WO1995026343A1 - Nouveaux derives de triazole et agent antimycosique renfermant ce derive comme principe actif - Google Patents

Nouveaux derives de triazole et agent antimycosique renfermant ce derive comme principe actif Download PDF

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Publication number
WO1995026343A1
WO1995026343A1 PCT/JP1995/000597 JP9500597W WO9526343A1 WO 1995026343 A1 WO1995026343 A1 WO 1995026343A1 JP 9500597 W JP9500597 W JP 9500597W WO 9526343 A1 WO9526343 A1 WO 9526343A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
triazole derivative
triazole
alkyl group
Prior art date
Application number
PCT/JP1995/000597
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English (en)
Japanese (ja)
Inventor
Masazumi Tomari
Osamu Sakuma
Hiroyuki Ohto
Kazuhiko Nagaoka
Michinori Tsuji
Yoko Osaka
Atsushi Takagi
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.)
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Publication date
Application filed by Tokyo Tanabe Company Limited filed Critical Tokyo Tanabe Company Limited
Priority to AU20839/95A priority Critical patent/AU2083995A/en
Publication of WO1995026343A1 publication Critical patent/WO1995026343A1/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 derivative having antifungal activity.
  • the present invention provides a compound represented by the following general formula (I): One R 3
  • R 1 and R 2 each represent a hydrogen atom, a lower alkyl group or a cycloalkyl group, or R 1 and R together represent an alkylene group
  • R 3 represents a lower alkyl group or a cycloalkyl group.
  • R 4 represents a hydrogen atom or a lower alkyl group;
  • X 1 represents a hydrogen atom, a halogen atom or
  • X 2 represents a hydrogen atom or a halogen atom, and
  • n represents 0 to 2.
  • the lower alkyl group may be a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert.-butyl group, a pentyl group, a hexyl group.
  • Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group; and alkylene groups such as methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, etc.
  • alkyl group having a double bond examples include a prenyl group, a geranyl group, and a phenyl group.
  • optionally substituted heterocyclic ring such as a nesyl group examples include 4-methyl-4H—1,2,4-triazolyl-3-yl group and 4H—1,2,4— Rear zone 3-inole group, imidazo group 2-inole group, imidazo group 41-yl group, tetrazole-5-yl group, 2-furyl group, 3-furyl group, 2 —Chenyl group, .3 —Cenyl group, thiazol-2-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2 — (methylsulfonyl) pyridin-5-yl Group, 2 — (methylsulfinyl) pyridin — 5 —yl group, 2 — (methylthio) pyridin-1-y
  • Examples of the group (—NR “R 6 ) include (3,5 dichloro-m-pyridin-2-yl) amino, (1-ethylfurazol-3-yl) amino, and (5— Methyl-1,3,4-thiadiazol-2-yl) amino group, (2-methoxypyridine-1-yl) amino group, (3 1-methylisothiazol-5-yl) amino group, (5-methylisoxazol-3-yl) amino group, (4-methylthiazol-2-yl) amino group, (thiazole-2— Amino group, (1,2,4—triazine--3-yl) amino group, (5-trifluoromethyl-1,3,4-thiadiazol-2-yl) amino And the like.
  • the triazole derivative (I) of the present invention has at least one asymmetric center, and has a plurality of optical isomers and diastereomers, each of which or a mixture thereof is included in the present invention.
  • the physiologically acceptable salts of the triazole derivative (I) of the present invention include salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, phosphoric acid, acetic acid, tartaric acid, fumaric acid and the like.
  • examples thereof include salts with organic acids such as acid, maleic acid, lingic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid, and salts with alkali metals such as sodium and potassium. Hydrates of the triazole derivative (I) and physiologically acceptable salts thereof are also included in the present invention.
  • the triazole derivative (I) of the present invention can be produced according to the following reaction steps (in each formula, RRR′RRRRXX 2 and n are as defined above.)
