JPS6346075B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel bistriazole derivatives that have antifungal activity and are useful in the treatment of fungal infections in animals, including humans. According to the invention, the following formula (): (In the formula, R is F, Cl, Br, I,
is a phenyl group optionally substituted with 1 to 3 substituents selected from CF ₃ , C ₁ -C ₄ alkyl group and C ₁ -C ₄ alkoxy group, or R is 5
-chloropyrid-2-yl group; R ¹ is H or CH ₃ ), as well as their O
-esters, O-ethers and pharmaceutically acceptable salts. The alkyl group having 3 or 4 carbon atoms and the alkoxy group may be linear or branched. According to the invention there is also provided a pharmaceutical composition comprising a compound of formula () or an O-ester, O-ether or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Ru. The invention further provides compounds of formula () or their O-esters for use in medicine, in particular in the treatment of fungal infections in animals, including humans;
O-ethers or pharmaceutically acceptable salts are provided. When R is the above-mentioned optionally substituted phenyl group, it preferably has 1 to 3 substituents independently selected from F, Cl, Br, I and _CF3 , more preferably 1 or It is a phenyl group substituted with two substituents. Preferred individual groups represented by R include 4-fluorophenyl group, 4-chlorophenyl group, 4-bromphenyl group, 4-iodophenyl group, 4-trifluoromethylphenyl group, 2-chlorophenyl group,
2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-4-chlorophenyl group,
2,5-difluorophenyl group, 2,4,6-trifluorophenyl group, 4-bromo-2,5-difluorophenyl group and 5-chloro-pyrido-
It is a 2-yl group. The most preferred group represented by R is 2,4-difluorophenyl group, 2,4
-dichlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group and 5-chloro-pyrid-2-yl group. In the most preferred individual compounds, R ¹ is
CH ₃ and R is a 4-chlorophenyl group. Representative O-esters are _C2 - _C4 alkanoyl (eg acetyl) and benzoyl esters. The phenyl ring of the benzoyl ester may be substituted, for example by one or two _C1 - _C4 alkyl groups or a halogen atom. Common O-ethers are _C1 - _C4 alkyl, _C2 - _C4
alkenyl, phenyl-( _C1 - _C4 alkyl) and phenyl-ether. In this case too, the phenyl group may be substituted, for example by one or two _C1 - _C4 alkyl groups or halogen atoms. The compound of formula () can be produced by a conventional method according to the reaction formula below. In a common reaction, epoxide (),
The 1,2,4-triazole and anhydrous potassium carbonate are heated together in a suitable solvent (eg anhydrous dimethylformamide) until the reaction is complete (usually 2 to 16 hours), for example at 40-120°C. The product (2) is then isolated and purified by conventional methods. If base salts of 1,2,4-triazoles are used, they are preferably alkali metal salts. The starting material of formula () can be obtained by conventional methods, for example as follows. In the first step of the reaction scheme above, about 1 equivalent of sodium hydride and about 1 equivalent of methyl iodide should be used if monomethylation is desired, and at least 2 equivalents of each if dimethylation is desired. Equivalent amounts should be used. Dimethyloxosulfonium methylide can also be generated in situ using trimethylsulfoxonium iodide and sodium hydride or sodium hydroxide/cetrimide. If R is a phenyl group without ortho substituents, the cetrimide/NaOH route should be adopted. Ketones ( ) are known compounds (for example, Pushou Patent Application No. 0044605 or British Patent Application No. 2099818A) or can be prepared by methods analogous to those of the prior art. According to another aspect of the invention, the following formula (): (wherein X and X ¹ are each a leaving group, preferably Cl, Br or I, and R is as defined with respect to formula 1,
Provided is a method for producing a compound in which R ¹ is H in formula (), which comprises reacting with 2,4-triazole or with a basic salt (preferably an alkali metal salt) of 1,2,4-triazole. . Preferably X and X ¹ are the same, most preferably Br. Generally, compound (), 1,2,4-triazole and potassium carbonate are heated together in a suitable organic solvent (eg dimethylformamide) to, for example, 40 DEG to 120 DEG C. until the reaction is complete. The product can be isolated and purified by conventional methods. The starting material () can be obtained by a conventional method, for example, by the following formula. There is no need to isolate the intermediate (). This can be used as is. O-esters and O-ethers are prepared by conventional methods, generally by combining the alkali metal salt of compound () with a suitable chloro or bromine compound, such as an alkanoyl or benzoyl-chloride, or an alkyl, alkenyl, benzyl or phenyl-chloride or -bromide. It can be produced by reaction. Pharmaceutically acceptable acid addition salts of compounds of formula () are those prepared from strong acids such as hydrochloric, hydrobromic, sulfuric, oxalic and methanesulfonic acids which form non-toxic acid addition salts. be. These salts are recovered in conventional manner, for example by mixing a solution containing approximately equimolar amounts of free base and the desired acid, and filtration if the required salt is insoluble, or by evaporation of the solvent. It has been found that the compounds of the present invention have unexpectedly good activity against infections caused by clinically important Aspergillus bacteria. Compounds of formula () and their O-esters, O-ethers and pharmaceutically acceptable salts thereof are antifungal agents and are useful in combating fungal infections in animals, including humans. For example, these include localized fungal infections caused in humans by species of Candida, Trichophyton, Microsporum, or Epidermophyton, or Candida albicans (C.
