WO1996025410A1 - Azole compounds, their production and use - Google Patents

Azole compounds, their production and use Download PDF

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Publication number
WO1996025410A1
WO1996025410A1 PCT/JP1996/000325 JP9600325W WO9625410A1 WO 1996025410 A1 WO1996025410 A1 WO 1996025410A1 JP 9600325 W JP9600325 W JP 9600325W WO 9625410 A1 WO9625410 A1 WO 9625410A1
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WIPO (PCT)
Prior art keywords
group
compound
phenyl
triazol
salt
Prior art date
Application number
PCT/JP1996/000325
Other languages
French (fr)
Inventor
Katsumi Itoh
Kenji Okonogi
Akihiro Tasaka
Original Assignee
Takeda Chemical Industries, Ltd.
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Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to US08/624,649 priority Critical patent/US6034248A/en
Priority to EP96902443A priority patent/EP0809640A1/en
Priority to AU46755/96A priority patent/AU4675596A/en
Priority to RU97115290A priority patent/RU2145605C1/en
Publication of WO1996025410A1 publication Critical patent/WO1996025410A1/en

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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
    • 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 azole compounds useful as antifungal therapeutic agents, methods for producing the same and use thereof.
  • the present invention provides
  • Ar is an optionally substituted phenyl group
  • R- 1 - and R ⁇ are a hydrogen atom or a lower alkyl group, or R 1 and R ⁇ 9 may combine together to fo a lower alkylene group;
  • R ⁇ is a hydrogen atom or an acyl group;
  • X is a nitrogen atom or a methine group;
  • n is an integer from 0 to 2; and Az is optionally substituted azolyl group, or a salt thereof,
  • substituents for "optionally substitut ed phenyl group" represented by Ar in the formula (I) in ⁇ clude halogen atoms (e.g. , ⁇ fluorine, chlorine, bromide and iodine), lower (C 1-4 ) haloalkyl , lower (C 1-4 ) haloalkoxy, lower (C 1-4 ) alkylsulfonyl , lower (C 1-4 ) haloalkyisulfony1 and the like.
  • the substituent is halogen atoms (e.g. , fluorine, chlorine, bromine and iodine), and more preferably it is fluorine.
  • the number of the substituents is preferably from one to three, more preferably from one t two .
  • Ar examples include halophenyl, lower (C ⁇ _ 4 ) haloal kyiphenyl, lower (C ⁇ _ 4 ) haloalkoxyphenyl , lower (C ⁇ _ ) alkyIsulfonylphenyl , lower (C ⁇ _ 4 ) haloalkylsulfonylphenyl and the like.
  • halophenyl groups examples include 2 , 4-difluoro phenyl , 2 ,4-dichloropheny1 , 4-chlorophenyl , 4-fluorophenyl , 2-chloropheny1 , 2-fluorophenyl , 2-fluoro-4-chloropheny1 , 2- chioro-4-fluorophenyl , 2 ,4 , 6-trifluoropheny , 4-bromophenyl and the like.
  • Examples of the lower (C ⁇ _ 4 ) haloalkylphenyl groups include 4-trifluoromethylphenyl group and the like.
  • Examples of the lower (C ⁇ _ ) haloalkoxyphenyl groups include 4-trifluoro ethoxypheny1 , 4-(1 , 1 , 2 , 2-tetrafluoro ⁇ ethoxy)phenyl , 4-(2 ,2 ,2-trifluoroethoxy)phenyl , 4-(2,2,3,3- tetrafluoropropoxy)phenyl , 4-(2 , 2 , 3 , 3 , 3-pentafluoro- propoxy)phenyl and the like.
  • Examples of the lower (C ⁇ _ 4 ) alkylsulfonylphenyl groups include 4-methanesulfonylphenyl and the like.
  • Examples of the lower (C ⁇ _ 4 ) haloalkylsulfonylphenyl groups include 4-(2 , 2 , 2-trifluoroethanesulfonyl)phenyl , 4- (2,2,3, 3-tetrafluoropropanesulfonyl )phenyl , 4-(2,2, 3,3,3- pentafluoropropanesulfonyl)phenyl and the like.