  • the epoxy compound (II) described in Japanese Patent Application Laid-Open No. 4-74168 is dissolved in a solvent, and carbonic acid lime, sodium carbonate, hydroxylic lime, sodium hydroxide, and potassium tert. — Presence of bases such as butoxide and metallic sodium
  • a solvent methanol, ethanol, propanol, butanol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene, or the like is used.
  • the reaction temperature is from 120 ° C to the boiling point of the solvent, preferably from room temperature to 120 ° C.
  • optically active epoxy material (II) and Chio one Luque tons member (III) after the (R 1 and R 2 are different) was reacted under the same conditions, resulting Jiasutereo mer (Epima) the Karamukuroma bets chromatography
  • Oxidizing agent eg, m-CPBA, hydrogen peroxide
  • the solvent methanol, ethanol, propanol, butanol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene and the like are used.
  • the reaction temperature is from ⁇ 30 ° C. to the boiling point of the solvent, and preferably from 110 to 70 ° C.
  • optically active thiol body (IV) and Harogenoke tons bodies (V) (R 1 are different) was reacted under the same conditions, resulting Jiasutereoma (E Pima) the Karamukuroma bets chromatography, fractional recrystallization, etc.
  • optically active thiol body (IV) is, (2 R-, 3 R * ) or (2 R *, 3 S ⁇ ) Chioru body and (IV) Nyu- Toshirupuro suitable optically active, such as Li down
  • an organic acid or its acid chloride with an appropriate dehydrating condensing agent such as hexylcarbodiimide
  • the obtained diastereomer is usually used in column chromatography, fractional recrystallization and the like. After splitting by a splitting method, it can be produced by hydrolysis.
  • the sulfonate (VI) is dissolved in a solvent, and the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, etc.
  • a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, etc.
  • 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 0 to 120 ° C.
  • Oxidizing agent eg, m-CPBA, hydrogen peroxide
  • An appropriate protecting group for a carbonyl group such as a thiol ketone compound (VIII) protected by acetal, is dissolved in a solvent, and potassium carbonate, sodium carbonate, hydroxylated sodium hydroxide, sodium hydroxide, and potassium hydroxide are dissolved in a solvent.
  • a base such as tert. butoxide, metal sodium, etc.
  • a healogenop-opened piofunone compound (VII) to produce an intermediate (IX).
  • an epoxy compound (X) is produced, and then an alkali metal salt of 1,2,4-triazole or 1,2, Suitable solvents in the presence of 4 -triazole and bases such as carbon dioxide, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and sodium metal to produce the intermediate (XI).
  • the diastereomer intermediate (IX) formed is separated by column chromatography and fractionation.
  • An epoxy compound (X) which is a diastereomer (epimer) is produced by a separation by a commonly used separation method such as a recrystallization method, and a reaction of this with dimethylsulfonium methylide or dimethyloxosulfonium methylide. .
  • a base such as sodium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, etc.
  • Intermediate (XI) can be produced by reacting 1-triazole-1-methyl) methyl magnesium halide.
  • an optically active intermediate ( ⁇ ) is used, the diastereomer (epimer) intermediate (XI) to be formed is separated by a commonly used separation method such as column chromatography, fractional recrystallization, etc.
  • R 1 is a thigh alkyl group and R 2 is a hydrogen atom
  • Oxidizing agent eg, m-CPBA, hydrogen peroxide
  • R 1 and R 2 in the triazole derivative (I) are a hydrogen atom, such as sodium metal, sodium hydride and potassium tert.-butoxide in an equivalent mole to the triazole derivative (I).
  • R 1 and R 2 in the triazole derivative (I) are a hydrogen atom, such as sodium metal, sodium hydride and potassium tert.-butoxide in an equivalent mole to the triazole derivative (I).
  • the triazole derivative (I) is reacted.
  • a base such as sodium metal, sodium hydride, potassium tert.-butoxide of about 2 moles
  • the triazole derivative (I) can be produced.
  • 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 0 to 120 ° C.