albicans), such as oral and vaginal candidiasis. These include Candida albicans, Cryptococcus neofrmans, Asperginus
Systemic fungal infections caused by A.flavus, A.fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces. It can also be used for therapy. In vitro evaluation of the antibacterial activity of the present compounds can be performed by determining the minimum inhibitory concentration (mic) of the test compound that inhibits the growth of a particular microorganism in a suitable medium. In practice, a series of agar plates containing a specific 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 plate is then examined for the presence or absence of growth of the fungi, and the appropriate mic value is recorded. Other microorganisms used in this type of test include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp, Microsporum
spp, Epidermophyton flotscosum (E.
floccosum), Coccidioides immitis (C.
immitis) and Torulopsis glabrata. In vivo evaluation of this compound is performed as follows. That is, Candida albicans ( Candida albicans ) Y0102 strain was incubated overnight at 37°C on a Saboraud dextrose agar plate as a bacterium for inoculation.
It is prepared by washing out the bacteria from the surface of the medium after culturing it. This bacterial suspension was diluted to 0.2
An inoculum containing approximately 10 ⁷ bacteria per ml is obtained. For each dose of test compound, groups of 5 female Tuck albino mice receive 0.2 ml of the inoculum via the tail vein. The test compound is dissolved in a phosphate buffer with a pH of 7 along with an appropriate solubilizer and orally administered to the mice 1 hour, 4 hours and 24 hours after inoculating the mice with the bacteria. The dosage of each compound is 10, 5, 1.0, 0.5 and 0.1 mg/Kg, but may be increased or decreased if necessary. In this test, mice in the control group that do not receive the test compound die within 48 hours. For each dose of compound, the amount of compound that protects half of the mice from death due to infection with the inoculated bacteria (PD ₅₀ ) is statistically calculated from the number of surviving mice 2 days after inoculation. The smaller the PD ₅₀ value, the greater the effect of the compound. For human use, antifungal compounds of the formula () and their salts, O-ethers and O-
Although the ester can be administered alone, it will generally be administered in a mixture with a pharmaceutical carrier chosen with respect to the intended route of administration and standard means of formulation. For example, they may be in the form of tablets containing excipients such as starch or lactose, or in capsules or ouules, alone or mixed with excipients, or containing flavorings or colorants. It can be administered orally in the form of an elixir or suspension. They can also be injected parenterally, eg intravenously, intramuscularly or subcutaneously. For parenteral administration, it is best employed in the form of a sterile aqueous solution which may contain other substances such as sufficient salt or glucose to make the solution isotonic with blood. For oral and parenteral administration to patients (humans), daily dosage levels of antifungal compounds of formula () and their salts, O-ethers and O-esters can be administered by either the oral or parenteral route. It may be 0.1-10 mg/Kg (in divided doses).
A tablet or capsule of the present compound will therefore contain from 5 mg to 0.5 g of active compound for administration one or more at a time, as appropriate. In any event, the physician will determine the actual amount that is likely to be optimal for an individual patient. This will vary depending on the age, weight and response of the 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. This is also within the scope of the invention. Alternatively, antifungal compounds of formula () can be administered in the form of suppositories or pessaries, or they can be administered topically in the form of lotions, solutions, creams, ointments or powders. For example, they can be contained in a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin, or they can be incorporated into a cream consisting of a white wax or white soft wax base and any necessary stabilizers and preservatives. It can also be contained at a concentration of %. The following examples illustrate the invention. All temperatures are in °C. Example 1 1,3-bis(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-methylbutan-2-ol 2-(2,
4-difluorophenyl)-2-[2-(1H-1,
2,4-triazol-1-yl)propyl-
2] To a solution of oxirane (0.49 g, 1.8 mmol) was added 1,2,4-triazole (0.25 g, 3.6 mmol) and anhydrous potassium carbonate (0.25 g, 1.8 mmol).
mmol) was added. Heated at 80° for 4 hours with stirring. The solvent was then evaporated, water (100ml) was added and the mixture was extracted with methylene chloride (3x30ml). The combined organic extracts were washed with water (3 x 20ml), dried over anhydrous magnesium sulphate and evaporated to give an impure solid. Weight 0.73g. Merck “Kieselgel 60” (Kieselgel 60,
), increasing amounts of methanol (1%
Purification was carried out by elution with methylene chloride containing up to 5%). Evaporation of the appropriate fractions gave an oil. This was crystallized from diisopropyl ether to give the title compound. 0.36
g, melting point 155-157° (yield 60%). Elemental analysis (%): Theoretical value (C ₁₅ H ₁₆ F ₂ N ₆ O):
C, 53.9; H, 4.8; N, 25.1 Found: C, 53.6; H, 4.8; N, 24.9 NMR and mass spectrometry data for this product were consistent with the above structure. Example 2 1,3-bis(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol 2-(2,
4-difluorophenyl)-2-[1-(1H-1,
1,2, 2,4-triazol-1-yl)ethyl]oxirane (0.5 g, 1.9 mmol).
4-triazole (0.27 g, 3.8 mmol) and anhydrous potassium carbonate (0.27 g, 1.9 mmol) were added. The mixture was heated at 85° C. for 3 hours while stirring. The solvent was evaporated, water (100ml) was added and the mixture was extracted with methylene chloride (3x30ml).
Combine the organic extracts and wash with water (3 x 20 ml).
