HU184845B - Process for producing 1-bracket-1,3-dioxol-2-nyl-methyl-bracket closed-1h-1,2,4-triazole derivatives - Google Patents

Abstract

The present invention relates to the novel triazole derivatives of formula I wherein Ar is optionally substituted with 2 halogens and Y is imidazol-1-yl of formula XXXVI (wherein R1 is hydrogen or C1-C5 alkylthio; C 1 -C 6 alkylsulfonyl, while R 4 is hydrogen), XXXVII 1 H-1,2,4-triazolyl (wherein R 6 is hydrogen and R 7 is C 1-4 alkyl), 4 H- 1,2,4-triazol-4-yl (wherein Rg is hydrogen or C1-C4 alkyl, C1-C4 alkylthio, C1-C4-alkyl-sulfmyl and R9 is hydrogen or C1-C4 alkyl) or 2,3-dihydro-4H-1,2,4-triazol-4-yl of formula XXXIX (wherein X is oxygen, R1 and Rn are independently hydrogen or 1-5 carbon atoms). refers to the preparation of cis-isomers and pharmaceutically acceptable acid addition salts thereof. These compounds can be prepared by methods well known in the art of organic chemistry, and have fungicidal and bactericidal activity. ch2-0, Y (I) (XXXVI) -1-

Description

The present invention relates to novel heterocyclic derivatives of 1- (1,3-dioxolan-2-ylmethyl) -1H-1,2,4-triazoles.

U.S. Patent Nos. 3,575,999 and 3,936,470, as well as Belgian Patent No. 835,579, show a number of fungicidal and bactericidal activity of 1- (1,3-dioxolan-2-ylmethyl) -1H-1,2, A 4-triazole derivative has become known; however, their fungicidal and bacterial umellic effects are not always satisfactory.

It has now been found that the novel compounds of Formula I, other than the compounds described in the preceding paragraph, are substituted in the 4-position of the dioxolane ring.

Ar is phenyl substituted with 2 halogens, and

Y is 1H-pyrazol-1-yl of formula XXXV (wherein R 1 is C 1 -C 4 alkyl); 1H-imidazol-1-yl of formula XXXVI (wherein R _{3 is} hydrogen or C 1-5 alkylthio or C 1-6 alkylsulfonyl, and R _{4 is} hydrogen): 1H-1,2 of formula XXXVII , 4-triazol-yl (wherein R _{6 is} hydrogen and R _{7 is C} 1-4 alkyl); 4H-1,2,4-triazol-4-yl of formula XXXVIII (wherein R _{g is} hydrogen or C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkylsulfinyl, and R _{9 is} hydrogen or It is alkyl of 1-4 carbon atoms), or 2,3-dihydro-4H-l, 2,4-triazol-4-yl group of general formula XXXIX (wherein X is oxygen, R ₁₀ and R _l are independently hydrogen or 1 - 5-carbon alkyl), their ace isomers and their pharmaceutically acceptable acid addition salts have excellent fungicidal and bactericidal activity and are thus useful in controlling harmful fungi and bacteria.

It will be appreciated by those skilled in the art that the radicals XXXIX containing R _n may be in the form of the corresponding enol. Although the above formulas do not encompass these forms, it is understood that the enols mentioned are within the scope of the invention.

As used herein and in the claims, "alkyl having from 1 to 6 carbon atoms" is intended to include straight or branched chain groups such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, , boutique, pentyl or hexyl, while the term "halogen" refers to halogens of less than 127, such as fluorine, chlorine, bromine and iodine.

Due to their beneficial effect, among the compounds of formula 1, we prefer compounds having a substituent Y on the benzene ring para to the dioxolanylmethoxy group. Particularly preferred are compounds of formula I wherein they are dichlorophenyl.

In order to facilitate the structural representation of the compounds of the formula I and certain starting and intermediate compounds, 2-Ar-2- (1H-1,2,4-triazol-q-1-ylmethyl) -1,3-dioxolane-4- Group i !, where Price is referred to above, is hereinafter referred to as the "D" symbol.

Compounds of formula I-a which form a narrower group of compounds of formula I - wherein D and Y have the same meaning as Y and Y, with the exception of> 5 that Rn is other than hydrogen, wherein Rn is hydrogen. ) can be prepared by reacting a reactive ester of formula II, wherein D is the above and W is a reactive ester of 5C, preferably a halogen or methylsulfonyloxy or 4-methylbenzenesulfonyloxy group.

