JPH0138785B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel triazole derivatives that have antifungal activity and are used in the treatment of fungal infections in animals, including humans. According to the invention, the following formula [In the above formula, R is a halophenyl group; R ¹ is -CN, -CSNH ₂ or -CONR ² R ³ , where (a) R ² is H or a C ₁ -C ₆ alkyl group, and R ³ is H, a C ₁ -C ₆ alkyl group, a benzyl group in which the benzene ring is substituted with a halogen, a phenethyl group in which the benzene ring is substituted with a halogen or a lower alkyl group, a halo-substituted phenyl group, -CH _{2 CF3} , adamantyl group, pyridylmethyl group, _C3 - _C7 cycloalkyl group, carbamoylmethyl group, ( _C2 - _C4 alkenyl)methyl group,
2-hydroxyethyl group, 2-(dimethylamino)
Ethyl group, 2-(methylthio)ethyl group, 2-(methylsulfinyl)ethyl group, 2-(methylsulfonyl)ethyl group or 2-(halofenoxy)
Is it an ethyl group; (b) R ² and R ³ together with the nitrogen atom to which they are bonded have the following formula:

【formula】 【formula】

【formula】

[expression] or

[Formula] (where R ⁴ is a (C ₁ -C ₄ alkyl)carbonyl group or a (C ₁ -C ₄ alkoxy)carbonyl group); (c) R ² is H or C ₁ - is a C ₄ alkyl group and R ³ is a C ₂ -C ₄ alkanoyl group or a halo-substituted benzoyl group; or (d) R ² and R ³ are both (C ₁ -C ₄ alkoxy)
carbonyl group; R ⁵ is H or CH ₃ ; and R ⁶ is H or CH ₃ ], and pharmaceutically acceptable salts thereof. The invention further comprises a compound of formula () or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
Pharmaceutical compositions are provided. Further according to the present invention there is provided a compound of formula () or a pharmaceutically acceptable salt thereof for use as a medicament, in particular for the treatment of fungal infections in humans. In one aspect R is preferably a phenyl group substituted with 1 to 3 substituents independently selected from F, Cl, Br and I, more preferably 1 or 2 substituents. R is preferably a 4-fluorophenyl group, 4-
Chlorphenyl group, 4-bromophenyl group, 4-
iodophenyl group, 2-chlorophenyl group, 2,
4-dichlorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2-
Fluoro-4-chlorophenyl group, 2-chloro-
They are a 4-fluorophenyl group, a 2,4,6-trifluorophenyl group, and a 4-bromo-2,5-difluorophenyl group. R is more preferably a 2,4-dichlorophenyl group, a 4-chlorophenyl group, or a 2,4-difluorophenyl group. R is most preferably a 2,4-dichlorophenyl group or a 2,4-difluorophenyl group. R ¹ is preferably -CN, _-CSNH2 , or
CONR ² R ³ where (a) R ² is H, CH ₃ or C ₂ H ₅ and R ³
is H, _C1 - _C6 alkyl group, p-chlorobenzyl group, p-chlorophenethyl group, p- _{methylphenethyl} group, _-CH2CF3 , 1-adamantyl group,
4-pyridylmethyl group, cyclopropyl group, carbamoylmethyl group, _-CH2.CH = _CH2 , 2-
Hydroxyethyl group, 2-(dimethylamino)
Ethyl group, 2-(methylthio)ethyl group, 2-
(methylsulfinylethyl) group, 2-(methylsulfonylethyl) group, p-chlorophenyl group, or 2-(p-chlorophenoxy)ethyl group; (b) R ² and R ³ are Together with the nitrogen atom, the following formula

【formula】

[expression] or

(c) R ² is H and R ³ is acetyl, propionyl or p-chlorobenzoyl; or (d) R ² and R ³ are both - COOCH ₃ . R ₁ is more preferably −CONH ₂ or −CONH
(C ₁ -C ₄ alkyl), most preferably -
CONH ₂ , −CONH・CH ₃ or −CONH・C ₂ H ₅
It is. Both R ⁵ and R ⁶ are preferably H. In the most preferred individual compounds, R is 2,
4-dichlorophenyl group or 2,4-difluorophenyl group; R ₁ is -CONH ₂ , -
CONHCH ₃ or -CONHC ₂ H ₅ ; R ⁵ and R ⁶ are H. In one aspect of the present invention, the following formula [In the formula, R is a halophenyl group; R ¹ is -CN or -CONR ² R ³ , where
^R2 is H or a _C1 - _C6 alkyl group, and
R ³ is H, C ₁ -C ₆ alkyl group, benzyl group whose benzene ring is substituted with halogen, -CH ₂ CF ₃ or adamantyl group, or R ² and R ³ are bonded together Together with the nitrogen atom, the following formula

【formula】 【formula】

【formula】 or

Compounds of _the formula and ^their _{pharmaceutically acceptable salts} are provided. In another aspect of the invention, the following formula [In the formula, R is a halophenyl group; R ¹ is CN or -CONR ² R ³ , where R ²
is H or a _C1 - _C6 alkyl group, and ^R3
is H, a C ₁ -C ₆ alkyl group, a benzyl group in which the benzene ring is substituted with a halogen, -CH ₂ CF ₃ or an adamantyl group, or R ² and
R ³ together with their bonding nitrogen atoms has the following formula:

