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WO1995025107A1 - Composes triazoliques et leurs procedes de preparation - Google Patents

Composes triazoliques et leurs procedes de preparation Download PDF

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Publication number
WO1995025107A1
WO1995025107A1 PCT/KR1995/000019 KR9500019W WO9525107A1 WO 1995025107 A1 WO1995025107 A1 WO 1995025107A1 KR 9500019 W KR9500019 W KR 9500019W WO 9525107 A1 WO9525107 A1 WO 9525107A1
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WO
WIPO (PCT)
Prior art keywords
triazol
butanol
thio
thiadiazol
difluorophenyl
Prior art date
Application number
PCT/KR1995/000019
Other languages
English (en)
Inventor
Jong Wook Lee
Jeong Seok Chae
Heui Il Kang
Chun Ho Lee
Soo Bong Park
Won Hui Yi
Chul Kim
Original Assignee
Yuhan Corporation
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
Priority claimed from KR1019940004917A external-priority patent/KR950026874A/ko
Priority claimed from KR1019940004918A external-priority patent/KR950026875A/ko
Priority claimed from KR1019940012285A external-priority patent/KR960000880A/ko
Application filed by Yuhan Corporation filed Critical Yuhan Corporation
Priority to EP95912490A priority Critical patent/EP0751943A1/fr
Priority to JP7523957A priority patent/JPH09505083A/ja
Priority to AU19616/95A priority patent/AU1961695A/en
Publication of WO1995025107A1 publication Critical patent/WO1995025107A1/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
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • 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 present invention relates to novel triazole compounds with an antifungal activity, processes for the preparation of these compounds, and pharmaceutical compositions containing same as active ingredients.
  • A represents an alkyl substituted sulfone (-S0 2 -), sulfoxy (-SO-) or sulfide (-S-) group,
  • EP Nos . 47338 and 100193 disclose the compounds of the above formula wherein A represents a substituted methylthio group (-S-CH 2 -).
  • A represents a disulfide group(-S-SO n -)
  • a compound wherein A represents -S-C- or -S-SO n - group are provided in JP 3-258764 and EP 0421210, respectively.
  • a compound having a substituted thio group EP 0061835, EP 0095828 and EP 0552974
  • a dithiocarbamate group EP 0446877
  • X and Y are independently a hydrogen or halogen
  • R is a group selected from the formulae consisting of (I-a),
  • R 1 represents a C._ A alkoxy, C._ ⁇ alkoxymethyl, C._ ⁇ alkylthio, C,_ A alkylthiomethyl, amino, C._ 4 alkylamino group which may form a ring with a nitrogen atom, or an optionally substituted C_._ A alkyl, styryl, phenyl or heteroaryl group;
  • R 2 represents a hydrogen or a C 1 _ 3 alkyl, phenyl, substituted phenyl, morpholinyl, pyrrolidinyl, thiomorpholinyl or piperidinyl group; and
  • R 3 represents a hydrogen or halogen or a C*_ 3 alkyl, C._ 3 alkoxy or nitro group.
  • the triazole compounds of formula (I) of the present invention are characterized by a pentagonal or fused heterocyclic ring coupled to a sulfur atom as a substituent in 3-position.
  • the compounds of formula (I-A) wherein Z is a nitrogen are those of formula (I) wherein R is a 1,2,4-thiadiazol group, and the compounds of formula (I-A) wherein Z is a carbon are those of formula (I) wherein R is a thiazol group.
  • preferred compounds of the present invention are those of formula(I) wherein R is a 1 , 2, 3-thiadiazol group, i.e., the compounds having the following formula(I- C): wherein X, Y and R 2 are the same as defined in formula(I). Representative compounds thereof are shown in Table 3 below.
  • triazole compounds of the present invention include those of formula(I) wherein R is a fused heterocyclic ring selected from (I-d) to (I-j), i.e., the compounds having the following formulae (I-D) to (I-J):
  • the triazole compounds of formula(I) of the present invention include two asymmetric carbons in 2 and 3 positions; and, therefore, the present invention encompasses, within its scope, racemic mixtures of (2R*,3R*) form and an enantiomer of (2R,3R) form, as well as each diastereomers, which can be collectively represented by the formula (I) .
