WO1995034542A1 - Compose de triazole et agent antifongique contenant ledit compose en tant qu'ingredient actif - Google Patents

Compose de triazole et agent antifongique contenant ledit compose en tant qu'ingredient actif Download PDF

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Publication number
WO1995034542A1
WO1995034542A1 PCT/JP1995/001166 JP9501166W WO9534542A1 WO 1995034542 A1 WO1995034542 A1 WO 1995034542A1 JP 9501166 W JP9501166 W JP 9501166W WO 9534542 A1 WO9534542 A1 WO 9534542A1
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WO
WIPO (PCT)
Prior art keywords
triazole
ethyl
thio
benzoyl
difluorophenyl
Prior art date
Application number
PCT/JP1995/001166
Other languages
English (en)
Japanese (ja)
Inventor
Masazumi Tomari
Osamu Sakuma
Hiroyuki Ohto
Kazuhiko Nagaoka
Michinori Tsuji
Original Assignee
Tokyo Tanabe Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tokyo Tanabe Company Limited filed Critical Tokyo Tanabe Company Limited
Priority to AU26307/95A priority Critical patent/AU2630795A/en
Publication of WO1995034542A1 publication Critical patent/WO1995034542A1/fr

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the compound of the present invention relates to a triazole compound having antifungal activity.
  • the present inventors have intensively studied to find compounds having more effective antifungal activity and safety, and found that newly synthesized triazole compounds and physiologically acceptable salts thereof are: Not only has a strong antifungal effect against Candida spp. Was found to be extremely low and had excellent safety, and reached the present invention.
  • a triazole compound useful as an antifungal agent is provided.
  • the present invention has the following general formula (I)
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a methyl group, a 4-methyl-4-H-1,2,4-triazole-3-yl group or a (4-methyl-4H-1,2 , 4-triazolyl-3-yl) represents a methyl group
  • R 3 represents a hydrogen atom or a methyl group
  • m and n represent 0 to 2.
  • triazole compound of the present invention examples include (2R *, 3R *)-2- (2,4-difluorophenyl) 13- [1- [4-1 (methylsulfonyl) benzoyl] ethyl ] Thio 1- (1H- 1,2,4-triazole-1-yl) butane 1- 2-ol, (2R .3R *)-2-(2,4-difluorophenyl)-3-[(1R- 1- [4-(Methylsulfonyl) benzoyl] ethyl] Thio 1- (1H- 1,2,4-triazo-1-yl) Butane 1- 2-year-old (2R, 3R) 1 2 — (2,4-difluorophenyl) 1 3— [(1S *) 1 1 1 [4 (Methylsulfonyl) benzoyl] ethyl] Thio 1 1 (1H 1 1,2,4 1 Triazo 1 1 1 ) 1-butane
  • the triazole compound (I) of the present invention has at least one asymmetric center.
  • optical isomers exist, each of which or a mixture thereof is included in the present invention.
  • the physiologically acceptable salts of the triazole compound (I) of the present invention include salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acetic acid, tartaric acid, and the like.
  • examples thereof include salts with organic acids such as fumaric acid, maleic acid, lingoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid, and salts with alkali metals such as sodium and potassium. Hydrates of the triazole compound (I) and a physiologically acceptable salt thereof are also included in the present invention.
  • the triazole compound (I) of the present invention can be produced according to the following reaction steps (wherein R ′′, R 3 , m and n are as defined above unless otherwise specified).
  • the epoxy compound ( ⁇ ) is dissolved in a solvent, and the thiol ketone compound (III) is dissolved in the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, and metal sodium.
  • a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, and metal sodium.
  • the solvent methanol, ethanol, propanol, butanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF;), benzene, toluene and the like are used.
  • the reaction temperature is from 120 ° C to the boiling point of the solvent, preferably from room temperature to 120 ° C.
  • the diastereomer (epima-1) formed is subjected to the usual separation method such as column chromatography and fractional recrystallization.
  • a base such as carbonated sodium, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, etc.
  • V halogenoketone
  • the triazole compound (I) (m 0).
  • the solvent methanol, ethanol, propanol, butanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene and the like are used.
  • the reaction temperature is from 130 ° C to the boiling point of the solvent, preferably from 110 to 0.70 ° C.
  • optically active thiol form (IV) is obtained from (2R *, 3R *) or (2R *, 3S *)-thiol form (IV) and an acid chloride of a suitable optically active organic acid such as N-tosylproline.
  • a suitable optically active organic acid such as N-tosylproline.
  • the resulting diastereomer may be reacted with the optically active organic acid in the presence of a suitable dehydrating condensing agent such as dicyclohexylcarposimide, and the resulting diastereomer may be subjected to a commonly used separation method such as column chromatography, fractional recrystallization, etc. And then hydrolyzed for production.
  • the sulfonate form (VI) is dissolved in a solvent, and the thiol ketone form ( ⁇ ) is dissolved in the presence of a base such as potassium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metallic sodium.
  • a base such as potassium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metallic sodium.
  • a base such as potassium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metallic sodium.
  • a base such as potassium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metallic sodium.
  • a base such as potassium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metallic sodium.
  • To produce the triazole compound (I) (m 0).
  • the solvent methanol, ethanol
  • a suitable protecting group usually used for a carbonyl group for example, a thiol ketone (VIII) protected by acetal is dissolved in a solvent, and potassium carbonate, carbonate After treatment with a base such as sodium, hydroxide hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, and the like, it is reacted with -halogenopropiononone (VII) to form an intermediate ( IX).
  • a base such as sodium, hydroxide hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, and the like
  • an epoxy compound (X) is produced, and then an alkali metal salt of 1,2,4-triazole or 1 , 2,4-triazole and appropriate bases in the presence of bases such as sodium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metal sodium
  • bases such as sodium carbonate, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and metal sodium
  • the intermediate (XI) is produced by reacting in a solvent.
  • the diastereomer intermediate (IX) to be formed is separated by a commonly used separation method such as column chromatography, fractionation and recrystallization, and this is separated with dimethyl sulfonium methylene.
  • a commonly used separation method such as column chromatography, fractionation and recrystallization
  • dimethyl sulfonium methylene By reacting with dimethyl or dimethyloxosulfonium methylide, the diastereomer (epima) epoxy compound (X) is produced.
