CS220333B2 - 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

^ 3 (I) wherein

R 1 and R ₂ are thienyl or one of R 1 and R ₂ is thienyl or ipyridyl and the other is optionally lower C 1 -C 4 alkoxy or halogen substituted phenyl,

R ₃ is hydrogen or C 1 -C 4 lower alkyl, n is 0 or 2 and

R ₄ represents a lower alkenyl group of up to 4 carbon atoms, a lower alkynyl group of up to 4 carbon atoms, a phenylalkyl group of 1 to 4 carbon atoms in the alkyl moiety or, optionally, at a position higher than the oro-lower alkoxy group of 1 to 4 carbon atoms or lower alkylthio of up to 4 carbon atoms substituted alkyl of 1 to 4 carbon atoms, and acid addition salts thereof.

Organic residues and compounds, hereinafter referred to as "lower", contain up to 4 carbon atoms.

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

Lower alkenyl of up to 4 carbon atoms is, for example, vinyl, allyl or methallyl.

An alkynyl group having up to 4 carbon atoms is, for example, ethynyl or propargyl.

C 1 -C 4 -phenylalkyl is, for example, benzyl or 2-phenylethyl.

Optionally, as mentioned, the substituted alkyl radicals having 1 to 4 carbon atoms in the meaning of R <1> are preferably: alkyl radicals having 1 to 4 carbon atoms, alkyloxyalkyl radicals having 1 to 4 carbon atoms in the alkoxy and alkyl moieties, such as 2-methoxyethyl , 2-ethoxyethyl or 2- or

3-methoxypropyl; alkylthioalkyl radicals of up to 7 carbon atoms in total, such as 2-methylthioethyl.

C 1 -C 4 alkyl is, for example, methyl, ethyl, 2-propyl, isopropyl, isopropyl or η-, iso-, sec- or tert-butyl.

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

C1-C4alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio or butylthio.

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

The 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 anti-inflammatory 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 the paw carrageenan edema test of Di Pasquale et al., Agents and Aotions 5, 256 (1975) at a dose range of about 20 up to 200 mg / kg orally, followed by rat administration four times in an arthritis-inducing adjuvant test at doses ranging from about 10 to 60 mg / kg orally, and in a mouse test for the pain reaction induced by phenyl-.beta.-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, said compounds in Vitro, in a concentration range of about 2 to 200 mg / liter, inhibit the synthesis of prostaglandin from arachidonic acid 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 inflammation of rheumatic forms, such as chronic joint inflammation (arthritis).

The invention preferably relates to a process for the preparation of compounds of the formula I, in which one of the radicals R1 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 or ethoxy, with a halogen atom of up to 35, such as chlorine,

R ₃ is hydrogen or C 1 -C 4 alkyl, such as methyl, n is O and

R ₄ represents an alkyl group having 1 to 4 carbon atoms, such as a methyl, ethyl, propyl, isopropyl or butyl group, furthermore an alkoxy- or alkylthioalkyl group having 1 to 4 carbon atoms in the alkyl or alkoxy groups containing at a position higher than the position; C 1 -C 4 alkoxy or C 1 -C 4 alkylthioscuipine, such as 2-methoxyethyl or 2-methylthioethyl, and acid addition salts thereof.

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 thienyl group, such as a 2-thienyl group, and the other is unsubstituted or 4 carbon atoms, such as methoxy, and / or halogen and an atomic number of up to 35, such as chloro or especially fluorine substituted phenyl,

R ₃ is hydrogen, n is 0 or 2 and

R ₄ represents a C 1 -C 4 alkyl group, 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 is an unsubstituted pyridyl group such as a 3-pyridyl group and the other is an unsubstituted or secondly C 1 -C 4 alkoxy group such as methoxy. or halogen, such as chloro or bromo, substituted phenyl,

R ₃ is hydrogen, n is 0, and

R ₄ represents a C 1 -C 4 alkyl group, for example a methyl or ethyl group, and their acid addition salts.

The invention relates to a method for výrobysloučenin of formula I in which one of the residues R _t and R ₂ represents pyridyl, such as 3-pyridyl and the other is phenyl,

R ₃ is hydrogen, n is 0 and

R ₄ represents a C 1 -C 4 alkyl group, such as an ethyl 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, for example by reacting compounds of formulas II and III with each other.

wherein one of X and Y is S (O) _n —Y _J; where

Υχ represents a halogen atom or, when n represents zero, an etherified mercapto group, and the other of these residues' represents the metal radical Y _{2 of the} formula —M ¹ , —M ⁿ / 2 or · —M ¹¹ —Hal, where

M ¹ is an alkali metal atom,

M ⁿ denotes an alkali earth metal and

Hal is a halogen atom, whereupon the optionally obtained compound of formula I wherein R ₃ is hydrogen is substituted with a C 1 -C 4 alkyl group, and / or the free compound obtained is optionally converted to an acid addition salt or an obtained addition salt with an acid is converted to the free compound or another salt.

The halogen atoms Υχ are, for example, chlorine, bromine or iodine. Etherified mercapto groups Υχ are when X 'is a group of the formula —S (O) _n —Υχ, where n is 0,1R ₃ -4-Rx-5-R ₂ -imidazolyl-2-thio and when Y is a group of the formula —S (O) _n - Υχ, where n is zero, groups of the formula —SR ₄ , wherein R x, R ₂ , R ₃ and R ₄ are as defined above.

In the metal radicals Y _{2 of the} formulas —M ¹ , —M ¹¹ / / 2 or M ^,! Hal represents M ¹ for example lithium or sodium and M ¹¹ represents for example magnesium, cadmium or zinc.

The reaction may be carried out in a customary manner, in particular a method known in the literature for analogous reactions, optionally in the presence of a catalytic agent, preferably under an inert gas atmosphere, for example under nitrogen, and optionally at elevated temperature, for example boiling.

The starting materials are partly known. The novel starting materials can be prepared by methods known per se.

The starting material of formula II in which X is an optionally esterified or anhydride sulfo group, such as sulfo, lower alkoxy or phenoxy sulfonyl or sulfonyloxy-sulfonyl group, can be obtained, for example, by oxidizing the mercapto group to a sulfo group in a compound of formula II wherein X is mercapto and this group is optionally halogenated, for example with phosphorus pentachloride, and the halosulfonyl group is converted with an alcohol, for example a lower alkanol or phenol, into an esterified sulfo group, or is anhydridized in a conventional manner, for example by reaction with a sulfonic acid salt.

Compounds of formula II wherein X is -S-S-R _4, can be obtained by mild oxidation meťkaptanů formula

for example ferric chloride or air oxygen.

As starting substances mentioned compounds, i.e. R ₃ -4-R ₁ -5-R ₂ -2-mercaptoimidazoles or R ₃ -4-R ₁ -5-R ₂ imidazoline thiones ^1, wherein R _4, R _2, and R ₃ are as defined above under formula I, can be prepared, for example, by intramolecularly cyclizing a compound of formula IIIa

in which

Xx represents a group of the formula —NH— —C (= S) —NHR ₃ a

X ₂ is hydroxy or

X ₂ represents a group of formula -NR ₃ -, -C (= _Si-NH2 and Xx represents hydroxy, and

R 1 and R ₂ are as defined above, or a tautomer thereof (which is optionally present in ketalized form).

Tautomeric compounds of formula IIIa are preferably enols of tautomeric ketones that correspond to formula IIIa. These tautomers can be ketalized 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 starting materials of the formula IIIa can themselves 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-CO-CH (NHR ₃ R j ₂ (IVj or from its acid addition salt and this is reacted with an acid or rhodanovodíkovou rhodanide metal. In this case, an intermediate is a compound of formula IIIa Particularly preferred is the reaction of a hydrohalide, e.g. hydrochlorides, of the compound of formula IV with an alkali metal or ammonium rhodanide, e.g. Celsius.

One variant of this process consists in reacting a compound of formula V in an analogous manner

R 1 -CH (NH ₂ J-CO-R ₂ (V) or an acid addition salt thereof with an isothiocyanate of formula VI

R ₃ -N = C = S (Vij

The starting materials of formula IIIa can be further produced by reacting to the compound of formula VIII

R 1 -CO-CHOH-R ₂ (VIII) or to a compound of formula X, R ₁ -CO-CH (halogen) -R ₂ (X) which is obtained by halogenation in position and a compound of formula IX _{R 1} -co-CH ₂ -R ₂ (IX), for example with bromine in acetic acid, reacts in a conventional manner with a thiourea derivative of the formula XI

R ₃ NH-CS-NH ₂ (XI) or an in situ compound, for example R ₃ -ammonium rhodanide.

At elevated temperatures, for example at 100 to 250 ° C, the primary compound of formula III is cyclized in the process according to the invention. It can be obtained when R and R ₂ are different and R ₃ is not hydrogen, the reactivity of the individual components of the formula VI and / or the reaction conditions, both or only one of the possible isomers, i.e. R ₃ -4-R ₁ -5 R ₂ -2 (@ 3 H-imidazolin-2-thione and / or R ₃ -4-R _{2 -5-R f} 2 (3H j-imidazolin-2-thione which can be separated by a conventional manner, for example by fractional crystallization or chromatography.

In the compounds of formula I obtained, substitution points 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-itoluenesulfonic acid, or with 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, for example 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 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 sodium, barium or silver, of some acid in a suitable solvent with an inorganic acid salt. the formed inorganic salt is insoluble and is thus excluded 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.

The pharmaceutical preparations according to the invention which contain the compounds of the formula I and / or II or their pharmaceutically usable salts are those suitable for enteral, such as oral or rectal, as well as parenteral and topical administration by a warm-blooded animal, containing a pharmacologically active substance. alone or together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of tep220333 of the turkey animal, on the age and on the individual istavus as well as on the mode of administration. Normally, for a warm-blooded weight of about 75 kg by oral administration, an approximate daily dose of up to several equal sub-doses is contemplated.

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 partenteral administration are, for example, unit dosage formulations 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 polyvinylpyrrolidine 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, istearic acid or its salts, such as magnesium or calcium stearic acid, and / or polyethylene glycol. Dragee cores are provided with suitable coatings, if necessary resistant to gastric juice, using, inter alia, concentrated cullet 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 differentiate different doses of the active ingredient.

Other orally administrable pharmaceutical formulations are gelatin insertable 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, are particularly suitable, as well as suspensions of the active compound, such as appropriate oily suspensions suitable for injection, using a suitable lipafile solvent or media such as fatty oils. 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. In particular, 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, wool wool or beeswax and / or hydrocarbons such as petrolatum are used as the oil bases. 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 glycerin or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene ethers or esters of fatty alcohols or fatty acids, as well as 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 include, but are not limited to, agents that prevent creams from drying out, for example polyalcohols such as glycerin, sorbitol, proipylene 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. Suitable fatty phases are, in particular, hydrocarbons, for example vaseline, paraffin oil and / or hard paraffin, which preferably contain suitable hydroxyl compounds, such as fatty alcohols or their esters, for example cetyl alcohol or wool 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.

Fatty ointments are anhydrous and contain, in particular, hydrocarbons such as paraffin, petrolatum and / or liquid paraffins as the matrix, furthermore natural or partially synthetic fat such as coconut oil triglyceride, or preferably hardened oils such as hydrogenated peanut or castor oil, further partial glycerin fatty acid esters, for example glycerin mono- and -distearate, as well as, for example, the fatty alcohols mentioned in connection with ointments which increase the ability to take up water, emulsifiers and / or additives.

• 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 / and aluminum silicates, which are designed 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 chlorofluoride (lower alkanes, for example dichlorodifluoromethane and diichlorotetrafluoroethane) as propellant. paraffin oil, fatty alcohols such as cetyl alcohol, fatty acid esters such as isopropyl myristate, and / or other waxes, and mixtures of such substances with predominantly hydrophilic properties such as polyoxyethylene sorbitan (Tweens) fatty acid esters and such substances are used as emulsifiers having predominantly lipophilic properties such as fatty acid esters of sorbitan (Spans), in addition conventional additives such as preservatives, etc. are added.

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-retardants to reduce evaporation, and fat re-imparting substances, ie, the aqueous mixture of soluble lipophilic substances as a replacement for fatty substances which 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

In a flask equipped with a stirrer and flushed with dry nitrogen, 1.265 g of 4 (S) -phenyl-5- (4? - (3-pyridyl) -1-methylimldazole in 25 ml of ether and 25 ml of tetrahydrofuran is cooled to -78 ° C and added dropwise. 3.8 ml of a 1.6 M solution of butyllithium in n-hexene diluted with 25 ml of diethyl ether, then a solution of 0.5 g of methanesulfenyl chloride in 5 ml of diethyl ether is added dropwise, the mixture is allowed to stir for 1 hour at -78 °. The organic phase was dried over sodium sulfate to give a mixture of 1-methyl-2-methylthio-4-phenyl-5- (3-pyridyl Jimidazole and 1-methyl). The 2-methylthio-5-phenyl-4- (3-pyridyl) imidazole can be separated by chromatography to elute the 5-phenyl-4- (3-pyridyl) isomer of the o 141 DEG-143 DEG C. and then eluting with a 4: 2 mixture of chloroform and ethyl acetate (8: 2 by volume). enyl-5- (3-pyridyl) -isomer, m.p. 125-127 ° C.

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

g of phenyl- (3-pyridyl) diketone, 52 g of ammonium acetate, 40 ml of formalin and 250 g of acetic acid are mixed and the mixture is heated to boiling for Θ hours, then the reaction mixture is evaporated to dryness under reduced pressure. The pH was corrected to pH 8 with ammonia 3e and extracted with ethyl acetate, and the extracts washed and evaporated to give 4-phenyl-5- (3-pyridyl) imidazole, m.p. 160-163 ° C.

A mixture of 11.05 g of 4-phenyl-5- (3-pyridyl) imidazole, 150 ml of benzene, 15 ml of 40% sodium hydroxide, 7.1 g of methyl iodide and 1.95 g of tetrabutylammonium bromide is heated to 60 DEG C. while stirring. for 6 hours. The reaction mixture was allowed to cool, the benzene phase was separated, dried over sodium sulfate and evaporated. There was obtained 4 (S) -phenyl-6 (4) - (3-pyridyl) -1-methylimidazole which could be used without further purification.

Example 2

1.2 g of 4 (S) - (p-fluorophenyl) -5 (4) - (2-thienyl) imidazole-2-sulfochloride are dissolved in 20 ml of hexamethylphosphoric triamide and a solution is added at -5 ° C with stirring. 0.13 g of ethyllithium in 5 ml of diethyl ether The reaction mixture was allowed to stir for 1 hour at 0 ° C and overnight at room temperature, poured out on ice, neutralized with dilute acetic acid, filtered and the product recrystallized from the mixture. ether and petroleum ether to give 2-ethanesulfonyl-4 (S) - (fluorophenyl) -5 (4) - (2-thienyl) imidazole, m.p. 180-181 ° C.

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

2.76 g of 4- (pfluorophenyl) -5- (2-thienyl jimidazoline-2-thione) are dissolved in 300 ml of warm 2% sodium hydroxide solution, allowed to cool to 15 ° C and added portionwise 3.16 g of potassium permanganate dissolved in 165 ml of water After standing overnight, the insoluble matter was filtered off, the filtrate was clarified with activated carbon and acidified to give 4- (pfluorophenyl) -5- (2-thienyl) imidazole-2- sulfonic acid, m.p. 282-285 ° C.

The acid is filtered off and dried. 3 grams of this acid are stirred in a solution of 0.23 g of sodium in 35 ml of ethanol for 30 minutes at room temperature. The reaction mixture was then evaporated to dryness. The sodium 4- (p-fluorophenyl) -5- (2-thienyl) imidazole-2-sulfonate thus obtained was sprayed, triturated with 1.5 g of phosphorus pentachloride and heated at 180 ° for 6 hours. The reaction mixture was then allowed to cool, poured onto ice and filtered. The obtained azole-2-sulfo-chloride 4- (p-fluorophenyl) -5- (2-thienyl) imide is dried over phosphorus pentoxide and can then be used further.

Example 3

In a flask equipped with a stirrer and flushed with dry nitrogen, 1.265 g of 4 (S) -phenyl-5 (4) - (3-pyridyl) -1-methylimidazole in 25 ml of ether and 25 ml of tetrahydrofuran was cooled to -78 ° and the mixture was stirred at room temperature. 3.8 ml dropwise

A 1.6 M solution of butyllithium in n-hexane diluted with 28 mL of diethyl ether. A solution of 0.56 g of dimethyl disulfide in 5 ml of diethyl ether is then added dropwise, the mixture is allowed to stir for 1 hour at -78 [deg.] C., allowed to warm to room temperature overnight and poured onto ice. The separated oil was extracted with ether. The organic phase was dried over sodium sulfate. It is obtained

1-Methyl 1-4 (S) -phenyl-5 (4) - (3-pyridyl) -2-methylthioimidazole, which was separated into the components as described in Example 1.

Example 4

2.5 g of di [4 (S) -phenyl-5 (4) - (3-pyridyl) imidazolyl] disulfide are suspended in 50 ml of carbon tetrachloride. Dry chlorine is then introduced into the suspension at room temperature until a clear solution is formed. The resulting solution containing 4 (S) -phenyl-5 (4) - (3-pyridyl) imidazole-2-sulfenyl chloride was evaporated and the residue was treated with ethyllithium as described in Example 2. 2-Ethylthio-4 (5) was obtained. 1-Phenyl-5- (4) - (3-pyridyl) imidazolyl mp 196-198 ° C.

Example 5

In addition, the following compounds can be prepared in an analogous manner to those described in Examples 1 to 4:

2-methylthio-4 (S) -phenyl-5 (4 &apos;-( 3-pyridyl) imidazole, m.p. 193-194 [deg.],

2-Propylthio-4 (S) -phenyl-5 (4 &apos;-( 3-pyridyl) imidazole, m.p. 197-198 [deg.];

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

2- (2-methoxyethylthio) -4 (5) 4-enyl-5 (4) - (3-pyridyl) imidazole, mp 118-120 °,

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

2-ethylthio-4 (S) - (1-fluorophenyl) -5 (4) - (2-thienyljimidazole, mp 160-163 °),

2-methylthio-4 (S) - (p-fluorophenyl) -5 (4) - (2-thienyljimidazole, mp 171-173 °),

2-Propylthio-4 (S) - (p-fluorophenyl) -5 (4) - (2-thienyl) imidazole;

2-isopropylthio-4- (p-fluorophenyl) -5- (4-pyridyljimidazole, m.p. 263-264 °);

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

Example 6

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 ingredient 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 formula (I) in Examples 1 to 5 can also be prepared in an analogous manner.

Example 7

Tablets containing 30 mg of the active ingredient, for example 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyljimidazoline), may 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, 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 to 5 can be prepared in an analogous manner.

Example 8

Tablets containing 100 mg of the active ingredient, for example 2-ethylthio-4 (5) dio 1-5 (4) - (3-pyridyl) imidazole, may be prepared as follows:

Ingredients (for 1000 tablets):

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 stearate 4.0 g demineralized water as needed

Production:

The solids are sieved as soon as possible 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 sieved through a 1.2 mm sieve and the concave tablets of about 10 millimeters in diameter are compressed from the mixture with a groove on the top.

Tablets containing 100 mg of some of the other compounds of Formula I which have been prepared according to Examples 1-5 can also be prepared in an analogous manner.

Example 9

In an analogous manner to that described in Examples 1 to 5, 2-ethanesulfonyl-4 (5) - (fluorophenyl) -5 (4) (2-thienyl) imidazole, mp 180-182 ° and 2-ethanesulfonyl- 4- (5) -phenyl-5- (4) - (3-pyridyl) imidazole.

