CS235337B2

CS235337B2 - Method of triazole derivatives production

Info

Publication number: CS235337B2
Application number: CS590983A
Authority: CS
Inventors: Kenneth Richardson; Peter J Whittle
Original assignee: Pfizer
Priority date: 1982-08-14
Filing date: 1983-08-11
Publication date: 1985-05-15
Also published as: JPS5948468A; JPS6345674B2; ZA835950B

Abstract

Způsob výroby derivátů triazolu obecného vzorce I ve kterém R znamená fenylovou Skupinu, popřípadě substituovanou jedním až třemi substituenty nezávisle na sobě vybranými ze skupiny zahrnující atomy fluoru, chloru, bromu a jodu, a trifluormethylovou skupinu, a jejich farmaceuticky upotřebitelných solí, vyznačující se tím, že se 1,2,4-triazol nebo jeho sůl s alkalickým kovem nechá reagovat se sloučeninou obecného vzorce kde H R má shora uvedený význam, načež se popřípadě výsledný produkt obecného vzorce I běžným způsobem převede na svoji farmaceuticky upotřebitelnou sůl.Process for preparing triazole derivatives formula I in which R represents a phenyl group, optionally substituted with one to three substituents independently selected from the group including fluorine, chlorine, bromine and iodine, and a trifluoromethyl group, and their pharmaceutically acceptable salts, characterized in that 1,2,4-triazole is present or an alkali metal salt thereof react with a compound of the formula wherein H R is as defined above, whereupon optionally the final product of formula (I) by conventional means it is converted to its pharmaceutically acceptable form usable salt.

Description

(54) A method for producing triazole derivatives

A process for the preparation of triazole derivatives of the general formula I

OH, I 'n-ch ₂ -cf ₃ (I) in which

R represents a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine atoms, and trifluoromethyl group, and pharmaceutically acceptable salts thereof, characterized in that 1,2,4-triazole or an alkali metal salt thereof is reacted with a compound of formula II

CF ₃ -CH 2, (II) wherein ^H

R is as defined above, whereupon the resulting product of formula (I) is optionally converted into its pharmaceutically acceptable salt in a conventional manner.

The present invention relates to novel triazole derivatives having efficacy and useful for the treatment of fungal infections in animals, including humans, and as agricultural fungicides, as well as a process for the production thereof.

Accordingly, the invention provides a process for the preparation of compounds of formula (I)

OH in which

NN-CH ₂ -C-CF ₃ '-ν' n

(and)

R is a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine atoms and a trifluoromethyl group, and pharmaceutically and agriculturally useful salts thereof.

When R is the aforementioned optionally substituted phenyl group, it is preferably a phenyl group substituted with one to three, more preferably one or two substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine, and trifluoromethyl . Thus, the radical R is in particular 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5-difluorophenyl.

Most preferably, R represents a 2,4-dichlorophenyl or 2,4-difluorophenyl group.

The compounds of the formula I according to the invention are prepared by reacting an oxirane of the formula II ^Cf 3-C

(II) in which

R is as defined in formula I with 1,2,4-triazole, preferably in the presence of a base, for example potassium carbonate. Alternatively, an alkali metal salt of 1,2,4-triazole may be prepared, for example, from triazole and sodium hydride. The reaction is usually carried out by heating the reactants to a temperature of up to 130 ° C (for example 50 to 130 ° C) in a suitable solvent, for example dimethylformamide, for about 24 hours. The product can be isolated and purified by conventional means.

The oxides of formula (II) above may be prepared in a conventional manner, usually from ketones of formula (111)

O

This preparation can be accomplished by reacting a compound of formula III with dimethyloxosulfonium methylide prepared from trimethylsulfonium iodide and either (a) sodium hydride in dimethyl sulfoxide or (b) cetrimide (cetyltrimethylammonium bromide) and sodium hydroxide in a mixture of water and toluene or water; 1,1,1-trichloroethane.

The reaction using sodium hydride is usually carried out by stirring the sodium hydride with trimethylsulfonium iodide at, for example, room temperature, then dropwise adding dimethylsulfoxide, stirring the mixture for about 30 minutes, then adding the ketone III in dimethylsulfoxide. The desired product is generally obtained by stirring at room temperature for about one hour. The reaction using cetrimide is typically carried out by stirring the ketone of formula III, trimethylsulfoxonium iodide and cetrimide in a mixture for about 2 hours.