【formula】 【formula】

【formula】 or

[Formula] represents a group in which R ⁴ is a (C ₁ -C ₄ alkyl) carbonyl group or a (C ₁ -C ₄ alkoxy) carbonyl group, and R ⁵ is H or CH ₃ ]. Compounds and their pharmaceutically acceptable salts are provided. In still another aspect of the present invention, the following formula [In the formula, R is a halophenyl group, R ⁵ and R ⁶ are H or CH ₃ independently of each other, (a) R ² is H or a C ₁ -C ₄ alkyl group, and R ³
is a C ₂ -C ₄ alkanoyl group or a halo-substituted benzoyl group; or (b) R ² and R ³ are both (C ₁ -C ₄ alkoxy)carbonyl groups], and their pharmaceutical Acceptable salts are provided. When a compound of formula () has at least one asymmetric center, the present invention includes both resolved and unresolved forms. The present invention is based on the following formula Also included are novel intermediates of the formula (wherein R, R ⁵ and R ⁶ are as defined above for formula ()). Other useful intermediates are (wherein R is defined with respect to formula ()). The compound of formula () can be produced as follows. (1) A compound in which R ¹ is -CN and R ⁵ and R ⁶ are H can be produced by the following general formula. Preferred sources of cyanide ions are alkali metal cyanides, especially sodium and potassium cyanide. In a typical method, compound () and sodium or potassium cyanide are heated in a suitable organic solvent (e.g. dimethylformamide) to 100°C, preferably 65-70°C.
℃ for up to 6 hours, for example. Cyanide is added dropwise to the solution of oxirane, for example over 1/2 hour. Cool the reaction mixture;
After injection into water, the desired product can be isolated and purified by conventional methods. The starting materials of formula () are often known compounds (e.g. European Patent Application Publication No. 44605).
(see IC) or by conventional methods likely to be known to those skilled in the art, for example as described below. (2) R ¹ is -CN, R ⁵ and R ⁶ are each H
or CH ₃ can be prepared by the general route described below. A preferred strong base is n-butyllithium. In a typical procedure, the nitrile is dissolved in a suitable solvent, such as dry tetrahydrofuran (THF), and the resulting solution is dissolved in about -
Cool to 70°C. Then n-butyllithium in hexane is slowly added dropwise. After stirring at -70℃ for about 1 hour, add a suitable solvent such as dry
Gradually add the ketone () in THF dropwise. -70
After stirring for about 1 hour at 0.degree. C., a small amount of glacial acetic acid in THF is added and the reaction mixture is allowed to warm to 0.degree. The product can then be isolated and purified by conventional methods. One of R ⁵ and R ⁶ is H,
When the other is _CH3 , the product exists in two diastereomeric forms, which can often be separated by chromatography (Example 34
reference). Is the starting material in formula () a known substance?
Alternatively, it can be produced by a conventional method (see, for example, Production Examples 3(i) and 4(B)). (3) A compound in which R ¹ is -CONH ₂ and R ⁵ and R ⁶ are H can be produced by the following method. Preferably the compound () is used in the form of its ethyl ester. The acid is preferably provided by using the compound () in the form of an acid addition salt, for example as a dihydrochloride. Alternatively, the free base can be used and hydrogen chloride gas bubbled through the solution. Generally, the reactants are heated together for a short period under reflux, preferably in a suitable high-boiling organic solvent such as 1,2-dichlorobenzene (boiling point 178 DEG). In this case, the reaction usually completes in about 15 minutes. The starting material of formula () can be obtained by conventional methods, for example as follows. (4) R ¹ is −CONH (C ₁ −C ₄ alkyl) or −
Compounds that are CON( _C1 - _C4 alkyl) ₂ can be prepared by alkylation of the corresponding starting materials where _R1 is _-CONH2 . Alkylation is generally carried out by dissolving the starting material in a suitable organic solvent, such as dry THF, and then cooling to 0-5°C. A strong base, such as sodium hydride, is then added. After stirring for several minutes, add the appropriate amount of alkylating agent. Preferred alkylating agents are alkali metal iodides and bromides. For monoalkylation only 1 equivalent of alkylating agent should be used and for dialkylation at least 2 equivalents. The alkylated product can be isolated from the reaction mixture using conventional methods. (5) R ¹ is −CONR ² R ³ (where R ² and R ³ are defined in (a) or (b) of formula ())
Compounds can also be produced as follows. Compound ( ) is preferably in its "functionally equivalent to the acylating agent" form, such as the acid chloride or bromide, or as a _C1 - _C4 alkyl, succinimide, phthalimide or benzodriazol-1-yl ester. All of these "functionally equivalents" can be prepared from acids () by conventional methods. Acid chlorides and bromides can be prepared, for example, by reacting the acid with thionyl chloride or thionyl bromide, mixed acid anhydrides by reaction with C ₂ -C ₅ alkanoyl chlorides, and C ₁ -C ₄ alkyl esters by simple reaction. By esterification, succinimide-, phthalimide- and benzotriazol-1-yl esters can also be prepared by reacting with N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole in the presence of a dehydrating agent such as dicyclohexycarbodiimide. Can be manufactured. In fact, the compound () is represented by the following formula It is preferred to use them in the form of their succinimide esters. For example, in a typical method, dicyclohexylcarbodiimide, eg, dissolved in dry dioxane, is added to a solution of acid () and N-hydroxysuccinimide, eg, in dry dioxane. After stirring for several hours at room temperature, the reaction is generally terminated by stirring a solution of compound () with the amine R ² R ³ NH for several hours at room temperature, for example in dry dioxane, and the product is then purified in the usual manner. It can be isolated and purified by When compound () is reacted in its free acid form, the reaction should generally be carried out in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide. _C1 - _C4 alkyl esters can also be produced as follows. Generally, some of the products () are cyclized in situ under the reaction conditions to form the intermediate lactone (A). Ester () and lactone (A) can be separated by chromatography. Benzotriazol-1-yl ester has the structure of the following formula. These can be produced as described above. For example, in a typical method, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, and acid () are stirred together in dry dioxane for a short period of time at room temperature. The reaction generally converts the resulting intermediate () into an amine
The reaction is terminated by stirring with R ² R ³ NH at room temperature until completion, after which the product can be isolated and purified by conventional methods. (6) The compound of formula () in which R ¹ is −CONH ₂ is
They can be prepared by controlled hydrolysis of the corresponding compounds in which R ¹ is -CN. Generally, this hydrolysis is carried out on the starting nitrile, for example at 70-100°C, preferably at 90-95°C, in aqueous sulfuric acid (preferably at
%) and heating until completion of amide formation as monitored by TLC. Furthermore, if desired, hydrolysis to convert _-CONH2 to -COOH can be carried out under similar conditions. Compounds in which R ¹ is -COOH are useful intermediates [see route (5) above]. (7) Amides of formula () in which R ¹ is −CONR ² R ³ , where R ² and R ³ are as defined in (a) or (b) with respect to formula ()) It can be produced from the intermediate of A) as follows. In these formulas, R, R ⁵ and R ⁶ are as defined with respect to formula (), and R ² and R ³ are as defined in (a) or (b) of formula (). The reaction can be carried out by stirring the reactants together in a suitable solvent such as ethanol at room temperature until the reaction is complete. If necessary, the reaction mixture can also be heated to accelerate the reaction. The product can be isolated and purified by conventional methods. (8) R ² is H or a C ₁ -C ₄ alkyl group, and R ³
is a _C2 - _C4 alkanoyl group or the above-mentioned optionally substituted benzoyl group, the compound of formula () is represented by the following formula: (wherein R ² is as defined earlier in this method and R, R ^{5 and} R ⁶ are as defined with respect to ^formula ) ₂ O (wherein R ³ is as previously defined in this process and X is Cl or Br) with an acid halide or acid anhydride. When using acid halides, the reaction is performed with a base,
For example, it is desirable to carry out the reaction in the presence of pyridine or sodium hydride. The reaction is generally carried out in a suitable organic solvent such as acetonitrile or tetrahydrofuran. Generally, there is no need to accelerate the reaction by heating, and the product is isolated and purified by conventional methods. (9) The compound of formula () in which R ² and R ³ are both (C ₁ -C ₄ alkoxy) carbonyl groups has the following formula: At least 2 equivalents of a compound of the formula It can be produced by reacting with an alkyl haloformate (wherein X is Cl or Br). This reaction can be carried out in a manner similar to route (8) above, and the presence of a base is also desirable in this case. (10) Compounds in which R ³ is a 2-(methylsulfinyl)ethyl group or a 2-(methylsulfonyl)ethyl group can be prepared using a conventional method using an appropriate amount of m-chloroperbenzoic acid. It can be produced by oxidizing a methylthio)ethyl compound. (11) A compound in which R ¹ is -CSNH ₂ can be produced by the following method. This reaction is generally carried out by heating the reactants to about 100° C. in the presence of water.
The product is then isolated using conventional methods. (12) A compound in which R ¹ is -CONH ₂ and R ⁵ and R ⁶ are H can also be produced by the following method. This reaction generally involves bis(trimethylsilyl)
This is carried out by stirring the acetamide in dry tetrahydrofuran (THF) at -70°C while slowly adding n-butyllithium dropwise.
The resulting solution is stirred briefly at about -70°C, then the ketone (), for example in THF, is slowly added and the resulting mixture is stirred at about -70°C for several hours. The reaction mixture is then warmed to room temperature and aqueous acid is added. The product can then be isolated and purified by conventional methods. (13) A compound in which R ² and R ³ together with the nitrogen atom to which they are bonded represents an aziridinyl group can be produced as follows. This reaction is generally carried out in dry tetrahydrofuran at room temperature. (14) The intermediate lactone of formula (A) can be prepared by cyclization according to the reaction scheme below, preferably using an ester. In the above formula, Q is a _C1 - _C4 alkyl group, a phthalimide group, a succinimide group, or a 1-benzotriazolyl group. These esters can be produced as described above.
