219366A0; DE3107599A1; JPS57158761A; ZA82460B; ES8301933A1; NL8200351A; IL64887A0; KR830009047A; FR2500828A1

Abstract

4-(5)-alkylmercaptoimidazole derivatives corresponding to the following general formula <IMAGE> in which R1 represents a methyl or ethyl group and X reprosents sulfur, an N-cyano group or a nitromethylene group, and their salts with pharmaceutically acceptable acids have activity as histamine antagonists.

Description

SPECIFICATION 4-(5)-alkylmercaptoimidazole derivatives, a process for their production and medicaments containing these compounds This invention relates to alkylmercaptoimidazole derivatives, to processes for the production thereof, and to their use in pharmacy.

N-cyano-N '-methyl-N "- (2-[(5-methylimidazol-4-yl)-methyhhio]-ethylj -guanidine (hereinafter referred to in short as cimetidine) is described in DE-PS No. 2,344,779 as a histamine-H2-receptor antagonist.

Histamine antagonists have been known since 1937 (D. Bovet and A.M. Staub, C.R. Seanc.

Soc, Biol. 124, 547 [1 937]). They block numerous effects of histamine, such as for example its bronchoconstrictory effect, its effect in increasing vascular permeability or its contracting effect upon the isolated ileum of guinea pigs. Therapeutically, histamine antagonists are used above all to weaken the effect of the histamine released in the body through allergic reactions.

The receptors responsible for the effect of histamine, which can be blocked by the antihistaminics discovered by Bovet and Staub, are situated mainly in the smooth musculature.

They were named "H-receptors'' by Ash and Schild (Brit. J. Pharmac. Chemoth. 27, 427 [1 966)). However, there are other effects of histamine which cannot be blocked by these conventional histamine antagonists. These effects include above all the stimulating effect which histamine has upon the heart and the secretion of gastric juices and its inhibiting effect on the electrically stimulated contraction of rats uterus.

Substances which block these effects of histamine are known as histamine-H2-receptor antagonists (J.W. Black, W.A.M. Duncan, G.J. Durant, C.R. Ganellin and E.M. Parsons, Nature 236, 385 (1 972]). The way in which these compounds act represents a new pharmacological principle.

The above-mentioned DE-PS No. 2,344,779 describes cimetidine as an antagonist of the histamine-induced inflammation of the right auricle of guinea pigs hearts.

The object of the present invention is to provide new C-4-(5)-thiourea, guanidine and nitromethylene derivatives of imidazole substituted by alkylthio radicals which may be used as histamine-H2-receptor antagonists.

It has now surprisingly been found that compounds corresponding to general formula I are distinguished by better properties than the known cimetidine.

Accordingly, the present invention relates to 4-(5)-alkylmercaptoimidazole derivatives corresponding to the following general formula

in which R, represents a methyl or ethyl group and X represents sulfur, an N-cyano group or a nitromethylene group, and to their salts with pharmaceutically acceptable acids.

Preferred compounds are characterised in that X represents a sulfur atom and R1 is a methyl or ethyl group.

Other preferred compounds are characterised in that X represents an N-cyano group and R, is a methyl or ethyl group.

Other preferred compounds are characterised in that X represents a nitromethylene group and R, is a methyl or ethyl group.

Particularly preferred compounds are N-cyano-N '-methyl-N"- (2-[(5-methylthioimidazol-4-yl)-methylthio]-ethyl) -guanidine, N-methyl-N'-[2-(5-methylthioimidazolA-yl)-(4)-methykhio)-ethyl]-thiourea-dihydrnbrnmide and N-methyl-N '-[2-(5-methylthioimidazol-4-yl-methylthio)-ethyl]Ahionitrnacetamidine.

The compounds according to the invention are produced by a process which is characterised in that 1) 2-formylaminoacetonitrile corresponding to the following formula

is converted by dehydration into 2-isocyanoacetonitrile which corresponds to the following formula

2) the 2-isocyanoacetonitrile thus obtained is reacted with a thioalcohol corresponding to the following general formula H-S-R, (lV) in which R1 is as defined in above to form a 5-substituted imidazole corresponding to the following general formula