1,1,1-trichloroethane and aqueous sodium hydroxide at about 70-100 ° C.

While in both cases the oxirane of formula (II) may optionally be isolated, it is often preferable to convert it in situ to the desired end product.

The ketones of formula (III) are either known or can be prepared in a conventional manner, for example according to the following reaction scheme:

Pharmaceutically useful edition salts of the compound of formula (I) are those prepared with strong acids forming nontoxic acid addition salts such as hydrobromic acid, hydrochloric acid, sulfuric acid, oxalic acid and methanesulfonic acid.

These salts may be prepared in a conventional manner, for example by mixing solutions containing equimolar amounts of the free base and the desired acid, the desired salt being isolated by filtration or isolated by evaporation of the solvent when insoluble.

Also included within the scope of the invention are alkali metal salts which can be prepared in a conventional manner.

The compounds of formula I and their pharmaceutically acceptable salts are antifungal agents which can be used to combat fungal infections in animals, including humans. For example, the compounds may be used to treat local fungal infections in humans caused, inter alia, by Candida, Trichophyton, Microsporum or Epidermophyton, or by mucosal infections caused by Candida albicans (e.g., oral and vaginal candidiases). The disclosed compounds can also be used to treat systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.

An in vitro evaluation of the antifungal activity of the disclosed compounds can be accomplished by determining the minimum inhibitory concentration (MIC), which is the concentration of the test compound in a suitable environment without growth of the particular microorganism. In practice, a series of agar plates, each containing the test compound at the appropriate concentration, are inoculated with a standard culture of, for example, Candida albicans, incubated for 48 hours at 37 ° C and evaluated for fungal growth (resp. absence of fungus) and the MIC value is determined. Other microorganisms which may be used include, for example, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spec., Microsporum spec., Epidermophyton floccosum, Coccidioides immitis, and Torulopsis glabrata.

To assess the in vivo efficacy of the disclosed compounds, the compounds may be administered by intraperitoneal or intravenous injection, or orally administered in a series of graduated doses to mice inoculated with Candida albicans. Efficiency is manifested by survival

In the treated group of mice after the death of the untreated group of mice as assessed after 48 hours. The dose of the test compound that provides 5056 protection against the lethal effect of the infection is determined.

When used in human medicine, the antifungal compounds of formula (I) may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice.

For example, they may be administered orally in the form of tablets containing, for example, starch or lactose as carrier, or in the form of capsules or globules containing the cell alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing flavorings; dyes. Said compounds may further be administered by parenteral injection, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compounds of the invention are best used in the form of a sterile aqueous solution which may contain other substances, for example, an appropriate amount of salts or glucose to render the solution isotonic.

For oral and parenteral administration in human medicine, daily dosages (both oral and parenteral) of the antifungal compounds of formula I range from 0.1 to 10 mg / kg (possible subdose applications). Thus, the active ingredient tablets or capsules of the present invention will contain from 5 mg to 0.5 g of active ingredient for single, double or multiple daily administration, as appropriate in each case. In any case, the physician will determine the particular dosage that will be most appropriate for the patient and will vary depending on the age, weight and response of the patient to the formulation. The above dosage is only an example of the average case and, of course, there may be individual cases in which lower or higher doses will have to be administered. All such cases are within the scope of the invention.

Alternatively, the antifungal compounds of formula I may be administered in the form of a suppository or pessary, or may be administered topically in the form of a lotion, solution, cream, ointment or powder. For example, the active compounds may be incorporated into a cream of an aqueous emulsion of polyethylene glycols or liquid paraffin, or may be incorporated at a concentration of between 1 and 10% into an ointment base consisting of white wax or white soft paraffin, optionally together with suitable stabilizers with preservatives. .

The compounds of formula I and their salts also have activity against a wide variety of phytopathogenic fungi, including, for example, various rusts, mildews and molds, and can therefore be used to treat plants and seeds to prevent or treat these diseases.