Cyclization can be carried out by stirring at room temperature in the presence of a suitable base. Preferred bases are tertiary amine bases such as triethylamine, and alkali metal hydrides such as sodium hydride. The compounds of the invention contain one or more asymmetric centers, and the invention includes both resolved and unresolved centers. Pharmaceutically acceptable acid addition salts of compounds of formula () are those formed from strong acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid and methanesulfonic acid, which form non-toxic acid addition salts. . The salts are obtained in conventional manner, for example by mixing a solution containing equimolar amounts of the free base and the desired acid, and the required salt is recovered by filtration if insoluble or by evaporation of the solvent. Also included are alkali metal salts that can be produced by conventional methods. Compounds of formula () and their pharmaceutically acceptable salts are antifungal agents and are useful in combating fungal infections in animals, including humans. For example, these are particularly common in humans, including Candida spp.
Local fungal infections caused by Trichophyton, Microsporum or Epidermophyton species or mucosal infections caused by C. albicans (e.g. oral candidiasis and vaginal candidiasis). It is useful in the treatment of symptoms. These are for example Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidiodes, Paracoccidioides, Histoplasma or Blastomyces. ) can also be used to treat systemic fungal infections caused by In vitro evaluation of the antifungal activity of the compounds can be performed by measuring the minimum inhibitory concentration (mic). This is the concentration of the test compound at which growth of the microorganism does not occur in a suitable medium. In practice, a series of agar plates, each containing a particular concentration of the test compound, are inoculated with, for example, a standard culture of Candida albicans, and each plate is then incubated for 48 hours at 37°C. The plates are then inspected for the presence of fungal growth and the appropriate mic values are recorded. Other microorganisms used in this type of test include Cryptococcus neoformans, Aspergillus fumigatus, and Trichophyton.
spp., Microsporum spp., E. floccosum, C. immitis, and Torulopsis. In vivo evaluation of the compounds can be performed by intraperitoneal or intravenous injection at a series of dose levels or by oral administration to mice inoculated with a strain of Candida albicans. Specifically, Candida albicans was surface cultured on Saboraud dextrose agar plates overnight at 37°C.
A Candida albicans inoculum is prepared by washing the Y0102 strain. Approximately 0.2ml of inoculum
Dilute the cell suspension to contain 10 ⁷ cells.
The cell suspension is injected through the tail vein of Tuck albino mice (5 mice for each dose concentration). Test compounds are dissolved in a suitable lysing agent in phosphate buffer, pH 7, and administered orally to infected mice at 1, 4 and 24 hours post-infection. Each compound is 10, 5, 1.0, 0.5 and 0.1
Administer at a dosage concentration of mg/Kg (which may be higher or lower as appropriate). Mice in the untreated control group die within 48 hours. The dose concentration that protects half of the group from the lethal effects of infection (PD ₅₀ ) is calculated by statistical interpolation from the number of survivors on day 2 post infection at each dose concentration.
More effective compounds have lower _PD50 values. Although antifungal compounds of formula () can be administered alone for human use, they are generally administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Will. in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or mixed with excipients;
Alternatively, they can be administered orally in the form of an elixir or suspension containing flavoring or coloring agents. They can also be injected parenterally, intravenously, intramuscularly or subcutaneously. For parenteral administration, it is best to use them in the form of sterile solutions, even if they contain other substances, such as sufficient salt or glucose to make the solution isotonic with the blood. good. For oral and parenteral administration to patients, the daily dose level of the antifungal compound of formula () is between 0.1 and 5 mg/Kg, whether administered by the oral or parenteral route. (in divided doses)
Will. A tablet or capsule of the present compound will thus contain from 5 mg to 0.5 g of active compound for one or more administrations at a time, as appropriate. The physician in any event will determine the actual dose likely to be optimal for an individual patient, which will vary depending on the age, weight, and response of that patient. The above dosages are exemplary of the average case, and there may, of course, be individual cases where higher or lower dosage ranges may be beneficial. These are also within the scope of this invention. Alternatively, antifungal compounds of formula () can be administered in the form of suppositories or pessaries, or they can be applied topically in the form of lotions, solutions, creams, ointments or powders.
For example, they can be included in creams consisting of aqueous emulsions of polyethylene glycols or liquid paraffin. Alternatively, they may be included in concentrations of 1 to 10% in a white wax or soft wax base and any necessary stabilizers and preservatives. The following examples illustrate the invention, and all temperatures are in °C. Example 1 1-cyano-2-(2,4-dichlorophenyl)
-3-(1H-1,2,4-triazole-1-
Production of propan-2-ol 2-(2,
4-dichlorophenyl)-2-(1H-1,2,4
-triazol-1-ylmethyl)oxirane (6.7 g) at 60° was added dropwise over 25 minutes with sodium cyanide (2.84 g) in water (49 ml).
Heating at 60° was continued for 5 hours. The reaction mixture was then cooled, poured into water (900 ml) and diluted with ethyl acetate (3
x 150 ml). The combined organic extracts were washed with saturated aqueous brine, dried (Na ₂ SO ₄ ) and
Evaporation to dryness gave a pale yellow solid (6.1 g). This was triturated with ether and the remaining solid was recrystallized from ether/methanol to give the title compound. 4.13g (56%), melting point 217-219°. Elemental analysis (%): Actual value C, 48.3; H, 3.4; N, 18.4 Theoretical value C, 48.5; H, 3.4; N, _{18.8 C12H10Cl2N4O} : Example 2 ₁ -cyano _- 2 -(2,4-dichlorophenyl)
-3-(1H-1,2,4-triazole-1-
Production of propan-2-ol Acetonitrile (2.25 g, 1.1 eq.) was dissolved in dry tetrahydrofuran (100 ml) and the resulting solution was cooled to -70° in a CO ₂ /acetone bath under nitrogen. A solution of n-butyllithium in hexane (39 ml, 1.55 M, 1.2 eq.) was added dropwise over 5 minutes. After stirring at -70° for about 45 minutes, 2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)acetophenone (12.8 g) in dry tetrahydrofuran (100 ml) was added to Added dropwise over a period of minutes. Stirring was continued at -70° for about an hour, then glacial acetic acid (20ml) in tetrahydrofuran (20ml) was added dropwise. The cooling bath was then removed. The reaction mixture was warmed to 0°C, quenched in water (400ml) and solid sodium carbonate was added to bring the pH to 8.0.
increased to After extraction with ethyl acetate (3 x 7.5.ml), the organic extracts were combined and washed with saturated brine (3 x
50ml), dried (Na ₂ SO ₄ ) and evaporated to give a pale yellow solid. This solid was thoroughly washed with ether to give the title compound (6.61 g, 44.5%). This was consistent with the product of Example 1, as confirmed by NMR and IR spectroscopy. Example 3 2',4'-difluoro-2- as starting ketone
1 in the same manner as in the above example using (1H-1,2,4-triazol-1-yl)acetophenone.
-Cyano-2-(2,4-difluorophenyl)-
3-(1H-1,2,4-triazol-1-yl)propan-2-ol was produced. this is
It had a melting point of 154-155°. Elemental analysis (%): Actual value C, 54.0; H, 3.8; N, 21.5 Theoretical value C, 54.6; H, 3.8; N, _{21.2 C12H10F2N4O} : Example _{4 1} -carbamoyl-2 -Production of (2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 3-(2,4-dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazole-1
-yl) butyrimidic acid ethyl ester dihydrochloride (3.42 g) was added to 1,2-dichlorobenzene (35
ml) and the reaction mixture was heated to the reflux temperature of the solvent (178°). A solution was obtained after refluxing for 5 minutes. Refluxing was then continued for an additional 10 minutes. The reaction mixture was then cooled, evaporated and the resulting gum was triturated with hexane and heated with acetone. On cooling a cream colored granular solid formed which was separated to give the title compound as a solvate (1.26g). When left in the refrigerator overnight, some additional solvate precipitated (0.62
g). After drying at 80° C. for 6 hours and removing the solvent, the pure title compound was obtained. Yield 1.5g,
Melting point 144-145°. Elemental analysis (%) (after drying as above): Actual value C, 45.5; H, 3.8; N, 17.5 Theoretical value C, 45.7; H, 3.8; N, 17.8 C ₁₂ H ₁₂ Cl ₂ N ₄ O ₂ : Implementation Example 5 2-(2,4-dichlorophenyl)-1-(N-
Methylcarbamoyl)-3-(1H-1,2,4
-Production of triazol-1-yl)propan-2-ol 1-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g) was dissolved in dry tetrahydrofuran (20 ml), The reaction mixture was cooled to 0-5°. Tonalium hydride (0.15 g, as a 50% dispersion in oil) was then added and stirred for 10 minutes before adding methyl iodide (0.45 g).
was added. Additional amounts of methyl iodide (90 mg) and sodium hydride (375 mg, as a 50% dispersion in oil) were added. After stirring for several minutes additional amounts of methyl iodide (90 mg) and sodium hydride (375 mg as a 50% dispersion in oil) were added. The mixture was then quenched in water and extracted with ethyl acetate (3x50ml). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give the crude product as a gum. A solution of this gum in methylene chloride (20 ml) was prepared as “Kieselgel”.
Methylene chloride (100 ml), followed by 2% by volume isopropanol and 0.2% by volume NH ₄ OH (300 ml) on a column (10 g) of 60H" (Merck & Co., trade name).
and finally methylene chloride containing 5% by volume isopropanol and 0.5% by volume NH ₄ OH (500 ml). Appropriate fractions were collected to yield the title compound. This was recrystallized from cyclohexane (yield 41 mg, melting point 151-154°) Elemental analysis (%): Actual value C, 47.3; H, 4.35; N, 17.2 Theoretical value C, 47.4; H, 4.3; N, 17.0 _{C13H14Cl2N4O2} : Example 6 2-(2,4 _- dichlorophenyl)-1-( _{morpholinocarbonyl} )-3- ₍ 1H- _1,2,4-
Production of triazol-1-yl)propan-2-ol monohydrate N,N′− dissolved in dry dioxane (5 ml)
Dicyclohexylcarbodiimide (“DCCD”)
(110 mg, 0.5 mmol) in dry dioxane (10 ml)
1-carboxy-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (150 mg, 0.5
mmol) and N-hydroxysuccinimide (“NHS”) (60 mg, 0.5 mmol) and the mixture was stirred at room temperature for 2 hours. The precipitate was separated and washed with dry dioxane (10 ml), then the combined liquid and washings were added to a solution of morpholine (300 mg, 3.4 mmol) in dry dioxane (2 ml). The resulting solution was left at room temperature for 18 hours, diluted with ethyl acetate (100ml), washed three times with saturated brine solution and dried over magnesium sulphate.
Evaporation of the liquid gave an oil (300 mg). This was then added to “Kieselgel 60H” (Merck & Co., trade name).
2% by volume isopropyl alcohol and 0.2% by volume ammonium hydroxide (specific gravity) on silica (10 g)
0.880) with CH ₂ Cl ₂ . After evaporation of the appropriate fractions the title compound was obtained as a colorless solid, 110 mg (57%). Melting point 92-93°. Elemental analysis (%): Actual value C, 47.8; H, 4.7; N, 13.9 Theoretical value C, 47.8; H, 5.0; N, 13.9 C ₁₆ H ₁₈ N ₄ Cl ₂ O ₃ H ₂ O: Example 7 ~32 Same acid, DCCD/
Starting from NHS and the appropriate amine, the following compounds were prepared.