3) the imidazole thus obtained is converted with para-formaidehyde/hydrohalic acid into a 4halogen methyl imidazole corresponding to the following general formula

in which Hal represents chlorine or bromine, 4) the halogen methyl imidazole VI is reacted without isolation with cysteamine hydrochloride corresponding to the following formula HS-CH2-CH2-NH2-HCI (Vli) and a free base corresponding to the following general formula

is obtained by subsequent alkalisation, and in that 5) a) to produce compounds corresponding to general formula I in which X represents an Ncyano group or a nitromethylene group, the free base corresponding to general formula VIII is reacted with a compound corresponding to the following formula

in which X represents an N-cyano group or a nitromethylene group, to form an isothiourea derivative corresponding to the following general formula

in which R, and X are as defined above, and the resulting thiourea derivative corresponding to general formula X is reacted with methylamine to form the compound of general formula I in which X is as defined above, or b) to produce compounds of formula I in which X represents sulfur, the free base corresponding to general formula VIII is reacted with methyl isothiocyanate to form the compound of general formula I in which X is as defined above, and the compound obtained is optionally converted into its salt with a pharmaceutically acceptable acid.

In the first stage of the process according to the invention, 2-formylaminoacetonitrile corresponding to formula II

is dehydrated with a dehydrating agent, such as phosphorus oxychloride, and a tertiary organic base, such as triethylamine for example, to form 2-isocyanoacetonitrile corresponding to formula Ill below

Suitable solvents are aprotic solvents, anhydrous dichloromethane being preferred. The reaction is carried out at temperatures of from ( - 10) to ( -- 40)"C, but preferably at ( -- 20)"C. The molar ratio of 2-formylaminoacetonitrile to phosphorus oxychloride to triethylamine is preferably 1:1.6:2.5. The reaction time amounts to between 30 minutes and 2 hours and preferably to 1 hour.To carry out the reaction, the 2-formylaminoacetonitrile is dissolved in anhydrous dichloromethane, the triethylamine is introduced into the resulting solution and the phosphorus oxychloride is added dropwise with stirring at (-- 20)"C. On completion of the reaction, the temperature of the reaction mixture is left to rise to (-- 10)"C, filtered off under suction from the salt precipitated and the filtrate stirred for 30 minutes with saturated potassium carbonate solution. The organic phase is then separated off and washed with sodium dihydrogen phosphate solution, dried over sodium sulfate and the solvent distilled off in a high vacuum at O"C. The residual oil is pure according to NMR and is further processed immediately on account of its poor thermal stability.

In the second stage, the 2-isocyanoacetonitrile, which is obtained in the form of a highly decomposible oil, is reacted with the thioalcohol IV in an aprotic solvent, such as dichloromethane, and in the presence of triethylamine as catalyst, a thioether group being introduced into the 5-position of the imidazole ring and a 5-substituted imidazole corresponding to the following formula

being obtained.

In this second stage, the molar ratio of 2-isocyanoacetonitrile to thioalcohol to triethylamine is 1:1:1, the reaction temperature is in the range from 10 to 30"C, the reaction preferably being carried out at 20"C, and the reaction time is between 1 and 3 hours, preferably amounting to 2 hours.

To carry out the second stage of the reaction, the 2-isocyanoacetonitrile is dissolved in icecold dichloromethane, the thioalcohol is introduced and the triethylamine added. After prolonged stirring, for example for 5 hours, at room temperature, the solvent is distilled off in vacuo and the residual oil is crystallised from a 1:1 mixture of dichloroethane and cyclohexane.

In the third stage, the 4-(5)-substituted imidazole is halogen methylated in the 4-(5)-position with paraformaldehyde in concentrated hydrohalic acid. The molar ratio of imidazole to paraformaldehyde is 1:1.5, the reaction is carried out at a temperature of from (+ 10) to (-- 10)"C and preferably at O"C over a period of from 2 to 8 hours and preferably over a period of 4 hours.

To carry out the third stage, the imidazole is dissolved in concentrated hydrohalic acid and the solution is saturated at O"C with gaseous hydrogen halide, the paraformaldehyde is added and the mixture is stirred for 4 hours at O"C. According to NMR, the reaction is then quantitatively complete. The halogen methyl compounds VI are so reactive that they are not isolated

Accordingly, the solutions of the 5-substituted 4-halogen methyl imidazole in hydrohalic acid are directly used for the synthesis of the next stage.

In the fourth stage, the solution of the 5-substituted 4-halogen methyl imidazole in hydrohalic acid obtained as described above is converted by reaction with cysteamine hydrochloride corresponding to formula Vll and subsequent alkalisation into the free amine corresponding to general formula VIII below

The solvent used is the hydrohalic acid used in the production of the compounds of formula VI.