- reacting a phenol derivative of formula III wherein Y 1 is as defined above (Scheme A). The reaction of the compounds of the formulas II and III is carried out by methods well known in the art for O-alkylation. For example, the reaction is carried out in an inert organic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, cxamethylphosphoric triamide, dimethylsulfoxide or 4-methyl-2-pentanone, optionally in another solvent. in an inert solvent such as an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene. It is also advantageous to add a suitable base to the reaction mixture, such as an alkali metal hydride or carbonate, to increase the reaction rate. On the other hand, it may be advantageous to convert a phenol derivative of the Formula III into a metal salt, such as the sodium salt, in a conventional manner, for example, by reacting a compound of Formula III with a metal-containing base such as sodium hydride or sodium hydroxide. It is also desirable to use slightly elevated temperatures to increase the reaction rate, and it is particularly preferred to carry out the reaction at a temperature of about 80 ° C to about 130 ° C.

Compounds of formula (Ib-2) containing a narrower group of compounds of formula I can be readily prepared according to process b) with an amidine of formula VIII-b, wherein D and X are as defined above, wherein R ₀ is as defined above. Or with an acid addition salt thereof. by cyclization with a cyclizing agent (Scheme D).

The ring closure is carried out in a manner known per se, for example by mixing and melting the reactants, optionally with a relatively high source.

184,845 in the presence of an inert organic solvent such as 1,1'-oxybis (2-methoxyethane).

Compounds of Formula I-b-4 which form a narrower group of compounds of Formula I can be prepared by reacting a compound of Formula I-b-2 with Process X, wherein X is O, with a reactive ester of Formula VII (Scheme E).

This N-alkylation reaction is also carried out in a known manner, for example by mixing the reactants, preferably at a slightly elevated temperature, in a suitable organic solvent (e.g. dimethylsulfoxide) in the presence of a suitable base such as an alkali metal hydride or carbonate.

I prepared a) by a process comprising a group of formula XXXVI A compound of formula I wherein R ₃ alkylthio group represented by R ₃ is appropriate alkylsulfonyl oxidized to the unloaded analog for at least two molar equivalents of an oxidizing agent, preferably 3-chloroperbenzoic acid. Using 1 molar equivalent of oxidizing agent, compounds of formula I having the formula XXXVIII, wherein _R8 is alkylthio, can be oxidized to the corresponding alkylsulfinyl analogs.

The compounds of Formula I, prepared as the free base by the methods described above, may, if desired, be converted into their pharmaceutically acceptable acid addition salts by treatment with a suitable organic or inorganic acid. For example, inorganic acids include halo acids (such as hydrochloric, hydrobromic or hydroiodic), sulfuric acid, nitric acid, thiocyanic acid and phosphoric acid, and organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2- oxopropanoic acid, ethane dicarboxylic acid, propane dicarboxylic acid, 1,4-butanedioic acid, (Z) -2-butenedicarboxylic acid, (E) -2-butenedicarboxylic acid, 2-hydroxy-1,4-butanedioic acid, 2,3-dihydroxy-1,4- butanedioic acid, 2-hydroxy-1,3-propanedioic acid, benzoic acid, 3-phenyl-2-propenoic acid, α-hydroxyphenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 4-methylbenzenesulfonic acid, 2-hydroxybenzoic acid, Amino-2-hydroxybenzoic acid, 2-phenoxybenzoic acid or 2-acetyloxybenzoic acid are used. Of course, these acid addition salts can, if desired, be converted into the corresponding free bases by conventional means, such as treatment with a base such as sodium or potassium hydroxide.

Most of the starting and intermediate compounds used in the reactions described above are known compounds and can be prepared in a known manner, but some are new and therefore their preparation will be described below.

Compounds of formula III can generally be prepared from the corresponding methoxy substituted compounds of formula X by converting the methoxy group of the latter to the hydroxyl group by acid hydrolysis (Scheme I). Acid hydrolysis is carried out with a strong but non-oxidizing acid such as a solution of hydrogen bromide in acetic acid. The compounds of formula X used as starting materials in this reaction may be prepared by a variety of methods, depending on the nature of the substituent Y.