【table】

【table】

[Table] Example 33 1-carboxy-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol, "DCCD",
Starting from "NHS" and methylamine, the following compound was prepared in the same manner as in Example 6. It had a melting point of 129-131°. Elemental analysis (%): Actual value C, 52.8; H, 4.9; N, 19.3 Theoretical value C, 52.7; H, 4.8; N, 18.9 C ₁₃ H ₁₄ F ₂ N ₄ O ₂ : Example 34 3-cyano- 2-(2,4-dichlorophenyl)
-1-(1H-1,2,4-triazole-1-
Production of yl)butan-2-ol (two diastereomeric forms) Propionitrile (1.21 g) in dry tetrahydrofuran (50 ml) was cooled to -72°. Then a solution of n-butyllithium in n-hexane (14.2
ml, 1.55M) was added gradually while maintaining the temperature of the reaction mixture below -45°. 2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroacetophenone (2.56 g) in dry tetrahydrofuran (THF) (50 ml) after stirring for approximately 30 minutes.
was added gradually over 20 minutes under stirring. The temperature of the mixture was maintained at -70°. Continue stirring at this temperature for 1 hour, then at -10° for 1/2 hour, at which point glacial acetic acid (10
ml) was added. The reaction mixture was then brought to room temperature (20°).
PH8 with solid sodium bicarbonate.
The mixture was made basic and extracted with ethyl acetate (3 x 75ml). The combined organic extracts were washed three times with water, dried (MgSO ₄ ), evaporated and the residue was dissolved in ether (30
ml) was added to give a white crystalline solid and a yellow solution. Separate the solid, dissolve it in a small amount of methylene chloride, and add Merck's "Kieselgel 60" (trade name) 230~
Loaded onto a 400 mesh silica (in ether) flash chromatography column (18 g). Elution was performed with 5% by volume acetone in ether at 1 p.si. "Diastereomer 1" of the title compound eluted first. 0.79g, melting point
178~180°. Elemental analysis (%): Actual value C, 50.0; H, 3.8; N, 17.9 Theoretical value _C , _50.2 ; H, _3.9 ; N, _18.0 Mar 2”
was eluted. 0.244g, melting point 202-205°. Elemental analysis (%): Actual value C, 50.4; H, 3.9; N, 17.6 Theoretical value C, 50.2; H, 3.9; N, 18.0 C ₁₃ H ₁₂ Cl ₂ N ₄ O: Examples 35 and 36 Appropriate acetophenone , n-BuLi/C ₂ H ₅ CN
Starting from and glacial acetic acid, the following compounds were prepared analogously to the above examples.