The reaction is carried out at a temperature of from 0 to (+ 40)"C and preferably at ( + 20)"C over a period of from 30 minutes to 2 hours and preferably over a period of 1 hour. The molar ratio of 5-substituted 4-halogen methyl imidazole to cysteamine hydrochloride is from 1:1 to 1:3 and generally amounts to 1:2.

To carry out the fourth stage, the cysteamine hydrochloride is added in solid form to the solution of the 5-substituted 4-halogen imidazole in hydrohalic acid, followed by stirring for 1 hour at room temperature. The acid is then completely distilled off in a high vacuum at (+ 40)"C, the semi-solid residue is dissolved in water and the resulting solution is alkalised with potassium carbonate solution. The free base is extracted with ethyl acetate and purified with active carbon. Removal of the solvent by distillation leaves the pure substance in the form of an oil.

Stages 3 and 4 may also be carried out under pressure on the one-pot principle, the molar ratios of imidazole to paraformaldehyde to cysteamine hydrochloride amounting to 1:1.3:1 and the reaction being carried out at a temperature in the range from 80 to 120"C and preferably at a temperature of 100"C. The reaction time amounts to between 3 and 10 hours and preferably to 5 hours and the pressure to between 0.5 and 3 bars, depending on the reaction conditions.

To carry out the third and fourth stages on the one-pot principle, the imidazole is dissolved in concentrated hydrohalic acid, paraformaldehyde and cysteamine hydrochloride are added and the reaction mixture heated for 5 hours to 100"C in an autoclave in which a pressure of 2 bars is built up. After cooling, the acid is completely distilled off in a high vacuum at (+ 40)"C, the semi-solid residue is dissolved in water and alkalised with potassium carbonate. The free base is extracted with ethyl acetate and purified with active carbon. Removal of the solvent by distillation leaves the pure substance in the form of an oil.

In the fifth stage, the amino group in the compound of general formula VIII is reacted with the compound of formula IX to form an isothiourea derivative corresponding to general formula X below

to produce compounds in which X represents an N-cyano group or nitromethylene group.

The molar ratio between the two reaction components is 1:1, an alcohol, such as ethanol for example, is used as the solvent and the reaction is carried out at a temperature of from (+ 10) to (+ 30)"C and preferably at a temperature of (+ 20)"C over a period of from 2 to 6 hours and preferably over a period of 4 hours.

To carry out the fifth stage, the two components are each dissolved in ethanol, the solutions are combined and then left standing for 4 hours at room temperature. After filtration, the solvent is distilled off in vacuo. The residual oil may be crystallised from a polar solvent, such as acetonitrile for example.

In another stage of this alternative embodiment of the process according to the invention, the isothiourea derivative of formula X is reacted with methylamine to form the compound according to the invention, i.e. the compound corresponding to formula I in which X represents an Ncyano group or a nitromethylene group.

Once again, the reaction medium used is a polar solvent, such as methanol, ethanol or even acetonitrile, and the reaction is carried out at a temperture in the range from 0 to (+ 40)"C, and preferably at (+ 20)"C, over a period of from 3 to 10 hours and preferably over a period of 5 hours.

More particularly, the isothiourea derivative X is dissolved in acetonitrile and a 30% solution of methylamine in acetonitrile is added. After standing for 5 hours at room temperature, the product is filtered, freed from the solvent by distillation in vacuo, redissolved in acetonitrile, purified with active carbon and crystallised.

In other alternative of the fifth stage of the process according to the invention, compounds of formula I in which X represents sulfur are obtained by reacting the amino group in the compound of general formula VIII with methyl isocyanate which gives the compound of general formula I in which X represents sulfur.

This alternative of the fifth stage of the process according to the invention is generally carried out for example by heating the two components under reflux for 2 hours in ethanol. The reaction solution is then concentrated by evaporation and the residual oil is converted with hydrobromic acid into the corresponding salt.

All the thiourea, guanidine and nitromethylene derivatives of the 5-substituted imidazoles according to the invention were identified by IR, NMR and elemental analysis.

Both with inorganic acids and with organic acids, the compounds according to the invention form physiologically acceptable salts such as, for example, hydrochlorides, hydrobromides, sulfates, embonates etc. Salts of aliphatic monocarboxylic or dicarboxylic acids are particularly suitable. Acetates, maleates or even fumarates are mentioned as examples.