Thus, compounds of formula X having Y, where XXX is XXXV, XXXVI or XXXVII, i.e. compounds of formula Xa wherein Y1 is Yj, as listed herein, are readily prepared from a halogen of formula XI and an azole of formula XII reaction (Scheme J).

The reaction of the compounds of formula XI and XII is carried out in a manner known per se, for example, for a period of several hours to several days, in a suitable organic solvent (e.g. N, N-dimethylformamide, form, Ν-dimethylacetamide, hexamethylphosphoric triamide or dimethyl). sulfoxide), particularly preferably by stirring in the presence of a suitable copper (I) salt, for example in the presence of a suitable chloride or bromide. The purpose of using the copper salt is to increase the icing speed.

Y _(site XXXVI group of formula hcrdozó -X mingled part, that is, Xc compounds can be produced near an XV isothiocyanate of formula is subjected to a V aminoetanonnal formula to ring closure and the resulting compound of formula XVI, R ₃ substituents were prepared (Scheme L).

Compounds of formula X wherein Y is XXXVII, i.e. compounds of formula Xd, may be prepared by sulfurizing a 1-methoxyphenyl-1H-1,2,4-triazol-3-thiol of formula XVII in a known manner. Scheme M shaking.

XVII of k used in this reaction <pielfí with a suitable XVIII general formula ^- prepared Ű l- (methoxyphenyl) -tioszemikarbazidból so that the latter is a corresponding XIX general formulas carboxylic acid or a reactive derivative thereof, for example a corresponding acyl halide , an ester or preferably an aridine of the formula ΧΙΧ-a. This reaction can be conveniently carried out by heating the two reagents with stirring using a suitable organic solvent, for example a C 1-6 alkanol, e.g. 2-propanol or butanol.

Alternatively, the compound of Formula XVII may be prepared by first reacting a compound of Formula XVIII with an ai hydride of Formula XX or an acyl halide of Formula ΧΙΧ-b, and then subjecting the compound of Formula XXI to a ring closure. while heating in an alcoholic solution of a base. The above reactions are illustrated in Scheme N.

A further possibility for the preparation of compounds of formula XVII is to react a hydrazine hydrochloride of formula ΧΙΙΙ-a with an acyl isothiocyanate of formula XXII in Ν, Ν-diethylethanamine (Scheme 0) and wash the reaction mixture with water. and the residue is heated under stirring in a mixture of dichloromethane and ethanol in the presence of a base, preferably sodium hydroxide.

Compounds of formula X wherein Y is XXXVIII or XXXIX can be readily prepared from the 4- (methoxyphenyl) semicarbazide or thiosemicarbazide of formula XXIII to give compounds of formula Ib-2 and Ib-4. by methods similar to those described for the preparation of compounds of the general formula.

Compounds of formula XVI11 are readily prepared as the corresponding hydrazine hydrochloride by potassium isothio

-3184 84?

reaction with cyanate as described in Chemical Abstracts, 59, 8651b (1963), otherwise the 4-substituted analog is disclosed.

Of the compounds of Formula XXIII, compounds having X as the sulfur atom include Chemical Abstracts, 18, 378 (1922), 47, 3342 (1953), Good, P 3681 (1962) and 51, 12016h (1957), and J. Am. Chem. Soc., 70, 3439 (1948).

Compounds of formula XXIII, wherein X is O, i.e. compounds of formula XXIII-b, can be prepared by reacting a phenyl ester of N-methoxyphenylcarbamic acid of formula XXV with a hydrazine hydrate (Scheme P).

The carbamates of formula XXV can be readily prepared by reacting an amine of formula XXIV with a phenyl formate of chloroformate. Of the compounds of Formula XXIII-b, the 4-methoxy-bearing compound is known from Chemical Abstracts, 31, 3891, ⁸ (1937).

In general, the reactive esters of formula II may be prepared in the following reaction sequence.

