JPS6345674B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel triazole 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 a phenyl group optionally substituted with 1 to 3 substituents independently selected from halogen and trifluoromethyl group, and n
is 0 or an integer from 1 to 5) and pharmaceutically acceptable salts thereof. According to the invention there is also provided a pharmaceutical composition comprising a compound of formula () or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable diluent or carrier. Further according to the present invention, there are provided compounds of formula () or their pharmaceutically acceptable acid addition salts for use in medicine, particularly for the treatment of fungal infections in animals, including humans. The present invention also provides a method for treating animals (including humans) with fungal infections, which method comprises administering to the animal an effective amount of a compound of formula () or a pharmaceutically acceptable salt. provided. When R is an optionally substituted phenyl group, it has 1 to 3 substituents independently selected from F, Cl, Br, I and _CF3 , more preferably 1 or 2 substituents. Preferably, it is a phenyl group substituted with a group. Particularly in this aspect, R is a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-trifluoromethylphenyl group, a 2-fluorophenyl group, a 2,4-dichlorophenyl group, a 2,4-difluorophenyl group, 2
-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl group or 4-bromo-2,5-difluorophenyl group. R is most preferably a 2,4-dichlorophenyl group or a 2,4-difluorophenyl group. “n” is preferably 0, 1 or 2;
or 1 is most preferred. The compound of formula () where n is 0 is the following formula The oxirane (wherein R is as defined for formula ()) is preferably a base (e.g. K ₂ CO ₃ ).
It can be produced by reacting with 1,2,4-triazole in the presence of. Or 1, 2, 4
- It is also possible to use alkali metal salts of triazoles (which can be prepared, for example, from the triazole NaH). In general, reactions involve the reaction participants together.
This is carried out by heating up to 130° C. in a suitable organic solvent such as dimethylformamide for up to about 24 hours. The product can then be isolated and purified by conventional methods. Oxirane () is generally obtained from a ketone of the following formula by conventional methods. This is trimethylsulfoxonium iodide and
(a) from sodium hydride in dimethyl sulfoxide or (b) from cetrimide (cetyltrimethylammonium bromide) and sodium hydroxide in a mixture of water and toluene or water and 1,1,1-trichloroethane. It can be carried out by reaction of () with dimethyloxosulfonium methylide. Reactions using sodium hydride are generally performed by stirring sodium hydride and trimethylsulfoxonium iodide, for example at room temperature, then adding dimethylsulfoxide (DMSO) dropwise and stirring the mixture for about 30 minutes before adding the ketone ().
This is done by adding it to DMSO. The desired product is generally obtained by stirring for about 1 hour at room temperature. Reactions using cetrimide generally involve reacting the ketone (), trimethylsulfoxonium iodide, and cetrimide in a mixture of 1,1,1-trichloroethane and aqueous sodium hydroxide at about 20%
This is carried out by stirring at, for example, 70 to 100°C. In both cases the product oxira ()
can be isolated if desired, but it is often more convenient to convert it in situ to the desired product. Ketones () are known compounds or can be prepared, for example, by conventional methods as described below. Compounds of formula () where n is 0 can also be produced as follows. In the above, "Hal" is Cl or Br. Alkali metal salts of 1,2,4-triazole (eg, prepared from NaH and the same triazole) can also be used in place of 1,2,4 _- triazole/ _K2CO3 . In a general procedure, the halothone () and the lithio or Grignard reagent are stirred together, for example in diethyl ether, at -78 DEG C. for about 1 hour. The intermediate halo-alkanol can then be recovered by conventional methods if necessary. Then haloalkanol () and 1,2,4-
The triazole is heated in, for example, dimethylformamide at, for example, 50-130°C in the presence of a base, such as potassium carbonate, for up to about 24 hours. The product (A) is then collected in a conventional manner. The compound of formula () in which n is an integer of 1 to 5 can be produced in the same manner as described above for producing compound (A), that is, as follows. [Hal=Cl or Br, n=1-5]. This reaction is carried out under the same conditions as above, for example by heating in dimethylformamide up to 130° C. for 24 hours. In this case as well, the product can be collected by conventional methods.
The starting materials can also be prepared by conventional methods, for example as described below. or All compounds of the invention contain an optically active center;
The present invention includes both split and undivided forms. Pharmaceutically acceptable acid addition salts of compounds of formula () include 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. is included. These salts can be prepared in conventional manner, for example by combining solutions containing equimolar amounts of the free base and the desired acid;
The required salt, if insoluble, can be obtained by filtration or by evaporation of the solvent. Also included are alkali metal salts that can be produced by conventional methods. Compounds of formula () and pharmaceutically acceptable salts are antifungal agents useful in combating fungal infections in animals, including humans. For example, these include localized fungal infections caused in humans by species of the genera Candida, Trichophyton, Microsporum or Epidermophyton, or Candida albicans (C.