  • phenyl groups of Ar are phenyl groups substituted with one to two halogen atoms such as 2 ,4-difluorophenyl , 2 ,4-dichloropheny1 , 4-chlorophenyl , 4- fluorophenyl , 2-chlorophenyl , 2-fluorophenyl , 2-fluoro-4- chlorophenyl , 2-chloro-4-fluorophenyl , 4-bromophen 1 and the like, among which phenyl groups substituted with one or two fluorine atoms such as 4-fluorophenyl , 2-fluorophenyl and 2 , 4-difluorophenyl are more preferable and 2-fluorophenyl and 2 ,4-difluorophenyl are most preferable.
  • halogen atoms such as 2 ,4-difluorophenyl , 2 ,4-dichloropheny1 , 4-chlorophen
  • Examples of the lower alkyl groups represented by R 1 or R 2 in the formula (I) include straight or branched C ⁇ _ alkyl groups such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, among which methyl is more preferable. It is particularly prefer ⁇ able that both of R 1 and R 2 are hydrogen atoms or methyl groups, or one of R 1 and R ⁇ ? is a hydrogen atom and the othe is a methyl group.
  • Examples of the lower alkylene groups formed by the combination of R and R 2 include straight lower (C2_ 4 ) alkylene groups such as ethylene, propylene, butylene and the like, among which ethylene is preferred.
  • R and R ⁇ is hydrogen atom and the other is a C ⁇ _ 4 alkyl group such as a methyl group and the like.
  • acyl groups represented by R° in the formula (I) include acyl groups derived from organic carbox ylic acids such as alkanoyl, preferably C 1 _ ⁇ alkanoyl (e.g. , formyl, acetyl , propionyl , butyryl , isobutyryl, pentanoyl , hexanoyl and heptanoyl) , more preferably C__ ⁇ alkanoyl; arylcarbonyl, preferably arylcarbonyl (e.g.
  • alkoxycarbonyl preferably C2.-.7 alkoxycarbony1 (e.g. , methoxycarbonyl , ethoxycarbony1 , propoxycarbony1 , isopro- poxycarbonyl , butoxycarbony1 , isobutoxycarbonnyl , sec-bu- toxycarbonyl and tert-butoxycarbony1 ) , more preferably C _ alkoxycarbonyl; aryloxycarbonyl , preferably C 7 _ 15 aryloxy- carbonyl (e.g.
  • phenoxycarbony1 ) , more preferably C _ ⁇ ⁇ ary loxycarbonyl ; aralkylcarbonyl group, preferably C Q _2 Q aral- kylcarbonyl (e.g. , benzylcarbonyl , phenetylcarbonyl , phenyl propylcarbonyl and naphthylethylcarbonyl) , more preferably Cg_ 1 aralkylcarbonyl ; and the like.
  • aralkylcarbonyl group preferably C Q _2 Q aral- kylcarbonyl (e.g. , benzylcarbonyl , phenetylcarbonyl , phenyl propylcarbonyl and naphthylethylcarbonyl) , more preferably Cg_ 1 aralkylcarbonyl ; and the like.
  • the above acyl groups are those being capable of hydrolyzing in vivo. Examples thereof are for- myl. acetyl, benzoyl, benzylcarbonyl and the like.
  • Pre ⁇ ferred R 3 is a hydrogen atom.
  • X in the general formula (I) is preferably a nitrogen atom.
  • one of Y and Z is a nitrogen atom and the other is methine; that both are methine; that both are nitrogen atoms; and one is a nitrogen atom and the other is ethylidyne. It is particularly preferable that one of Y and Z is a nitrogen atom and the other is methine or both of Y and Z are methine.
  • examples of the lower alkyl groups include straight or branched C ⁇ _ 4 alkyl groups (methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl, ethyl and the like are preferable , and methyl and the like are more preferable.
  • Examples of the ethylene groups optionally substitute with a lower alkyl group represented by A include ethylene 1-methylethylene , 1 , 1-dimethylethylene , 1 , 2-dimethy1- ethylene, 1-ethylethylene , 1 , 2-diethylethylene and the lik among which ethylene and the 1ike are preferred.