First, a 1-Ai-2-bromoethanone of Formula XXVI is ketalized with 1,2,3-propanetriol by methods analogous to those described in Synthesis, I, 23, 1974. In carrying out this reaction, it is preferable that a solution of the two reactants in a suitable organic solvent, preferably in the presence of a simple alcohol (e.g. ethanol, propanol, butanol or pentanol) and a suitable strong acid such as 4-methylbenzenesulfonic acid, reflux for a few hours, removing the water formed during the reaction by azeotropic distillation. Organic solvents which may be used include aromatic hydrocarbons such as methylbenzene, benzene or dimethylbenzene, and saturated hydrocarbons such as cyclohexane.

The dioxolane XXVII thus obtained is then reacted with benzoyl chloride to give a benzoate XXVIII. The latter is then reacted with 1H-1,2,4-triazole, preferably by heating a solution of the reactants in a suitable solvent such as Ν, Ν-dimethylformamide with stirring in the presence of a suitable strong metal base such as sodium methylate. . The compound XXXIX thus obtained is then hydrolyzed in a basic medium and the hydroxyl group of the compound XXX thus obtained is converted into a reactive ester residue in a manner known per se. For example, methanesulfonates and 4-methylbenzenesulfonates can be readily prepared by reacting an alcohol of formula XXX with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, while the halides of formula II are an alcohol of formula XXX with a suitable halogenating agent such as sulfuryl. by treatment with chloride, phosphorus pentachloride, phosphorus pentabromide or phosphoryl chloride. If the iodide of formula II is to be prepared, it is preferable to start from the corresponding chloride or bromide and replace their halogen atoms with iodine. To illustrate the above reactions, see Scheme R.

The starting compounds of formula IV-b can be prepared by the following reactions.

First, a suitable compound of formula II is reacted with N-hydroxyphenylacetamide XXXI in a known manner, and then the amide group of the compound KXX1I thus obtained is subjected to basic hydrolysis, for example using an alcoholic alkali metal hydroxide solution. An amine of formula IV-c is obtained.

Compounds of formula IV-b may be prepared by reacting a compound of formula IV-c with phenyl formate of boronic acid to form a phenyl carbamate of formula XXIII and then reacting the latter with hydrazine hydrate.

The above reactions are illustrated in Scheme S.

The compounds of formula IV-b or their stereochemically isomeric forms are believed to be novel. The compounds of formulas XXXII, IV-c and XXXIII are also novel and, in addition to being useful as intermediates in the process of the present invention, have antifungal and antibacterial activity in themselves.

It can be seen from formula I that the compounds of the present invention have at least two asymmetric carbon atoms, the carbon atoms at the 2- and 4-positions of the dioxolane ring being asymmetric, and consequently these compounds may exist in different stereochemically isomeric forms. The cis isomers of the compounds of formula I and their pharmaceutically acceptable acid addition salts are intended to be encompassed within the scope of the present invention.

The diastereomeric racemates of the compounds of Formula I, which are referred to in the chemical abstracts, 78, Index Guide, Section IV, p. 85 (1972) as cis and trans, can be prepared in conventional manner. For this purpose, for example, selective crystallization or chromatographic separation, such as column chromatography, are advantageously used.

Given that the stereochemical configuration already exists with the intermediates of formulas II and IV-b, it is possible to separate the cis and trans forms in their preparation or even in an earlier synthesis step, and thus the already separated cis Starting from compounds of formula II or IV-b, the synthesis leading to compounds of formula I can be continued as described above. In the case of the general formulas II and IV-b and other intermediates, the separation of the cis and trans forms may be effected by one of the methods mentioned for the compounds of the formula I.

It will be appreciated by those skilled in the art that the cis and trans diastereomeric racemates can be resolved into their optical isomers in a manner known per se whereby the cis (+), cis (-), trans (+) and trans (-) isomers are available. .

The compounds of the formula I and their acid addition salts, as mentioned, can be used against fungi and bacteria. For example, these compounds have been found to be highly effective in a variety of fungi such as Microsporum canis, Ctenomyces mentagrophytes, Trichophyton rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Candida albicans, Mucor species, Aspcrgillus fumigatus, Sporotactus schiz For example, Erysipelotrix insidiosa, Staphylosoceus such as Staphylococcus hemolyticus and Sterptococcus such as Streptococcus pyogenes. It is considered to have potent local and systemic antimicrobial activity

The compounds of the present invention are useful in inhibiting and preventing the growth of fungi and bacteria and in the treatment of individuals suffering from such microorganisms.