It is useful in the treatment of mucosal infections caused by C. albicans, such as oral and vaginal candidiasis. These include, for example, Candida albicans, Cryphococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma and Blastomyces. ) can also be used systemically in the treatment of systemic fungal infections caused by In vitro evaluation of the antifungal activity of the compound is determined by determining the minimum inhibitory concentration (mic) of the test compound in a suitable medium at which growth of a particular microorganism does not occur.
This can be done by measuring. In practice, a series of agar plates, each containing a particular concentration of the test compound, are inoculated with a standard culture of, for example, Candida albicans, and each plate is then incubated at 37°C.
Incubate for 48 hours. 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, Trichophyton SPP: Microsporum SPP; Epidermophyton flotscosum (E.
floccosum), Coccidioides immitis (C.
immitis) and Torulopsis glabrata. In vivo evaluation of the present 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. This bacterial suspension is diluted and
An inoculum containing approximately 10 ⁷ bacteria in 0.2 ml is obtained.
For each dose of test compound, groups of five Tuck albino female mice receive 0.2 ml of the inoculum via the tail vein. The test compound was dissolved in a phosphate buffer solution with a pH of 7 and an appropriate solubilizer, and 1 day after inoculating the above mice with the bacteria.
Orally administered to mice for 4 hours, 4 hours and 24 hours. 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 more effective the compound is. While antifungal compounds of formula () can be administered alone for human use, they will generally be administered in a mixture with a pharmaceutical carrier chosen with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be taken orally in the form of tablets containing excipients such as starch or lactose, or as capsules or ovules, alone or mixed with excipients, and with flavorings or colours. It can be administered in the form of an elixir or suspension containing the agent. 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 salts to render the solution isotonic with blood. For oral and parenteral administration to patients (human bodies), the daily dosage level of the antifungal compound of formula ( (in form) Therefore, tablets or capsules of the present compound should be administered only once at a time.
One or more doses can be expected to contain from 5 mg to 0.5 g of active compound for administration as appropriate. The actual dosage likely to be optimal for an individual patient will be determined by the physician. This will vary depending on the age, weight and response of each patient. The above dosages are examples of average cases; there are, of course, individual examples corresponding to higher or lower dosage ranges, and these are included within the scope of the invention. Alternatively, antifungal compounds of formula () can be administered in the form of suppositories or pessaries, or applied 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 present at a concentration of 1 to 10% in a white wax or ointment consisting of a white wax base and the necessary stabilizers and preservatives. It can also be included. The following examples are provided to specifically illustrate the present invention. All temperatures are in °C. Example 1 2-(4-chlorophenyl)-1-(1H-1,
2,4-triazol-1-yl)-3,3,
Production of 3-trifluoropropan-2-ol 2,2,2-trifluoro-4'-chloroacetophenone (0.8 g, 3.84 mmol), trimethylsulfoxonium iodide (1.02 g, 4.6 mmol)
and cetyltrimethylammonium bromide (0.1
g, 0.27 mmol) was stirred in a mixture of 1,1,1-trichloroethane (40 ml) and 18% aqueous sodium hydroxide solution (20 ml) at 75°C for 2 hours. The mixture was then allowed to cool, the organic layer was separated and evaporated, and the residue was dissolved in 1,2,4-triazole (1
g, 14.5 mmol) and anhydrous potassium carbonate (2
g, 14.5 mmol) in dimethylformamide (50 ml) at 90°C for an hour. The mixture was then allowed to cool, ethyl acetate (100ml) and water (50ml) were added, and the aqueous layer was separated. The organic layer was washed six more times with water (200 ml total), dried over magnesium sulfate and evaporated to give a gum (104 mg).