Example 10

1.5 g of 4,5-bis- (2-thienyl) imidazoline-2-thione are suspended in 50 ml of carbon tetrachloride. Chlorine gas is then introduced into the suspension until a clear solution is formed. This solution was evaporated under reduced pressure and the remaining crude

4,5-Bis- (2-thienyl) imidazole-2-sulfenyl chloride is dissolved in a small amount of hexamethylphosphoric triamide. The resulting solution is then slowly added dropwise to a solution of 0.1 g of methyllithium in 50 ml of dimethyl ether, with vigorous stirring, and which is cooled to -5 ° C. The reaction mixture was further stirred at 0 ° C for 3 hours, then poured onto ice, extracted with ethyl acetate, dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from diethyl ether / hexane. 2-methylthio-4,5-bis- (2-thlenyl imidazole), m.p. 204-206 ° C, is obtained.

2-Ethylthio-4,5-bis- (2-thienyl) imidazole, m.p. 209 DEG-210 DEG C., can also be prepared in an analogous manner.

Example 11

In an analogous manner to that described in Example 4, by reaction of 4 (5j-phenyl-1-5 (4) - (3-pyridyljimidazole-2-sulfenyl chloride) with 1] benzylmagnesium bromide, 2) allylmagnesium bromide, 3) 2-ethoxyethylene magnesium bromide, optionally with 4j propargylnatrium the following compounds:

1) 24-benzylthio-4 (5'-phenyl-5 (4'- (3-pyridyljimidazole), m.p. 165-167 ° C);

2-allylthio-4 (S) -phenyl-5- (4 - (3-pyridyl) imidazole, m.p. 177-178 ° C);

3) 2- (2-ethoxyethylthio) -4- (5'-phenyl-5 (4'- (3-pyridyl) imidazole, m.p.

102 ° C a

4) 2-propargylthio-4 (5'-phenyl-5 (4) - (3-pyridylimidazole), m.p. 148-149 ° C.

Claims (12)

Subject A process for the preparation of novel mercaptoimidazole derivatives of the general formula I (I) wherein R ₄ and R ₂ are thienyl or one of R 1 and R ₂ is thienyl or pyridyl, and the other of these is phenyl optionally substituted by C 1 -C 4 alkoxy or halogen, R ₃ represents hydrogen or alkyl with 1 to 4 carbon atoms, n is 0 or 2, and * R ₄ is an alkenyl group having up to 4 carbon atoms, alkynyl having up to 4 carbon atoms, phenylalkyl having 1 to 4 carbon atoms an alkyl moiety or a (C 1 -C 4) alkyl group which is optionally substituted at a position higher than the position with a (C 1 -C 4) alkoxy or (C 1 -C 4) alkylthio group, and acid addition salts thereof, characterized by: by reacting compounds of formulas II and III in the reaction OF THE INVENTION wherein one of the radicals X and Y represents a group of the formula —S (O) _n —Y _b wherein Y _x represents a halogen atom or, when n - 0, an etherified mercapto-capsule, and the other of these residues represents the metal radical Y _{2 of the} formula —M ¹ , —M ^{I [} / 2 or —M ^{n —-} Hal, where M ¹ is an alkali metal atom M ¹¹ represents an alkali earth metal and Hal is halogen, and optionally the obtained compound of formula I wherein R ₃ represents hydrogen, a substituted alkyl group having 1 to 4 carbon atoms, R _3, and / or a resulting free compound is converted into an acid addition salt or a resulting acid addition salt with an acid is converted to the free compound or another salt. 2. Method according to claim 1, characterized in that as starting materials are used compounds of the formulas II and III in which one of the residues R _t and R ₂ is pyridyl and the other is an optionally C 1 -C 4 alkoxy or halogen substituted phenyl, R ₃ is hydrogen or C 1 -C 4 alkyl, n is 0 and R ₄ is C 1 -C 4 alkyl or C 1 -C 4 alkoxyalkyl in the alkoxy and alkyl moieties, wherein the alkoxy group is in a position higher than in position a, or is a C 1 -C 4 alkylthioalkyl group in both alkyls, wherein the alkylthio group is in a position higher than or, and X and Y are as defined in point 1, whereupon optionally obtained compound of formula I wherein R ₃ represents hydrogen, a substituted alkyl group having 1 to 4 carbon atoms, R _3, and / or Channel for zís220333 free compound is converted to an acid addition salt or the resulting acid addition salt is converted into the free compound or another salt. 3. Process according to claim 1, characterized in that as starting materials are used compounds of the formulas II and III in which one of the residues R _t and R ₂ represents a pyridyl or thienyl group, and the other of these radicals represents a phenyl group which is optionally substituted with C 1 -C 4 alkoxy and / or halogen with an atomic number of up to 35, R ₃ is hydrogen, n is 0 or 2, and R ₄ is C 1 -C 4 alkyl, and X and Y are as defined above in step 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. 4. A process according to claim 1, wherein the starting materials are compounds of formulas II and III in which one of the radicals R @ 1 and R @ ₂ is a pyridyl group and the other one is a phenyl group, R @ ₃ is hydrogen. and R ₄ is C 1 -C 4 alkyl, n is 0 and X and Y are 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. 5. 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 general formula I are used as starting materials. 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, n is 0 and R ₄ is ethyl, and X and Y are as described 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. 6. A process as claimed in claim 1 for the preparation of 2-propylthlo-4 (5'-phenyl-5 (4) - (3-pyridyl) imidazole or an acid addition salt thereof, characterized in that compounds of the general formula I are used as starting materials. of formulas II and III wherein one of R 1 and R ₂ is 3-pyridyl group and the other of these radicals represents a phenyl radical and R _i represents hydrogen, n represents 0 and R ₄ represents a propyl group, and X and Y have the meanings given in point 1, and optionally the 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. / 7. 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 it is The starting materials used are 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, n is 0 and R ₄ is 2-methoxyethyl, and X and Y are 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. 8. The process of claim 1 for the preparation of 2- (2-methylthioethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) imidazole or an acid addition salt thereof, characterized in that it is starting materials are used compounds of the formulas II and III in which one of the radicals R _x and R ₂ represents a 3-pyridyl group and the other of these radicals represents a phenyl group, R ₃ represents hydrogen, n represents 0 and R ₄ represents a 2-methylthloethylovou group , and X and Y are 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. 9. The process of item 1 for the preparation of 2-ethylthio-4 (S) - (pfluorophenyl) -5 (4) - (2-thienyl) imidazole or an acid addition salt thereof, characterized in that the the compounds employ compounds of formulas II and III wherein one of the radicals R ₄ and R ₂ is a 2-thienyl group and the other one is a p-fluorophenyl group, R ₃ is hydrogen, n is 0 and R ₄ is an ethyl group, and X and Y are 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. 10. A process according to claim 1 for the preparation of 2-propylthio-4 (S) - (fluorophenyl) -5 (4) - (2-thienyl) imidazole or an acid addition salt thereof, characterized in that the starting materials are: uses compounds of formulas II and III wherein one of R ₄ and R ₂ is 2-thienyl and the other is p-fluorophenyl, R ₃ is hydrogen, n is 0 and R ₄ is propyl, and Y and X are 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. 11. The process according to claim 1 for the preparation of 2-ethanesulfonyl-4 (5) -phenyl-1-5 (4) - (3-pyridyl) imidazole or an acid addition salt thereof, characterized in that the starting materials used are: compounds of 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, n is 2 and R ₄ is ethyl, and X and Y are as defined in step 1, and optionally converting the obtained free compound into an acid addition salt of 203333, or converting the obtained acid addition salt into a free compound or another salt. 12. A process according to claim 1 for the preparation of 2-ethanesulfonyl-4 (5J- (pfluorophenyl) -5 (4) - (2-thienyljimidazole or its acid addition salts), characterized in that the starting materials are: uses compounds of formulas II and III, in which one of the radicals R, and R ₂ represents a 2-thienyl group and the other represents p-fluorophenyl group, R ₃ is hydrogen, n is 2 and R ₄ stands for ethyl group and X and Y have the meanings given in point 1, and optionally the resulting free compound is converted into an acid addition salt or is converted into an acid addition salt. the resulting acid addition salt is converted into the free compound or another salt.