[Alternative method to (B) above]

4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H
A solution of -1,2,4-triazol-1-yl-methyl)-β-propiolactone (70 mg) was treated with ammonia (6 ml) having a specific gravity of 0.88 and left at room temperature for 5 days. The reaction mixture was then evaporated in vacuo, extracted and chromatographed as described in (B) above to give the title compound. Melting point 162-163°. 41 mg. Elemental analysis (%): Actual value C, 48.6; H, 4.7; N, 15.9 Theoretical value C, 49.0; H, 4.7; N, _{16.3 C14H16Cl2N4O2} : Example _{42 2-} ( ₂ ,4-dichlorophenyl)-3-methyl-3-(N-methylcarbamoyl)-1-(1H-
Production of 1,2,4-triazol-1-yl)butan-2-ol 4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H-1,
2,4-triazol-1-yl-methyl)-β
- A solution of propiolactone (200 mg) was treated with a 35% by volume solution of methylamine in ethanol (5 ml) and the resulting solution was left at room temperature (20°) overnight.
After evaporating the remaining methylamine and ethanol, the residue was triturated with hexane and the resulting solid was recrystallized from ethyl acetate/hexane to give the title compound. Melting point 145-146°. 120mg. Elemental analysis (%): Actual value C, 50.2; H, 5.0; N, 15.9 Theoretical value C, 50.4; H, 5.0; N, 15.7 C ₁₅ H ₁₈ Cl ₂ N ₄ O ₂ : Example 43 (A) 4 -(2,4-dichlorophenyl)-4-(1H
-1,2,4-triazol-1-yl-methyl)-β-propiolactone production 3-carboxy-2- in dioxane (20 ml)
(2,4-dichlorophenyl)-1-(1H-1,
2,4-triazol-1-yl)butane-2
-ol (948 mg) was dissolved, then 1-hydroxybenzotriazole hydrate (0.61 g),
followed by dicyclohexylcarbodiimide (1.85
g) was added. The resulting mixture was kept at room temperature (20
C) for 2 hours, at which point triethylamine (455 mg) was added and stirring continued overnight (19 hours). The mixture was then added to water (100ml) and extracted with ethyl acetate (3x50ml). The dicyclohexylurea precipitate was separated after the first extraction. The combined organic extracts were washed with water, dried (MgSO ₄ ) and evaporated. The obtained residue was dissolved in a small amount of methylene chloride, and Merck's "Kieselgel 60" (trade name) silica (12 g, 230 ~
400 mesh) on a flash column (in ether). Elute with ether (100ml),
The title compound was then obtained after elution with 5% by volume acetone in ether and collection of the appropriate fractions. 600mg, melting point 178-180°. Elemental analysis (%): Actual value C, 48.1; H, 3.0; N, 14.0 Theoretical value C, 48.4; H, 3.0; N, 14.1 C ₁₂ H ₉ Cl ₂ N ₃ O ₂ : (B) 3-(N -methylcarbamoyl)-2-(2,
4-dichlorophenyl)-1H-(1,2,4-
Production of triazol-1-yl)propan-2-ol This reaction was carried out in the same manner as in Example 42 using the starting materials shown in the above reaction formula to obtain the title compound. This was confirmed by spectroscopic analysis to be the desired product and to be identical to the product of Example 5. Example 44 3-carbamoyl-2-(2,4-dichlorophenyl)-1H-(1,2,4-triazole-
Production of 1-yl)propan-2-ol This reaction was carried out in the same manner as in Example 41(C) using the starting materials shown in the reaction formula above to obtain the title compound. This was confirmed by spectroscopic analysis to be the desired product and to be identical to the product of Example 4. Example 45 3-(N-acetylcarbamoyl)-2-(2,
4-dichlorophenyl)-1-(1H-1,2,
4-triazol-1-yl)propane-2-
Production of all-1/2 hydrate A solution of acetyl chloride (0.12 g, 1.5 mmol) in dry acetonitrile (2 ml) was prepared at -20° as a solution of 3-carbamoyl-2- in dry acetonitrile (2 ml).
(2,4-dichlorophenyl)-1-(1H-1,
2,4-triazol-1-yl)propane-2
-ol (0.314 g, 1 mmol) and pyridine (0.12 g, 1.5 mmol) dropwise under stirring. The solution was allowed to warm up to room temperature and stirred for an additional 18 hours at room temperature. The solvent was then removed under reduced pressure and the residue partitioned between water (10ml) and chloroform (40ml). The organic phase was separated, dried over _MgSO4 and evaporated. The residue was chromatographed on silica eluting with chloroform/methanol 10:1 (v/v), the fractions containing the product were combined and evaporated and recrystallized from diisopropyl ether to give the title compound. I got it. 67mg (19
%), melting point 148-150°. Elemental analysis (%): Actual value C, 45.8; H, 3.9; N, 15.0 Theoretical value C, 45.9; H, 4.1; N, 15.3 C ₁₄ H ₁₄ N ₄ O ₃ Cl ₂・1/2H ₂ O: Implementation Examples 46 and 47 Analogously to Example 45, starting from the same amide, pyridine and the appropriate acid chloride of formula R ³ Cl,
The following compounds were prepared.