I got it. This was chromatographed on silica (230-400 mesh) eluting with ethyl acetate to give 84 mg (8%) of the title compound as a colorless solid. Recrystallization once from dichloromethane/hexane gave colorless crystals. 64 mg, melting point 117-118°. Elemental analysis (%) Actual value: C, 45.36; H, 3.06; N, 14.76 Theoretical value C ₁₁ H ₉ ClF ₃ N ₃ O:
C, 45.28; H, 3.09; N, 14.4 Example 2 2-(2,4-dichlorophenyl)-1-(1H-
1,2,4-triazol-1-yl)-3,
Production of 3,3-trifluoropropan-2-ol Sodium hydride (0.36 g, 9.05 mmol) as a 60% dispersion in oil was washed with distilled hexane, dried and stirred with trimethylsulfoxonium iodide (1.99 g, 9.05 mmol) at room temperature. Dimethyl sulfoxide (10 ml) was then added dropwise over 5 minutes and the mixture was stirred until the effervescence stopped (approx. 30 minutes). Then 2',4'-dichloro-2,2,2 in dimethyl sulfoxide (8 ml)
A solution of -trifluoroacetophenone (2 g, 8.23 mmol) was added and the mixture was stirred at room temperature for 45 minutes. Then water (50ml) and ether (100ml)
ml), the organic layer was separated and washed once with water,
Drying over magnesium sulphate and evaporation gave a pale yellow liquid (1.8g). This was added to a mixture of 1,2,4-triazole (2g, 29mmol) and anhydrous potassium carbonate (4g, 29mmol) in dimethylformamide (100ml). The mixture was heated at approximately 75° for 18 hours and then poured into a mixture of ethyl acetate (500ml) and water (200ml). The organic layer was separated and washed with water (5 x 100ml);
Drying over magnesium sulphate and evaporation gave a pale yellow sticky solid. Add this to silica (230 to 400
After chromatography on a mesh eluting with ethyl acetate and recrystallization from ethyl acetate, the title compound was obtained. 1.49g (56%), melting point 133.5-134.5°. Elemental analysis: Actual value: C, 40.58; H, 2.58; N, 12.96 Theoretical value: C ₁₁ H ₈ Cl ₂ F ₃ N ₃ O:
C, 40.49; H, 2.45; N, 12.88 Example 3 A pharmaceutical composition for treating fungal infections is described below. (a) Capsules: 71 parts by weight of the compound of Example 1 were granulated with 3 parts of corn starch and 22 parts of lactose, then a further 3 parts of corn starch and 1 part of magnesium sulfate were added. The mixture was re-granulated and filled into hard gelatin capsules. (b) Cream: 2 parts by weight of the compound of Example 1 dissolved in 10 parts of propylene glycol and 88 parts by weight of vanishing cream base.
It got mixed into the section. (c) Vaginal suppository: 2 parts by weight of the compound of Example 2 was suspended in 98 parts of a suppository base heated and changed, and this was poured into a mold and solidified. Example 4 2-(2,4-difluorophenyl)-1-(1H
-1,2,4-triazol-1-yl)-3,
Production of 3,3-trifluoropropan-2-ol Hexane solution of n-butyllithium (1.55M,
9.6 ml, 14.9 mmol) in diethyl ether (6
ml) and the solution was cooled to -78°. A solution of 2,4-difluorobromobenzene (3.03 g, 15.7 mmol) in diethyl ether (100 ml)
It was added dropwise over 15 minutes and the mixture was stirred at -78° for a further 15 minutes. Then 1-bromo-3,3,3-trifluoropropan-2-one (2.4 g, 12.6 mmol) in diethyl ether (100 ml)
solution was added dropwise over 15 minutes and the mixture was
Stirred for an additional 30 minutes at 78°. A solution of glacial acetic acid (2ml) in diethyl ether (5ml) was then added followed by water (15ml) and the mixture was allowed to warm to 0°C. The aqueous layer was separated and washed with diethyl ether (2x30ml). The combined diethyl ether extracts were dried over magnesium sulphate, evaporated and the remaining oil was dissolved in dimethylformamide (40ml). 1,2,4-triazole (2.5 g, 36.2 mmol) and anhydrous potassium carbonate (10 g, 72.5 mmol) were then added to this solution and the mixture was stirred and heated at 70° for 18 hours. The mixture was then cooled and poured into water (150ml),
Extracted with ethyl acetate (3x300ml). The combined ethyl acetate extracts were washed with water (100ml), dried over magnesium sulphate and evaporated. The residue was chromatographed on silica (230-400 mesh) eluting with 60:40 ethyl acetate:hexane (by volume) and after one recrystallization from ethyl acetate/hexane the title compound was obtained. . 1.7g
(47%), melting point 110-111°. Elemental analysis (%) Actual value: C, 45.16; H, 2.73; N, 14.56;
C ₁₁ H ₈ F ₅ N ₃ O Theoretical value: C, 45.05; H, 2.75; 6, 8 and 9) or Grignard reagent (Examples 7 and
10) were used to produce the compounds of Examples 5 to 10.