The in vitro activity of the disclosed compounds against phytopathogenic fungi can be determined by measuring their minimum inhibitory concentrations in the same manner as described above except that the plates are incubated at 30 ° C for 48 hours or more before assessing the growth (or absence) of the fungus.

Among the microorganisms useful in these tests are Cochliobolus cerbonum, Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea and Rhizoetonia solani.

When used in agriculture and horticulture, the compounds of the invention and their agriculturally useful salts are preferably used in the form of compositions made with regard to the respective use and desired purpose. Thus, the compounds can be applied in the form of dusts or granules, seed dressings, aqueous solutions, dispersions or emulsions, wetting agents, sprayings, aerosols or smoke formers. These compositions may also be presented in the form of dispersible powders, granules or grains or concentrates to be diluted prior to use. Such compositions may contain conventional carriers, diluents or excipients as known and commonly used in agriculture and horticulture and are manufactured in conventional manner. The disclosed compositions may also contain other active ingredients, for example compounds exhibiting herbicidal or insecticidal activity, or other fungicides. The compounds and compositions of the present invention can be applied in a variety of ways, for example, directly to plant leaves, stems, branches, seeds or roots of plants, or to soil or other growth media and can be used not only to treat disease but also prophylactically to protect plants or plants. they are killed before being infected by the disease.

The invention is illustrated by the following non-limiting examples.

Example!

Preparation of 2- (4-chlorophenyl) -1 - (1H-1,2,4-triazol-1-yl) -3,3,3-trifluoro-2-ol, l triaethylsulfoxonluitjodld ^CF 3 ^C \ _ / cetrimide ^Cl , aqueous NaOH,

1,1,1-triethloroethane (known)

Jlk

Znn, K ₂ CO ₃ , dimethylformamide

Cl

0.8 g (3.84 mmol) of 2,2,2-trifluoro-4'-chloroacetophenone, 1.02 g (4.6 mmol) of trimethylsulfoxonium iodide and 0.1 g (0.27 mmol) of cetyltrimethylammonium bromide are added in a mixture of 40 g. ml

Of 1,1,1-trichloroethane and 20 ml of 18% aqueous sodium hydroxide solution were stirred at 75 ° C for 2 hours. The mixture is allowed to cool, the organic layer is separated, and the residue is stirred in 90 ml of dimethylformamide for 1 hour at 90 DEG C. with 1 g (14.5 mmol) of 1,2,4-triazole and 2 g (14.5 mmol). ) of anhydrous potassium carbonate. The reaction mixture was allowed to cool, 100 ml of ethyl acetate and 50 ml of water were added, the aqueous layer was separated, the organic layer was extracted six more times with water (total 200 ml) and dried over magnesium sulphate and evaporated to give 104 mg of gummy residue. which was chromatographed on silica gel (230-400 mesh) using ethyl acetate as eluent. 84 mg (8%) of a colorless title compound are obtained which, after recrystallization from dichloromethane / hexane, yields 64 mg of colorless crystals, m.p. 117-118 ° C.

For C ^ HHgClF ^N ^O O requires C, 45.28; H, 3.09; N, 14.4. Found: C, 45.36; H, 3.06; N, 14.76.

Example

Preparation of 2- (2,4-dichlorophenyl) -1- (1H-1,2,4-triazol-1-yl) -3,3,3-trifluoropropan-2-ol

trimethylsulfoxoniumCl iodide, NaH, dimethylsulfoxide

Cl

CFG-C -CH ₂

0.36 g (9.05 mmol) of sodium hydride (60% dispersion in oil) was washed with distilled hexane, dried and stirred at room temperature with 1.99 g (9.05 mmol) of trimethylsulfoxonium iodide. 10 ml of dimethylsulfoxide are added dropwise over 5 minutes, the mixture is stirred until the foaming ceases (about 30 minutes), and a solution of 2 g (8.23 mmol) of 2 ', 4'-dichloro-2,2,2- Trifluoroacetophenone in 8 ml of dimethylsulfoxide and stirred at room temperature for 45 minutes. After addition of 50 ml of water and 100 ml of ether, the organic layer is separated, washed once with water, dried over magnesium sulphate and evaporated to a pale yellow liquid residue. 8 g was added to a mixture of 2 g (29 mmol) of 1,2,4-triazole and 4 g (29 mmol) of anhydrous potassium carbonate in 100 ml of dimethylformamide. The resulting mixture was heated at about 75 ° C for 18 hours. The reaction mixture was poured into a mixture of 500 ml of ethyl acetate and 200 ml of water. The organic layer was separated, washed with water (5 x 100 ml) and dried (MgSO 4) to give a pale yellow, oily residue which was chromatographed on silica gel (230-400 mesh) using ethyl acetate as eluent. Subsequent recrystallization from ethyl acetate gave 1.49 g (56%) of the title compound, mp 133.5-134.5 ° C.