  • This epoxy compound (X) is separated by a commonly used separation method such as column chromatography, fractional recrystallization and the like, and then 1,2,4-triazole metal salt or 1,2,4-triazole and carbonic acid are separated.
  • An optically active intermediate by reacting in a suitable solvent in the presence of a base such as sodium, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, and metal sodium.
  • a base such as sodium, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, and metal sodium.
  • the diastereomer (epimer) epoxy compound (X) can be converted by an ordinary method.
  • the compound ( ⁇ ) is reacted with an equimolar amount of a base such as sodium metal, sodium hydride, and potassium tert.-butoxide, and then reacted with an equimolar amount of methyl halide to obtain a triazole compound (I ) Can be manufactured.
  • a base such as sodium metal, sodium hydride, and potassium tert.-butoxide
  • An optically active compound ( ⁇ ) is reacted with an equimolar amount of a base such as sodium, sodium hydride, or potassium tert.-butoxide, and then reacted with an equimolar amount of methyl halide.
  • a lyazole compound (I) (a diastereomer (epima-1)) can be produced. This is performed using commonly used separation methods such as column chromatography and fractional recrystallization. By resolving, an optically active triazole compound (I) can be produced.
  • m-CPBA m-chloroperbenzoic acid
  • the reaction solvent chloroform, dichloromethane, carbon tetrachloride, methanol, acetic acid, ethyl acetate and the like are used.
  • the reaction temperature is from ⁇ 40 ° C. to the boiling point of the solvent, preferably from 0 ° C. to room temperature.
  • the triazole compound (I) produced by the above method can be converted to a physiologically acceptable salt by adding an appropriate acid, and can be a hydrate thereof.
  • the dose varies depending on the symptoms, age, body weight, and route of administration, but can usually be adjusted as appropriate within the range of OlSOmgZkg per day. They can also be used as external preparations such as ointments, creams, sprays, jellies, solutions, etc., and the amount added is, for example, usually in the range of 0.1 to 150 mg per gram of additive. preferable.
  • Hydrazine hydrate lO.Og was dissolved in 100 ml of methanol, and 20.8 g of ethyl glycolate was added dropwise under ice cooling while maintaining the reaction temperature at 10 ° C. After stirring at room temperature for 3 hours, the mixture was cooled on ice, and 14.6 g of methyl isothiocyanate dissolved in 10 ml of methanol was added dropwise at 10 ° C. or lower. After stirring at room temperature for 2 hours, 50 ml of ice water was added and the mixture was stirred for 15 minutes. After dropping 38 ml of a 5N aqueous sodium hydroxide solution, the mixture was stirred at room temperature for 2 hours.
  • the mixture was concentrated under reduced pressure, and extracted twice with 150 ml of ethyl acetate.
  • the ethyl acetate layers were combined, dehydrated with a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 150 ml of toluene, and extracted with 60 ml of 1N sodium hydroxide. Further, the mixture was extracted with 40 ml of water, the aqueous layers were combined, acidified with 6N hydrochloric acid, extracted twice with 100 ml of ethyl acetate, dehydrated with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.18 g of 4'-mercaptopropionophthalone.
  • mice weighing 22-26 g were infected with Candida albicans TTB 273 by injecting them from the tail vein. One hour later, the test compound was orally administered, and once after the infection 1, 2, 3, and 4, the same compound was orally administered once. The dose at which 50% of the animals survived 14 days after infection (ED5 () ) was determined. The results are shown in Table 1.
  • mice weighing 22-26 g were infected with Aspergillus fumigatus TTB 1776 injected into the tail vein. One hour later, the test compound was orally administered, and once after the infection 1, 2, 3, and 4, the same compound was orally administered once. The dose at which 50% of mice survive (ED 5 () ) It was measured. The results are shown in Table 2.
  • the compound of the present invention shows extremely high efficacy against experimental infectious diseases of Candida albicans and Aspergillus fumigas as compared with Comparative drug I and Comparative drug I. Was.
  • Test compound was orally administered to a male ICR mouse (body weight: 24-26 g) at a dose of 25 mgZkg for 5 consecutive days using an oral probe for mice. On day 6, the liver weight was measured, and the liver weight per mouse body weight was compared with the control to calculate the relative liver hypertrophy rate. The results are shown in Table 3.
  • Hepatic hypertrophy caused by drugs is caused by stimulation of drug metabolizing enzymes in the mouth and activation of the reticular system, and is considered as one of the indicators of hepatotoxicity. Therefore, measurement of hepatic hypertrophy is often used in tests to predict drug hepatotoxicity.
  • Comparative Drug B showed a significant (p ⁇ 0.005; Student t-test) In contrast, the compound of the present invention did not show significant liver hypertrophy. Comparative B showed significant liver hypertrophy (p ⁇ 0.05; Student t-test) for all of Compounds 5, 7, and 8.
  • the compound of the present invention had a strong antifungal activity against Candida albinius vaspergillus fumigatus. Furthermore, it was extremely safe.
  • the compounds of the present invention and physiologically acceptable salts or hydrates thereof are effective for treating superficial or deep mycosis in animals and humans, for example, Trichophyton 'rubrum (Trichophyton). rubrum) Microsporum canis, etc., tinea, dermatophytosis, Candida 'Candida albicans, etc., aspergillosis, Aspergillus fumigatus, Aspergillus', etc.
  • Coccidioides immitis which is called imported mycosis
  • Coccidioides disease caused by Coccidioides immitis
  • Histoplasmosis caused by Histoplasma capsulatum Ides Bra Zilienci It can be used for the treatment of paracoccidioides caused by paracoccidioides brasiliensis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composé de triazole de formule générale (I) ou sel ou hydrate physiologiquement acceptable dudit composé, et agent antifongique contenant ledit composé en tant qu'ingrédient actif. Dans ladite formule, R1 représente hydrogène ou méthyle, R2 représente méthyle, 4-méthyl-4H-1,2,4-triazol-3-yle ou (4-méthyl-4H-1,2,4-triazol-3-yl)méthyle, R3 représente hydrogène ou méthyle et m et n valent chacun de 0 à 2. Ces composés ont un effet antifongique remarquablement puissant et présentent une excellente sécurité, ils sont efficaces pour traiter des mycoses humaines ou animales superficielles ou profondes.
PCT/JP1995/001166 1994-06-10 1995-06-09 Compose de triazole et agent antifongique contenant ledit compose en tant qu'ingredient actif WO1995034542A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26307/95A AU2630795A (en) 1994-06-10 1995-06-09 Triazole compound and antifungal agent containing the same as active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP12843394 1994-06-10
JP6/128433 1994-06-10

Publications (1)

Publication Number Publication Date
WO1995034542A1 true WO1995034542A1 (fr) 1995-12-21

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PCT/JP1995/001166 WO1995034542A1 (fr) 1994-06-10 1995-06-09 Compose de triazole et agent antifongique contenant ledit compose en tant qu'ingredient actif

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AU (1) AU2630795A (fr)
WO (1) WO1995034542A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0332387A1 (fr) * 1988-03-04 1989-09-13 Sankyo Company Limited Dérivés du triazole, leur préparation et leur application comme fongicides
EP0421210A2 (fr) * 1989-09-26 1991-04-10 Takeda Chemical Industries, Ltd. Composés dérivés de triazole, leurs préparation et application
JPH03200773A (ja) * 1989-12-27 1991-09-02 Sumitomo Pharmaceut Co Ltd 光学活性スルフィド誘導体の取得方法
JPH03223266A (ja) * 1989-12-25 1991-10-02 Ss Pharmaceut Co Ltd トリアゾール誘導体
EP0552974A1 (fr) * 1992-01-24 1993-07-28 ROUSSEL MORISHITA Co., Ltd. Dérivé de 1-aryl-2-(1H-1,2-4-triazol-1-yl)éthanol et composition fongicide le contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0332387A1 (fr) * 1988-03-04 1989-09-13 Sankyo Company Limited Dérivés du triazole, leur préparation et leur application comme fongicides
EP0421210A2 (fr) * 1989-09-26 1991-04-10 Takeda Chemical Industries, Ltd. Composés dérivés de triazole, leurs préparation et application
JPH03223266A (ja) * 1989-12-25 1991-10-02 Ss Pharmaceut Co Ltd トリアゾール誘導体
JPH03200773A (ja) * 1989-12-27 1991-09-02 Sumitomo Pharmaceut Co Ltd 光学活性スルフィド誘導体の取得方法
EP0552974A1 (fr) * 1992-01-24 1993-07-28 ROUSSEL MORISHITA Co., Ltd. Dérivé de 1-aryl-2-(1H-1,2-4-triazol-1-yl)éthanol et composition fongicide le contenant

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AU2630795A (en) 1996-01-05

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