In Examples 7 and 9, tetrahydrofuran was used in place of dimethylformamide in the final stage of the reaction.

[Table] *Example 1 as methanesulfonate salt (A) Production of 1-bromo-3,3,4,4,4-pentafluorobutanone CF ₃ CF ₂ COCH ₃ Br ₂ -----→ CF ₃ CF ₂ COCH ₂ Br Methylpentafluoroethyl ketone (3.9g,
0.02407 mol) (JACS, 78, 2268-70 [1956])
was stirred in concentrated sulfuric acid (10ml) at room temperature under a dry ice condenser. Bromine (1.92g,
0.012035 mol) was added gradually over 2 hours with vigorous stirring. The mixture was then stirred at room temperature for 1 hour and then at 50° for 1 hour.
The resulting yellow-brown solution was distilled under atmospheric pressure and 94
4.41 g (76%) of the main fraction boiling at ~97° was obtained.
Parent ions are shown at 240 and 242, C ₄ H ₂ BrF ₅ O
A structure corresponding to (two isotopes of Br) was confirmed by mass spectrometry. (B) 2-(2,4-difluorophenyl)-3,
3,4,4,4-pentafluoro-1-(1H-
Production of 1,2,4-triazol-1-yl)-butan-2-ol n-Butyllithium (3.32 ml of a 1.5 M solution in hexane) in diethyl ether (5 ml),
0.00498 mol) was cooled to -78° and stirred. A solution of 2,4-difluorobromobenzene (1.0 g, 0.00519 mol) in ether (8 ml) was added slowly over 15 minutes. The reaction mixture was held at -78° for 15 minutes. Then 6 ml of ether
1-bromo-3,3,4,4,4-pentafluorobutanone was added at -78° over 15 minutes. The mixture was stirred at -78° for 30 minutes.
Acetic acid (0.7g) in ether (5ml) was added,
Water (8ml) was then added and the mixture was allowed to warm to room temperature. The ether layer was separated and the aqueous layer was washed with ether (2 x 15 ml). The combined ether layers were dried over magnesium sulfate and evaporated to give an oil. This oil has 1,2,4-
Triazole (0.86 g, 0.01245 mol), anhydrous potassium carbonate (5.73 g, 0.0415 mol) and anhydrous dimethylformamide (15 ml) were added. The mixture was heated and stirred at 80° for 3 1/2 hours, cooled to room temperature and poured into 150 ml of water. The mixture was then extracted with 3 x 60 ml of methylene chloride, the combined organic extracts were dried over magnesium sulfate, evaporated and the remaining brown oil was washed on silica (230-400
Flash chromatography was performed on a mesh plate. Elution with ethyl acetate/hexane (60/40, vol.) gave the title compound as a white solid (400 mg, 28%). Melting point 95-6° (after crystallization from cyclohexane). Elemental analysis (%) Actual value: C, 41.8; H, 2.3; N, 12.0 Theoretical value C ₁₂ H ₈ F ₇ N ₃ O:
C, 42.0H, 2.3; N, 12.2 Examples 12-16 The following compounds were prepared from appropriate starting materials in a similar manner to the above examples.

[Table] Example 17 2-(2.4-difluorophenyl)-3,3,4,
4,5,5,5-heptafluoro-1-(1H-
Production of 1,2,4-triazol-1-yl)pentan-2-ol A solution of heptafluoropropyl iodide (5 g, 0.017 mol) in ether (20 ml) (cooled to -78°) was added with phenylmagnesium bromide (in ether).