  • a peroxide such as m-chloroperbenzoic acid (m-CPBA) or hydrogen peroxide. It can be synthesized by reacting with an oxide.
  • m-CPBA m-chloroperbenzoic acid
  • the reaction temperature ranges from 140 ° C to the boiling point of the solvent, and is preferably from 0 ° C to room temperature.
  • the triazole derivative (I) of the present invention can be converted into a physiologically acceptable salt by adding an appropriate acid or base.
  • the compounds of the present invention can be used as such or in combination with commonly used pharmaceutical additives. It can be administered orally or parenterally in the form of tablets, capsules, powders, granules, injections, syrups, suspensions, emulsions, suppositories, etc. Although it depends on the body weight and the route of administration, it can usually be adjusted appropriately within the range of 0.1 llS OmgZkg 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, 0.1 to 1 g per 1 g of additives. A range of 50 mg is preferred. BEST MODE FOR CARRYING OUT THE INVENTION
  • 3-Propionyl-1-4-methyl-4H-1,2,4-triazonole 4-methyl-4H-1,2,4-triazonole 1.65 g is added to tetrahydrofuran (80 ml). After dissolving, 25.9 ml of lithium bis (trimethylsilyl) amide (1 M tetrahydrofuran solution) was added dropwise at 125 ° C. under a stream of argon over 5 minutes. Thereafter, the mixture was stirred at ⁇ 20 to ⁇ 25 ° C. for 15 minutes, cooled to 130 ° C., and N, N-dimethylpropionamide 2.84 ml was added dropwise over 1 minute.
  • Example 2 obtained in Example 2 (2R *, 3R- ) — 2— (2,4-difluorophenyl) 1 3— [1.-[(4-Methyl-4H—1,2,4-triazole-1-3-yl) carbonyl] ethyl] thiol 70 mg of 1- (1H-1,2,4-triazole-1yl) butan-2-ol (diastereomer B) was dissolved in chloroform (5 ml) and allowed to stand at room temperature.
  • Example 1 According to Example 1, 2 or 4, the compounds described in Examples 6 to 12 in Tables 1 to 6 were synthesized.
  • Example 13 the compounds described in Examples 14 to 15 in Tables 7 to 8 were synthesized.
  • 2,4-triazo-1-yl) butane-2-ol (Compound No. 10): (2R, 3R) -12- (2,4-difluorophenyl) -13- under an argon gas stream Dissolve 0.40 g of mercapto-11- (1H-1,2,4-triazo-1-yl) tan-2-ol in ethanol (20 ml) and add potassium t under ice-cooling. — 0.58 g of toxide was added. Then, 0.66 g of 4- (2-lomopropionyl) pyridine hydrobromide was added, and the mixture was stirred for 2 hours.
  • the compounds of the present invention and physiologically acceptable salts thereof are effective in treating superficial or deep mycosis in animals and humans, and include, for example, Trichophyton * Noref "Norem (T richophytonrubrum), microspornolem., tinea due to force varnish (Microsporum canis), dermatophytosis, candidiasis due to Candida a bicans (C andidaa 1 bicans), etc., Aspergillus fumigatus.
  • Coccidioidesi mititis Cocciidioidesi mmitis, called imported mycosis
  • Coccidioidomycosis Coccidioidomycosis
  • Histoplasma and Rivus ratum Histop 1 asmacap su 1 atum
  • ICR male mice (weighing 22 to 26 g) were infected with Candida albicans TTB273 from the tail vein. One hour later, 1 mg of the test compound was orally administered, and 1 day, 2, 3, and 4 days after the infection, the compound was orally administered once a day. The average number of surviving days was measured after 14 days of infection. Table 9 shows the results.
  • mice weighing 22 to 26 g were infected with Aspergillus fumigas (Aspergii11usfmuigatus) TTB1776 injected from the tail vein. One hour later, 40 mg / kg of the test compound was orally administered, and further, once a day, once, two, three, and four days after the infection. The average number of surviving days was measured 14 days after infection. Table 10 shows the results. Table 10
  • test compound (compounds 1 to 9) was administered to ICR male mice (body weight 24,426 g) at 400 mg / kg for 5 consecutive days using an oral probe for mice. No cases were found.
  • the compound of the present invention has extremely high efficacy against experimental infections of Candida albicans and experimental infections of Aspergillus fumigatus, and is useful as an antifungal agent.

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

Abstract

Dérivé de triazole à effet antimycosique représenté par la formule générale (I), celle physiologiquement acceptable de ce dérivé et agent antimycosique renfermant ce dérivé comme principe actif: (dans laquelle R1 et R2 représentent indépendamment l'un de l'autre l'hydrogène, un alkyle inférieur ou un cycloalkyle, ou R1 et R2 sont combinés pour représenter un alkylène; R3 représente un alkyle inférieur, un cycloalkyle, un alkyle comportant une (ou plusieurs) liaisons, un hétérocycle à substitution facultative ou -NR5R6; R5 représente l'hydrogène ou un alkyle inférieur et R6 représente un hétérocycle à substitution facultative, ou R5 et R6 sont combinés pour représenter un alkylène contenant du soufre; R4 représente l'hydrogène ou un alkyle inférieur; X1 représente l'hydrogène, un halogène ou du trifluorométhyle; X2 représente l'hydrogène ou un halogène; et n correspond à un chiffre de 0 à 2). Ces substances présentent une activité antimycosique particulièrement puissante et sont utiles pour soigner les mycoses superficielles ou profondes chez l'animal comme chez l'être humain.
PCT/JP1995/000597 1994-03-29 1995-03-29 Nouveaux derives de triazole et agent antimycosique renfermant ce derive comme principe actif WO1995026343A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20839/95A AU2083995A (en) 1994-03-29 1995-03-29 Novel triazole derivative and antimycotic agent containing the same as active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/59392 1994-03-29
JP5939294 1994-03-29

Publications (1)

Publication Number Publication Date
WO1995026343A1 true WO1995026343A1 (fr) 1995-10-05

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03223266A (ja) * 1989-12-25 1991-10-02 Ss Pharmaceut Co Ltd トリアゾール誘導体
JPH04356471A (ja) * 1991-03-25 1992-12-10 Takeda Chem Ind Ltd トリアゾール化合物およびその用途
JPH054975A (ja) * 1990-08-26 1993-01-14 Sankyo Co Ltd トリアゾール抗真菌剤
JPH05230038A (ja) * 1989-09-26 1993-09-07 Takeda Chem Ind Ltd トリアゾール化合物およびその用途
JPH05345768A (ja) * 1992-06-13 1993-12-27 Nippon Nohyaku Co Ltd 新規トリアゾール化合物及び該化合物を有効成分とする抗真菌剤
JPH06128239A (ja) * 1992-02-29 1994-05-10 Nippon Nohyaku Co Ltd 新規トリアゾール化合物及び該化合物を有効成分とする抗真菌剤
JPH06247944A (ja) * 1992-12-28 1994-09-06 Sumitomo Pharmaceut Co Ltd 新規な１，２，４−トリアゾール誘導体

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05230038A (ja) * 1989-09-26 1993-09-07 Takeda Chem Ind Ltd トリアゾール化合物およびその用途
JPH03223266A (ja) * 1989-12-25 1991-10-02 Ss Pharmaceut Co Ltd トリアゾール誘導体
JPH054975A (ja) * 1990-08-26 1993-01-14 Sankyo Co Ltd トリアゾール抗真菌剤
JPH04356471A (ja) * 1991-03-25 1992-12-10 Takeda Chem Ind Ltd トリアゾール化合物およびその用途
JPH06128239A (ja) * 1992-02-29 1994-05-10 Nippon Nohyaku Co Ltd 新規トリアゾール化合物及び該化合物を有効成分とする抗真菌剤
JPH05345768A (ja) * 1992-06-13 1993-12-27 Nippon Nohyaku Co Ltd 新規トリアゾール化合物及び該化合物を有効成分とする抗真菌剤
JPH06247944A (ja) * 1992-12-28 1994-09-06 Sumitomo Pharmaceut Co Ltd 新規な１，２，４−トリアゾール誘導体

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