  • n is preferably 0 or 1, more preferably 0.
  • Examples of the azolyl groups for "an optionally sub ⁇ stituted azolyl group" represented by Az in the formula (I) include five-membered aromatic heterocyclic groups contain ⁇ ing one to four nitrogen atoms as ring-constituent atoms, which may further contain a hetero atom selected from sulfur or oxygen as a ring-constituent atom, such as pyrrolyl, pyrazolyl, imidazolyl, 1 , 2 ,3-triazolyl , 1 , 2 ,4-triazoly1 , tetrazolyl, thiazolyl, isothiazoly1 , oxazolyl, isoxazolyl, furazanyl, 1 , 3 ,4-thiadiazolyl , 1 ,2 ,3-thiadiazoly1 , 1,2,5- thiadiazolyl , 1 , 2 ,4-thiadiazolyl and the like.
  • the azolyl groups are preferably pyrazo ⁇ lyl, imidazolyl, 1 ,2 , 3-triazolyl , 1 ,2 ,4-triazolyl , tetrazo ⁇ lyl and the like, more preferably lH-pyrazol-1-yl , 1H- imidazol-1-yl , 1H-1 , 2 , 3-triazol-l-yl , 2H-1 ,2 , 3-triazol-2-y1 , 1H-1 , 2,4-triazol-l-yl , 4H-1 , 2 ,4-triazol-4-y1 , lH-tetrazol- 1-yl, 2H-tetrazol-2-y1 and the like, and further more pref- erably lH-pyrazol-1-yl , 1H-1 , 2 , 3-triazol-l-yl , 2H-1.2.3- triazol-2-yl , 1
  • Examples of the substituents for "an optionally substi tuted azolyl group” represented by the above Az include hydroxyl group, optionally esterified carboxyl group (e.g. , carboxyl, C ⁇ _g alkoxycarbonyl such as methoxycarbonyl , ethoxycarbony1 and butoxycarbony1 ) , nitro group, a ino group, acylamino group (e.g. , C ⁇ . ⁇ Q alkanoylamino such as acetylamino, propionylamino and butyrylamino) , mono-C ⁇ - o o di-C ⁇ _ ⁇ Q alkylamino group (e.g.
  • C 1 _g alkyl group e.g. , methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, sec- butyl, pentyl and hexyl
  • C ⁇ .g alkoxy group e.g. , methoxy, ethoxy and butoxy
  • halogen atom e.g. , fluorine, chlorine and bromine
  • C ⁇ _ haloalkyl group e.g.
  • C ⁇ _ haloalkoxy group e.g.
  • C 1 _ 6 alkylsul- fonyl group e.g., methanesulfonyl , ethanesulfony1 and butanesulfonyl
  • C ⁇ _ I Q alkanoyl group e.g., acetyl, formyl propionyl and butylyl
  • phenyl group C ⁇ _ alkylphenyl group (e.g.
  • C ⁇ _g alkoxyphenyl group e.g., 4-methoxyphenyl and 4-isopropoxyphenyl
  • halo ⁇ phenyl group e.g. , 4-chlorophenyl and 4-fluorophenyl , 2 ,4,-difluorophenyl
  • C ⁇ _ haloalkylphenyl group e.g. , 4- trifluoromethylphenyl
  • C j _g haloalkoxyphenyl group [e.g.
  • Az are preferably diazolyl, triazolyl and tetrazolyl such as
  • a preferred example of the compound (I) is a compound represented by the formula (I')
  • Ar' is a monofluorophenyl (e.g. , 2- fluorophenyl ) or difluorophenyl (e.g. , 2 ,4-difluorophenyl ) group;
  • Az ' is an azolyl group selected from the group consisting of a diazo- lyl , triazolyl, tetrazolyl, thiazolyl or oxazolyl which are optionally substituted with one or two substituents selecte from the group consisting of an oxo group, a C ⁇ _g alkyl group (e.g.
  • A' is preferably -CH 2 -CH -
  • Az ' is preferably a triazolyl group and a tetrazolyl group.
  • the compound represented by the formula (I), (I') may be used as a salt thereof.