  • Suitable pharmacologically acceptable salts of the triazole compounds(I) may include salts of inorganic and organic acids, such as hydrochloride, nitrate, oxalate and methanesulfonate; and, in addition, other salts known in the art.
  • Such pharmacologically acceptable salts of the compounds of formula(I) may be prepared by a conventional method.
  • the triazole compounds( I ) of the present invention may be prepared in accordance with the following methods.
  • the triazole compounds of formula(I) of the present invention may be prepared by reacting a compound of formula(II) with a compound of formula(III) or its an alkali metal salt in the presence of lithium perchlorate (LiC10 A ) .
  • the compound of formula(II) used in the present invention may be prepared, e.g., in accordance with the procedures described in EP Patent No. 421210.
  • the compound of formula(III) may be prepared by methods disclosed in various references, e.g., in accordance with the procedures described in Adv. Heterocycl. Che . , 5_, 119 (1965) for the compound of formula(Ill-a) ; J. Heterocycl. Chem. , 15 , 1295 (1978) for the compound of formula(III-c) ; and Adv. Heterocycl. Chem., 14, 43 (1972) and J. Org. Chem. , 47 , 5255 (1982) for the compounds of formulae (Ill-d) to (III-j); or, alternatively, by reacting a corresponding isothiazol-3-thione derivatives with a thiol.
  • R 1 , R 2 and R 3 are the same as defined previously and M represents an alkali metal.
  • the compound( II ) , the compound( III ) and LiC10 ⁇ are preferably employed in a molar ratio of 1 : 1 to 5 : 1 to 5, more preferably 1 : 1 to 2 : 1 to 2.
  • the above reaction may be conducted in an organic polar solvent such as methanol, acetonitrile, dimethylformamide and the like, at a temperature ranging from 50 to 130 °C, preferably from 80 to 110 °C, for a period ranging from 4 to 18 hours, preferably from 4 to 10 hours.
  • an organic polar solvent such as methanol, acetonitrile, dimethylformamide and the like
  • the triazole compounds of formula(I) of the present invention may be prepared by reacting a compound of formula(IV) with a compound of formula(V) in the presence of a base.
  • the compound of formula(IV) may be prepared, e.g., in accordance with the procedures described in EP Patent No. 421210.
  • the compound of formula(V) may be prepared by methods disclosed in various references, e.g., in accordance with the procedures described in Adv. Heterocycl. Chem., 5_, 119 (1965) for the compound of formula (V-a); and Adv. Heterocycl. Chem. , 14, 43 (1972), J. Orq. Chem., 45 , 617 (1980), Aust. J. Chem. , 24, 2405 (1971), Can. J. Chem. , 51, 1741 (1973), and Chem.
  • the base which may be used in the above reaction includes an inorganic base such as sodium hydride (NaH), potassium carbonate (K 2 C0 3 ) or sodium methoxide (MeONa), and an organic base such as triethylamine or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) .
  • an inorganic base such as sodium hydride (NaH), potassium carbonate (K 2 C0 3 ) or sodium methoxide (MeONa)
  • an organic base such as triethylamine or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) .
  • the above reaction may be conducted in an organic polar solvent such as methanol, acetonitrile, dimethoxyethane, dimethylformamide and the like, at a temperature ranging from 0 to 25 °C, preferably from 0 to 5 °C, for a period ranging from 15 minutes to 2 hours, preferably from 15 to 30 minutes .
  • the present invention also provides pharmaceutical compositions containing the compounds of formula(I) and pharmacologically acceptable salts thereof as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary.
  • the pharmaceutical compositions of the present invention may be administered orally or by injection.
  • the pharmaceutical composition for oral administration may take various forms such as tablets, granules, solutions and gelatin capsules, which may contain conventional additives such as a diluent, lubricant, absorbent, colorant, favour, sweetener and the like.
  • the composition for injection may be an isotonic solution or a suspension, and may be sterilized and/or contain an adjuvant such as a preservative, stabilizer, wetting agent, emulsifier, a salt for controlling an osmotic pressure and/or a buffer solution, and other pharmaceutically effective materials.
  • the pharmaceutical composition may be administered for the treatment of fungal infections in a dosage ranging from 0.05 to 10 mg/kg/day, more preferably from 1.0 to 5 mg/kg/day, depending on the routes and frequency of administration, although the dosage may vary in accordance with the kind and severity of the disease.
  • a dosage ranging from 0.05 to 10 mg/kg/day, more preferably from 1.0 to 5 mg/kg/day, depending on the routes and frequency of administration, although the dosage may vary in accordance with the kind and severity of the disease.
  • the following Examples are given for the purpose of illustration only and are not intended to limit the scope of the invention.
  • the reaction mixture was diluted with 100 ml of ethyl acetate, and washed with 5% sodium hydroxide aqueous solution (30 ml x 2) and then saline (30 ml x 1).
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography and recrystallized from isopropyl ether/n-hexane to afford the title compound.
  • reaction mixture was evaporated under reduced pressure, diluted with 100 ml of ethyl acetate, and washed with 5% sodium hydroxide aqueous solution (30 ml x 2) and then saline (30 ml x 1).
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography to afford the title compound. M.p.
  • Example 20 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[3-(4-(2,2,3, 3-tetrafluoropropoxy ) styryl)-l,2,4- thiadiazol-5-yl]thio-1-(1H-1,2,4-triazol-l-yl)-2-butanol
  • Example 22 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(3-phenoxymethyl-l,2,4-thiadiazol-5-yl)thio-1-( 1H-1,2, 4- triazol-l-yl)-2-butanol HCl
  • the same procedures as in Example 3 above were repeated using 0.680 g (0.003 mol) of 5-chloro-3-phenoxymethyl-l,2,4- thiadiazole in place of 5-chloro-3-cyclopropyl-l,2,4- thiadiazole and then the resulting product was recrystallized from ethylether by the addition of 5 ml of HCl-saturated ethyl ether to afford the title compound.
  • M.p. 143 to 146 °C
  • Example 25 Synthesis of ( 2R , 3R ) -2- ( 2 , 4-dif luorophenyl ) - 3- [ 3- ( 4-f luorophenyl ) - 1 , 2 , 4-thiadiazol-5 -yl ] thio- 1 - ( 1H- 1 , 2 , 4-triazol-l-yl ) -2-butanol
  • the same procedures as in Example 1 above were repeated using 0.637 g (0.003 mol) of 3-(4-£luorophenyl)-1, 2,4- thiadiazol-5-thiol in place of 3-t-butyl-l,2,4-thiadiazol-5- thiol to afford the title compound.
  • Example 28 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(3-phenyl-l ,2,4-thiadiazol-5-yl)thio-1-(1H-1,2,4-triazol- l-yl)-2-butanol
  • the same procedures as in Example 1 above were repeated using 0.583 g (0.003 mol) of 3-phenyl-l,2,4-thiadiazol-5- thiol in place of 3-t-butyl-l,2,4-thiadiazol-5-thiol to afford the title compound.
  • M.p. 135 to 138 °C
  • Example 30 Synthesis of ( 2R* , 3R* ) -2- ( 2 , 4-dif luorophenyl ) - 3 - [ 3 - ( 4-pyridyl ) -1 , 2 , -thiadiazol-5-yl ] thio- 1- ( 1H- 1 , 2 , 4- triazol-1-yl ) -2-butanol
  • Example 31 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3- [ 4- ( 1-(N-hydroxyiminoethyl)phenyl)-1, 2 , 4-thiadiazol-5- yl]thio-1-(1H-1,2,4-triazol-l-yl)-2-butanol
  • the same procedures as in Example 1 above were repeated using 0.754 g (0.003 mol) of 4-(1-(N-hydroxyiminoethyl) phenyl)-l,2,4-thiadiazol-5-thiol in place of 3-t-butyl- l,2,4-thiadiazol-5-thiol to afford the title compound.