The potent antimicrobial activity of the compounds of formula I is demonstrated by the results of the experiments described below.

Ghost A. 10

Investigation of the effect of compounds of formula I on vaginal candidiasis in rats

Female Wistar rats weighing about 100 g were used as experimental animals. The animals were subjected to hysterectomy and ovariectomy, and 100 g of estradiol dissolved in sesame oil was administered subcutaneously three times a week for three weeks after surgery. The pseudocycle thus induced is examined by microscopic examination of the vagina. The experimental animals have access to food and water of their choice.

Rats are Sabouraud medium and cultured with dilute sodium chloride solution at 37 to 25 ° C for 48 hours intravaginally, Candida 8Ί0 containing ⁵ cells infected with a culture albicans. The infection is performed between the 25th and the 32nd day after surgery, depending on the appearance of the triggered pseudocycle. 30

Test compounds are administered orally daily for two days starting from the day of infection. Placebo-treated control animals were also used in each experiment. The results were evaluated by taking sterile tampons a few days after infection, placing the tampons on Sabouraud's medium in Petri dishes and incubating them for 48 hours at 37 ° C. If Candida albicans does not grow, i.e., the animals are considered negative at the end of the experiment, then this is the result of 40 treatments with the test compound, since none of the placebo treated animals is negative, ie all are infected.

Table I below shows the lowest oral dose of the test compound which is active 14 days after infection.

Experiment B

Effect of compounds of Formula I in case pulykabegy-candidiasis day turkeys crop infested grown for 48 hours at 55 37 ° C on Sabouraud's medium and dilute sodium chloride, 4 · culture of Candida albicans containing 10 ⁶ cells ml of 1 vaccine using. The test compound is premixed with 500 mg of lactone and then mixed with 1000 g of flour without addition of any 60 additives. The concentration of the test compound is thus expressed in mg / kg of flour.

For 13 consecutive days from the day of infection, the experimental animals receive 65 co-flours of the test compound. At the end of the experiment all animals are sacrificed. At autopsy, the specimens were removed, emptied, and comminuted with 15 ml of sterile sodium chloride solution in a UE-Rachrax mixer. Counting of possible cultures was performed on Sabouraud agar and the results are also reported in Table I in Et 5 ₀ , which corresponds to the dose ranges of the test compound that were negative for Candida albicans infection in half of the test animals. do.

Table 1

Compound of Formula I

Price

Vaginal candidiasis in rats, minimum effective oral dose in mg / kg

Craw candidiasis turkeys _{ED! O} mg / kg of power supplies

2 _λ <1 ₂ -Ε ₆ Π ₃ 4- (II-imidaz-1,25 8 zol-1-yl) In view of their antifungal and antibacterial activity, the compounds of the formula 1 and their acid addition salts with solid, semi-solid or liquid carriers or diluents when used in antimicrobial formulations, or, when used in human medicine, in admixture with pharmaceutically acceptable carriers or excipients, to form conventional pharmaceutical compositions.

Dosage units containing an effective amount of the active ingredient in association with carriers and / or excipients may be advantageously employed. The amount of active ingredient in these dosage units may vary widely, and it has been found advantageous to employ from about 50 mg to about 500 mg, more preferably from about 100 mg to about 250 mg, of active ingredient per dosage unit.

The following examples illustrate the invention.

Example 1

A mixture of 1.6 parts of 1 H, 2,4-triazole, 54 parts of Ν, Ν-dimethylformamide and 45 parts of benzene was stirred at reflux for 2 hours and then cooled to 0.78 parts of 78% mineral oil. sodium hydride dispersion was added and the resulting mixture was stirred at room temperature for 30 minutes. Subsequently, 8.9 parts by weight of cis [2- (bromomethyl) -2- (2,4-dichlorophenyl) -1,3-dioxolan-4-ylmethyl] benzoate are added to the reaction mixture, followed by stirring was continued at 150 ° C overnight. The reaction mixture was cooled and poured into water. The aqueous mixture was extracted three times with benzene, and the combined extracts were washed twice with water, dried, filtered and evaporated to give 8.5 parts by weight of cis [2- (2,4-dichlorophenyl)] l-1,2,4- triazol-1-ylmethyl] -1,3-dioxolan-4-ylmethyl] -benzoate is obtained.