  • salts are pharmacologically acceptable salts such as inorganic acid salts (e.g. , hydrochloride , hydrobromide , sulfate, nitrate and phosphorate), organic acid salts (e.g. , acetate, tarta- rate, citrate, fumarate, maleate, toluenesulfonate and methanesulfonate) .
  • carboxyl group is included in the formula (I) as a substituent, it may be an alkali methal (sodium, pottasium and the like) salt.
  • the compounds represented by the formula (I) or a salt thereof have two or more stereoisomers thereof because of having one or more asymmetric carbon atom in their molecule. It should be understood that any of such stereoisomers as well as a mixture thereof is within a scope of the present invention.
  • R is hydrogen and R ⁇ is methyl
  • both the carbon atom to which the option ⁇ ally substituted phenyl group represented by Ar is bonded and the carbon atom to which R is bonded are preferred to be in (R)-configuration.
  • the compound of the present invention can be produced by, for example, reacting a compound represented by the formula (II ) :
  • the reaction can be carried out in a solvent which doe not inhibit the reaction.
  • solvents are water, ketones (e.g. , acetone), sulfoxides (e.g. , dimethyl sulfoxide), ethers (e.g. , diethyl ether, tetrahydrofuran an dioxane), nitriles (e.g. , acetonitrile) , aromatic hydrocar ⁇ bons (e.g. , benzene, toluene and xylene) , halogenated hydro carbons (e.g., dichloromethane , chloroform and 1 ,2-dichloro ethane), esters (e.g.
  • ethyl acetate ethyl acetate
  • amides e.g. , di eth ylformamide, acetamide, dimethylacetamide and l-methyl-2- pyrro1idinone
  • ureylenes e.g. , 1 , 3-dimety1-2-imidazo1idi- none
  • solvents may be used either singly or as a mixture of two or more solvents in a suitabl mixing ratio.
  • the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g. , potassium hydride and sodium hydride) , alkali metal carbonates (e.g. , lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate), alkali metal alcoholates (e.g. , sodium methylate, potassium tert-butylate and sodium tert- butylate), tetrabutylammonium fluoride, bis (tri-n-butylstan- nyl)oxide and the like.
  • a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g. , potassium hydride and sodium hydride)
  • the desired compound can also be pre ⁇ pared by the reaction in the above solvent using a metal salt (e.g., alkali metal salt such as sodium and potassium salt) of the compound (III) instead of the compound (III) .
  • a metal salt e.g., alkali metal salt such as sodium and potassium salt
  • the amount of the base used is usually about 0.01 to at 100 equivalents, preferably about 0.1 to about 50 equiva ⁇ lents per equivalent of the compound of formula (III) or a salt thereof.
  • the amount of the compound (III) or a salt thereof is about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (II) or a salt thereof.
  • the reaction temperature is not especially limited, but usually within the range of about 0 to about 150°C, prefera ⁇ bly about 10 to about 120°C.
  • the reaction time is usually within the range of about several minutes to tens of hours (e.g. , from five minutes to fifty hours) .
  • the compound of the present invention can also be prepared by, for example, reacting a compound represented by the formula (IV):
  • the compound of the formula (V) may be a compoun represented by the formula (V" ) :
  • the reaction is usually carried out in a solvent which does not inhibit the reaction.
  • the solvents ar water, ketones (e.g. , acetone), sulfoxides (e.g. , dimethyl sulfoxide), ethers (e.g. , diethyl ether, tetrahydrofuran an dioxane), nitriles (e.g. , acetonitrile) , aromatic hydrocar- bons (e.g. , benzene, toluene and xylene), halogenated hydro ⁇ carbons (e.g.
  • reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide, sodium hydroxide), alkali metal hydrides (e.g. , potassium hydride and sodium hydride), alkali metal carbonates (e.g. , lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate) , alkali metal alcoholates (e.g.
  • a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide, sodium hydroxide), alkali metal hydrides (e.g. , potassium hydride and sodium hydride), alkali metal carbonates (e.g. , lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate) , alkali metal alcoholates (e.
  • the desired compound can also be prepared by the reaction in the above solvent using a metal salt (e.g. , alkali metal salt such as sodium and potassium salt) of the compound (V) or (V") instead of the compound (V) or (V) .
