CS220334B2 - Method of producing new mercaptoimidazole derivatives - Google Patents

Description

Salts of the compounds of the formula I are in particular pharmaceutically usable acid addition salts with strong acids such as mineral acids, for example salts with hydrohalic acids, in particular hydrochloric or hydrobromic acid, i.e. hydrohalides, especially hydrochlorides and hydrobromides, or salts with sulfuric acid, i.e. hydrogen sulphates and sulfates.

The compounds of formula I have valuable pharmacological properties. In particular, they have significant antiinflamatory activity, antlnociceptive and / or antithrombotic activity, and have an inhibitory effect on prostaglandin synthesis.

Thus, the compounds have been shown to be excellent in a single administration to a rat in the Helv paw test for kaolin edema. Physiol. Acta 25, 156 (1967) at a dose range of about 15 to 150 mg / kg orally, as well as the paw carrageenan edema test of Di Pasquale et al., Agents and Actions 5, 256 (1975) at a dose range of about 20 to 200 mg / kg orally, followed by rat administration four times in an arthritis-inducing adjuvant test at doses of about 10 to 60 mg / kg orally, and in a mouse test for the pain reaction induced by phenyl-p-benzoquinone according to J. Pharmacol. exp. Therap. 125, 237 (1959) at a dose range of about 30 to 300 mg / kg orally, as well as a rabbit arachidonate-induced pulmonary embolism test at a dose range of about 0.1 to 3 mg / kg orally.

Further, the compounds in vitro inhibit the synthesis of prostaglandin from arachidonic acid at concentrations ranging from about 2 to 200 mg / liter by the action of bovine seminal vesicle enzymes, as demonstrated by the experimental design of Prostaglandins 7, 123 (1974).

The compounds of formula I are therefore excellently useful as pharmaceutical active compounds for the treatment of inflammatory diseases, in particular chronic inflammations of rheumatic forms such as chronic joint inflammation (arthritis.

In particular, the invention relates to a process for the preparation of compounds of the formula I in which one of the radicals R 1 and R ₂ represents an unsubstituted pyridyl group such as a 3-pyridyl group or a thienyl group such as a 2-thienyl group and the other means an unsubstituted or lower alkoxy group. 1-4 carbon atoms, such as methoxy, or halogen with an atomic number of up to 35, such as chlorine or especially fluorine, substituted phenyl, n is 1 or 2, and R ₄ is lower alkyl of 1 to 4 carbon atoms, such as ethyl and salts thereof.

The invention relates to a method for preparing compounds of formula I in which one of the radicals R, and R ₂ represents pyridyl, such as 3-ipyridylovou group, and the other is phenyl, n is 1 or 2 and R ₄ represents a lower alkyl group with 1-4 carbon atoms, such as ethyl, and their acid addition salts.

In particular, the invention relates to a process for the preparation of the compounds of the general formula (I) mentioned in the examples and their acid addition salts.

The compounds of formula (I) and their salts can be prepared by methods known per se, for example by reacting in a compound of formula (II)

AND

H (li) in which

R _b R ₂ and R ₄ are as hereinbefore defined, or in the salt thereof, the thio group is oxidized to a sulfinyl or sulfonyl group and, optionally, a pyridyl group R ₁ , R ₂ , R ₂ and R ₄ . and / or R ₂ is oxidized at a nitrogen atom and optionally the obtained free compound is converted to an acid addition salt or the obtained acid addition salt is converted to the free compound or another salt.

The oxidation is preferably carried out by treatment with a suitable oxidizing agent, preferably in a solvent inert to the reagent, optionally with cooling or heating, for example in a temperature range of about -30 to +100 ° C, preferably at about 0 ° to 60 ° C, in closed a container and / or under an inert gas atmosphere such as nitrogen.

Suitable oxidizing agents are, for example, peroxy compounds such as hydrogen peroxide, organic hydroperoxides such as tert-butyl hydroperoxide, organic peracids such as aromatic or aliphatic percarboxylic acids such as n-chloroperoxybenzoic acid, peroxyacetic acid or permonophthalic acid, heavy metal oxidizing compounds such as hexavalent compounds chromium or divalent or tetravalent manganese, for example chromium trioxide, chromic acid, manganese dioxide or potassium permanganate, oxidising inorganic oxygen acids such as nitrogen oxides, halogens or chalcogenes, or their anhydrides or salts, for example nitric acid, nitrogen dioxide, oxide selenium or sodium meta periodate, then ozone.

Suitable solvents are, for example, halogenated hydrocarbons, such as haloalkyls, for example carbon tetrachloride, chloroform or methylene chloride, or carboxylic acids, such as alkanoic acids, for example acetic acid or its anhydrides.

In a preferred embodiment of the oxidation process, for example, thioethers of formula II may be oxidized by reaction with an organic perselin, for example m-chloroperbenzoic acid, in a haloalkane, for example chloroform, to the corresponding sulfinyl or sulfonyl derivatives wherein n is 1 or 2; R @ 2 and / or R @ ₂ on the nitrogen atom N.

In a further preferred embodiment, the thioethers of formula II can be oxidized by treatment with sodium meta periodate, preferably in a haloalkane, for example carbon tetrachloride or chloroform, selectively to the corresponding sulfoxides in which n is 1 or oxidized with hydrogen peroxide in acetic acid to sulfones in n is 2.

The starting materials of the formula II and their salts can be prepared by methods known per se, for example by reacting the compounds of formulas III and IV with N

I ^ - ^{X and} Y-RJIV)

AND

H (lil)

Wherein one of X and Y is optionally in the form of an alkali metal salt a mercapto group present, and the other is halogen, a hydroxy group esterified with sulfuric acid or an organic sulfonic acid, or in the case of X a sulfonyl group derived from an organic sulfonic acid, and

R 1, R ₂ and R ₄ are as defined above, and optionally converting the obtained free compound into an acid addition salt or converting the obtained acid addition salt into a free compound or another salt.

Mercaptos, the pin present in the form of the alkali metal salt is, for example, its sodium, potassium or ammonium salt.

Halogen atoms are, for example, chlorine, bromine or iodine.

Sulfonyl groups derived from organic sulfonic acids are, for example, methane, ethane, benzene, p-bromobenzene or p-toluenesulfonyl groups. It is also necessary to mention hydroxyl groups esterified with an organic sulfonic acid, such as hydroxy groups esterified with, for example, methane, ethane, benzene, p-bromobenzene or p-toluenesulfonic acid.

The reaction may be carried out in a customary manner, in particular in a manner known from the literature for analogous reactions, optionally in the presence of a catalytic reagent, in the reaction of mercaptans or mercaptides of formula III with halides of formula IV, for example in an alcohol such as methanol, ethanol, ethylene glycol or ethylene glycol monomethyl ether; an inert gas atmosphere, for example under a nitrogen atmosphere, and optionally at an elevated temperature, for example at a boiling point.

A preferred embodiment of the process described above comprises, for example, reacting the optionally present 2-mercaptoderivative of formula III in the form of an alkali metal salt in a lower alcohol such as methanol or ethanol with an ester of hydrochloric, hydrobromic or hydroiodic or sulfuric acid of formula IV .

Some of the starting materials of formulas II and III are known. The novel starting materials can be prepared by methods known per se.

As starting substances mentioned compounds of formula III wherein X represents a mercapto group, i.e. 4-R ₁ -5-R ₂ -2-dipstick ptoimidazoly or 4-R ₁ -5-R ₂ -imidazolinthiony wherein R _s and R ₂ have the meaning given above under formula I, can be produced, for example, by intramolecularly cyclizing a compound of formula V

(V) in which

X 1 is --NH - C (= Sj - NH ₂ a)

X ₂ is hydroxy or

X ₂ represents a group of the formula —NH — —C (= S) -NH ₂ a

X ₁ is hydroxy, a

R ₄ and R ₂ are as defined above, or a tautomer thereof, which is optionally present in ketalized form.

Tautomeric compounds of formula V are preferably enols of tautomeric ketones which correspond to formula V. These tautomers can be catalysed by treatment with lower alkanols or lower alkanediols, for example by treatment with methanol, ethanol or ethylene or 1,3-propylene glycol.

Intramolecular cyclization can be carried out as described in the literature for analogous reactions, for example in a solvent such as water or an alcohol, for example water, ethanol, butanol, ethylene glycol or ethylene glycol monomethyl ether, optionally in the presence of an acidic condensing agent such as a mineral acid such as hydrochloric acid. and / or at an elevated temperature, for example at the boiling point of the reaction mixture.

The compounds of formula V can be obtained by methods known per se, preferably produced in situ and cyclized without isolation. It is preferable to use the compound of formula R ₁ -CO-CH (NH ₂₎ -R ₂ (Vaj or from its acid addition salt and this is reacted with rhodanovo220334 hydrohalic acid, or with a metal thiocyanate. In this case, forming an intermediate compound Particularly preferred is the reaction of a hydrohalide, for example the hydrochloride, of a compound of formula Va with an alkali metal or ammonium rhodanide, for example sodium rhodanide or potassium rhodanide, in aqueous solution, optionally with heating to 60 to 60 ° C. 100 degrees Celsius.

One variant of this procedure is that it is left in an analogous manner

to react a compound of formula Vb R-CH (NH ₂ J-CO-R ₂ (Vb) or a cyanate acid addition salt thereof of formula Vc 3 isothio- H N = C = S (Vc)

The starting materials of the formula V can be further prepared by reacting to the compound of the formula Vd

R _{a -CO-CHOH-R} (Vd) or a compound of formula Vf

Ro-CO-CH (halogen) -R ₀ (Vf) which is obtained by halogenation at the position of a compound of formula Ve

R _a -CO-CH ₂ -R (In), for example bromine in acetic acid, wherein one of R _a is a group R _t and the other is a residue R ₂ an usual manner thiourea derivative of formula Vg

NH _{2 -} CS - NH ₂ (Vg) or a compound produced in situ, for example by ammonium rhodanide.

At elevated temperatures, for example at 100 DEG to 250 DEG C., the primary compound of formula (V) is cyclized in the process according to the invention.

In the compounds of formula I obtained, the substituents can be introduced, converted or cleaved within the meaning of the general symbols.

Furthermore, the free compounds obtained can be converted into acid addition salts in a manner known per se by reacting, for example, a solution of the free compound in a suitable solvent or solvent mixture with one of the abovementioned acids or a solution thereof or with a suitable ion exchanger.

The acid addition salts obtained can be converted into the free compounds in a known manner, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or ammonia, or with a suitable ion exchange resin.

The acid addition salts obtained can be converted into other acid addition salts in a manner known per se, for example by reaction with an anion exchange resin or by treating a suitable metal salt, such as the sodium, barium or silver salts of some acids in a suitable solvent, with an inorganic acid salt. wherein the forming inorganic salt is insoluble and thereby precipitated from the reaction mixture.

The compounds, including their salts, can also be obtained in the form of their hydrates or containing the solvent used for crystallization.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, in the preceding and in the following part the free compounds or their salts according to the meaning and purpose, if appropriate, also mean corresponding salts or free compounds.

In the process according to the invention, preference is given to starting materials which lead to compounds which have been initially emphasized as being particularly valuable.

The pharmaceutical preparations according to the invention which contain the compounds of the formula I or their pharmaceutically usable salts are those which are suitable for enteral, such as oral or rectal, as well as parenteral and toipical administration by warm blood, and which contain a pharmacologically active substance. alone or together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the age and the individual condition as well as the mode of administration.