289 parts by weight of cis [2- (2,4-dichlorophenyl) -2- (1S-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl] benzoate, 200

A mixture of 50 parts by weight of 50% aqueous sodium hydroxide solution, 1500 parts by weight of 1,4-dioxane and 300 parts by weight of water is heated under reflux for 2 hours, then cooled and poured into water. The resulting aqueous mixture was extracted with dichloromethane and the extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: 95: 5 trichloromethane: methanol). The first fraction was collected and evaporated to give 89 parts by weight of cis-2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyl melting at 138.2 ° C. ) -4- (hydroxymethyl) -1,3-dioxolane.

With stirring at room temperature, 30.6 parts by weight of cis-2- (2,4-dichlorophenyl) -2- (1H, 2,4-triazol-1-ylmethyl) -4- (hydroxymethyl) -1, To a mixture of 3-dioxolane and 75 parts by weight of pyridine was added dropwise 17.2 parts by weight of methanesulfonyl chloride. After the addition was complete, the reaction mixture was stirred at room temperature overnight, then poured into ice water and the resulting aqueous mixture was extracted twice with dichloromethane. The combined extracts were washed twice with dilute hydrochloric acid and twice with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: 95: 5 trichloromethane: methanol). The first fraction was separated and evaporated to give 21 parts by weight of cis [2- (2,4-dichlorophenyl) -27H-1,2,4-triazol-1-ylmethyl) -1, m.p. 3-dioxolan-4-ylmethyl] -methanesulfonate.

Example 2

To a mixture of 3.2 parts by weight of 4- (1H-imidazolyl) -phenol and 100 parts by weight of dimethylsulfoxide was added with stirring, 0.7 parts by weight of a 76.5% sodium hydride dispersion in mineral oil, and the resulting mixture was stirred at room temperature for 30 minutes. stir. Then, 8.2 parts by weight of cis [2- (2,4-dichlorophenyl) -2- (1- [1,2,4,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl]. methanesulfonate was added and stirring continued at 130 ° C for 3 hours. The reaction mixture was cooled, poured into water and extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: trichloromethane: methanol = 97: 3). The fractions containing pure product were evaporated and the residue was crystallized from 4-methyl-2-pentanone. The precipitated product is finally filtered off and dried. Thus, cis-1- (2- (2,4-dichlorophenyl) -4- [4- (1H-imidazol-1-yl) phenoxymethyl), m.p. -1,3-dioxolan-2-ylmethyl] -1H-1,2,4-triazole is obtained.

The following starting materials can be prepared from appropriate starting materials, chemically equivalent, as described herein:

cis-1- (2- (2,4-Dichlorophenyl) -4- [4- (2-methylthio-1H-imidazol-1-yl) phenoxymethyl] -1,3-dioxolan-2-yl -methyl) -1H-1,2,4-triazole, m.p. 185.6 ° C;

cis-4- <4- [2- (2,4-Dichlorophenyl) -2- (1H, 2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl -methoxy] -phenyl) -3-methylthio-4H-1,2,4-triazole, m.p. 184-7 ° C;

cis-1- (2- (2,4-Dichlorophenyl) 4- [4- (2-ethylthio-1H-imidazole-16]

-i ') -phenoxymethyl] -1,3-dioxolan-2-ylmethyl) -1H-1,2,4-triazolidinedione, m.p. 149.6-150.8 ° C; cis -4 (4- [2- (2,4-Dichloro-phenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxo-4-ylmethoxy] -phenyl) 4H-1,2,4-triazole, m.p. 190.6 ° C;

cis -1- (2- (2,4-Dichlorophenyl) 4- [4- (3-methyl-1H-pyrazol-1-yl) phenoxymethyl] -1,3-dioxolan-2-ylmethyl ) -1H-1,2,4-triazole, m.p. 148.6 ° C;

cis-1- (2- (2,4-Dichlorophenyl) 4- [4- (2-propylthio-1H-imidazol-1-yl) phenoxymethyl] -1,3-dioxolan-2-yl; methyl 1 H -1,2,4-triazole dihydrochloride monohydrate, m.p. 157.8 ° C; cis-1- (4- (2- (2,4-dichloro-phenyl) -2- (1) Η-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) -5-methyl-1H-1,2,4-triazole, m.p. 160.3 ° C; and cis -4- (4- [2- (2,4-dichlorophenyl) -2- (1H, 2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl); methoxy] phenyl> -3-methyl-5-methylthio-4H-1,2,4-triazole, m.p. 173 ° C.