3M solution (5.6 ml, 0.017 mol) was added dropwise at such a rate that the temperature of the reaction mixture did not exceed -50°. Once all the phenylmagnesium bromide was added, the mixture was stirred at -50° for 1/2 hour and then cooled again to -78°. 2-chloro- in ether (20ml)
2′,4′-difluoroacetophenone (3.6g,
A solution of 0.019 mol) was added dropwise at such a rate that the temperature of the reaction mixture did not exceed -50°, and when the addition was complete the reaction mixture was warmed to -20° and stirred at this temperature for 2 hours. A solution of glacial acetic acid (3ml) in ether (5ml) was then added followed by water (15ml) and the mixture was allowed to warm to about 5°. Separate the aqueous layer;
Extracted with ether (2 x 50ml), the combined ethereal extracts were dried ( _MgSO4 ) and evaporated to give a pale yellow oil (6.7g). This oil was added to 1,-triazole (5.87g, 0.085mol) and anhydrous potassium carbonate (17.5g, 0.127mol) in dimethylformamide (60ml) and the mixture was stirred at a temperature of 80° for 3 hours. The reaction mixture was then cooled, the dimethylformamide was evaporated and the residue was partitioned between water (200ml) and ethyl acetate (150ml). The aqueous layer was separated and extracted with ethyl acetate (3 x 150 ml). The combined ethyl acetate extracts were washed successively with aqueous sodium bisulfite and water, dried (MgSO ₄ ), evaporated and the residue was dissolved on silica (230 ~
Flash chromatography on 400 mesh), hexane; isopropyl alcohol:
0.88 ammonium hydroxide (80:20:1.5, volume ratio)
After recrystallization once from hexane:dichloromethane, 1.51 g of the title compound (23
%) was obtained. Melting point: 128°. Elemental analysis (%) Actual value: C, 39.8; H, 2.0; N, 10.6
C ₁₃ H ₈ F ₉ N ₃ O Theoretical value: C, 39.7; H, 2.1; N, 10.7 Example 18 2-(4-fluorophenyl)-3,3,4, 4,5,5,5-heptafluoro-1-(1H-1,2,4-triazol-1-yl)-pentan-2-ol was prepared from the appropriate starting materials. Yield 7%, melting point 126~
127°. Elemental analysis (%) Actual value: C, 41.9; H, 2.4; N, 11.3
C ₁₃ H ₉ F ₈ N ₃ O Theoretical: C, 41.6; H, 2.4; N, 11.2 The following Preparation Example is illustrative of the preparation of the new starting material. All temperatures are in °C. Production example 2',4'-dichloro-2,2,2-trifluoroacetophenone production 2,4-dichloroiodobenzene (27.3g,
A solution of 2,4-dichlorophenylmagnesium iodide prepared from 0.1 mol) and magnesium (3.3 g, 0.138 mol) in ether (50 ml) was dissolved in trifluoroacetic anhydride (24 ml) in ether (20 ml).
g, 0.114 mol) at -78°. Stirring was continued for 10 minutes at -78°, then the mixture was allowed to warm up to room temperature over 4 hours, and at this temperature for a further 18
After stirring for an hour, the mixture was heated under reflux for 3 hours. The mixture was then cooled and treated with concentrated hydrochloric acid (25ml) in ice water (125ml). The ether layer was separated and the aqueous layer was washed with ether four more times (200 ml total).
The combined ethereal extracts were washed successively with aqueous sodium bisulfite, aqueous sodium bicarbonate and water, dried over magnesium sulfate and distilled to give the title compound as a pale yellow liquid (solidifies on cold). 14.2g (58%), boiling point 46° (0.2mmHg),
Melting point 38°, m/e242. The following _PD50 values (oral in mice for Candida albicans) were obtained using the test method described above. Compound PD ₅₀ (oral; mg/Kg) Product of Example 1 0.3 2 0.1 4 0.1 5 0.1 6 1.5 7 1.5 8 0.1 9 1.1 10 0.1 11 0.15 12 0.2 13 0.2 14 0.1 15 0.2 16 0.4 17 0. 1 18 0.2 preferred The compounds are those of Examples 2, 4 and 11. Acute toxicity was investigated by intravenously administering 20 mg and 40 mg/Kg of the compound of Example 2 to mice, respectively.
No acute toxicity was observed even after administration of 40 mg/Kg.

Claims (1)

[Claims] Linear formula (wherein R is a phenyl group substituted with 1 to 3 substituents independently selected from halogen and trifluoromethyl group, and n is 0 or an integer of 1 to 5), or A pharmaceutically acceptable salt of. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein 2n is zero. 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is an integer of 1 to 5. 4. The compound or salt according to claim 1, wherein n is 0, 1 or 2. 5 R is a 4-fluorophenyl group, 4-chlorophenyl group, 4-trifluoromethylphenyl group,
2-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4-chlorophenyl group, 2,5-difluorophenyl group, 2,4,6-trifluorophenyl group or 4-bromo-2,5-difluorophenyl group. 6. The compound according to claim 1, wherein n is 0 or 1 and R is a 2,4-difluorophenyl group, or n is 0 and R is a 2,4-difluorophenyl group. compound or salt. 7th equation (wherein R is a phenyl group substituted with 1 to 3 substituents independently selected from halogen and trifluoromethyl group, and n is 0 or an integer of 1 to 5) or their An antifungal pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier.