WO2004033432A1 - Nouveaux composes de pyrazole presentant une activite antifongique - Google Patents

Nouveaux composes de pyrazole presentant une activite antifongique Download PDF

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WO2004033432A1
WO2004033432A1 PCT/JP2003/012856 JP0312856W WO2004033432A1 WO 2004033432 A1 WO2004033432 A1 WO 2004033432A1 JP 0312856 W JP0312856 W JP 0312856W WO 2004033432 A1 WO2004033432 A1 WO 2004033432A1
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compound
group
phenyl
pyrazole
bis
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PCT/JP2003/012856
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English (en)
Japanese (ja)
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Fujiko Konno
Kyoko Nakazawa
Hiroyuki Hirota
Kazuya Ishida
Yasushi Kaneko
Hisako Okouchi
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Ssp Co., Ltd.
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Priority to JP2004542837A priority Critical patent/JP4537855B2/ja
Priority to AU2003271117A priority patent/AU2003271117A1/en
Publication of WO2004033432A1 publication Critical patent/WO2004033432A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to virazo / le compounds having high antifungal activity and useful for preventing and treating infectious diseases caused by fungi in mammals.
  • Mycosis includes superficial mycosis represented by various tinea, vulgaris, psoriasis, cutaneous candidiasis, etc., fungal meningitis, fungal respiratory infections, mycemia, urinary tract mycosis, etc. And mycosis profound.
  • deep-seated mycosis such as dysbiosis and aspergillosis, has been increasing in recent years, especially due to the frequent use of cancer chemotherapeutics and immunosuppressants, and a decrease in in vivo immunity due to HIV infection and the like. There is a need for a drug that is effective against these bacteria.
  • amphotericin B-diazole compounds such as fluconazole and itraconazole are known, but they are sufficient in terms of antifungal spectrum, pharmacokinetics, resistance and the like. Not satisfactory.
  • azole compounds which have been studied for many years in this field, have different structures from conventional compounds because of the problems of their effectiveness in severe patients and resistance to long-term use of the same drug. It is desired to develop a compound having excellent antibacterial activity against deep mycosis and excellent safety.
  • an object of the present invention is to provide a virazole compound which is highly safe and has an effective antifungal activity against deep mycosis and superficial mycosis.
  • the present invention provides the following general formula (I)
  • R 1 represents an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic group which may have a substituent
  • R 3 represents a hydrogen atom, an alkyl group, an alkenyl group, a substituted or unsubstituted biphenyl group, or a substituted or unsubstituted heteroaromatic ring group
  • R 2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, a CH 2 OH group or a CH 2 NR 6 R 7 group ( R 6 and R 7 represents a) the same or different and each represents a hydrogen atom or a lower alkyl group;.
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, Ashiru group, a lower alkyl group, a cycloalkyl group or Fueniruaru It may have, or R 4 and R 5 indicates a Le group to form a lower alkylenedioxy O alkoxy group with together such connexion two oxygen atoms; X represents a methine group or a nitrogen atom).
  • the present invention also provides a pyrazole compound represented by the general formula (I) or a salt thereof. It is intended to provide a medicine as an active ingredient.
  • the present invention also provides a pharmaceutical composition containing the pyrazole compound represented by the general formula (I) or a salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides use of the pyrazole compound represented by the general formula (I) or a salt thereof for producing a medicament.
  • the present invention provides a method for treating a fungal infection, which comprises administering an effective amount of the pyrazole compound represented by the general formula (I) or a salt thereof.
  • the pyrazole aldehyde compound represented by the general formula (I) of the present invention may be a fungal disease, particularly a deep fungal disease caused by fungi such as Candida and Aspergillus and a superficial fungus caused by fungi such as trichophyton. It is useful as a prophylactic or therapeutic agent for diseases.
  • the alkyl group represented by R 1 and R 3 is preferably an alkyl group having 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms, and particularly preferably 1 to 6 carbon atoms.
  • the alkyl group may be linear or branched, and examples thereof include a methyl group, an ethyl group, an isopropyl group, an n-butyl group, an n-hexyl group, and an n-octyl group.
  • the alkenyl group is preferably an alkenyl group having 2 to 16 carbon atoms, more preferably 2 to 10 carbon atoms, and particularly preferably 2 to 6 carbon atoms.
  • the alkenyl group may be linear or branched, and includes, for example, a butyl group, a propenyl group and a pentyl group.
  • Examples of the substituent on the phenyl group, biphenyl group and heteroaromatic group represented by R 1 and R 3 include a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitrile group, and a NR.
  • R 8 and R 9 group may be the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkoxyalkyl group, or R 8 and R 9 together with a nitrogen atom have a substituent May form a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group or a thiomorpholinyl group.), A halogeno-lower alkyl group, a halogeno-lower alkoxy group, a lower-alkylthio group, an acyl group, a carboxy group Xyl groups, lower alkoxycarbonyl groups, rubamoyl groups, N-lower alkyl rubamoyl groups, N, N-di-lower alkyl rubamoyl groups and the like.
  • substituents may be on the phenyl, biphenyl or heteroaromatic groups: You may have up to three.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the lower alkyl group an alkyl group having 1 to 6 carbon atoms, particularly an alkyl group having 1 to 4 carbon atoms is preferable. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group.
  • the same may be mentioned as the lower alkyl group represented by R 8 and R 9 .
  • an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms is preferred, and specific examples include a methoxy group, an ethoxy group, an isopropyloxy group, and a butoxy group.
  • a CM alkoxy-C 6 alkyl group, particularly a C W alkoxy monoalkyl group is preferred, and a methoxyethyl group, a methoxypropyl group, an ethoxyshetyl group, and an ethoxypropyl group are preferred. And the like.
  • NR 8 R 9 groups include amino group, dimethylamino group, ethylamino group, methoxypropylamino group, pyrrolidinyl group, 3-oxopyrrolidinyl group, piperidinyl group, piperazinyl group, N-phenylpipe Radinyl group, morpholino group, thiomorpholino group and the like can be mentioned.
  • halogeno lower alkyl group an alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, which is substituted by 1 to 3 halogen atoms is preferable.
  • Specific examples are chloromethyl group, trifluoromethyl group, and chloromethyl group.
  • a tyl group As the halogeno lower alkoxy group, an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, which is substituted by 1 to 3 halogen atoms is preferable, and a specific example is a trifluoromethoxy group.
  • a lower alkylthio group and
  • an alkylthio group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, is preferable, and specific examples include a methylthio group, an ethylthio group, and an isopropylthio group.
  • an acyl group an alkenyl group having 2 to 6 carbon atoms is preferable, and examples thereof include an acetyl group and a propionyl group.
  • the lower alkoxycarbonyl group an alkylcarbonyl group having a total of 2 to 7 carbon atoms is preferable, and specific examples include a methoxycarbonyl group and an ethoxycarbonyl group.
  • heteroaromatic ring group represented by R 1 and R 3 a 5-membered ring group, a 6-membered ring group or a 9- to 12-membered ring having 1 to 4 hetero atoms selected from oxygen, nitrogen and sulfur atoms And a condensed ring group of Examples of the five-membered ring include thiophene, furan, pyrrole, thiazole, imidazole, pyrazole, oxazole, triazole and the like. Examples of 6-membered rings include pyridine, pyrimidine, pyrazine, triazine and the like. Examples of the condensed ring include benzothiazole, benzimidazole, benzoxazole and the like.
  • an alkyl group having 1 to 6 carbon atoms is preferable, and specifically, a methyl group, an ethyl group, and an n-propyl group Isopropyl group, n-butyl group, tert-butyl group and the like.
  • the lower alkoxy group represented by R 2 is preferably an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, and specific examples include a methoxy group, an ethoxy group, an isopropyloxy group and a butoxy group.
  • an alkanol group having a total of 2 to 7 carbon atoms is preferable, and specific examples include a methoxycarbonyl group and an ethoxycarbonyl group.
  • An CH 2 NR f 'R 7 group represented by R 2 aminomethyl group, dimethyl ⁇ amino methyl, Mechirua Minomechiru group, Jefferies chill ⁇ amino methyl group, and the like.
  • an alkanoyl group having 2 to 6 carbon atoms is preferable, and examples thereof include an acetyl group and a propionyl group.
  • the cycloalkyl group represented by R 4 and R 5 is preferably a cycloalkyl group having 3 to 6 carbon atoms, For example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the like can be mentioned.
  • the phenylalkyl group represented by R 4 and R 5, phenylene rules CM alkyl Le group is preferred, for example, base Njiru group, phenethyl group, phenylpropyl group and the like.
  • As the lower alkylenedioxy group an alkylenedioxy group having 1 to 3 carbon atoms is preferable, and examples thereof include a methylenedioxy group and an ethylenedioxy group.