All the compounds of general formula I may exist in tautomeric form and may form various conformers through the development of intramolecular hydrogen bridges. Formula I is intended to cover all tautomeric and conformeric compounds.

The activity of the histamine-H2-receptor antagonist may be demonstrated by standard tests, for example by the ability of a compound of general formula I to inhibit the histamine-induced positive chronotropic response in the spontaneously beating right atrium of guinea pigs.

The guinea pig atrium test, modified in accordance with Black et al., Agents and Actions 3, 1 33 (1973), is carried out as follows: Cross-bred male guinea pigs weighing 300 to 400 g were killed by a blow behind the neck and their blood drained off. After the thorax had been opened, the heart was removed and immediately placed in an oxygen-permeated McEwens solution at 32.5"C. The right auricles were isolated and were attached under a load of approximately 1 g to an HSE flexible rod (type K 30, a product of Messrs. Hugo Sachs Elektronic) in a 60 ml capacity organ bath. The bath liquid used was a McEwens solution tempered to 32.5"C which was continuously replaced during the 30 minute equilibration period.After electrical amplification (Hellige TF 1 9 preamplifier), the isometrically recorded pulses were delivered to a heart beat counter (Hellige Recomed) which recorded the beat frequency through a direct recorder (Helcoscripter He-1 7).

Each organ preparation was used for only one test. A histamine standard curve (1 x 107 to 1 X 10-5mole/l bath concentration) was first recorded by the cumulative technique. After thorough rinsing (30 to 40 minutes) and return of the frequency to its starting position, the substance to be studied was introduced in concentrations of 1 x 10-6, 1 x 10-5 and 1 x 10-4 mole/l. After a contact time of 10 minutes, histamine was introduced in geometrically increasing concentrations for stimulation purposes. The pA2-values were determined with the aid of grafts. Two determinations were carried out with the test substance in each of the abovementioned concentrations.

Table I provides a comparison of the apparent dissociation constants K8 and of the associated pA2-values of cimetidine and the compound of Example 1.

Table I Antagonistic activity Compound KBM pA2 Cimetidine 0.79 x 10-6 6.1 N-cyano-N'-methyl-N"-{2-[(5 methylthioimidazol-4-yl)-methyl- thio]-ethyl}-guanidine (Example 1) 2.51 x 10-7 6.6 The dissociation constant K8 is calculated in accordance with the equation K8 = B/(X - 1), in which X is the ratio between the histamine concentrations which is required for producing semimaximal reactions in the presence or absence of different concentrations B of the antagonist. The pA2-value is the negative decadic logarithm of KB(pA2 = - log KB).

Now, the present invention also relates to a medicament, more particularly a histamine-H2receptor antagonist, which contains at least one compound of the type claimed in Claim 1 together with a non-toxic pharmaceutically acceptable diluent or vehicle.

The compounds according to the invention may be administered orally, topically or parenterally or in the form of suppositories. They are preferably administered perorally. They may be administered in the form of the base or in the form of physiologically acceptable salts. To produce a medicament, they are generally mixed with a pharmaceutically acceptable vehicle or diluent.

If necessary, the compounds according to the invention may also be administered in combination with other active substances, for example conventional antihistaminics.

For oral administration, the medicament is best made up in the form of capsules or tablets, including tablets of the delayed-release type. Finally, the medicaments may also be made up in the form of dragees or syrups. Suitable topical preparations are, for example, salves, lotions, creams, powders or sprays.

In the case of oral administration, a suitable daily dose may be for example of the order of 100 mg to 1.2 g per day in the form of dosage units containing from 20 to 200 mg per dosage unit. In the case of delayed-release tablets, a suitable administration pattern is 2 to 3 times daily.

Parenteral formulations may be administered by injection at intervals or by continuous infusion. Injectable solutions may contain from 10 to 100 mg of active principle per ml.

Sprays, salves, creams, powders or lotions may be used for topical application. These preparations may contain the substance in an active quantity of for example from 1.5 to 2% by weight, based on the composition as a whole.

The invention is illustrated by the following Examples.

EXAMPLE 1 Production of N-cyano-N '-methyl-N"- (2-(5-methylth ioimidazol-4-yI)-methylth io]-ethylj -guan dine: 1. Isocyanoacetonitrile 0.5 mole of 2-formylaminoacetonitrile are dissolved in 500 ml of dichloromethane, 1.25 moles of triethylamine are added and the mixture cooled to ( - 30)"C. A solution of 0.8 mole of phosphorusoxychloride in 1 50 ml of dichloromethane is added dropwise with vigorous stirring at such a rate that the temperature does not exceed (- 25)"C. The temperature is then allowed to rise to (- 1 0)'C over a period of 30 minutes and the salt precipitated is isolated by filtration under suction.A solution of 1 70 g of potassium carbonate in 500 ml of water is carefully added to the filtrate with vigorous stirring, followed by stirring for 30 minutes at (+ 25) to (+ 30)"C.

After separation in a separation funnei, the organic phase is washed twice with 100 ml of sodium dihydrogen phosphate solution. After drying over sodium sulfate, the solvent is removed in a water jet vacuum at (+ 20) to (+ 22)"C. The title compound remains behind in the form of a red-brown oil which is pure according to its NMR spectrum.

2. 5-methylthioimidazole The 2-isocyanoacetonitrile obtained as described in 1. is dissolved in 500 ml of ice-cold methylene chloride, 24 g of gaseous methyl mercaptan are introduced while cooling and 25 g of triethylamine added. The mixture is stirred first 1 hour at 0 C and then for 2 hours at room temperature, after which the solvent is completely distilled off and the semi-solid black residue recrystallised from dichloroethane/cyclohexane (1:1). Pale yellow crystals melting at 87"C.

3. 5-methylthio-4-1(2-aminoeth yl)-thiometh yl]-im idazole 0.03 mole of 5-thiomethylimidazole, 0.03 mole of cysteamine hydrochloride, 0.04 mole of paraformaldehyde and 20 ml of concentrated hydrochloric acid are heated with stirring for 5 hours to 100"C in a pressure vessel, the pressure rising to 2 bars. After cooling, the hydrochloric acid is distilled off in vacuo at (+ 40)"C and the semi-solid residue is dissolved in 100 ml of water. The addition of 30 ml of saturated potassium carbonate solution results in the separation of an oil which is extracted with ethyl acetate and purified with active carbon.

Removal of the solvent leaves the free base behind in the form of a colourless oil which is pure according to NMR.

4. N-cyano-N'-methyl-N"- (2-[(5-methylthioimidazol-4-yl)-methylthio]-ethyl} -guanidine 0.017 mole of 5-methylthio-4-[(2-aminoethylì-thiomethyl]-imidázole and 0.017 mole of dime thyl cyanodithioimidocarbonate are dissolved in 100 ml of ethanol and the resulting solution stirred under nitrogen for 4 hours at room temperature. 100 ml of a 50% solution of methylamine in ethanol are then added, followed by stirring under nitrogen for another 2.5 hours. The solvent is then completely distilled off in vacuo at (+ 40)"C and the semi-solid residue is recrystallised twice from acetonitrile. Colourless needles melting at 138.9 to 140.1 C.

C10H16N6S2 (284.4) Calculated: C = 42.23%, H = 5.67%, N = 29.55% S = 22.55% Observed: C = 42.18%, H = 5.66%, N = 29.64%, 5=22.62%.

EXAMPLE 2 Production of N-methyl-N '-[2-(5-methylth ioim idazol-4-yl)-(4)-methylthio)-ethyl]-thiourea-dihydrobromide: 2.7 g (0.01 mole) of 5-methylthio-4-[(2-aminoethyl)-thiomethyl)-imidazole dihydrochloride obtained in accordance with Example 1.3 are dissolved in 50 ml of water and 1.4 g (0.01 mole) of potassium carbonate are added to the resulting solution with stirring at room temperature.

After the evolution of CO2 has stopped, 0.7 g (0.01 mole) of methylisothiocyanate dissolved in 3 ml of ethanol is added and the mixture heated under reflux for 2 hours. The reaction solution is then concentrated by evaporation and the pale yellow oil left behind is converted with hydrobromic acid into the dihydrobromide. Recrystallisation from isopropanol M.p. 137.3 to 139.1"C CgH,8Br2N4S3 (438.28) Calculated: C = 39.10%, H = 5.84% Observed: C = 39.18% H = 5.95% EXAMPLE 3 1. S-methyl-N'-[2-(5-methylthioimidazol-4-yl-methylthio)-ethyl]-thionitroacetamidine 5.6 g of 5-methylthio-4[(2-aminoethyl)-thiomethyl)-imidazole dihydrochloride are added under nitrogen to a solution of 3.4 g of 1-nitro-2,2-bis-methylmercaptoethylene and 8.4 ml of triethylamine in 60 ml of ethanol. The mixture is heated under reflux for 12 hours, concentrated to dryness, extracted with ether, taken up in water and then repeatedly extracted with dichloromethane. The combined dichloromethane phases are concentrated to dryness and the residue sublimated.