Analysis: calculated for C, 40.49% C, 2.45% H, 12.88% N;

Found: C 40.58, H 2.58, N 12.96.

Example 3

This example illustrates pharmaceutical compositions for treating fungal infections.

(a) A capsule of parts by weight of the compound of Example 1 is granulated with 3 parts of corn starch and 22 parts of lactose, followed by an additional 3 parts of corn starch and 1 part of magnesium stearate. The mixture is regranulated and the hard gelatin capsules are filled with the granulate.

(b) Cream parts by weight of the compound of Example 1 were dissolved in 10 parts propylene glycol and blended with 88 parts fast-absorbing cream base.

(c) The pessary parts by weight of the compound of Example 2 are suspended in 98 parts of a warm liquid suppository base, the mixture is poured into molds and allowed to solidify.

The following preparation illustrates the production of a new starting material,

Ex, right

Preparation of 2 ', 4'-dichloro-2,2,2-trifluoroacetophenone.

Cl + Mg -

Cl

Cl (c ^ co ^ o)

C = O

Cl

To a solution of 24 g (0.114 mol) trifluoroacetic anhydride in 20 ml of ether at -78 ° C is added a solution of 2,4-dichlorophenylmagnesium iodide prepared from 27.3 g (0.1 mol) 2,4-dichloroiodobenzene and 3, 3 g (0.138 mol) of magnesium in 50 ml of ether. Stirring was continued at -78 ° C for 10 minutes, then the mixture was allowed to warm to room temperature over 4 hours, stirred at this temperature for an additional 18 hours, then refluxed for 3 hours. The mixture was cooled, concentrated hydrochloric acid (25 ml) and ice-water (125 ml) were added, the ether layer was separated and the aqueous layer was washed four more times with ether (200 ml total). The combined electrical extracts were washed successively with aqueous sodium bisulfite solution, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and distilled to give a pale yellow liquid which solidified on standing to give 14.2 g (58%) of the title compound. in the title, with the following physical constants:

boiling point 46 ° C / 27 Pa mp 38 ° C m / e = 242

In the above test, the following ΡΒ ^ θ values (oral administration to mice against Candida albicans) were found:

Test substance PD ₅₀ (mg / kg, oral)

The product of Example I 0.3

A preferred compound is the product of Example 2.

The results of the anti-phytopathogenic activity tests carried out as described above are presented below. These results are given in minimum inhibitory concentration (MIC) values in µg / ml.

235337 ⁸

Experimental fungi are identified by capital letters with the following meanings:

A = Glomerella cingulata

B = Helminthosporium carbonum

C = Penicillium digitatum

D = Botrytis einerea

E = Pyricularia oryzae

The sign indicates that the test has not been performed in this case.

Test substance

Claims

A process for the preparation of triazole derivatives of the general formula I

OH

CH ₂ -C-CR ² I ³

R (I) wherein

R is phenyl optionally substituted with one to three substituents independently selected from fluoro, chloro, bromo and iodo and trifluoromethyl, and pharmaceutically acceptable salts thereof, characterized in that 1,2,4-triazole or its alkali metal salt is reacted with a compound of formula (II)

CLJ-C-CH ₂ (II) wherein

2. The process of claim 1 wherein the reaction is carried out either using 1,2,4-triazole in the presence of a base or using the sodium salt of 1,2,4-triazole.

3. The process of claim 2 wherein the base is potassium carbonate.

4. A process according to any one of claims 1 to 3, wherein the corresponding starting materials are used to form compounds of formula I wherein R is 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2- fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,

2,5-difluorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5-difluorophenyl.