  • M.p. 177 to 180 °C
  • Example 56 Synthe ⁇ i ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[3-(4-biphenyl)-l,2,4-thiadiazol-5-yl]thio-l-(lH-l,2,4- triazol-1-yl)-2-butanol
  • Example 57 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[3-(4-(2,2,3, 3-tetrafluoropropoxy) phenyl ) -1 , 2 , 4- thiadiazol-5-yl]thio-1-(1H-1,2,4-triazol-l-yl)-2-butanol
  • Example 62 Synthesi ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[3-(4-methanesulfonylphenyl)-1,2,4-thiadiazol-5-yl]thio-1- (1H-1,2,4-triazol-l-yl)-2-butanol
  • Example 64 Synthesi ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[ 3-(2,5-difluorophenyl)-1,2,4-thiadiazol-5-yl]thio-1-(1H- 1,2,4-triazol-l-yl)-2-butanol
  • Example 68 Synthe ⁇ is of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[3-(3-pyrrol-l-yl)phenyl-l,2,4-thiadiazol-5-yl]thio-1-(1H- 1,2,4-triazol-l-yl)-2-butanol
  • Example 72 Synthesis of (2R, 3R)-2-(2,4-difluorophenyl)-3- (3-styryl-l,2,4-thiadiazol-5-yl)thio-1-(1H-1,2,4-triazol-l- yl)-2-butanol
  • the same procedures as in Example 3 above were repeated using 0.571 g (0.002 mol) of (2R, 3R)-2-(2,4- difluorophenyl)-3-mercapto-l- (lH-l,2,4-triazol-l-yl)-2- butanol and 0.668 g (0.003 mol) of 5-chloro-3-styryl-l, 2,4- thiadiazole in place of (2R*, 3R*)-2-(2,4-difluorophenyl)-3- mercapto-l-(lH-l,2,4-triazol-l-yl)-2-butanol and 5-chloro-3-
  • Example 78 Synthe ⁇ i ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[4-(2,4-dichlorophenyl)-thiazol-2-yl]thio-1-(1H-1 ,2,4- triazol-1-yl)-2-butanol
  • Example 80 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(4-ethylthiazol-2-yl)thio-l-(lH-l,2,4-triazol-l-yl)-2- butanol- oxalate
  • Example 2 The same procedures as in Example 1 above were repeated using 0.436 g (0.003 mol) of 4-ethylthiazol-2-thiol in place of 3-t-butyl-l,2,4-thiadiazol-5-thiol and to the compound thus obtained was added 0.18 g (0.002 mol) of oxalic acid in the presence of ethyl acetate/n-hexane to afford the title compound.
  • Example 84 Synthe ⁇ i ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-[4- (2, 3-dichlorostyryl)-thiazol-2-yl]thio-1-(1H-1, 2,4- triazol-1-yl)-2-butanol
  • Example 85 Synthesi ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(1,2, 3-thiadiazol-5-yl)thio-1-(1H-1,2,4-triazol-l-yl)-2- butanol
  • the reaction mixture was diluted with 100 ml of ethyl acetate, and washed with 5% sodium hydroxide aqueous solution (30 ml x 2) and then saline (30 ml x 1).
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a residue, which wa ⁇ purified by ⁇ ilica gel column chromatography to afford the title compound.
  • Example 88 Synthe ⁇ is of (2R*, 3R* ) -2- (2, 4-dif luorophenyl )- 3- ( 4-methyl-l , 2 , 3-thiadiazol-5-yl ) thio-1- ( 1H-1 , 2 , 4-triazol- l-yl)-2-butanol
  • Example 85 The same procedures as in Example 85 above were repeated using 0.502 g (0.002 mol) of (2R*, 3S*)-2-(2,4- difluorophenyl)-3-methyl-2-[ (lH-l,2,4-triazol-l- yl)methyl]oxirane and 0.753 g (0.003 mol) of 4-(2,4- difluorophenyl)-1,2,3-thiadiazol-5-thiol-Na ⁇ alt, and thereto was added 0.19 g (0.002 mol) of oxalic acid in the presence of ethyl acetate/n-hexane to afford the title compound.
  • reaction mixture wa ⁇ diluted with 100 ml of ethyl acetate, and washed with 5% sodium hydroxide aqueous solution (30 ml x 2) and saline (30 ml x 1). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography and recrystallized from isopropyl ether to afford the title compound. M.p. : 155 to 158 °C
  • the re ⁇ ulting mixture was stirred for 1 hour and evaporated to obtain a concentrate, which was diluted with 100 ml of ethyl acetate, and washed with 5% sodium hydroxide aqueous solution (30 ml x 2) and then saline (30 ml x 1). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography to afford the title compound.
  • Example 100 Synthesi ⁇ of (2R*, 3R*)-2-(4-fluorophenyl)-3- (1,2-benzoisothiazol-3-yl)thio-1-(1H-1,2,4-triazol-l-yl)-2- butanol oxalate
  • Example 103 Synthesis of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(5, 6-dimethoxy-l,2-benzoisothiazol-3-yl)thio-1-(1H-1,2,4- triazol-1-yl)-2-butanol
  • Example 105 Synthesi ⁇ of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(7-chloro-l, 2-benzoisothiazol-3-yl)thio-1-(1H-1,2,4- triazol-1-yl)-2-butanol
  • Example 109 Synthesi ⁇ of (2R*, 3R*)-2-(2,4- difluorophenyl)-3-(2, l-benzoisothiazol-3-yl)thio-1- ( 1H- 1,2,4-triazol-l-yl)-2-butanol
  • Example 110 Synthe ⁇ is of (2R*, 3R*)-2-(2,4-difluorophenyl)- 3-(5-nitro-2,l-benzoi ⁇ othiazol-3-yl)thio-l-(lH-l,2,4- triazol-1-yl)-2-butanol
  • Example 113 Synthesi ⁇ of (2R, 3R)-2-(2,4-difluorophenyl)- 3-(thieno[3,4-d]isothiazol-3-yl)thio-1-(1H-1,2,4-triazol-l- yl)-2-butanol
  • mice Male ICR mice (22 to 25 g) were divided into 48 groups, each consisting of ten mice. The first was a control group employing no te ⁇ t compound, the second was a comparative group employing Fluconazole, a commercially available triazolic antifungal agent, and the 3rd to 48th were employed the compounds of the present invention.
  • Candida albicans B02630 wa ⁇ cultured in SDA medium for 24 hours, and then su ⁇ pended in a sterilized saline in a concentration of 4.0 x 10 7 CFU/ml. All the test animals were infected by injecting 0.2 ml of the fungi ⁇ u ⁇ pension into tail vein.
  • Fluconazole and the inventive compound ⁇ dis ⁇ olved in polyethylene glycol 200 were admini ⁇ tered orally in an amount of 2 mg/kg into the second group and the 3rd-48th group, respectively.
  • the test compounds were administered three times at an interval of 24 hours. The number of the mice survived was counted at 24 hour interval and the results are shown in Table 5.
  • mice Male ICR mice (22 to 25 g) of 36 group ⁇ , each group consisting of eight mice, were infected by Candida albicans in accordance with the same procedures a ⁇ de ⁇ cribed previou ⁇ ly.
  • the inventive compound prepared in Example 5 of the pre ⁇ ent invention
  • polyethylene glycol 200 was administered orally in each amount of 20, 10, 5, 2.5 and 1.25 mg/kg into the 2nd-6th group five ti e ⁇ at an interval of 24 hours. No compound was administered into the first group.
  • the inventive compounds prepared in Example 47, 72, 73, 93, 97 and 98 were also administered orally into the remaining 7th- 36th groups in each amount of 20, 10, 5, 2.5 and 1.25 mg/kg. The number of the mice survived was counted at 24 hour interval.
  • mice Male ICR mice (22 to 25 g) were divided into 36 group ⁇ , each group con ⁇ isting of eight mice.