  • the dissociated ion of the pyrazole compound (I) is different depending on the pyrazole derivative (I) on which the pyrazole compound (I) is based, and when the pyrazole compound (I) is basic, hydrochloride, nitrate, Hydrobromide, p-toluenesulfonate, methanesulfonate, fumarate, maleate, malonate, succinate, citrate, tartrate, etc., and pyrazole compounds (I When) is acidic, sodium salts, potassium salts, ammonium salts and the like can be mentioned.
  • the pyrazole compound (I) or a salt thereof may exist in the form of hydrates and various solvates, and these hydrates and solvates are also included in the present invention. Further, the pyrazole compound (I) or a salt thereof may have an isomer in some cases, and the present invention includes a mixture of the isomers, an optically active substance, and the like.
  • the pyrazole compound represented by the general formula (I) of the present invention is obtained, for example, by condensing an aromatic aldehyde (1) and a ketone (2) into an enone (3) as shown below, and converting the enone (3) into hydrazine. It is produced by reacting with (4) to obtain pyrazoline (5) or hydrazone (6), which is then oxidized.
  • R 4 and R 5 of the pyrazole compound (I) are a benzyl group or a methyl group, and R 4 and R 5 are joined together to form an alkylene group, O—R 4 and.
  • the pyrazole compound (I) is also produced by adding R 4 and R 5 to two hydroxyl groups of the pyrazole compound (I).
  • Enone (3) can be obtained by converting an aromatic aldehyde (1) and a ketone (2) into an alcohol such as methanol or ethanol in sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, potassium hydroxide or potassium hydroxide.
  • Aqueous solution, hydroxide It can be obtained by reacting at room temperature for 10 to 24 hours in the presence of thorium or an aqueous solution thereof, a base such as pyridine, piperidine and pyrrolidine, or an acid such as acetic acid and sulfuric acid. Alternatively, it can be obtained by reacting at room temperature for 10 to 24 hours in the presence of a base such as pyridine, piperidine and pyrrolidine and an acid such as acetic acid.
  • the ketone (2) is converted to a Honey-Emmons reagent or a Wittig reagent (for example, J, Org. Chem. 1986, 51 (231,4342. Synthesis 1985 (11), 1048, J. Org. Chem. 1968, 33,
  • the enone (3) can be obtained by heating at room temperature to 100 ° C in the presence of an appropriate base in a solvent such as 3504) and an aromatic aldehyde (1) and dimethylformamide or tetrahydrofuran.
  • aromatic aldehyde (1) and the ketone (2) are commercially available, but may be produced by a known method.
  • hydrazine (4) is commercially available, it is manufactured by the method described in “New Experimental Chemistry Lecture 14” edited by The Chemical Society of Japan, and synthesis and reaction of organic compounds III, p.1573-1585 (1985) or a modified method thereof. You may do it.
  • Virazolin (5) or hydrazone (6) is dissolved in a solvent such as toluene, benzene, xylene, or acetic acid, in a solvent such as 2,3-dichloromethane_5,6-dicyano-1,4-benzoquinone (DDQ), chloranil, and superatom.
  • a solvent such as toluene, benzene, xylene, or acetic acid
  • DDQ 2,3-dichloromethane_5,6-dicyano-1,4-benzoquinone
  • chloranil chloranil
  • the pyrazole (I) can be isolated from the final reaction mixture by a conventional method, for example, solvent extraction, recrystallization, column chromatography, or the like.
  • R 1 in the general formula (I) is a phenyl group which may have a substituent, a biphenyl group which may have a substituent, or a heteroaromatic ring group which may have a substituent, It is also produced by the following reaction formula.
  • R 1 ⁇ represents a phenyl group, a biphenyl group or a heteroaromatic ring which may have a substituent, wherein the substituent is the same as the substituent of the phenyl group in which R 1 has a substituent.
  • Y represents a chlorine atom, a bromine atom or an iodine atom, and R 2 , R 3 , R 4 , R 5 and X are as defined above.
  • the aromatic aldehyde (1) and the ketone (2) are condensed to obtain an enone (3), which is then reacted with hydrazine, and then oxidized to obtain a pyrazole (7).
  • 7) is subjected to a coupling reaction using copper (for example, J. CH CH. S0C. 2002, 124/7421), followed by separation of positional isomers to obtain pyrazole compound (I) -12.
  • the ligand used in this coupling reaction include N, ⁇ '-dimethylethylenediamine, trans- ⁇ , ⁇ 'dimethyl-1,2-cyclohexanediamine, and the like.
  • the pyrazole compound (I) -2, (I) -13 can be isolated from the final reaction compound by a conventional method, for example, solvent extraction, recrystallization, column chromatography, etc.
  • the pyrazole compound (I) or a salt thereof thus obtained has an excellent antibacterial activity against various fungi, as shown in Examples described later, and has a superficial and deep fungal infection to mammals including humans. It is useful as a drug for the prevention and treatment of diseases.
  • compositions containing one or more of the pyrazole compound (I) or a pharmaceutically acceptable salt thereof are usually prepared using carriers, excipients, and additives used in formulation. Tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, vaginals, ointments, creams, gels, patches, etc., orally or parenterally Administered.
  • the excipient and, if necessary, a binder, a disintegrant, a bulking agent, a coating agent, a sugar-coating agent, etc. are added to the pyrazole compound (I).
  • the pyrazole compound (I) is previously dissolved in an aqueous carrier such as distilled water for injection, dispersed, emulsified, etc. to make a liquid, or a powder for injection for dissolution before use. do it.
  • Administration methods for injections include intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, and intravenous infusion.
  • the pyrazole compound (I) is dissolved, dispersed, or emulsified in an aqueous or oily base to prepare an ointment, cream, liquid, or gel. What should I do?
  • the dose of the pyrazole compound (I) to a human varies depending on the state of infection and the method of administration.
  • oral administration of about 0.01 to 1 : L 0 O mg / kg / day, preferably about 0.1 to 50 mg / kg / day. More preferably, it is about 1-2 Omg / kg / day.
  • Getyl 2-oxo-2-phenylphenylphosphonate 0.45 g (1.76 wake 1) was dissolved in 2 mL of tetrahydrofuran (THF), and sodium hydride 0.07 at 0 ° C under an argon stream. g (1.76 mmol) was added and stirred for 10 minutes. Then, a solution of 0.28 g (1.41 liters) of 6-formyl-14-methoxy-3-pyridinyl acetate in 2 mL of THF was added dropwise and stirred at 0 ° C. for 1 hour. After the completion of the reaction, the reaction product was poured into water and extracted with ethyl acetate.
  • THF tetrahydrofuran
  • the hydrazone (6) shown in Table 14 was produced.
  • reaction mixture was dissolved in ethyl acetate, washed with an aqueous solution of ImolZL sodium hydroxide, water and saturated saline in that order, dried over sodium sulfate, and the solvent was distilled off.
  • the residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give 1.41 g (93.0) of the title compound as an oil.
  • the compound was obtained from compound 107 in the same manner as compound 70 (26.0%).
  • reaction solution was extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate and saturated saline in that order, dried over sodium sulfate, and the solvent was distilled off.
  • the residue was purified by silica gel chromatography (chloroform: hexane 3: 1). 5 mL of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 0.5 hour.
  • the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, washed successively with saturated sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and evaporated.
  • Table 23 shows the pyrazole compounds (I) obtained in Examples 14 to 23.
  • Test compound solution The test compound was dissolved in dimethyl sulfoxide (DMSO) to make a solution of up to 6.4 mg / mL, and diluted with DMSO to prepare a two-fold dilution series. These solutions were added to the test medium at a rate of 1% (v / v).
  • DMSO dimethyl sulfoxide
  • Test medium 10.44 g of RPMI 1640 was dissolved in 90 OmL of distilled water, and dissolved by adding a MOPS buffer (0.165 M). Next, the pH was adjusted to 7.0 with a 5 mol ZL sodium hydroxide aqueous solution, and distilled water was added to make 100 OmL.
  • Inoculum C. albicans AT CC 90028 and C. krusei ATCC 6258 were cultured on Sabouraud dextrose agar medium at 35 ° C for 24 hours, and then subcultured once more under the same conditions. Five colonies were picked and suspended in 5 mL of sterile physiological saline. After adjusting the permeability of the suspension to McFarland O.5, the suspension was diluted 1000-fold with a test medium to obtain an inoculum.
  • Antifungal activity measurement Dispense 100 ⁇ L of each concentration dilution of the sample in the test medium into each well of a 96-well round bottom microplate, and add 100 ⁇ L of the inoculated bacterial solution described above (final bacterial concentration: 0.5 2.52.5 ⁇ 10 3 cells / mL) at 35 ° C. for 48 hours. After the culture was completed, the absorbance at 60 Onm was measured, and the minimum drug concentration that inhibited the growth of the bacteria by 80% or more compared to the control without drug was defined as MIC (ii g / niL).