Normally, for a warm-blooded weight of about 75 kg by oral administration, an approximate daily dose of about 30 to 30 mg is expected, which is preferably divided into several equal sub-doses.

The novel pharmaceutical preparations contain, for example, about 10 to about 80%, preferably about 20% to about 60%, of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, unit dose preparations such as dragees, tablets, capsules or suppositories, as well as ampoules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, the resulting mixture optionally being granulated and, if desired or necessary, processing the mixture or the granulate, if desired or necessary, to temperatures or cores dragee.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium tertiary phosphate or secondary calcium phosphate, binders such as greasy starch using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidine and / or optionally disintegrants such as the aforementioned starches, further carboxymethylated starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. The auxiliaries are in particular flow regulators and glidants such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearic acid, and / or polyethylene glycol. Dragee cores are provided with suitable coatings, optionally resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, and lacquer solutions in suitable organic solvents or mixtures solvents, or to produce gastric juice-resistant coatings, solutions of suitable cellulose-based preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

Tablets or coatings for dragee cores may additionally contain dyes or pigments, for example to identify or distinguish different doses of the active ingredient.

Other orally administrable pharmaceutical formulations are gelatin retractable capsules as well as soft, sealed gelatin capsules and a plasticizer such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as lactose, binders such as starches, and / or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is dissolved or suspended preferably in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

Possible rectally usable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable bases for suppository preparation are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. In addition, gelatin rectal capsules may be used which contain a combination of the active ingredient with a matrix. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral administration, aqueous solutions of the active compound in water-soluble form, for example water-soluble salts, and suspensions of the active compound, such as appropriate oily suspensions suitable for injection, using a suitable lipophilic solvent or medium such as fatty oils, are particularly suitable. for example, sesame oil, or synthetic fatty acid esters, for example ethyl oleic acid or triglycerides, or aqueous suspensions suitable for injection, which contain viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

Suitable topical pharmaceutical preparations are, in particular, creams, ointments, pastes, foams, elixirs and solutions containing from about 0.5 to about 20% of the active ingredient.

Creams are represented by oil-in-water emulsions containing more than 50% water. Fatty alcohols such as lauryl, cetyl or stearyl alcohol, fatty acids such as palmitic acid or stearic acid, liquid to solid waxes such as isopropyl myristate, sheep wool or beeswax and / or hydrocarbons such as vaseline or paraffin oil. Suitable emulsifiers are surfactants having predominantly hydrophilic properties, such as the corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or their adducts with ethylene oxide, such as polyesters of fatty acids and glycerine or polyoxyethylene sorbitan fatty acid esters («weens », hereinafter polyoxyethylene ethers). or fatty acid esters or fatty acids, further corresponding ionic emulsifiers, such as alkali metal sulfated fatty alcohol salts, for example sodium lauryl sulfate, sodium acetate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols such as cetyl alcohol or stearyl alcohol. other anti-drying agents, for example polyalcohols such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols, preservatives, fragrances etc.

Ointments are water-in-oil emulsions containing up to 70%, preferably from about 20 to about 50%, water or aqueous phase. Particularly suitable as the fat phase are hydrocarbons, for example vaseline, paraffin oil and / or hard paraffin, which preferably contain suitable hydroxy compounds, such as fatty alcohols or their esters, for example cetyl alcohol or alcohol220334 bare waxes, or sheep wool wax.

The emulsifiers are represented by appropriate lipophilic substances, such as a sorbitan fatty acid ester (Spans), for example sorbitan oleate and / or sorbitan isostearate. Additions to the aqueous phase include, but are not limited to, moisture-retaining agents such as polyalcohols such as glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

The fatty ointments are anhydrous and contain, in particular, hydrocarbons, for example paraffin, vaseline and / or liquid paraffins, as a base material, natural or partially synthetic fat, for example coconut oil triglyceride or preferably hardened oils, for example hydrogenated peanut or castor oil, partial esters glycerol with fatty acids, for example glycerin mono- and -distearate, as well as, for example, the fatty alcohols mentioned in connection with ointments which increase the ability to absorb water, emulsifiers and / or additives.