Example 3

With stirring and cooling, 4.4 parts by weight of cis-1- (2- (2,4-dichlorophenyl) 4- [4- (2-methylthio-1H-imidazol-1-yl) phenoxymethyl] -1, To a mixture of 3-dioxolan-2-ylmethyl) -1H-1,2,4-triazole and 130 parts by weight of dichloromethane was added 6.8 parts by weight of 3-chloroperbenzoic acid and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was then washed with sodium bicarbonate solution, dried, filtered and evaporated. The residue was purified by silica gel column chromatography (eluent: 98: 2 trichloromethane: methanol). The pure fractions were combined and evaporated. The residue was crystallized from 4-methyl-2-pentanone. The crystallized product is filtered off and dried. Thus, 1.3 parts by weight of cis-1- (2- (2,4-dichlorophenyl) 4- [4- (2-methylsulfonyl-1H-imidazol-1-yl) phenoxy) melting point 169.4 ° C are obtained. methyl] -1,3-dioxolan2-ylmethyl> -1H1,2,4-triazole is obtained.

Example 4 To 46 parts by weight of bis (2-methoxyethyl) ether was added 46.8 parts by weight of formamidine acetate and 45 parts by weight of cis-N- (4- [2- (2,4-dichlorophenyl) -2- (1 1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) hydrazinoformamide and the resulting mixture was stirred at 160 ° C for 1 hour. The reaction mixture was cooled and water was added and stirred for 45 minutes. The precipitated product is filtered off and crystallized from 2-propanol. After filtration again, the filtered product is recrystallized from 4-methyl-2-pentanol. Thus, 11 parts by weight of cis -4- (4- [2- (2,4-dichlorophenyl) -2- (1H, 2,4,4-triazol-1-ylmethyl) -1), m.p. 3-dioxolan-4-ylmethoxy] -phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one is obtained.

Proceeding as described above, acetarrtidine hydrochloride. and cis-N- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-methyl) -1,3-dioxolan-4-ylmethoxy) - by reaction of phenyl) hydrazino-formamide with m.p. 196 C, cis -4- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) 3-Dioxolan-4-ylmethoxy] -phenyl] -2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one can be prepared.

Claims (2)