  • Test compound solution and test medium In accordance with the above-mentioned method for measuring in vitro antifungal activity against C. albicans and C. krusei.
  • Inoculated spore fluid Aspergillus ilavus I FM41 935 and A, fumigatus I FM For 40808, after culturing on a potato dextrose agar medium at 27 ° C for 7 days, spores were suspended in sterile saline containing 0.05% (w / v) Tween 80, and a cell strainer (pore size: 70 m) was used. Passed through. This was prepared using a test medium to a concentration of 6.0 ⁇ 10 4 conidia / mL. The medium was supplemented with alamar Blue TM to a final concentration of 10% (w / v). For Trichophyton mentagrophytes IF40769 and T.
  • rubrum IFO6204 a high salt medium (neopeptone 0.1% (w / v), glucose 0.2% (w / v), magnesium sulfate v), potassium dihydrogen phosphate 0.1% (w / v), agar 2.0% (w / v)) at 27 ° C for 14 days, and then sterilized with 0.05% (w / v) Tween 80 suspended spores in physiological saline to prepare this P having passed through the cell stra INER 2. with 0 x 10 5 conidia / mL test culture areas to a concentration of.
  • Antifungal activity measurement Dispense 100 ⁇ L of each concentration dilution of the sample in the test medium into each well of a 96-well round bottom microplate, add 100 L of the inoculated spore solution described above, and use Aspergillus fungus at 35 ⁇ l. 48 h (final spore concentration: 3. Ox 10 4 conidia / m L), Trichophyton Shokumakin at 27 ° C 72 h (final spore concentration: 1. Ox 10 5 conidia / m L) and cultured.
  • the absorbance (ref: 600 ⁇ ) of 57 Onm was measured for Aspergillus spp., And visually determined for Trichophyton spp., The growth of the fungus was suppressed by 50% or more compared to the drug-free control.
  • the minimum drug concentration was MIC (/ ig / mL).
  • Table 24 shows the results of measurement of the antifungal activity MIC (xg / mL) of the compound of the present invention and the control drug. Table 2 4
  • C. alb Candida albicans ATCC 90028
  • the compounds of the present invention exhibited excellent antibacterial activity against various deep mycosis and the causative bacteria of superficial mycosis.
  • aspergillus was confirmed to have significantly better antibacterial activity than the control drug fluconazole.

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Abstract

La présente invention concerne un composé de pyrazole représenté par la formule générale suivante (I) ou son sel, ainsi qu'un médicament contenant ledit composé en tant que principe actif. Dans la formule (I), R1, R2, R3, R4 et R5 représentent chacun un substituant ; et X représente un groupe méthine ou un atome d'azote. Ledit composé est utile en tant qu'agent préventif ou remède contre la mycose, notamment, la mycose profonde provoquée par des champignons profonds tels que candida et aspergillus et la mycose superficielle provoquée par des champignons tels que trichophyton.
PCT/JP2003/012856 2002-10-09 2003-10-08 Nouveaux composes de pyrazole presentant une activite antifongique WO2004033432A1 (fr)

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JP2004542837A JP4537855B2 (ja) 2002-10-09 2003-10-08 抗真菌活性を有する新規ピラゾール化合物
AU2003271117A AU2003271117A1 (en) 2002-10-09 2003-10-08 Novel pyrazole compounds having antifungal activity

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Cited By (32)

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WO2007002559A1 (fr) * 2005-06-27 2007-01-04 Exelixis, Inc. Modulateurs des lxr a base de pyrazoles
WO2007052615A1 (fr) 2005-10-31 2007-05-10 Eisai R & D Management Co., Ltd. Dérivé de pyridine substitué par un hétérocycle et fongicide contenant celui-ci
WO2008045663A2 (fr) * 2006-10-06 2008-04-17 Kalypsys, Inc. Inhibiteurs hétérocycliques de pde4 aryl-substitués
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JPWO2019220962A1 (ja) * 2018-05-18 2021-02-18 富士フイルム株式会社 ３−ジフルオロメチルピラゾール化合物の製造方法及び３−ジフルオロメチルピラゾール−４−カルボン酸化合物の製造方法、並びに、ピラゾリジン化合物
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