Dry with anhydrous magnesium sulfate, evaporate,
An impure solid was obtained. Weight 0.6g. Purification was carried out using a Merck "Kieselgel 60", 230-400 mesh silica flash column, eluting with methylene chloride containing increasing amounts of methanol (1% to 5%). Evaporation of the appropriate fractions gave a solid. This was recrystallized from isopropanol to give the pure title compound. 0.42g, melting point 186-188° (yield 60%). Elemental analysis (%): Theoretical value (C ₁₄ H ₁₄ F ₂ N ₆ O):
C, 52.5; H, 4.4; N, 26.2 Found: C, 52.4; H, 4.5; N, 26.5 NMR, IR and mass spectrometry data for this product were consistent with the above structure. Example 3 1,3-bis(1H-1,2,4-triazol-1-yl)-2-(5-chloropyrid-2-
yl)butan-2-ol 2-[5- in dimethylformamide (5 ml)
Chlorpyrid-2-yl]-2-[1-(1H-1,
In a solution of 2,4-triazol-1-yl)ethyl]oxirane (70 mg, 0.28 mmol), 1,
2,4-triazole (39 mg, 0.56 mmol) and anhydrous potassium carbonate (39 mg, 0.28 mmol) were added. The mixture was heated at 80° C. for 3 hours while stirring. The solvent was then evaporated, water (20ml) was added and the mixture was extracted with methylene chloride (3x10ml). The combined organic extracts were washed with water (3x5ml), dried over anhydrous magnesium sulphate and evaporated to give an oil (100mg). Merck “Kieselgel 60”,
Using a 230-400 mesh silica flash column, increasing amounts of methanol (1% to 5%
Purification was carried out by elution with methylene chloride containing %). Evaporation of the appropriate fractions gave the pure title compound. 25 mg, melting point 156-157° (yield 28.1%). NMR and IR data of the product were consistent with the above structure. Example 4 1,3-bis-(1H-1,2,4-triazol-1-yl)-2-(4-chlorophenyl)-
3-Methylbutan-2-ol (A) 4'-chloro-2-methyl-2-(1H-1,
2,4-triazol-1-yl)propiophenone 4'-chloro-2-(1H-1,2,4-triazole-) in dry tetrahydrofuran (30 ml)
1-yl) propiophenone (2 g) was added to sodium hydride (480 mg of a 60% dispersion in oil) in dry tetrahydrofuran (20 ml) at 0° under a nitrogen atmosphere. After stirring for 10 minutes, methyl iodide (2.28 g) in dry tetrahydrofuran (10 ml) was added and the reaction mixture was then stirred at 0° for 1 hour and then at room temperature overnight. The reaction mixture was then diluted with water (20ml) and extracted with ether (3 x 25ml) and the combined organic extracts were washed with water and dried ( _MgSO4 ). After removing the solvent, the resulting residue was placed on silica (150 g).
Ethyl acetate/hexane/diethylamine (50:
Flash chromatography was performed using 50:3 V/V/V) for elution. The title compound (1.68 g, 84% yield) was obtained by evaporating the fractions containing the product and then crystallizing the residue from ethyl acetate/hexane. melting point
118-119°. Elemental analysis (%): Actual value: C, 57.8; H, 4.9; N, 16.9 Theoretical value (C ₁₂ H ₁₂ ClN ₃ O):
C, 57.7; H, 4.8; N, 16.8 Starting material 4'-chloro-2-(1H-1,
2,4-triazol-1-yl)propiophenone was prepared according to Preparation Example 6. (B) 2-(4-chlorophenyl)-2-[2-(1H
-1,2,4-triazol-1-yl)-propyl-2]oxirane 4'-chloro-2-methyl-2-(1H-1,
2,4-triazol-1-yl)propiophenone (1.375 g), trimethylsulfoxonium iodide (1.6 g), aqueous sodium hydroxide solution (5N, 13.5 ml), cetrimide (80 mg) and 1,
A mixture of 1,1-trichloroethane (30ml)
It was heated to 80° for 24 hours. The solution was cooled, diluted with methylene chloride (30ml) and the organic layer was separated and dried (MgSO ₄ ). The solvent was removed and the residue was dissolved on silica (100 g) in ethyl acetate/hexane/diethylamine (40:60:3 V/V/V).
The appropriate fractions were collected and evaporated to yield the title oxirane as an oil.
Obtained at 79% (1.15g). Mass spectrometry: Actual value, parent ion m/e263 (M ⁺ ) Theoretical value (C ₁₃ H ₁₄ ClN ₃ O): 263 (M ⁺ ) (C) 1,3-bis(1H-1,2,4-triazole -1-yl)-2-(4-chlorophenyl)
-3-Methylbutan-2-ol 2-(4-chlorophenyl)-2-[2-(1H
-1,2,4-triazol-1-yl)propyl-2]oxirane (1.1 g), 1,2,4-
Triazole (2g), potassium carbonate (5g)
and dry dimethylformamide (25ml) was heated at 80° under nitrogen atmosphere for 16 hours.
The reaction mixture was then cooled, filtered, washed with xylene and the liquid was evaporated in vacuo. The residue was azeotroped with xylene (2x30ml) and then partitioned between methylene chloride (50ml) and water (50ml). The aqueous phase was extracted with methylene chloride (3x50ml) and the combined organic phases were washed with water (50ml) and dried ( _MgSO4 ). The residue obtained after removing the solvent was dissolved on silica (150 g) in methylene chloride/methanol/saturated aqueous ammonia (93:7:
Flash chromatography was performed using 1V/V/V) for elution. The title compound 983 was obtained by evaporation of the product-containing fractions followed by recrystallization from ethyl acetate/hexane.
mg (yield 71%) was obtained. Melting point 128-129°. Elemental analysis (%): Actual value: C, 54.1; H, 5.2; N, 25.4 Theoretical value (C ₁₅ H ₁₇ ClN ₆ O):
C, 54.1; H, 5.1; N, 25.3 Example 5 1,3-bis-(1H-1,2,4-triazol-1-yl)-2-(4-chlorophenyl)butan-2-ol 4-Chlorphenylmagnesium bromide [prepared from 4-chlorobromobenzene (15.2 g) and magnesium turnings (2.8 g)] in ether (80 ml) was dried with a double-ended needle under nitrogen atmosphere for 30 min. 1,3,-Dibromobutan-2-one (9.2g) in ether (50ml)
(Org.Synthesis, 53 , 123) at -78°. After stirring for 1 hour at -78°, the resulting mixture was quenched with saturated ammonium chloride solution and allowed to reach room temperature. The ethereal layer was separated, the aqueous layer was extracted with ether (3 x 20ml) and the combined ethereal extracts were washed with brine and dried ( _MgSO4 ). The residue obtained after removing the ether was mixed with 1,2,4-triazole (8 g), potassium carbonate (20 g) and dimethylformamide (50 g).
ml) to the mixture under nitrogen atmosphere and the mixture
Heat to 70° overnight. The cooled solution was filtered, the solid washed with xylene (50ml) and the liquid evaporated in vacuo. The last traces of dimethylformamide were removed by azeotroping with xylene (2 x 30ml). The crudely purified residue was dissolved in methylene chloride (200
ml) and water (100ml), the methylene chloride extract was washed with water and dried ( _MgSO4 ). After removing the methylene chloride in vacuo, the residue was flash chromatographed on silica (150 g) using methylene chloride containing 8% methanol by volume for elution. The appropriate fractions (i.e. fractions 29-39, 50 ml each) were combined and evaporated.
1.1 g of a mixture of diastereomer pairs was obtained. This isomer pair was purified on silica (100 g) with ethyl acetate:diethylamine:methanol (80:20:2 volume ratio).
It was separated by flash chromatography by elution with . Fractions 13−16 (25 ml each)
were combined and evaporated to give isomer pair 1 (114 mg). Melting point 112-113° (ethyl acetate/hexane). Mass spectral data: m/e318 (M ⁺ ); theoretical value (C ₁₄ H ₁₅ ClN ₆ O): M ⁺ =318. After evaporation of fractions 31-49 (again, 25 ml each), ethyl acetate/
By crystallizing from hexane, isomer 2
(246ml) was obtained. Melting point 50-51°. Mass spectral data: m/e318 (M ⁺ ); theoretical value (C ₁₄ H ₁₅ ClN ₆ O): M ⁺ =318. Isomer pair 1 NMR (CDCl ₃ ), δ=1.25 (d, J
=7Hz, 3H , CH3 ) _, 3.76(d, J=13Hz, 1
H, N- CH ₂ ), 4.32 (d, J = 13Hz, 1 H , N
- CH ₂ ), 4.92 (q, J=7Hz, 1 H , N- CH
[CH ₃ ]) 5.48 (s, -OH : exchangeable with D ₂ O),
7.12 (m, 4H, C ₆ H ₄ ), [7.55 (s, 1H), 7.70
(s, 1H), 7.92 (s, 1H), 8.30 (s, 1H)-triazole proton]. Isomer pair 2 NMR (CDCl ₃ ), δ=1.53 (d, J
=7Hz, 3H , _CH3 ), 4.56(s, 2H, N- CH
₂ ), 4.72 (J = 7Hz, 1H [formula]), 5.52 (s, OH: exchangeable with D ₂ O), 6.95 (m, 4H, C ₆ H ₄ ),
[7.65 (s, 1H), 7.78 (s, 2H) 7.88 (s, 1H)
-triazole proton]. 2-(4-chlorophenyl)-2-[1-(1H-
1,2,4-triazol-1-yl)ethyl]
Oxirane methanesulfonate (1.82 g) with 1,2,4-triazole (2 g) and potassium carbonate (3.4 g) in dimethylformamide (30 ml).
are reacted under the same reaction conditions as for route (a), and route
Using extraction and isolation procedures similar to (a), isomer pair 1 (796 mg, mp 112-113°) and isomer pair characterized spectroscopically as identical to the product of route (a). 2 (70 mg, melting point 50-52°) was obtained. Example 6 Using a method similar to that in route (a) of the example above and using the corresponding starting materials, 1,3-bis(1H-1,2,4-triazol-1-yl)-
2-(2,4-difluorophenyl)butane-2
-ol was prepared and separated into its two pairs of diastereomers. Isomer pair 1 was characterized and found to be identical to the product of Example 2. Isomer pair 2 had a melting point of 123-125° and gave the following microanalytical values. Elemental analysis (%): Actual value: C, 52.55; H, 4.5; N, 26.1 Theoretical value (C ₁₄ H ₁₄ F ₂ N ₆ O):
C, 52.5; H, 4.4; N, 26.2 Example 7 1,3-bis(1H-1,2,4-triazol-1-yl)-2-(4-fluorophenyl)butan-2-ol 2-(4-) in dimethylformamide (30ml)
fluorophenyl)-2-[1-(1H-1,2,4
-triazol-1-yl)ethyl]oxirane (0.5 g, 2.1 mmol) was added 1,2,4-triazole (0.29 g, 4.2 mmol) and anhydrous potassium carbonate (0.29 g, 2.1 mmol). Heated at 85° for 3 hours with stirring. The solvent was evaporated, water (65ml) was added and the mixture was extracted with methylene chloride (3x20ml). The combined organic extracts were washed with water (3 x 10 ml), dried over anhydrous sodium sulfate and evaporated to give a gum (1.1 g).
I got it. Purification of the gum was carried out using Merck “Kieselgel 60”, a 230-400 mesh silica flash column, with increasing amounts of methanol (5
% to 10%) containing methylene chloride. Evaporation of the appropriate fractions gave the title compound. 318 mg, melting point 103-106° (yield 49.1%). Elemental analysis (%): Actual value: C, 55.3; H, 5.0; N, 27.8 Theoretical value (C ₁₄ H ₁₅ FN ₆ O):
C, 55.6; H, 5.0; N, 27.7 NMR and mass spectral data for the product were consistent with the above structure. Example 8 1,3-bis(1H-1,2,4-triazol-1-yl)-2-(4-fluorophenyl)
-3-methylbutan-2-ol 2-(4-) in dimethylformamide (50ml)
fluorophenyl)-2-[2-(1H-1,2,4
-triazol-1-yl)propyl-2]oxirane (1.0 g, 4.0 mmol) was added 1,
2,4-triazole (0.56 g, 8.0 mmol)
and anhydrous potassium carbonate (0.56 g, 4.0 mmol)
was added. The mixture was heated at 80° for 19 hours with stirring. The solvent was then evaporated, water (75ml) added and the mixture extracted with methylene chloride (3x50ml). The combined organic extracts were washed with water (3 x 30ml), dried over anhydrous magnesium sulphate and evaporated to give an impure gum (1.15g). Purification of the gum was accomplished using Merck's "Kieselgel 60" 230-400 mesh silica, eluting with methylene chloride and 5% methanol in methylene chloride. Evaporation of the appropriate fractions gave a solid. This was recrystallized from diisopropyl ether and isopropyl alcohol to obtain the title compound.
0.4g, melting point 156-158° (yield 31.9%). Elemental analysis (%): Actual value: C, 56.9; H, 5.4; N, 26.6 Theoretical value (C ₁₅ H ₁₇ FN ₆ O):
C, 57.1; H, 5.3; N, 26.4 NMR and mass spectral data for the product were consistent with the above structure. Examples 9 and 10 The following compounds were prepared from the appropriate starting materials as in the above examples. TABLE TABLE The following Preparation Examples (all temperatures are in °C) illustrate the preparation of specific starting materials. Production example 1 (A) 2',4'-difluoro-2-methyl-2-(1H
-1,2,4-triazol-1-yl)propiophenone 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone (3.7 g, 16.6
mmol) was cooled to 5° under stirring, where the sodium hydride was added as a 50% dispersion in oil.
1.58 g (which contains 33.2 mmol of sodium hydride) was added. After 30 minutes, methyl iodide (5.2 g, 36.5 mmol) was added over 5 minutes. Stirring was continued for 20 hours at room temperature. The mixture was then poured into ice water (150ml) and extracted with ethyl acetate (3x50ml). The combined organic extracts were washed with water (3 x 20ml) and dried over anhydrous sodium sulfate. Evaporation gave an impure solid (weight 4.6 g). Purification is performed under slight pressure (2p.si approx. 0.14Kg/
cm ² ) Performed by flash column chromatography on a Merck "Kieselgel 60" 230-400 mesh silica column, eluting with ether. Evaporation of the appropriate fractions gave a solid. This was recrystallized from cyclohexane/n-pentane to give the pure title compound. 1.5g, melting point 45~
47° (yield 36.3%). Elemental analysis (%): Theoretical value (C ₁₂ H ₁₁ F ₂ N ₃ O):
C, 57.4; H, 4.4; N, 16.7 Found: C, 57.6; H, 4.1; N, 16.4 NMR, IR and mass spectral data of the product were consistent with the above structure. (B) 2-(2,4-difluorophenyl)-2-
[2-(1H-1,2,4-triazole-1-
yl)propyl-2]oxirane 2',4'-difluoro-2-methyl-2-(1H
-1,2,4-triazol-1-yl) propiophenone (1.45 g, 5.8 mmol), trimethylsulfoxonium iodide (2.10 g, 9.6 mmol) and cetrimide (0.16 g).
1,1-trichloroethane (50ml) and 20%
Aqueous sodium hydroxide solution (50ml) was added.
Heating under reflux was carried out for 3 hours with vigorous stirring. The organic layer was separated, washed with water (3 x 30ml), dried over anhydrous magnesium sulphate and evaporated to give a gum. 2.25g. Purification was carried out on a Merck "Kieselgel 60", 230-400 mesh silica (15 g) flash chromatography column with slight additions of n-pentane containing increasing amounts of methylene chloride (from 0 to 50%). This was done by elution under pressure (2 p.si, approximately 0.14 Kg/cm ² ). Evaporation of the appropriate fractions gave a solid. This is cyclohexane/n
- Recrystallization from pentane gave the title compound. 0.52g, melting point 76-78° (yield 33.8%). Elemental analysis (%): Theoretical value (C ₁₃ H ₁₃ F ₂ N ₃ O):
C, 58.8; H, 4.9; N, 15.8 Found: C, 58.9; H, 4.9; N, 15.8 NMR and mass spectral data for the product were consistent with the above structure. Production example 2 (A) 2',4'-difluoro-2-(1H-1,2,4
-triazol-1-yl)propiophenone hydrochloride A solution of 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone (4 g, 17.9 mmol) in tetrahydrofuran (75 ml) was cooled to 5° with stirring, Here sodium hydride as a 50% dispersion in oil
0.86 g (which contains 17.9 mmol of sodium hydride) was added. After 20 minutes, methyl iodide (2.8 g, 19.7 mmol) was added over 5 minutes. Stirring was continued for 19 hours at room temperature. The mixture was then poured into ice water (100ml) and extracted with methylene chloride (3x30ml). The combined organic extracts were washed with water (3x40ml) and dried over anhydrous magnesium sulfate. Evaporation gave 4.7 g of an oil. Purification is done under slight pressure (2p.si approx. 0.14Kg/
cm ² ) Below is Merck “Kieselgel 60”, 230~
This was carried out by flash column chromatography on a 400 mesh silica column, eluting with ether. The appropriate fractions were combined and reduced to a volume of 50 ml by evaporation and then treated with hydrogen chloride gas. The resulting hydrochloride salt was separated and recrystallized from isopropanol to yield the pure title compound. 1.66g, melting point 147-150°. Fine crystalline (yield 33.9%). Elemental analysis (%): Theoretical value (C ₁₁ H ₉ F ₂ N ₃ O.HCl):
C, 48.3; H, 3.7; N, 15.4 Found: C, 48.1; H, 3.5; N, 15.7 NMR, IR and mass spectral data of the product were consistent with the above structure. (B) 2-(2,4-difluorophenyl)-2-
[1-(1H-1,2,4-triazole-1-
yl)ethyl]oxirane 2',4-difluoro-2-(1H-1,2,4
-triazol-1-yl) propiophenone hydrochloride (1.36 g, 5.0 mmol), trimethylsulfoxonium iodide (1.32 g, 6.0 mmol)
1,1,1-trichloroethane (25 ml) and 20% aqueous sodium hydroxide solution (25 ml) were added to cetrimide (0.15 g). Heated under reflux with vigorous stirring for 1 1/2 hours. The separated organic phase was washed with water (3x10ml) and dried over anhydrous magnesium sulphate. Evaporation gave 1.6 g of gum. Purification is carried out under slight pressure (2 p.si,
Approximately 0.14Kg/cm ² ) Below is Merck's "Kieselgel"
60", 230-400 mesh silica, eluting with ether containing increasing amounts of ethanol (1% to 5%). Appropriate fractions were evaporated. A solid was obtained. This was recrystallized from cyclohexane to obtain the title compound. 0.6 g, melting point 85-87° (yield 39.5%). Elemental analysis (%): Theoretical value (C ₁₂ H ₁₁ F _{2 N3O} ):
C, 57.4; H, 4.4; N, 16.7 Found: C, 57.3; H, 4.4; N, 16.8 NMR, IR and mass spectral data of the product were consistent with the above structure. Production Example 3 (A) 2-[2-(1H-1,2,4-triazol-1-yl)acetyl]-5-chloropyridine This intermediate was produced by a conventional method according to the reaction formula below. Ta. (B) 2-[2-(1H-1,2,4-triazol-1-yl)propionyl]-5-chloropyridine 2-[2- in tetrahydrofuran (60ml)
(1H-1,2,4-triazol-1-yl)
A solution of acetyl]-5-chloropyridine (1 g, 4.5 mmol) was cooled to 5° with stirring, and sodium hydride was added as a 50% dispersion in oil.
0.32 g (which contains 6.7 mmol of sodium hydride) was added. After 40 minutes, methyl iodide (0.7 g, 4.9 mmol) was added over 5 minutes. Stirring was continued for 20 hours at room temperature. The reaction mixture was then poured into ice water (100ml) and extracted with ethyl acetate (3x30ml). The combined organic extracts were washed with water (3 x 30 ml), dried over anhydrous magnesium sulphate and evaporated to an oil (1.2 g).
I got it. Purification is carried out under slight pressure (2 p.si, approx. 0.14
Kg/ ^cm2 ) Below is Merck “Kieselgel 60”, 230
This was performed by flash column chromatography on a ~400 mesh silica column, eluting with ether. Evaporation of the appropriate fractions gave the title compound as a crystalline solid.
0.22g, melting point 99-101° (yield 20.7%). Elemental analysis (%): Theoretical value (C ₁₀ H ₉ ClN ₄ O):
C, 50.8; H, 3.8; N, 23.7 Found: C, 50.7; H, 3.8; N, 23.8 NMR and mass spectral data of the product were consistent with the above structure. (C) 2-(5-chloropyrid-2-yl)-2-
[1-(1H-1,2,4-triazole-1-
yl)ethyl]oxirane 2-[2-(1H-1,2,4-triazol1-yl)propionyl]-5-chloropyridine (0.17 g, 0.71 mmol), trimethylsulfoxonium iodide (0.19 g, 0.85 mmol)
1.1,1-trichloroethane (10 ml) and 20% aqueous sodium hydroxide solution (10 ml) were added to cetrimide (0.02 g). Stirred under reflux with vigorous stirring for 1 1/2 hours. The separated organic phase was washed with water (3 x 5 ml) and dried over anhydrous magnesium sulfate. Evaporation gave a gum (0.13g). Purification is done under slight pressure (2p.si approx. 0.14Kg/cm ² )
It was carried out by flash column chromatography on Merck "Kieselgel 60", 230-400 mesh silica, eluting with ether containing increasing amounts of ethanol (1% to 5%). Evaporation of the appropriate fractions gave the title compound as a fine crystalline solid. 0.07g, melting point
101-104° (yield 39.5%). NMR and IR were consistent with the above structure. Production example 4 (A) 4'-fluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone 1,2,4-triazole (14g) was mixed with 2-chloro-4'-fluoroacetophenone (8.6g).
The title compound was obtained by alkylation in dry acetone (150ml) in the presence of potassium carbonate (20g). This was crystallized from water. Melting point: 134° (5.4g). Elemental analysis (%): Actual value: C, 58.4; H, 3.9; N, 20.5 Theoretical value (C ₁₀ H ₈ FN ₃ O):
C, 58.5; H, 3.9; N, 20.5 (B) 4'-Fluoro-2-(1H-1,2,4-triazol-1-yl)propiophenone hydrochloride 4'-Fluoro-2-(1H-1,2,4-triazole-1) in tetrahydrofuran (40 ml)
-yl) acetophenone (2.05 g, 10 mmol) To a solution maintained at 5° was added 0.53 g (containing 11 mmol of sodium hydride) of sodium hydride as a 50% dispersion in oil under stirring. 15
After a few minutes, methyl iodide (1.56 g, 11 mmol) was added over 5 minutes. Stirring was continued for 19 hours at room temperature. Then add the mixture to saturated saline solution (100ml)
and extracted with ethyl acetate (3 x 40ml). The combined organic extracts were washed with water (3x30ml) and dried over anhydrous magnesium sulfate. Evaporation gave an impure oil (2.2g). Purification of this oil is carried out under slight pressure (2 p.si, approximately 0.14
Kg/ ^cm2 ) Merck “Kieselgel 60”, 230~
This was carried out by flash column chromatography on a 400 mesh silica packed column, eluting with ether. The appropriate fractions were evaporated to give a gum. This was dissolved in ether (35ml) and treated with hydrogen chloride gas. The resulting hydrochloride salt was separated and recrystallized from isopropanol to yield the pure title compound. 1.38g, melting point
141-145° (yield 53.9%). Elemental analysis (%): Theoretical value: C, 51.7; H, 4.3; N, 16.4 Actual value (C ₁₁ H ₁₀ FN ₃ O.HCl):
C, 51.5; H, 4.3; N, 16.3 NMR and mass spectral data of the product were consistent with the above structure. (C) 2-(4-fluorophenyl)-2-[1-
(1H-1,2,4-triazol-1-yl)
ethyl oxirane 4'-fluoro-2-(1H-1,2,4-triazol-1-yl)propiophenone hydrochloride (1.1 g, 4.3 mmol) trimethylsulfoxonium iodide (1.6 g, 7.7 mmol) and cetrimide ( 1,1,1-trichloroethane (25 ml) and 20% aqueous sodium hydroxide solution (25 ml) were added to the solution (150 mg). Heated under reflux with vigorous stirring for 2 hours. The separated organic phase was washed with water (3x10ml) and dried over anhydrous magnesium sulphate. Evaporation gave the title compound as a solid. 1.0g (99% yield). NMR and IR spectral data of the product were consistent with the above structure. Production example 5 (A) 4'-fluoro-2-methyl-2-(1H-1,
2,4-triazol-1-yl)propiophenone 4'-Fluoro-2-(1H-1,2,4-triazole-1) in tetrahydrofuran (40 ml)
1.06 g of sodium hydride as a 50% dispersion in oil (containing 22 mmol of sodium hydride) was added to a solution (5°) of acetophenone (2.05 g, 10 mmol) under stirring. After 15 minutes, methyl iodide (2.84 g, 20 mmol) was added over 3 minutes. Stirring was continued for 19 hours at room temperature. The mixture was then poured into saturated saline (100ml) and extracted with ethyl acetate (3x40ml).
The combined organic extracts were washed with water (3x30ml) and dried over anhydrous magnesium sulfate. Evaporation gave an impure solid (2.0g). Purification of this solid is carried out under slight pressure (2 p.si, approx. 0.14 Kg/cm ² )
The reaction was carried out by flash column chromatography on a Merck "Kieselgel 60" 230-400 mesh silica-packed column, eluting with ether. Evaporation of the appropriate fractions gave a solid. This was recrystallized from cyclohexane to give the pure title compound. 0.76g, melting point 111
~112° (yield 32.6%). Elemental analysis (%): Actual value: C, 61.8; H, 5.2; N, 18.0 Theoretical value (C ₁₂ H ₁₂ FN ₃ O):
C, 61.8; H, 5.2; N, 17.8 NMR and mass spectral data of the product were consistent with the above structure. (B) 2-(4-fluorophenyl-2-[2-(1H
-1,2,4-triazol-1-yl)propyl-2]oxirane 4'-Fluoro-2-methyl-2-(1H-1,
2,4-triazol-1-yl)propiophenone (0.75 g, 3.2 mmol), trimethylsulfoxonium iodide (1.16 g, 5.3 mmol)
1,1,1-trichloroethane (30 ml) and 20% aqueous sodium hydroxide solution (30 ml) were added to cetrimide (100 mg). Heated under reflux with vigorous stirring for 5 hours. The organic layer was then separated, washed with water (3 x 20ml), dried over anhydrous magnesium sulphate and evaporated to give the title compound as a solid. 0.7g (yield 88.3
%). NMR and IR spectral data of the product were consistent with the above structure. The following ketones were prepared from appropriate starting materials in the same manner as in Part (A) above. [Table] The following oxirane was produced from the above ketone in the same manner as in Part (B). (R=5-chloro-2-pyridyl and 2,4
-dichlorophenyl) Production Example 6 (A) 4'-chloro-2-(1H-1,2,4-triazol-1-yl)propiophenone 4'-chloro-2-(1H-1,2,4-triazol-1-yl)acetophenone (3g)
(see DE 24 31 407) was mixed with methyl iodide (2.05 g) in tetrahydrofuran (50 ml) in the presence of sodium hydride (550 mg total dispersion as a 60% dispersion by weight in oil).
alkylation in a medium to give the title compound. melting point
85°. 2.4g. The properties were investigated by spectroscopic analysis. Mass spectral data: m/e234 (M ⁺ ), 139,
111. Theoretical value ( _C11H10ClN3O ), ^M+ _{= 234} . (B) 2-(4-chlorophenyl)-2-[1-(1H
-1,2,4-triazol-1-yl)ethyl]oxirane methanesulfonate The title compound was prepared in the same manner as in Preparation Example 5(B),
4'-chloro-2-(1H-1,2,4-triazol-1-yl)propiophenone (2.35g),
Trimethylsulfoxonium iodide (2.72g),
Prepared starting from cetrimide (150 mg), 1,1,1-trichloroethane (30 ml) and 20% aqueous sodium hydroxide solution (25 ml). After evaporating the organic layer, the remaining residue was dissolved in acetone (25
ml) and treated with methanesulfonic acid (0.8g) to precipitate the title methanesulfonate salt. 2.05g, melting point 154-155°. The properties were investigated by spectroscopic analysis. Mass spectral data: m/e249 (M ⁺ ), 233,
180, 153, 125, 96, 82 Theoretical value (C ₁₂ H ₁₂ ClN ₃ O): M ⁺ = 249 PD obtained for the compound of formula () against Candida ambicans in mice by the test method described in the text ₅₀ value (oral) is as follows. Compound PD ₅₀ (mg/Kg) Product of Example 1 0.4 Product of Example 2 0.1 Product of Example 3 0.2 Product of Example 4 0.2 Product of Example 5 (diastereomer pair 1)
0.1 Product of Example 5 (diastereomer pair 2)
0.3 Product of Example 6 (diastereomer pair 2)
0.5 Product of Example 7 0.1 Product of Example 8 0.3 Product of Example 9 0.5 Product of Example 10 1.6 The compound of Example 1 was administered intravenously to mice at 20 mg and 40 mg/Kg, respectively, for acute administration. I investigated the toxicity, but
No acute toxicity was observed even after administration of 40 mg/Kg. In an activity test against systemic aspergillosis in mice, mice were infected with the Pfizer stock strain of Aspergillus flavus by tail vein injection. Untreated (control) mice usually die within 5-10 days of Aspergillus flavus infection. Each test compound was administered to groups of infected mice at an oral dose level of 20 mg/Kg 1 and 4 hours after infection and then twice daily for the next 4 days. In this way, we investigated the prolongation of the mean survival time (MST) of treated mice compared to a control group of mice co-infected with the same strain. A compound of formula () was found to be unexpectedly effective against a major pathogenic bacterial strain, Alpergillus flavus. Homologues with “-CH ₂ −” instead of [formula] in the chain (UK patent no.
2078719A) and the compound of the present invention are shown below. [Table] [Table] [Table]

Claims (1)

[Claims] Primary formula (): (In the formula, R is a 2,4-difluorophenyl group,
2,4-dichlorophenyl group or 5-chloropyrid-2-yl group; R ¹ is H or CH ₃
However, when R is a 2,4-dichlorophenyl group, R ¹ represents only CH ₃ . ) or a pharmaceutically acceptable salt thereof. Quadratic formula (): (In the formula, R is a 2,4-difluorophenyl group,
2,4-dichlorophenyl group or 5-chloropyrid-2-yl group; R ¹ is H or CH ₃
However, when R is a 2,4-dichlorophenyl group, R ¹ represents only CH ₃ . ) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Cubic formula (): (In the formula, R is a 2,4-difluorophenyl group,
2,4-dichlorophenyl group or 5-chloropyrid-2-yl group; R ¹ is H or CH ₃
However, when R is a 2,4-dichlorophenyl group, R ¹ represents only CH ₃ . ) or a pharmaceutically acceptable salt having the following formula (): (wherein R and R ¹ are as defined in formula () above) is reacted with a 1,2,4-triazole or a basic salt thereof, and the product is then optionally made pharmaceutically acceptable. The method consists of turning it into salt. 4. The method according to claim 3, which is carried out using 1,2,4-triazole in the presence of potassium carbonate. Quintic formula (): (In the formula, R is a 2,4-difluorophenyl group or a 5-chloropyrid-2-yl group; R ¹ is H
It is. ) or a pharmaceutically acceptable salt thereof, the method comprising the following formula (): (In the formula, X and X ¹ are each a leaving group, and R
is defined in the above formula (). ) with 1,2,4-triazole or a basic salt thereof, and then optionally converting the product into a pharmaceutically acceptable salt. 6. The method according to claim 5, which is carried out by using 1,2,4-triazole in the presence of potassium carbonate.