Example 5 With stirring, 1.1 parts by weight of bromoethane and 4 parts by weight of cis-4- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyl ) To a solution of 50 parts by weight of dimethyl sulfoxide in 50 parts by weight of a solution of -1,3-dioxolan-4-ylmethoxy] -phenyl] -2,4-dihydro-3H-1,2,4-triazol-3-one is added 0.4 parts by weight of 60 parts by weight. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then at 50 DEG C. The reaction mixture was poured into water and extracted with trichloromethane. The extract was washed with water, dried and evaporated to give a residue which was crystallized from 4-methyl-2-pentanone to give 3 parts by weight of cis -4- [4- (2- (2,4-dichlorophenyl) 2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl> -2-ethyl-2,4-dihydro-3H-1, 2,4-Triazol-3-one is obtained. The following starting materials can be prepared from equivalent starting materials in equivalent amounts, as described above: cis -4- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazolylmethyl) -1,3-dioxolan-4-ylmethoxy) ] -phenyl> -2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one, m.p. 171.2 DEG C., cis-4- (4- [2- (2,4) (dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 173.8 ° C; cis-4- <4- [2- (2,4-dichlorophenyl) -2 - (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) -2,4-dihydro-2-propyl-3H-1,2 , 4-triazol-3-one, m.p. 158.7 ° C; cis-4- (4- [2- (2,4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl- methoxy] phenyl> -2-ethyl-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one, m.p. 189.5 ° C, cis-4- (4- [2 - (2,4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) -2,4 -dihydro-5-methyl-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 177.9 ° C, and cis-4- <4- [2- ( 2,4-dichlorophenyl) -2- (1H, 2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl> -2,4- dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one, m.p. 196.5 ° C. Example 6 With stirring, 3.4 parts by weight of cis-4- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3- To a mixture of dioxolan-4-ylmethoxy-phenyl-3-methyl-5-methylthio-4H-1,2,4-triazole and 130 parts by weight of dichloromethane was added 1.1 parts by weight of 2-chloroperbenzoic acid, followed by After stirring at room temperature for 12 hours, the reaction mixture was washed with sodium bicarbonate solution, dried, filtered and evaporated to give a residue which was purified by silica gel column chromatography (eluent: trichloromethane: methanol = 98: 2). After evaporation, the residue is stirred with diisopropyl ether, the product is filtered off and dried under vacuum at 80 DEG C. to give 0.8 parts by weight of cis-1- (2- (2,4-dichlorophenyl) melting at 156 DEG C.). -4- [4- (3-Methyl-5-methylsulfinyl-4H-1,2,4-triazol-4-yl) -phenoxymethyl] -1,3-dioxolan-2-ylmethyl} -1 H , 2,4-Triazole. I. Process Triazole Derivatives 1 - in formula i Ar is phenyl substituted with 2 halogens, and Y is XXXV, wherein R ¹ is C 1 -C 4 alkyl; 1H-imidazol-1-yl (XXXVI) (wherein R _{3 is} hydrogen or C 1-5 alkylthio or C 1-6 alkylsulfonyl and R _{4 is} hydrogen); 1H-1,2,4-triazolyl of the formula XXXVII (wherein R _{6 is} hydrogen and R 1 is C 1-4 alkyl); 4H-1,2,4-triazol-4-yl of formula XXXVIII (wherein R _{8 is} hydrogen or C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkylsulfinyl, and R _{9 is} hydrogen) or a C1-C4 alkyl group) or a 2,3-dihydro-4H-1,2,4-triazol-4-yl group XXXIX (wherein X is O, R10 and R11 are independently hydrogen or 1). -C 5 alkyl) - cis-isolols and its pharmaceutically acceptable acid addition salts, characterized in that a) Compounds of formula 1a which form a narrower group of compounds of formula 1, wherein Y 1 has the same meaning as defined in Y, except that R 1 is different from XXXIX containing hydrogen, while D 2 For the preparation of an Ar-2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl (wherein Ar is as defined above), a compound of formula II wherein D represents the above ester, while W represents a reactive ester residue, preferably a halogen atom or a methylsulfonyloxy and thus a 4-methylbenzenesulfonyloxy group, with a compound of formula III wherein Yj is as above, in an inert organic solvent, preferably a suitable base. at an elevated temperature and optionally reacting a compound of formula III with a compound of formula II turning it into a metal salt, or b) for the preparation of compounds of formula Ib-2, which is a narrower group of compounds of formula I, wherein R _w and X are phenite, a compound of formula IV-b, wherein D and X are as defined above, in a inert organic solvent is prepared of the formula - wherein. R ₁₀ is as defined above - or an acid addition salt thereof to cyclization reaction, and if desired, forming a narrower group of compounds of formula I-B4, one of the compounds of formula - wherein D and R ₁₀ are as defined above and the alkyl group contains 1-5 carbon atoms - to prepare the resulting compounds of formula Ib-2, wherein D, X and R ₁₀ are any of the above with a reactive ester of formula VIII: wherein W is as defined in formula 11 of process a) and alkyl is as defined above, in organic solvent in the presence of a base: -7184 845 optionally a compound of formula I having the formula XXXVI of formula XXXVI, wherein R ₃ is alkylthio, wherein R ₄ is as defined in the above, optionally wherein Ar is the present invention. specified - R ₃ with appropriate oxidizing analog alkylsulfonyl two molar equivalents of an oxidizing agent, or obtained by a process a), R ₈ XXXVIII by oxidizing appropriate 4H-1,2,4-triazol-4-yl group of formula: - wherein _R9 is the is carried out by treating a compound of formula I, wherein Ar is an alkylsulfinyl group, as defined herein, with a molar equivalent of an oxidizing agent and / or treating a compound of formula I obtained by any of the above processes with an appropriate acid. satin elf to an acid addition salt. A process for the preparation of a pharmaceutical composition comprising mixing a triazole derivative of the Formula I, wherein the substituents have the meaning given in claim 1, with a carrier and / or excipient commonly used in the manufacture of a medicament. into a pharmaceutical composition.