CS220335B2 - Method of producing new mercaptoimidazole derivatives - Google Patents

Description

The present invention relates to a process for the preparation of the novel substituted 2-mercaptoimidazoles of formula (I)

^R 3 wherein at least one of R 1 and R ₂ is unsubstituted thlenylovou or pyridyl and the other is phenyl which is optionally substituted by lower alkoxy having 1-4 carbon atoms or halogen,

R 3 represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and

R 2 _t is optionally at a position higher than the α position of the hydroxy group, a lower C 1 -C 4 alkoxy group, a lower C 1 -C 4 alkylthio group, or a phenyl substituted by a C 1 -C 4 lower alkyl group or a lower C 1 -C 4 alkenyl group Or lower alkynyl groups having up to 4 carbon atoms, and their acid addition salts.

In the foregoing and the following sections, the organic moieties and compounds referred to as "lower" are those moieties or compounds having up to 4 carbon atoms.

Thienyl is, for example, 2-thienyl and pyridyl is, for example, 2-, 3- or 4-pyridyl.

For example, phenyl (C1-C4) substituted by a phenyl group or at a position higher than that of the hydroxy group, a lower C1-C4 alkoxy group or a lower C1-C4 alkylthio group substituted by a lower C1-C4 alkyl group is, for example, phenyl (lower) C1-C4 alkyl. carbon atoms in alkyl, such as 1- or 2-phenyl (lower) alkyl; 7 to 10 carbon atoms, for example benzyl or 2-phenylethyl, hydroxy (lower) alkyl of 2 to 4 carbon atoms, such as 2-hydroxyethyl or 2-or 3-hydroxypropyl, 2,3-dihydroxypropyl, (lower) alkoxy (lower) alkyl in each case having 1 to 4 carbon atoms, such as 2-methoxyethyl, 2-ethoxyethyl or 2- or 3-methoxypropyl, or a lower alkylthio (lower) alkyl group having up to 7 carbon atoms in total, such as 2-methylthioethyl.

A lower alkyl group having 1 to 4 carbon atoms is, for example, methyl, ε20335 thyl, propyl, isopropyl or η-, iso-, sec- or tert-butyl.

Lower C 1 -C 4 alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or η-, sec., Iso- or tert-butoxy.

Lower alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio or butylthio.

Lower alkenyl and lower alkynyl of up to 4 carbon atoms are, for example, vinyl, allyl, methallyl, further ethynyl or propargyl.

Halogen is preferably halogen with an atomic number of up to 35, such as fluorine, chlorine or bromine.

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 marked antiinflamatory activity, antinociceptive 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 in the paw carrageenan edema test of Di Pasquale et al., Agente and Actions 5, 256 (1975) at a dose range of about 20 up to 200 mg / kg orally, further in rat and quadruple in the arthritis-inducing adjuvant test at doses of about 10 to 60 mg / kg orally, and in the 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.

Furthermore, the compounds in vitro inhibit the synthesis of prostaglandin from arachidonic acid in the concentration range of 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 suitable as active ingredients of pharmaceutical preparations for the treatment of inflammatory diseases, in particular chronic inflammations of rheumatic forms such as chronic joint inflammation (arthritis).

The invention relates preferably to a process for the preparation of compounds of the formula I in which one of the radicals R ₃ and R ₂ is a pyridyl group and the other of these radicals is a phenyl group which is optionally substituted by C 1 -C 4 alkoxy such as methoxy, halogen and atomic number up to 35, such as chlorine,

R ₃ represents hydrogen or alkyl having 1 to 4 carbon atoms such as a methyl group,

R ₄ represents a C 1 -C 4 alkyl group such as methyl, ethyl, propyl or isopropyl, furthermore a C 1 -C 4 hydroxyalkyl group containing a position higher than the position and a hydroxy group such as 2-hydroxyethyl or alkoxy - or a (C1-C4) alkylthioalkyl group containing a higher than position and a (C1-C4) alkoxy or (C1-C4) alkylthio group such as a 2-methoxyethyl or a 2-methylthioethyl group , and their acid addition salts.

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

R ₃ represents hydrogen or the second row, an alkyl group having 1 to 4 carbon atoms such as a methyl group,

R ₄ represents a C 1 -C 4 alkyl group, such as an ethyl group, and salts thereof.

In particular, the invention relates to a process for the preparation of compounds of the formula I in which one of R ₄ and R ₂ represents an unsubstituted pyridyl group such as a 3-pyridyl group and the other represents an unsubstituted or secondly C 1 -C 4 alkoxy group such as methoxy. or a halogen-substituted phenyl group,

R ₃ represents hydrogen or alkyl with 1 to 4 carbon atoms, for example methyl or ethyl,

R ₄ represents a C 1 -C 4 alkyl group, for example a methyl or ethyl group or a C 2 -C 4 hydroxyalkyl group, bearing at a higher position than the α-position a hydroxy group, for example a 2-hydroxyethyl group, and their acid addition salts .

The invention relates to a process for the preparation of the compounds of the formula I, specifically 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, na220333

By way of example, the compound of formula (II)

in which

R 1 and R ₂ are as defined above and

X is a reactive esterified hydroxy group, such as a halogen, or an acid addition salt thereof, reacted with an isothiourea derivative of formula III

R 3 -NH-C (= NH) -SR ₄ (III) wherein

R ₁ and R ₄ are as defined above, or with a salt thereof, and optionally the compound of formula I in which R ₃ is hydrogen is substituted with a lower C 1 -C 4 alkyl group as R ₃ , and / or the resulting free compound is converted to an acid addition salt or the resulting acid addition salt is converted to the free compound or another salt.

This reaction is carried out in a conventional manner, preferably by liberating the isothiourea derivative of the formula III or the compound of the formula II, for example, with a base such as an alkali metal hydroxide or an alkali metal carbonate such as sodium or potassium hydroxide or sodium carbonate or potassium carbonate. or by treatment with a nitrogenous base such as ammonia, a tri (lower) alkylamine such as triethylamine or N, N-diisopropylethylamine or pyridine, in situ from a NR ₃ -SR ₄ -isothiouronium salt such as alkyl sulfate or halides such as bromide or chloride; If the starting materials of the formula II present in the salt form are required, 3 or otherwise 2 equivalents of the base are required, preferably in a solvent such as a lower alkanol, for example methanol, ethanol, butanol, or amyl alcohol, optionally at elevated temperature, e.g. ad at the boiling point.

The starting materials of the formula II can be prepared by methods known per se, for example by treating a compound of the formula R _{1 -} CH = O or R _{2 -} CH = O (IV) in the presence of di (lower) alkylamine, for example dimethylamine hydrochloride, an alkali anchor cyanide, then the resulting 2-R _x - or 2-R ₂ -di (lower) alkylaminoacetonitrile (V) in dimethylforimamide is treated with sodium hydride and then the compound of formula R ₂ - or R ₁ -> CH ₂ -halogen ( Vij, the condensation product is hydrolyzed by heating several hours in a mixture of concentrated hydrochloric acid and chloroform, and the obtained compound of the formula R _T - -CO-CH ₂ -R ₂ (VII) is halogenated such as bromine in acetic acid or cupric bromide in ethyl acetate.

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

Thus, for example instead of the hydrogen atom R ₃ introduced by reaction with an agent introducing the radical R ₃ organic radical R _3rd Such agents are, for example, reactive esters, such as esters with hydrohalic acid, for example hydrochloric, hydrobromic or hydroiodic acid, esters with organic sulfonic acids, for example esters with methane, ethane, benzene, p-bromobenzene or p-toluenesulfonic acid, or sulfuric acid esters of the corresponding alcohols R ₃ OH.