  • a metal salt e.g. , alkali metal salt such as sodium and potassium salt
  • the amount of the base used is usually about 0.01 to about 100 equivalents, preferably about 0.1 to about 50 equivalents per equivalent of the compound of formula (V)
  • the amount of compound (V) or (V") or a salt thereof is about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (IV) or a salt thereof.
  • the reaction temperature is not especially limited, bu usually within the range of about 0 to about 150°C, prefera bly about 10 to about 120°C.
  • the reaction time is usually within the range of about several minutes to tens of hours (e.g. , from five minutes t fifty hours) .
  • the compound of the present invention can be prepared by, for example, reacting a compound represented by the formula (VI) :
  • L is a leaving group [e.g. , halogen atom (e.g. , chlorine, bromine and iodine) or R S0 3 (wherein R 4 i lower (C 1-4 ) alkyl group or optionally substituted phenyl group)] and the other symbols have the same meaning as defined above ⁇ or a salt thereof with a compound represented by the formula (III):
  • Examples of the C 1-4 lower alkyl group represented by R 4 are methyl, ethyl, propyl, butyl and tert-butyl.
  • Examples of the optionally substituted phenyl group are the same as those of the optionally substituted phenyl group represented by Ar.
  • the reaction is usually carried out in a solvent which does not inhibit the reaction.
  • the solvents are water, ketones (e.g. , acetone), sulfoxides (e.g. , dimethyl sulfoxide), ethers (e.g. , diethyl ether, tetrahydrofuran and dioxane), nitriles (e.g. , acetonitrile) , aromatic hydrocar ⁇ bons (e.g. , benzene, toluene and xylene), halogenated hydro ⁇ carbons (e.g. , dichloromethane , chloroform and 1 , 2-dichloro- ethane), esters (e.g.
  • amides e.g. , dimeth ⁇ ylformamide, acetamide, dimethylacetamide and l-methyl-2- pyrrol idinone
  • ureylenes e.g. , 1 , 3-dimetyl-2-imidazolidi- none
  • solvents may be used either singly or as a mixture of two or more solvents in a suitable mixing ratio.
  • the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal carbonates (e.g. , lithiu carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate), alkali metal alcoholates (e.g. , sodium methylate, potassium tert-butylate and sodium tert- butylate), tetrabutylammonium fluoride, bis (tri-n-butylstan nyl)oxide and the like.
  • a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g., potassium hydride and sodium hydride), alkal
  • the desired compound can be prepared by the reaction in the above solvent using a metal salt (e.g. , alkali metal salt such as sodium and potassium salt) of the compound (III) instead of the compound (III) .
  • a metal salt e.g. , alkali metal salt such as sodium and potassium salt
  • the amount of the base used is usually within the rang of about 2 to about 100 equivalents, preferably about 2 to about 50 equivalents per equivalent of the compound of formula (III) or a salt thereof.
  • the amount of the compound (III) or a salt thereof is usually within the range of about 1 to about 100 equiva ⁇ lents, preferably about 1 to about 50 equivalents per equiv alent of the compound of formula (VI) or a salt thereof.
  • the reaction temperature is not especially limited, bu usually about 0 to about 150°C, preferably about 10 to abou 120°C.
  • the reaction time is about tens of minutes to tens of hours (e.g. , from thirty minutes to fifty hours) .
  • the compound of the present invention wherein A is an ethylene group optionally substituted with a lower alkyl or salt thereof can be prepared by, for example, subjecting to a catalytic reduction a compound of the formula (I") :
  • A' ' ' is a vinylene group optionally substitut ⁇ ed with lower alkyl group and the other symbols have the same meanings as defined above
  • a salt thereof or a salt thereof.
  • the above-mentioned reaction is usually carried out in the presence of a single or mixed solvent(s) such as water and organic solvents which do not inhibit the reaction such as ketones (e.g. , acetone and methylethyl ketone), alcohols (e.g. , methanol, ethanol, propanol, isopropyl alcohol and butanol), esters (e.g. , ethyl acetate), hydrocarbons (e.g. , benzene, toluene, hexane and xylene), organic carboxylic acids (e.g. , acetic acid and propionic acid) and the like.