Yield: 2 g Melting point: 123 to 124.5 on 2. N-meThyl-N'j2-(5-meThylthioimidazol-4-yi-meThy!Thio)-eThyiJ-nitroacetamidine 3.0 g of S-methyl-N '-[2-(5-methylth ioimidazol-4-yi-methylth io)-ethyl]-thionitrnacetamidine are stirred into 50 ml of ethanol at room temperature and methylamine is introduced into the resulting suspension. After introduction for 1 hour, a clear solution has formed. This solution is left standing overnight, after which n-pentane is added. The required product precipitates, is filtered off under suction and recrystallised from ethanol. M.p. 1 58 to 162"C.

C10H17N502S2 (303.41) Calculated: C = 39.59%, H = 5.65%, N = 23.08%, 0 = 10.55%, S = 21.13% Observed: C = 39.62%, H = 5.67%, N = 23.20%, 0 = 10.60%, S = 21.04%

Claims

1. 4-(5)-aikylmercaptoimidazole derivatives corresponding to the following general formula

in which R1 represents a methyl or ethyl group and X represents sulfur, an N-cyano group or a nitromethylene group, and their salts with pharmaceutically acceptable acids.

2. 4-(5)-alkylmercaptoimidazole derivatives as claimed in claim 1 in which X represents a sulfur atom and R1 represents a methyl or ethyl group.

3. 4-(5)-alkylmercaptoimidazole derivatives as claimed in claim 1 in which X represents an N-cyano group and R, represents a methyl or ethyl group.

4. 4-(5)-alkylmercaptoimidazole derivatives as claimed in claim 1 in which X represents a nitromethylene group and R, represents a methyl or ethyl group.

5. N-cyano-N'-methyl-N"- {2-[(5-methykhioimidazol-4-yI)-methykhio]-ethyl} -guanidine.

6. N-methyl-N '-(2-(5-methylthioim idazol-4-yl)-(4)-methylthio)-ethyl]-thiourea-d ihydrobrom ide.

7. N-methyl-N '-[2-(5-methylthioim idazol-4-yl-methylth io)-ethyl]-thionitroacetamidine.

8. A process for producing the 4-(5)-alkylmercaptoimidazole derivatives as claimed in claim 1 in which X represents an N-cyano group or a nitromethylene group wherein a compound of the general formula (VIII)

in which R1 has the meaning given in claim 1 is reacted with a compound of the formula

in which R, and X are as defined above, and the resulting thiourea derivative corresponds to general formula (X) is reacted with methylamine to form the compounds of general formula I in which X is as defined above, or to produce compounds in which X represents sulfur, the free base corresponding to general formula VIII above is reacted with methyl isothiocyanate to form the compound of general formula I in which X is as defined above, and the compound obtained is optionally converted into its salt with a pharmaceutically acceptable acid.

9. A process as claimed in claim 5 in which the base of the formula VIII is prepared by the steps of 1) converting a 2-formylaminoacetonitrile corresponding to the following formula

by dehydration into a 2-isocyanoacetonitrile which corresponds to the following formula

2) reacting the thus-obtained 2-isocyanoacetonitrile with a thioalcohol corresponding to the following general formula H-S-R1 (IV) in which R1 has the meaning given in claim 1, to form a 5-substituted imidazole corresponding to the following general formula

3) converting the thus-obtained imidazole with paragormaldehyde and a hydrohalic acid into a 4-halogen methyl imidazole corresponding to the following general formula

in which Hal represents chlorine or bromine, 4) reacting the thus-obtained halogen methyl imidazole VI without isolation with a cysteamine hydrochloride corresponding to the following formula HS-CH2-CH2-NH2 HC, (VII) whereby a free base of the general formula (VIII) is obtained.

10. A process as claimed in claim 8 substantially as herein described with reference to the Examples.

11. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 8 to 10.

1 2. A pharmaceutical composition containing a compound as claimed in any of claims 1 to 7 or 11 in association with a pharmaceutically acceptable carrier.

1 3. A compound as claimed in claim 1 when sold for use in pharmacy, more particularly for the treatment of those conditions associated with the release of histamine.