[Table] Example 48 2-(2,4-dichlorophenyl)-3-(N,
N-dimethoxycarbonylcarbamoyl)-1
-Production of (1H-1,2,4-triazol-1-yl)propan-2-ol 3-Carbamoyl-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.94 g, 3
mmol) was added to a suspension of oil-free sodium hydride (0.14 g, 5.8 mmol) in dry tetrahydrofuran (10 ml). This suspension was stirred for 1 hour and then mixed with dry tetrahydrofuran (10 ml).
A solution of methyl chloroformate (0.6 g, 6.3 mmol) in solution was added dropwise over 15 minutes. The mixture was stirred at room temperature for 3 hours, then the solvent was evaporated in vacuo. The residue was dissolved in saturated aqueous sodium bicarbonate solution (10
ml) and ethyl acetate (40ml), the organic phase was separated, washed with brine (10ml), dried ( _MgSO4 ) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/methanol 95:5 (v:v), the fractions containing the product were combined, evaporated and recrystallized from ethyl acetate-hexane. The title compound was obtained. 62mg
(5%), melting point 155-156°. Elemental analysis (%): Actual value C, 44.5; H, 3.7; N, 13.2 Theoretical value C, 44.5; H, 3.7; N, 13.0 C ₁₆ H ₁₆ N ₄ O ₆ Cl ₂ : Example 49 1-carbamoyl- Production of 2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol Bis(trimethylsilyl)acetamide (1.99
g) was stirred at -70° in dry tetrahydrofuran (15ml) while n-butyllithium (6.3ml, 1.55M) in hexane was added dropwise over 10 minutes. The resulting solution was stirred at -70° for 30 min and then dissolved in 2-(1H) in dry tetrahydrofuran (10 ml).
-1,2,4-triazol-1-yl)-2',
A solution of 4'-dichloroacetophenone (1.0g)
It was added dropwise over 10 minutes and the mixture was stirred at -70° for 1/2 hour. The reaction mixture was then warmed to room temperature and water (5ml) and hydrochloric acid (7ml, 2N) were added. The mixture was then adjusted to pH 8 by the addition of solid sodium bicarbonate, then ethyl acetate (3 x 10
ml). The combined extracts were washed with saturated sodium chloride solution (3 x 10ml), dried ( _MgSO4 ) and evaporated to give a gum. 1.1g. This gum was chromatographed on silica ("Kieselgel 60", Merck & Co.), eluting with ether containing 5% by volume of ethanol. After eluting the unreacted ketone, the product was eluted and the fractions containing this material were combined and evaporated to give the pure title compound (0.21 g). This was confirmed by spectroscopic analysis to be identical to the product of Example 4. Example 50 Preparation of 1-carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-cyano-2-(2,4-dichlorophenyl)
-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0g) was added to sulfuric acid (10
ml, 80%) at 60° for 2 1/2 hours. The reaction mixture was then cooled to room temperature, treated carefully with water (100ml) and adjusted to PH9 with solid sodium hydroxide. The resulting solution was diluted with methylene chloride (3 x 50
ml) and the extracts were combined and evaporated to give a gum. This was mixed with silica (“Kieselgel 60”,
Merck & Co., Ltd.) eluting with methylene chloride containing methanol increasing from 3% to 6% by volume. Fractions containing product as determined by TLC were combined and evaporated to give 0.91 g of a white solid. This was dissolved in a mixture of acetone and methylene chloride at reflux temperature and the product was precipitated by addition of hexane to obtain fine crystals. Melting point 144-145.5°, 0.61g. This was confirmed to be identical to the product of Example 4 by spectroscopic analysis after drying under vacuum at 80° for 7 hours. Example 51 2-(2,4-dichlorophenyl)-1-{N-
Production of (2-[methylsulfinyl]ethyl)carbamoyl}-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 2-(2,4-dichlorophenyl)-1-{N-
2-[methylthio]ethyl)carbamoyl}-3-
(1H-1,2,4-triazol-1-yl)propan-2-ol (0.8 g) and m-chloroperbenzoic acid (85%, 0.35 g, 1 eq.) were dissolved in isopropanol and methylene chloride at room temperature. Stirred in the mixture (1:1, v/v, 40 ml) for 2 days. The solvent was then removed under reduced pressure and the residue was applied on silica (Merck "Kieselgel 60", 25 g).
Chromatography was carried out, eluting with a mixture of chloroform, methanol and ammonia (specific gravity 0.880) (160:20:5, v/v). The first eluting isomer fraction was obtained in pure form. 116mg,
Melting point 168-170°. Elemental analysis (%): Actual value C, 44.1; _H , 4.4 _; N, 13.5 Theoretical value C, 44.4; H, _4.5 ; N _{, 13.8} Eluted as a mixture (330 mg) containing stereomers. This material was used in the preparation of the sulfone described below. Example 52 2-(2,4-dichlorophenyl)-1-{N-
(2-[methylsulfonyl]ethyl)carbamoyl}-3-(1H-1,2,4-triazole-
Production of 1-yl)propan-2-ol An unresolved mixture of diastereomers (330 g) obtained in the above example and m-chloroperbenzoic acid (140 g)
mg) were stirred together in a mixture of isopropanol and methylene chloride (1:1, v/v, 20 ml) at 0°. After 1 hour at 0°, the reaction mixture was allowed to reach room temperature and stirred overnight. The solvent was then removed under reduced pressure and the residue was dissolved in ethyl acetate (50ml). The resulting solution was washed with saturated sodium bicarbonate solution (2 x 20 ml), then with saturated sodium chloride solution (2 x 20 ml), dried ( _MgSO4 ) and
Evaporation gave a gum. This was triturated with diisopropyl ether to give a white solid.
209 mg, melting point 123-124°. Elemental analysis (%): Actual value C, 42.6; H, 4.3; N, 13.2 Theoretical value C, 42.8; H, 4.3; N, 13.3 C ₁₅ H ₁₈ Cl ₂ N ₄ O ₄ S: Example 53 1-Azi Lysinylcarbonyl-2-(2,4-
dichlorophenyl)-3-(1H-1,2,4-
Production of triazol-1-yl)propan-2-ol 1-(N-[2-hydroxyethyl]carbamoyl)-2-(2,4-dichlorophenyl)-3-
(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g), triphenylphosphine (1.09 g) and diethyl azodicarboxylate (0.72 g) were dried at room temperature in tetrahydrofuran (20 ml). The mixture was stirred for 20 hours. The reaction mixture was then diluted with water (70ml) and diluted with ethyl acetate (3x
50ml). The combined organic extracts were washed with saturated sodium chloride solution (2 x 20ml), dried ( _MgSO4 ) and evaporated to give a brown gum.
This material was chromatographed on Merck "Kieselgel 60" silica, eluting with 5% ethanol by volume in ether to 10% ethanol in ether. The eluted material (which was a single compound as determined by TLC) was collected in ethyl acetate/
Crystallization from n-pentane gave colorless crystals of the title compound. 441 mg, melting point 151-153°. Elemental analysis (%): Actual value C, 49.2; H, 4.0; N, 16.3 Theoretical value _C , 49.3; H, 4.1; N, _{16.4 C14H14Cl2N4O2} : Example _{54 2-} (2 , 4-dichlorophenyl)-1-thiocarbamoyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 3-cyano-2-(2,4-dichlorophenyl)
-1H-1,2,4-triazol-1-yl)
A mixture of propan-2-ol (250 mg), 0,0-diethyl-dithiophosphoric acid (0.5 ml) and water (0.1 ml) was heated on a steam bath for 3 hours and evaporated under reduced pressure to an oil. “Merck 60H” (product name)
Chromatographed on silica (10 g) eluting with ethyl acetate. The eluted product was evaporated and triturated with petroleum ether (boiling point 40-60°) to give the title compound as a yellow solid (143 mg).
obtained as. Melting point 158-159°. Elemental analysis (%): Actual value C, 43.8; H, 3.6; N, 16.9 Theoretical value C, 4.36; H, 3.6; N, 16.9 C ₁₂ H ₁₂ Cl ₂ N ₄ OS: Example 55 1 shows a pharmaceutical composition for treatment. (a) Capsules: 71 parts by weight of the compound of Example 1 or 2, 3 parts of corn starch and 22 parts of lactose.
3 parts corn starch and 1 part magnesium stearate were added. The mixture was re-granulated and filled into hard gelatin capsules. (b) Cream: 2 parts by weight of the compound of Example 3 was dissolved in 10 parts of propylene glycol and mixed into 88 parts of vanishing cream base. (c) Vaginal suppository: 2 parts by weight of the compound of Example 5 was suspended in 98 parts of a heated and liquefied vaginal suppository, poured into a mold, and left to solidify. Example 56 Preparation of 1-carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol oxalate 1-carbamoyl-2 -(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (806 mg, 2
This amide compound contains exactly 1 equivalent of ethyl acetate according to the NMR spectrum, which was confirmed by elemental analysis of C, H and N) in ethyl acetate (25 ml). A solution of (180 mg, 2 mmol) in ethyl acetate (10 ml) was added. The reaction mixture was stirred at room temperature for 5 minutes and the solvent was removed under reduced pressure. The title compound was isolated as a glass, which was purified under high vacuum.
It was dried at 50° C. for 8 hours (yield: 800 mg). _Elemental analysis (%): Actual value C, 41.55; H, 3.7; N, 13.45 Theoretical value _C , 41.5; H, 3.5; N, _{13.8 C12H12Cl2N4O} : (COOH) ₂ : Production of the following The examples (all temperatures are in °C) describe the preparation of specific starting materials. Production Example 1 Production of 1-carboxy-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol 1-cyano-2-(2,4-dichlorophenyl)
-3-(1H-1,2,4-triazol-1-yl)-2-propanol (4 g, 13.9 mmol)
was dissolved in 40% aqueous sulfuric acid (100 ml) and incubated at 100% in an oil bath.
Heated to ~110° for 18 hours. The solution is then cooled and
It was diluted with water (200ml) and made alkaline by gradual addition of solid sodium bicarbonate. The mixture was then extracted several times with ethyl acetate (3x100ml) and the aqueous phase was made acidic (PH3) by addition of dilute orthophosphoric acid. The aqueous phase was then extracted with ether (3 x 150ml) and the combined ethereal extracts were washed once with water and then dried over magnesium sulfate. Evaporation of the ether gave the title compound as a pale yellow solid. 2.7g (62%), melting point
158-159°. Element frequency (%): Actual value C, 46.3; H, 3.5; N, 13.6 Theoretical value C, 45.6; H, 3.5; N, 13.3 C ₁₂ H ₁₁ Cl ₂ N ₃ O ₃ : Similarly, 1-carboxy- 2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol was also prepared. Melting point 185-187°. Elemental analysis (%): Actual value C, 50.8; H, 3.9; N, 14.8 Theoretical value C, 51.0; H, 3.9; N, 14.8 C ₁₂ H ₁₁ F ₂ N ₃ O ₃ : Production example 2 3-(2 ,4-dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazole-
Production of 1-yl)butyrimidic acid ethyl ester dihydrochloride 1-cyano-2-(2,4-dichlorophenyl)
-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1 g) was dissolved in dry ethyl alcohol (100 ml) and dry hydrogen chloride gas was blown into the solution at 0° for 10 minutes. The reaction mixture was then stirred at room temperature overnight before the solvent was decanted from the solids. The solid was then washed with dry ether and
After drying, the title compound (1.15 g, melting point 154 ~
156°) was obtained. The product was used in Example 4. Elemental analysis (%): Actual value C, 40.6; H, 4.4; N, 13.6 Theoretical value C, 40.4; H, 4.4; N, 13.5 C ₁₄ H ₁₆ Cl ₂ N ₄ O ₂・2HCl: Production example 3 (i ) 2-(1H-1,2,4-triazole-1-
yl)-2',4'-dichloroacetophenone (Y)
Preparation of this compound This compound was prepared analogously to the method described in GB 1512918. (ii) 2-(2,4-dichlorophenyl)-2-(1H
-Production of 1,2,4-triazol-1-ylmethyl)oxirane (Z) Sodium hydride (50% dispersion in oil) 3.78
g (0.079 mol) in 20 ml of dry ether with stirring.
suspended in. The ether was then removed by decantation and the sodium hydride was dried in a stream of dry nitrogen. dry dimethyl sulfoxide
100 ml and then 17.34 g (0.079 mol) of dry powdered trimethylsulfoxonium iodide
was added in small portions over 15 minutes. The resulting mixture was stirred at room temperature (20°) for 30 minutes. Then 18.33 g (0.072 mol) of compound (Y) was added as a solution in 50 ml of dry dimethyl sulfoxide. The mixture was heated to 60° for 3 hours and then left at room temperature overnight. The reaction mixture was cooled and quenched in ice. The product was then extracted into ethyl acetate (600ml). The ethyl acetate layer was separated, dried over magnesium sulfate, and concentrated to give a red gum. This gum was subjected to column chromatography on silica, eluting with ether to obtain the product (Z). Evaporation gave 6.62 g (34.4%) of the title compound (Z) as a gum, which solidified on trituration. The pure product melted at 57-59°. Elemental analysis (%): Actual value C, 48.6; H, 3.3; N, 15.3 Theoretical value C, 49.0; H, 3.4; N, 15.5 C ₁₁ H ₉ Cl ₂ N ₃ O: Production example 4 (A) 2- Production of chloro-2′,4′-difluoroacetophenone Chloracetyl chloride (113g, 1.0mol)
in 1,3-difluorobenzene (114 g, 1.0 mol) and anhydrous aluminum chloride (146.6 g,
1.1 mol) at room temperature (20°).
The mixture was stirred for a further 5 hours at 50-55°. Methylene chloride (48.5ml) was added slowly as the mixture was allowed to cool to room temperature. Separate the methylene chloride phase, wash with water (2 x 320 ml) and
The solvent was removed by distillation under reduced pressure, leaving a pale yellow solid (180g). A portion of the crude product (145 g) was crystallized from n-hexane (435 ml) to give the title compound (113
g, 73%). Melting point 47-49° (Reference: D. Ehlers, H. Berger and A. Griske,
According to J. Prakt.Chem., 315, 1169 (1973)
46.5°). IR (KBr) and NMR (CDCl ₃ ) were consistent with the desired structure. (B) 2',4'-difluoro-2-(1H-1,2,4
-Production of triazol-1-yl)acetophenone hydrochloride 1,2,4- in refluxing ethyl acetate (186 ml)
A mixture of triazole (30.4 g, 0.44 mol) and triethylamine (15.1 g, 0.15 mol) was added with 2-chloro-2',
A solution of 4'-difluoroacetophenone (38.1 g, 0.2 mole) was added. The mixture was refluxed for 6 hours, then cooled to room temperature and the insolubles were removed.
The liquid was washed with water (2 x 200ml) and the solvent was then removed by distillation under reduced pressure. The crude product was dissolved in ethyl acetate (150ml) and 25% (v/v) HCl gas in isopropanol was added.
The mixture was granulated at 0° for 1 hour, then the solid was removed and dried to yield the title compound (21.6 g, 40
%) was obtained. Melting point 167-170°. IR and NMR
(DMSO) matched the desired structure. This intermediate is the free base and was prepared by the method described below. Sodium bicarbonate (16.8 g, 0.2 mol) and 1,2,4-
A slurry of triazole (27.6 g, 0.4 mol) was dissolved in 2-chloro- in toluene (45 ml) with stirring.
2′,4′-difluoroacetophenone (38.1g,
0.2 mol) solution was added. The mixture was stirred under reflux for 3 hours and the water formed during the reaction was removed by a Dean-Stark trap. The reaction mixture was cooled to room temperature and then water (180ml) was added. The toluene layer was separated and the solvent was removed by distillation under reduced pressure. The resulting light brown solid was mixed with 1:1 ethyl acetate:n-hexane (70 ml).
The title compound (3.9 g, melting point
103-105°C). IR (KBr) and NMR
(CDCl ₃ ) matched the desired structure. Elemental analysis (%): Actual value C, 53.6; H, 3.15; _N , 18.7 Theoretical value C, 53.8; H, 3.2; N, _{18.8 C10H7F2N3O} : _4' -chloro-2-( Regarding 1H-1,2,4-triazol-1-yl)acetophenone, see DE 24 31 407. Activity data Oral PD ₅₀ value in mice (mg./Kg.) : - Product (Example number) PD ₅₀ (mg/Kg) 1 1.3 2 1.3 3 ~40 4 0.2 5 0.2 6 ~20 7 0.4 8 0.1 9 0.4 10 0.1 11 ~30 12 3.1 13 ~40 14 0.4 15 0.2 16 ~20 17 1.5 Product (Example number) PD ₅₀ (mg/Kg) 18 0.4 19 2.2 20 0.1 21 0.6 22 0.2 23 0.2 24 0 .4 25 3.5 26 2.2 27 4.2 28 4.2 29 4.2 30 0.1 31 3.1 32 0.2 33 0.3 34 0.1 35 2.0 36 10 Product (Example number) PD ₅₀ (mg/Kg) 37 0.4 38 0.4 39 0.5 40 0.2 41 3.1 42 0.6 43 0.2 44 0.2 45 0.1 46 0.1 47 0.1 48 ~0.3 49 0.2 50 0.2 51 (isomer that melts at 168-170°)
0.2 52 0.1 53 4.2 54 0.5 The following shows the results of an acute toxicity test ( _LD50 ) when the following compound of the present invention was orally administered to mice. Compound (Example number) LD ₅₀ (mg/Kg) 4 >750 5 403 10 >750 14 296