  • Cryptococcus neoformans IFM 40092 was cultured in SDA medium for 24 hours, and then suspended in a sterilized ⁇ aline in a concentration of 2.0 x 10 8 CFU/ml.
  • cyclophosphamide as a immunosuppressive agent was administered intraperitoneally in an amount of 2 mg/mouse. 24 hour ⁇ after the administration, each group was infected by injecting into tail vein 0.2 ml of the fungi suspension.
  • Example 5 2 hours after the infection, the inventive compounds prepared in Example 5, 47, 72, 73, 93, 97 and 98 of the present invention were administered into the the test animals in each amount of 20, 10, 5, 2.5 and 1.25 mg/kg as described previously The ED 50 values measured are shown in Table 6.
  • mice Male ICR mice (22 to 25 g) were divided into 36 groups, each group consisting of eight mice. To each group cyclophosphamide (immuno ⁇ uppres ⁇ ive agent) was administered intraperitoneally in an amount of 2 mg/mouse. 24 hours after the administration, each group was infected by injecting into tail vein 0.2 ml of a suspension of Asperqillus fumi ⁇ atus 3319119 spore (2.0 x 10 6 CFU/ml in a sterilized saline) .
  • cyclophosphamide immuno ⁇ uppres ⁇ ive agent
  • the inventive compounds prepared in Example 5, 47, 72, 73, 93, 97 and 98 of the present invention were administered into the the test animals in each amount of 100, 50, 25, 12.5 and 6.25 mg/kg as described previously.
  • the ED 50 values measured are shown in Table 6.
  • the compounds of formula(I) and their pharmacologically acceptable salts of the present invention have a potent antifungal activity against variou ⁇ fungi, e.g., Candida albican ⁇ , Cryptococcus neoformans, and Asperqillus fumigatu ⁇ and, therefore, can be used for the treatment of fungal infections in mammals including human beings.
  • variou ⁇ fungi e.g., Candida albican ⁇ , Cryptococcus neoformans, and Asperqillus fumigatu ⁇

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Abstract

Nouveaux composés triazoliques de la formule (I), et leurs sels pharmacologiquement acceptables, présentant des activités antifongiques puissantes, et utilisables dans le traitement des infections fongiques.
PCT/KR1995/000019 1994-03-12 1995-03-13 Composes triazoliques et leurs procedes de preparation WO1995025107A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95912490A EP0751943A1 (fr) 1994-03-12 1995-03-13 Composes triazoliques et leurs procedes de preparation
JP7523957A JPH09505083A (ja) 1994-03-12 1995-03-13 トリアゾール化合物およびその製造方法
AU19616/95A AU1961695A (en) 1994-03-12 1995-03-13 Triazole compounds and processes for the preparation thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR94-4917 1994-03-12
KR1019940004917A KR950026874A (ko) 1994-03-12 1994-03-12 트리아졸 유도체 및 그의 제조방법
KR1019940004918A KR950026875A (ko) 1994-03-12 1994-03-12 트리아졸 유도체 및 그의 제조방법
KR94-4918 1994-03-12
KR94-12285 1994-06-01
KR1019940012285A KR960000880A (ko) 1994-06-01 1994-06-01 트리아졸 유도체 및 그의 제조방법

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WO1995025107A1 true WO1995025107A1 (fr) 1995-09-21

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PCT/KR1995/000019 WO1995025107A1 (fr) 1994-03-12 1995-03-13 Composes triazoliques et leurs procedes de preparation

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033778A1 (fr) * 1997-02-04 1998-08-06 Sankyo Company, Limited Derives triazole