  • the reaction is usually carried out in the presence of catalyst.
  • a suitable metal catalyst such as palladium- carbon is used as the catalyst.
  • the reduction reaction is carried out at a pressure from atmospheric pressure up to about 150kg/cm 2 at a temperature from room temperature up t about 100 ⁇ C.
  • the obtained compound or a salt thereof can be converted into by the conventional method to provide a compound of the formula (I) wherein R ⁇ is an acyl group, by treating it with an appropriate acylating agent of R L [wherein R 3 is an aliphatic or aromatic carboxylic acid residue (e.g. , acetyl, propionyl, butylyl, ethoxycarbony1 , benzoyl, substituted benzoyl) and L 1 is group to be removed (e.g., a halogen atom such as chlorine, bromine and the like, an active ester)] in accordance with the conventional method.
  • R 3 is an aliphatic or aromatic carboxylic acid residue (e.g. , acetyl, propionyl, butylyl, ethoxycarbony1 , benzoyl, substituted benzoyl)
  • L 1 is group to be removed (e.g., a halogen atom such as chlorine, bromine and the like, an active
  • the above-mentioned reaction is usually carried out in the presence or absence of a solvent which does not inhibit the reaction.
  • solvents are water, ketones such as acetone, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, aromatic hydrocarbons such as benzen, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1 , 2-dichloroethane , esters such as ethyl acetate, amides such as di ethylformamide , acetamide, dimethylacetamide, ureylenes such as 1,3-dimeth- yl-2-imidazolidinone , and the like.
  • a base e.g. , dimethylaminopyridine , pyridine, pyrroline and triethyla- mine
  • the amount of the base used is usually about 1 to about 100 equivalents per equivalent of the compound of formula (I) or a salt thereof.
  • the compound of the present invention obtained as above can be isolated and purified from the reaction mixture by a known procedure per se such as extraction, concentration, neutralization, filtration, recrystal1ization, column chromatography, thin layer chromatography and the like.
  • the compound of the present invention may have at least two stereoisomers as mentioned above.
  • a stereoisomer can be separately prepared if desired.
  • a single isomer can be obtained by the above reaction using each single isomer cf the starting compounds (II), (IV), (VI), (I") and (I' " ') or salts thereof.
  • the obtained product is a mixture of two or more isomers, they can be separated into each isomer by the conventional separating method such as a method for producing a salt wi an optically-active acid (e.g., camphorsulfonic acid and tartaric acid), various types of chromatographies, fractio al recrystallization and the like.
  • an optically-active acid e.g., camphorsulfonic acid and tartaric acid
  • the salt of the compound of the present invention can be prepared by a known method per se such as adding the aforesaid inorganic or organic acid to the compound (I) .
  • the starting compound (II) or a salt thereof in the present invention wherein R 1 is hydrogen, R 2 is methyl, th carbon atom to which Ar is bonded is an (S)-configuration and the carbon atom to which R 2 is bonded is an (Reconfig ration [i.e. , a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the fol ⁇ lowing reaction scheme:
  • the starting compound (VIII) in the reaction can be prepared, for example, by a method represented by the fol ⁇ lowing reaction scheme:
  • THP is tetrahydropyranyl group
  • Ts is p- toluenesulfonyl group
  • L 2 is a halogen atom (e.g., chlorin bromine, iodine)
  • DMSO is dimethylsulfoxide, and the other symbols have the same meaings as defined above] .
  • the intermediate compound (IX) can be synthesized, fo example, by a method represented by the following reaction scheme :
  • R-*- is a hydrogen atom
  • R 2 is a methyl group
  • the carbon atom to which Ar is bonded in (S)- configuration the carbon atom to which R 2 is bonded in (R)-configuration
  • L is a leaving group represented by R 4 S0 3 (wherein R 4 has the same meaning as mentioned above) [i.e.
  • R 1 is a hydrogen atom
  • R 2 is a methyl group
  • the carbon atom to which Ar is bonded in (S)-configuration and the carbon atom to which R 2 is bonded in (R)-configuration [i.e. , a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the following reac ⁇ tion scheme:
  • each of L , L , L 5 and L is a halogen atom (e.g. , chlorine, bromine, iodine) and the other symbols have the same meanings as defined above] .