The pastes are creams and ointments with powder components capable of absorbing secretions, such as metal oxides, for example with the addition of titanium dioxide or zinc oxide, as well as talc and / or aluminum silicates, which are intended to bind the moisture or secretions present.

Foams are prepared from pressurized containers and are represented by oil-in-water emulsions present in the form of an aerosol using halogenated hydrocarbons such as chlorofluoro (lower) alkanes, such as dichlorodifluoromethane and dichlorotetrafluoroethane as propellant. The oily phase used is, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and / or other waxes.

Mixtures of such substances having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and such substances having predominantly lipophilic properties, such as fatty acid esters and sorbitan esters (Spansj) are used as emulsifiers. In addition, conventional additives such as preservatives are added. resources, etc.

(Tinctures and solutions generally have an aqueous-ethanolic base to which, inter alia, polyalcohols, such as glycerin, glycols, and / or polyethylene glycol, are added as moisture-retaining agents to reduce evaporation, and fat re-injectors such as lower fatty acid esters polyethylene glycols, i.e., a water-soluble, lipophilic substance to replace fatty substances that have been removed from the skin with ethanol and, if necessary, other excipients and additives.

The preparation of topical pharmaceutical preparations is carried out in a manner known per se, for example by dissolving or suspending the active substance in the base substance or part thereof, if necessary. When the active substance is formulated in solution, it is generally dissolved in one of the two phases prior to emulsification; in suspension formulations, the active ingredient is mixed with a portion of the base after emulsification, and then the remainder of the formulation is added.

The present invention also relates to the use of compounds of formulas I and II and salts of such compounds with salt-forming properties, preferably for the treatment of inflammatory diseases, in particular inflammatory chronic diseases of rheumatic origin, in particular chronic arthritis.

The following examples illustrate the invention described above. However, these examples are not intended to limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

He did

To a suspension of 8 g of 2-methylthio-4 (S) -phenyl-5 (4) - (3-pyridyl Jimidazole in 400 ml of chloroform) is added dropwise a solution of 6.3 g of 85% m-chloroperbenzoyl acid in 70 ml of chloroform. The resulting solution was allowed to stand overnight, then washed successively with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness, and the residue was recrystallized twice from isopropanol / petroleum ether to give 2-methanesulfinyl-4 (5). 166-169 °) -phenyl-5- (4) - (3-pyridylimidazole), m.p.

In an analogous manner, 2-ethylthio-4 (5) -phenyls 1-5 (4) - (3-pyridyl) imidazole, 2-ethanesulfonyl 1-4 (5) -phenyl-5 (4) - (3-) is obtained. mp 162-164 °.

Starting materials can be prepared, for example, as follows:

g of 2-mercapto-4 (5) 4-phenyl-5 (4) - (3-pyridyl) imidazole was dissolved in 50 ml of methanol and 10 ml of 2N sodium hydroxide solution. 2.85 g of methyl iodide are then added dropwise, the mixture is allowed to stir for 2 hours at room temperature, 50 ml of water are added, the product is filtered off and washed with water. Crude 2-methylthio-4 (S) -phenyl-5 (4) - (3-pyridyl Jimidazole) is obtained, which is recrystallized from isopropanol / petroleum ether (8: 5 parts by volume) and melts at 193-194 °.

In an analogous manner, starting from 7.6 g of 2-mercapto-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, the following can be prepared as starting material:

2-ethylthio-4 (S) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 196-198 ° (from a mixture of iopropanol and petroleum ether),

2-propylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 143-144 ° (from a mixture of isopropanol and petroleum ether); and

2-isopropylthio-4 (S) -phenyl-5 (4) - (3-pyridyl) 220334 imidatzole, m.p. 182-184 ° (from a mixture of isopropanol and petroleum ether).

Example 2

To 1.0 g of 2-ethanesulfinyl-4 (5) -phenyl-5 (4j- (3-pyridyl) imidazole was added 8 ml of acetic acid and 0.38 ml of ^30%! Hydrogen peroxide and the mixture stirred overnight at The mixture was allowed to cool, neutralized with sodium hydroxide, and filtered to give 2-ethanesulfonyl-4 (5) -phenyl-5- {4- [3- (1-oxidopyridino) imidazole, mp 208-210 ° C.

Example 3

In an analogous manner to Examples 1 and 2, the following can be produced:

2-isopropanesulfinyl-4- (p-methoxyphenyl) -5- (4-pyridyl) imidazole, m.p. 180-181.5 °,

2-isopropanesulfonyl-4- (p-methoxyphenyl) -5- (4-pyridyl) imidazole, m.p. 262-266 °;

2-ethanesulfinyl-4 (5 S - (p-fluorophenyl) -5 (4) - (2-thienyljimidazole) m.p. 143-145 °,

2-ethanesulfonyl-4 (5 '- (p-fluorophenyl) -5 (4) - (2-thienylimididazole) m.p. 180-182 °; and

2-Ethanesulfonyl-4 (S) -phenyls 1-5 (4 '-( 3-pyridylimidazole).

Example 4

Tablets containing 25 mg of the active ingredient, for example 2-ethanesulfinyl-4 (5 J-phenyl-5 (4 J - (3-pyridyl) imidazole), may be prepared as follows:

Ingredients (for 1000 tablets):

Active ingredient 25.0 g lactose 100.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talc 5.0 g magnesium stearic acid 1.8 g demineralized water as needed and concave tablets are compressed on both sides of the mixture. diameter about 6 mm.

Tablets containing in each case 25 mg of some of the other compounds of the formula I which are mentioned in Examples 1 or 2 can also be prepared in an analogous manner.

Example 5

Tablets containing 30 mg of the active ingredient, for example 2-etbenesulfinyl-4 (5'-phenyl-5 (4) - (3-pyridyl) imidazoline) can be prepared, for example, as follows:

Ingredients (for 1000 tablets) active substance mannitol lactose grinds glycine stearic acid saccharin

5% gelatin solution

30.0 g 267.0 g 179.5 g

20,0 g

12,5 g

10.0 g 1.0 g as needed

Production:

All solids are first sieved through a 0.25 mm sieve. The mannitol and lactose are mixed, granulated with the addition of a gelatin solution, the granulate is passed through a 2 mm sieve, dried at 50 ° and re-sieved through a 1.7 mm sieve. The active ingredient, glycine and saccharin are mixed intimately, mannitol, granulated lactose, stearic acid and talc are added, mixed thoroughly and the concave tablets are compressed on both sides with a concave score of about 10 mm in diameter and scored on the upper side.

Tablets containing in each case 30 mg of some of the other compounds of the formula I mentioned in Examples 1 and 2 can also be prepared in an analogous manner.

Example 6

Tablets containing 100 mg of the active ingredient, for example 2-ethanesulfinyl-4 (S) -phenyl-5- (4 - (3-pyridyl) imidazole), can be prepared by the following method:

Production

Ingredients (for 1000 tablets):

All solids are first screened through a 0.6 mm sieve. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water. The greased starch obtained is added to the bulk and the mixture is granulated if necessary with the addition of water. The granulate is dried overnight at 35 °, passed through a 1.2 mm sieve. Active ingredient 100.0 g lactose 248.5 g corn starch 17.5 g polyethylene glycol 6000 5.0 g talc 15.0 g magnesium acid salt stear 4.0 g demineralized water as needed

Production:

The solids are first sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed intimately. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The obtained greasy starch is added to the pulverulent substances, mixed thoroughly and granulated, optionally with the addition of water. The granulate is dried at room temperature overnight

35 [deg.], Then sieved through a 1.2 mm sieve and the concave tablets of about 10 mm diameter were compressed from the mixture with a groove on the top side.

Tablets containing 100 mg of some of the other compounds of Formula I prepared according to Example 1 or 2 can also be prepared in an analogous manner.

Claims (8)

I will invent the object A process for the preparation of novel mercaptoimidazole derivatives of the general formula I H (I) wherein at least one of R ₍ and R ₂₎ is unsubstituted thienyl, pyridyl or 1-oxidopyridyl and the other is phenyl optionally substituted by C 1 -C 4 alkoxy or halogen, n is a number 1 or 2, and R ₄ represents a C 1 -C 4 alkyl group and their acid addition salts, characterized in that in the compound of formula II H (II) wherein R _{(R 2} and R ₄ are as defined above, or a salt thereof is oxidized thio group to a sulphinyl or sulphonyl and optionally a pyridyl radical R _t and / or R ₂ on the nitrogen atom and, optionally, a resulting free compound into an acid addition salt with an acid or the resulting acid addition salt is converted into the free compound or another salt. 2. The process of claim 1 wherein the oxidation is carried out with m-chloroperbenzoic acid. 3. A process according to claim 1, wherein one of the radicals R _{@ 1} and R _{@ 2} is unsubstituted pyridyl or thienyl and the other is optionally alkoxy of 1 to 4. carbon atoms or halogen having an atomic number of up to 35 substituted phenyl, and R ₄ represents an alkyl group having 1 to 4 carbon atoms, and optionally converting the obtained free compound into an acid addition salt or converting the obtained acid addition salt into a free compound or another salt. 4. A method according to claim 1 or 2, characterized in that as the starting material used is a compound of formula II wherein one of the residues R _t and R ₂ is pyridyl and the other is phenyl, R ₄ represents alkyl with 1 and optionally converting the obtained free compound into an acid addition salt or converting the obtained acid addition salt into a free compound or another salt. 5. A process according to claim 1 or 2 for the preparation of 2-ethanesulfinyl-4 (5) -phenyl-1-5 (4) - (3-pyridyljimidazole or an acid addition salt thereof), characterized in that wherein one of the radicals R _{@ 1} and R _{@ 2} is 3-pyridyl and the other is phenyl and R _{@ 4} is ethyl, and optionally the free compound obtained is converted to an acid addition salt or an acid addition salt obtained. acid is converted to the free compound or another salt. ' 6. A process according to claim 1 or 2 for the preparation of 2-ethanesulfonyl-4 (S) -phenyl-5 (4) - (1-oxido-3-pyridyl) imidazole or an acid addition salt thereof, which comprises: starting from compounds of formula II wherein one of R 1 and R ₂ is 3-pyridyl and the other is phenyl, and R ₄ is ethyl, and optionally the free compound obtained is converted to an acid addition salt or the resulting acid addition salt is converted into the free compound or another salt. 7. A process according to claim 1 or 2 for the preparation of 2-ethanesulfinyl-4 (S) - (pfluorophenyl) -5 (4) - (2-thienyl) imidazole or an acid addition salt thereof, characterized in that the starting material is: The compounds of formula (II) are used in which one of R 1 and R ₂ is 2-thienyl and the other is p-fluorophenyl, and R ₄ is ethyl, and optionally the free compound obtained is converted to an acid addition salt or the acid addition salt obtained is converted to the free compound or another salt. 8. The process of item 1 or 2 for the preparation of 2-ethanesulfonyl-4- (5'- (p-fluorophenyl) -5 (4) - (2-thienyl) imidazole or an acid addition salt thereof, that as in the compound of formula II wherein one of R and R ₂ represents a 2-thienyl group and the other represents p-fluorophenyl group and R ₄ represents an ethyl group and optionally a resulting free compound is converted to an acid addition salt or the acid addition salt obtained is converted to the free compound or another salt.