WO2000027852A1 (fr) * 1998-11-10 2000-05-18 Meiji Seika Kaisha, Ltd. Nouveaux derives d'imidazo[5,1-b]thiazole et fongicides contenant ces derives en qualite de principe actif
WO2005007636A1 (fr) * 2003-07-16 2005-01-27 Skw Stickstoffwerke Piesteritz Gmbh Composes 1,2,4-thiadiazol-5-thio et leurs derives, procedes pour les preparer et leur utilisation en tant qu'inhibiteurs d'urease et de nitrification
WO2006077217A1 (fr) * 2005-01-20 2006-07-27 Adamed Sp. Z O.O. Nouveaux derives de l'acide 3-phenylpropionique
US7230023B2 (en) 2001-02-22 2007-06-12 Sankyo Company, Limited Water-soluble triazole fungicide
US7309791B2 (en) 2005-01-19 2007-12-18 Adamed Sp. Z.O.O 3-phenylpropionic acid derivatives
US7919515B2 (en) 2004-12-20 2011-04-05 Adamed Sp. Z O.O. 3-phenylpropionic acid derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5804811B2 (ja) * 2010-07-13 2015-11-04 住友化学株式会社 縮合環化合物の製造方法、および該方法に用いられる原料化合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0091309A2 (fr) * 1982-04-07 1983-10-12 Pfizer Limited Composés de triazole comme fongicides
EP0100193A1 (fr) * 1982-07-24 1984-02-08 Pfizer Limited Triazoles antifongiques
EP0421210A2 (fr) * 1989-09-26 1991-04-10 Takeda Chemical Industries, Ltd. Composés dérivés de triazole, leurs préparation et application
EP0446877A2 (fr) * 1990-03-15 1991-09-18 Takeda Chemical Industries, Ltd. Triazoles, leur préparation et application
EP0473387A2 (fr) * 1990-08-26 1992-03-04 Sankyo Company Limited Dérivés du triazole antifongiques, leurs préparation et applications

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0091309A2 (fr) * 1982-04-07 1983-10-12 Pfizer Limited Composés de triazole comme fongicides
EP0100193A1 (fr) * 1982-07-24 1984-02-08 Pfizer Limited Triazoles antifongiques
EP0421210A2 (fr) * 1989-09-26 1991-04-10 Takeda Chemical Industries, Ltd. Composés dérivés de triazole, leurs préparation et application
EP0446877A2 (fr) * 1990-03-15 1991-09-18 Takeda Chemical Industries, Ltd. Triazoles, leur préparation et application
EP0473387A2 (fr) * 1990-08-26 1992-03-04 Sankyo Company Limited Dérivés du triazole antifongiques, leurs préparation et applications

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033778A1 (fr) * 1997-02-04 1998-08-06 Sankyo Company, Limited Derives triazole
WO2000027852A1 (fr) * 1998-11-10 2000-05-18 Meiji Seika Kaisha, Ltd. Nouveaux derives d'imidazo[5,1-b]thiazole et fongicides contenant ces derives en qualite de principe actif
US7230023B2 (en) 2001-02-22 2007-06-12 Sankyo Company, Limited Water-soluble triazole fungicide
WO2005007636A1 (fr) * 2003-07-16 2005-01-27 Skw Stickstoffwerke Piesteritz Gmbh Composes 1,2,4-thiadiazol-5-thio et leurs derives, procedes pour les preparer et leur utilisation en tant qu'inhibiteurs d'urease et de nitrification
US7919515B2 (en) 2004-12-20 2011-04-05 Adamed Sp. Z O.O. 3-phenylpropionic acid derivatives
US7309791B2 (en) 2005-01-19 2007-12-18 Adamed Sp. Z.O.O 3-phenylpropionic acid derivatives
US7629370B2 (en) 2005-01-19 2009-12-08 Adamed Sp. Z O.O. 3-phenylpropionic acid derivatives
WO2006077217A1 (fr) * 2005-01-20 2006-07-27 Adamed Sp. Z O.O. Nouveaux derives de l'acide 3-phenylpropionique
US7220766B2 (en) 2005-01-20 2007-05-22 Adamed, Sp. Z.O.O. 3-phenylpropionic acid derivatives

Also Published As

Publication number Publication date
JPH09505083A (ja) 1997-05-20
AU1961695A (en) 1995-10-03
EP0751943A1 (fr) 1997-01-08

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