The reaction with these reagents is carried out in a conventional manner, for example in the presence of a basic condensing agent such as an alkali metal hydroxide or carbonate such as sodium or potassium hydroxide or carbonate, an alkoxide such as an alkali metal lower alkoxide such as sodium methoxide, sodium hydride, preferably in an inert solvent. for example in dimethylformamide or N-methylpyrrolidone.

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 manner known per se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or metal carbonate, or ammonia, or with a suitable ion exchange resin.

The acid addition salts obtained can be converted in a manner known per se into other acid addition salts, for example by reaction with an anion exchange resin or by treating a suitable metal salt with a salt of an inorganic acid, such as sodium, barium or silver salts, some acids in a suitable solvent. 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, the preceding and the following are understood to mean the free compounds or their salts according to purpose and purpose, optionally also the 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.

Pharmaceutical compositions according to the invention which contain the compounds of the formula I or their pharmaceutically usable salts are those suitable for enteral, such as oral or rectal, as well as parenteral and topical administration by warm-blooded animals, which contain the 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 300 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 00%, 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 granulate into tablets or cores after the addition of suitable excipients. 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 polyvinylpyrrolldone and / or optionally disintegrating agents 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 solvent mixtures. or for the manufacture of gastric juice-resistant coatings, solutions of suitable cellulose-based preparations such as acetylcellulose phthalate or hydroxyipropylmethylcellulose 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 preparations are push-fit capsules of gelatin, as well as soft, sealed capsules of gelatin 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 suppository bases are, for example, natural or synthetic triglycerides, paraffinic 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 active ingredient.

Creams are represented by oil-in-water emulsions containing more than 50% water. Fatty alcohols such as laurylcetyl 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 petrolatum or paraffinic are used as the oil bases. 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 glycerin or polyoxyethylene sorbitan fatty acid esters (Twoens), furthermore polyoxyethylene ethers or esters of fatty alcohols or fatty acids, and corresponding ionic emulsifiers, such as alkali metal sulfated fatty alcohol salts, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols such as cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents which prevent the drying of creams, for example polyalcohols such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols, preservatives, fragrances, etc.

Ointments are water-in-oil emulsions which contain up to 70, preferably from about 20 to about 50%, of water or an aqueous phase. Suitable fatty phases are, in particular, 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 wax alcohols, 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 or aluminum silicates, which are intended to bind the moisture or secretions present.

Foams are prepared from pressurized containers and are 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 includes, but is not limited to, hydrocarbons such as paraffin oil, fatty alcohols such as cetyl alcohol, fatty acid esters such as 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 of sorbitan (Spans), are used as emulsifiers. In addition, conventional additives such as preservatives, etc. are added.

Tinctures and solutions usually have an aqueous-ethanolic base to which other polyalcohols, such as glycerin, glycols, and / or polyethylene glycol, are added as a moisture-retardant to reduce evaporation, and fat-releasing substances such as lower fatty acid esters polyethylene glycols, i.e., water-soluble, lipophilic substances 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 as a 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.

Example 1

2.86 g of α-bromobenzyl- (3-pyridyl) ketone hydrobromide and 1 g of S-methylisothiouronium bromide are suspended in 30 ml of acetonitrile, 3.1 g of 3,1, Ν-diisopropylethylamine are added and the mixture is stirred overnight. The orange-red suspension is filtered and the filtrate is filtered

2201 was evaporated under reduced pressure. The residue is taken up in chloroform, dried over sodium sulfate, evaporated and recrystallized from a mixture of chloroform and petroleum ether. There was obtained 2-methylthio-4- (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 193-194 °.

For example, the starting material can be produced as follows:

A solution of 17 g of bromine in 150 ml of acetic acid was added dropwise to 20 g of benzyl- (3-pyridyl) ketone in 200 ml of acetic acid and the mixture was allowed to stir overnight. The precipitated .alpha.-bromobenzyl- (3-pyridyl) ketone hydrobromide is filtered off and can be used further without further purification.

Example 2

In an analogous manner to that described in Example 1, it can be further produced

2-ethylthio-4 (5) - (p-fluorophenyl) -5 (4) - (2-thienyljimidazole, m.p. 160-163);

2- (2-Hydroxyethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 128-1-methyl-2-methylthio-4-phenyl-5- [3- pyridyl) imidazole, m.p. 125-127 °,

1-methyl-2-methylthio-5-phenyl-4- (3-pyridyl) imidazole, m.p. 141-143 °;

2- (2-methoxyethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 118-120 °,

2- (2-methylthioethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 164-168 °;

2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 197-198 °,

2-Propyl thio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 143-144 °;

2-isopropylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 182-184 °,

2-methylthio-4 (S) - (p-fluorophenyl) -5 (4) - (3-pyridyl) imidazole, m.p. 171-173 °,

2-Allylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 176-178 °,

2-ethoxyethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 100-102 °;

3-hydroxypropylthio-4 (5) -, phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 115-120 °,

147-149 °, 2-propylcarbonyl-4 (S) -phenyl-5 (4) - (3-pyrityl) imidazole, m.p.

2-Benzylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole, m.p. 165-167 °;

2-methylthio-4 (S) - (p-fluorophenyl-5 (4) - (2-thienyl) imidazole, m.p. 171-173 °),

2-Propylthio-4 (5) - (p-fluorophenyl) -5 (4) - (2-thienyl) imidazole, (2-hydroxyethylthio) -4,5-bis- (2-pyridyl) imidazole hydrobromide, m.p. 249 to 250 °

2- (2-hydroxyethylthio) -4,5-bis- (2-thienyl) imidazole, m.p. 124-125 °,

2-Isopropylthio-4- (p-fluorophenyl) -5- (4-pyridyl) imidazole, m.p. 263-264 °; and

2-Isopropylthio-4- (p-methoxyphenyl) -5- (4-pyridyl) imidazole, m.p. 201-206 °.

Example 1 a d 3

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

Ingredients (for 1000 tablets):

active substance 25.0 g lactose 100.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talc 5.0 g magnesium stearate 1.8 g demineralized water as needed • Production: ´

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 and pressed into a concave tablet of about 6 mm diameter on both sides.

Tablets containing, in each case, 25 mg of some of the other compounds of the formula I as shown in Examples 1 and 2 can also be prepared in an analogous manner.

Example 4

Tablets containing 30 mg of the active ingredient, for example 2-ethylthio-4 (S) -phenyl-5 (4) - (3-py22033S ridyljimidazoline) can be prepared, for example, as follows:

Ingredients (for · 1000 tablets):

active substance mannitol lactose talc 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 together, granulated with the addition of a gelatin solution, the granulate is passed through a 2 mm sieve, dried at 50 ° and sieved again through a sieve

1.7 mm. The active ingredient, glycine and saccharin are mixed intimately, mannitol, granulated lactose, stearic acid and talc are added, mixed thoroughly, and the concave tablets, about 10 millimeters in diameter, are scored on the top side of the mixture.

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

Example 5

Tablets contain 100 mg of the active ingredient, for example 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyljimidazole), may be prepared as follows:

Ingredients (for 1000 tablets):

Active ingredient 100.0 g lactose 248.5 g maize starch 17.5 g polyethylene glycol 6000 5.0 g talc 15.0 g magnesium stearate 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 thoroughly mixed. 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 overnight at 35 °, then passed through a 1.2 mm screen and two-sided concave tablets of about 10 mm diameter are compressed from the mixture with a score line on the top.

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

Example 6

A suspension of 15 g of 2-ethylthio-4 (S) -phenyl-5 (4) - (3-pyridylimidazole) in 15 ml of ethanol is acidified by addition of ethanolic hydrogen chloride to pH 1, then dissolved to give a clear solution. The crystalline precipitate is filtered off and recrystallized twice from ethanol to give 2-ethylthio-4 (S) -phenyl-5- (4J- (3-pyridyl) imidazole-bis-hydrochloride, m.p. 176 °.

Bis-methanesulfonate with a melting point of 150 to 152 ° can also be prepared in an analogous manner.

Claims (14)

A process for the preparation of novel mercaptoimidazole derivatives of the general formula ( _III ) in which at least one of R 1 and R ₂ is an unsubstituted thienyl or pyridyl group and the other is a lower alkoxy group having 1 to 4 carbon atoms or a halogen substituted phenyl group. R ₃ represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and R ₄ is optionally at a position higher than the α-hydroxy position, a lower C 1 -C 4 alkoxy group, a lower C 1 -C 4 alkylthio group, or a phenyl substituted lower C 1 -C 4 alkyl group, or a lower alkenyl group with 1 to 4 carbon atoms up to 4 carbon atoms or a lower alkynyl group having up to 4 carbon atoms, and their acid addition salts, characterized in that the compound of the formula R ₄ and R ₂ are as defined above, and X is a reactive esterified hydroxy group, such as halogen, or an acid addition salt thereof, is treated with an isothiourea of formula III R ₃ NH - C (= NH 3 - SR ₄ (III)) in which R ₃ and R ₄ are as defined above, or a salt thereof, whereupon the optionally obtained compound of formula I in which R ₃ is hydrogen is substituted with a lower alkyl group having 1 to 4 carbon atoms as the radical R ₃ , and / or the compound is optionally converted into an acid addition salt or the resulting acid addition salt is converted into the free compound or another salt. 2. A process according to claim 1, wherein the starting material is an isothiourea of formula III released from the corresponding isothiouronium salt by treatment with a weakly basic condensing agent. 3. The method according to claim 2, characterized in that it uses as starting materials compounds of formula II and the salt of isothiourea of general formula III, wherein one of the radicals R ₄ and R ₂ is pyridyl and the other is a lower alkoxy group optionally having from 1 to 4 carbon atoms or halogen having an atomic number of up to 35 substituted phenyl, R ₃ represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and R ₄ represents a lower alkyl group having 1 to 4 carbon atoms, a hydroxy (lower) alkyl group having 1 up to 4 carbon atoms bearing a hydroxy group in a position higher than or a lower alkoxy or lower alkylthio (lower) alkyl group having 1 to 4 carbon atoms in the alkoxy and alkyl portions bearing an alkoxy group or an alkylthio group higher than the position and X is as defined in 1 above, whereupon the optionally obtained compound of formula I wherein R ₃ is hydrogen, is substituted by a lower alkyl group having 1 to 4 carbon atoms as the radical R ₃ and / or the obtained free compound is converted into an acid addition salt or the obtained acid addition salt is converted into a free compound or another salt. 4. A process according to claim 1, wherein the starting materials are a compound of formula II and a thiourea salt of formula III, wherein one of R _{@ 1} and R _{@ 2} is a pyridyl group and the other is optionally lower alkoxy of 1 to 4. carbon atoms or a halogen-substituted phenyl group, R ₃ represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and R ₄ represents a lower alkyl group having 1 to 4 carbon atoms or a hydroxy (lower) alkyl group having 2 to 4 carbon atoms carrying a hydroxy group at a position higher than the a position, and X is as defined in point 1, whereupon the optionally obtained compound of formula I in which R ₃ is hydrogen is substituted with a lower C 1 -C 4 alkyl group as R ₃ and / or the resulting free compound is converted to an acid addition salt or the resulting acid addition salt is converted to a free compound or other salt. l. 5. A method according to claim 1, characterized in that as starting materials · uses a compound of formula II and III in which one of the residues R _t and R ₂ represents an unsubstituted pyridyl or thienyl and the other is an optionally lower C1 R ₄ represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms and R ₄ represents a lower alkyl group having 1 to 4 carbon atoms and X is as defined in the group consisting of 4 carbon atoms and / or halogen having an atomic number of up to 35 substituted phenyl; 1, whereupon the optionally obtained compound of formula I in which R ₃ is hydrogen is substituted with a lower alkyl group having 1 to 4 carbon atoms as the radical R ₃ and / or the free compound obtained is converted into an acid addition salt or an obtained addition salt with an acid is converted into the free compound or another salt. 6. Method according to claim 1, characterized in that the starting materials used are compounds of formulas II and III in which one of the residues R _t and R ₂ is pyridyl and the other of these radicals represents a phenyl group, R ₃ represents hydrogen and R ₄ represents a C 1 -C 4 alkyl group and X is as defined in item 1, and optionally the free compound obtained is converted to an acid addition salt or the obtained acid addition salt is converted to a free compound or another salt. 7. A process according to claim 1, for the preparation of 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole or an acid addition salt thereof, characterized in that compounds of the formulas are used as starting materials. II and III, wherein one of the radicals R ₁ and R ₂ is a 3-pyridyl group and the other of these radicals is a phenyl group, R ₃ is hydrogen and R ₄ is an ethyl group, and X is as defined in point 1 and optionally the obtained free compound is converted to an acid addition salt or the resulting acid addition salt is converted to the free compound or another salt. and 8. A process according to claim 1, for the preparation of 2-propylthio-4 (S) -phenyl-5 (4 ' - (3-pyridyl) imidazole or an acid addition salt thereof, characterized in that the compounds used are: formulas II and III in which one of the radicals R _(and R ₂ is 3-pyridyl and the other is phenyl, R ₃ is hydrogen and R ₄ is a propyl group and X is as defined in 1, and optionally the obtained the free compound is converted to an acid addition salt or the resulting acid addition salt is converted to the free compound or another salt. 9. A process according to claim 1, for the preparation of 2- (2-hydroxyethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyljimidazole or an acid addition salt thereof), characterized in that uses compounds of formulas II and III in which one of R 1 and R ₂ is 3-pyridyl and the other is phenyl, R ₃ is hydrogen and R ₄ is 2-hydroxyethyl, and X is as defined in point 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. 10. A process according to claim 1 for the preparation of 2- (2-methoxyethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole or an acid addition salt thereof, characterized in that the starting materials are: materials are used compounds of the formulas II and 'ffl, in which one of the radicals R _(and R ₂ is 3-pyridyl and the other is phenyl, R ₃ is hydrogen and R ₄ represents a 2-methoxyethyl group, and X is as defined in point 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. 11. A process according to claim 1, for the preparation of 2- (2-methylthioethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyljimidazole or an acid addition salt thereof, characterized in that the starting materials are: uses compounds of formulas II and III wherein one of R 1 and R ₂ is 3-pyridyl and the other is phenyl, R ₃ is hydrogen and R ₄ is 2-methylthloethyl and X is as in 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. 12. The process according to claim 1, for the preparation of 2-ethylthio-4- (5 ' - (fluorophenyl) -5 (4) - (2-thienyl) imidazole or an acid addition salt thereof, characterized in that the starting materials used are: compounds of formulas II and III wherein one of R 1 and R ₂ is 2-thienyl and the other is p-fluorophenyl, R ₃ is hydrogen and R ₄ is ethyl, X is as defined in 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. • 13. A process according to claim 1 for the preparation of 2-propylthio-4- (5 '-( psfluorophenyl) -5 (4) - (2-thienyljimidazole or an acid addition salt thereof), characterized in that the compounds used are: of formulas II and III wherein one of R ₁ and R ₂ is 2-thienyl and the other is p-fluorophenyl, R ₃ is hydrogen, R ₄ is ethyl and X is as defined in 1, and optionally converting the obtained compound into an acid addition salt or converting the obtained acid addition salt into a free compound or another salt. 14. The process according to claim 2 or claim 7, wherein the starting material is isothiourea of the formula III in the form of salts.