Claims (1)

[Claims] Primary formula: [In the formula, R is a halophenyl group; R ¹ is -CN,
−CSNH ₂ or −CONR ² R ³ , where (a)
^R2 is H or a _C1 - _C6 alkyl group, and
^R3 is H, a _C1 - _C6 alkyl group, a benzyl group in which the benzene ring is substituted with a halogen, a phenethyl group in which the benzene ring is substituted with a halogen or a lower alkyl group, a halo-substituted phenyl group, -
CH ₂ CF ₃ , adamantyl group, pyridylmethyl group,
_C3 - _C7 cycloalkyl group, carbamoylmethyl group, ( _C2 - _C4 alkenyl)methyl group, 2-hydroxyethyl group, 2-(dimethylamino)ethyl group,
2-(methylthio)ethyl group, 2-(methylsulfinyl)ethyl group, 2-(methylsulfonyl)ethyl group or 2-(halofenoxy)ethyl group; (b) R ² and R ³ are Together with the bonded nitrogen atom, the following formula, [Formula] [Formula] [Formula] [Formula] or [Formula] (where R ⁴ is a (C ₁ -C ₄ alkyl) carbonyl group or (C _{1 -C4alkoxy} )carbonyl group; (c)
^R2 is H or _C1 - _C4 alkyl group, ^R3 is _C2
-C ₄ alkanoyl or halo-substituted benzoyl; or (d) R ² and R ³ are both (C _1
-C4alkoxy )carbonyl group; ^R5 is H or _CH3 ; and ^R6 is H or _CH3 ] or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R is a phenyl group substituted with 1 to 3 substituents independently selected from F and Cl. 3 R is 2,4-dichlorophenyl group, 2,4-
The compound according to claim 2, which is a difluorophenyl group or a 4-chlorophenyl group. 4 R is 2,4-dichlorophenyl group or 2,
The compound according to claim 3, which is a 4-difluorophenyl group. 5 ^R1 is -CN ^, _-CSNH2 ^{or -CONR2R3} , where (a) ^R2 is H, _CH3 or _C2H5 , and _R3
is H, _C1 - _C6 alkyl group, p-chlorobenzyl group, p-chlorophenethyl group, p- _{methylphenethyl} group, _-CH2CF3 , 1-adamantyl group,
4-pyridylmethyl group, cyclopropyl group, carbamoylmethyl group, _-CH2CH = _CH2 , 2-hydroxyethyl group, 2-(dimethylamino)ethyl group, 2-(methylthio)ethyl group, 2-(methylsulfate) (b) R ² and R ³ are the nitrogen atoms to which they are bonded; (c) R ² is H and R ³ is an acetyl group, a propionyl group or a p-chlorobenzoyl group; or (d) ^R2 and ^R3 are both _-COOCH3 . Sixth order formula, [wherein R is a halophenyl group; and R ¹ is -CN, or -CONR ² R ³ , where R ² is H or a C ₁ -C ₆ alkyl group, and R ³ is H, C ₁ -C ₆ alkyl group, benzyl group in which the benzene ring is substituted with halogen, -CH ₂ CF ₃
or is an adamantyl group, or R ² and R ³ together with the nitrogen atom to which they are attached are of the following formula: [Formula] [Formula] [Formula ^] _2. A compound according to _{claim 1} , and _a pharmaceutically acceptable salt thereof. 7th equation, [wherein R is a halophenyl group; R ¹ is -CN, or -CONR ² R ³ , where R ² is H or a C ₁ -C ₆ alkyl group, and R ³ is H, C ₁ -C ₆ alkyl group, benzyl group whose benzene ring is substituted with halogen, -CH ₂ CF ₃
or an adamantyl group, or R ² and R ³ together with the nitrogen atom to which they are bonded form the following formula: [Formula] [Formula] [Formula ^] a _C1 - _C4 alkyl)carbonyl group or a ( _C1 - _C4 alkoxy)carbonyl group; and ^R5 is H or _CH3 ]. and pharmaceutically acceptable salts thereof. 8th equation, [wherein R is a halophenyl group; R ⁵ and R ⁶ are independently H or CH ₃ ; and (a) R ² is H or a C ₁ -C ₄ alkyl group; and R ³ is a C ₂ -C ₄ alkanoyl group or halo-substituted benzoyl group; or (b) R ² and R ³ are both (C ₁ -C ₄ alkoxy)carbonyl groups] and pharmaceutically acceptable salts thereof. 9. A compound of formula () according to any one of claims 1 to 7, wherein ^R1 is _-CONH2 or -CONH ( _C1 - _C4 alkyl group). 10 A compound of formula () according to any one of claims 1 to 5, 7 and 8, wherein R ⁵ and R ⁶ are H. 11 R is a 2,4-dichlorophenyl group or a 2,4-difluorophenyl group, R ⁵ and R ⁶ are H, and R ¹ is -CONH ₂ , -
A compound of formula () according to claim 1, which is CONH.CH ₃ or -CONHC ₂ H ₅ . 12th equation, [In the formula, R is a halophenyl group; R ¹ is -CN,
−CSNH ₂ or −CONR ² R ³ , where (a)
^R2 is H or a _C1 - _C6 alkyl group, and
^R3 is H, a _C1 - _C6 alkyl group, a benzyl group in which the benzene ring is substituted with a halogen, a phenethyl group in which the benzene ring is substituted with a halogen or a lower alkyl group, a halo-substituted phenyl group, -
CH ₂ CF ₃ , adamantyl group, pyridylmethyl group,
_C3 - _C7 cycloalkyl group, carbamoylmethyl group, ( _C2 - _C4 alkenyl)methyl group, 2-hydroxyethyl group, 2-(dimethylamino)ethyl group,
2-(methylthio)ethyl group, 2-(methylsulfinyl)ethyl group, 2-(methylsulfonyl)ethyl group or 2-(halofenoxy)ethyl group; (b) R ² and R ³ are Together with the bonded nitrogen atom, the following formula, [Formula] [Formula] [Formula] [Formula] or [Formula] (where R ⁴ is a (C ₁ -C ₄ alkyl) carbonyl group or (C _{1 -C4alkoxy} )carbonyl group; (c)
^R2 is H or _C1 - _C4 alkyl group, ^R3 is _C2
-C ₄ alkanoyl or halo-substituted benzoyl; or (d) R ² and R ³ are both (C _1
-C4alkoxy )carbonyl group; ^R5 is H or _CH3 ; and ^R6 is H or _CH3 ] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dilution thereof. An antifungal composition comprising an agent or carrier.