  • halogen atom e.g. , chlorine, bromine, iodine
  • the starting compound (XX) or a salt thereof and the starting compound (XXI) or a salt thereof in the above reaction wherein L 3 is a chlorine atom [i.e. , a compound (XXVI) or a salt thereof] can be each prepared, for example, by a method represented by the following reactions scheme:
  • R is a lower alkyl group
  • L is a halogen atom (e.g. , chlorine, bromine, iodine) and the other symbols have the same meanings as defined above] .
  • H 2 /Pd-C denotes a catalytic reduction using palladium-carbon catalyst and the other symbols have the same meanings as defined above
  • a compound (XXI) or a salt thereof wherein L 3 is a halogen atom except chlorine can be prepared using the corresponding halogenating agent [e.g. , (COBr) 2 , PBr ] instead of (C0C1) 2 in a similar way to the above reaction.
  • halogenating agent e.g. , (COBr) 2 , PBr
  • the starting compounds or synthesized intermediate compounds above-obtained can be isolated and purified from the reaction mixtures by a known procedure per se such as extraction, concentration, neutralization, filtration, recrystal1ization, column chromatography, thin layer chrom tography and the like.
  • the reactant mixture itself can be used as a material in the next step without isolation.
  • the compound of the present invention has low toxicit and exhibits potent antifungal activity with broad antifun gal spectrum against, for example, microorganisms cf genus Candida (e.g., Candida albicans, Candida utilis, Candida grabrata, etc.), those of genus Histoplasma (e.g. , Histo- plasma capsulatum, etc.), those of genus Aspergillus (e.g. , Aspergillus niger, Aspergillus fumigatus, etc.), those of genus Cryptococcus (e.g.
  • the compound of the invention can be used as an antifungal agent for agricultural use.
  • the compound of the present invention When the compound of the present invention is adminis ⁇ tered to a human being, it can be safely administered either orally or parenterally in the form of pharmaceutical compo ⁇ sitions such as oral administration preparations (e.g. , powders, granules, tablets, capsules), parenteral prepara ⁇ tions [e.g. , injections and external preparations (e.g. , nasal and dermatological ones), suppositories (e.g. , rectal and vaginal ones)] and the like in per se or in mixture with suitable pharmacologically-acceptable carriers, fillers or diluents.
  • the content of the compound of the present inven tion in a whole pharmaceutical composition is usually 5 to 100 wt , preferably 20 to 100 wt% in an oral drug and 5 to 30 wt% in a parenteral drug.
  • preparations can be manufactured by methods whic are known per se and commonly used in the manufacture of pharmaceutical preparations.
  • the compound of the present invention can be made into an injection such as aqueous injections togeth er with dispersing agents [e.g., Tween 80 (Atlas Powder, U.S.A.), HCO60 (Nikko Chemicals, Japan), carboxymethylcellu lose or sodium alginate], preservatives (e.g. , methylpara- ben, propylparaben, benzyl alcohol and chlorobutanol ) , iso- tonic agents (e.g. , sodium chloride, glycerol, sorbitol and glucose) and the like, or as oily injections by dissolving, suspending or emulsifying in a plant oil (e.g. , olive oil, sesame oil, peanut oil, cotton seed oil and corn oil), propylene glycol and the like.
  • aqueous injections togeth er with dispersing agents e.g., Tween 80 (Atlas Powder, U.S.A.
  • the compound of the present invention is compression- molded together, for example, with fillers (e.g. , lactose, sugar and starch), disintegrating agents (e.g. , starch and calcium carbonate), binders (e.g. , starch, arabic gum, carboxymethylcellulose, polyvinyIpyrrolidone and hydroxypro pylcellulose) , lubricants (e.g. , talc, magnesium stearate and polyethylene glycol 6000) and the like, followed, if necessary, by coating in accordance with a known method per se with an object of taste-masking or of providing the preparation with enteric or sustained release property.
  • fillers e.g. , lactose, sugar and starch
  • disintegrating agents e.g. , starch and calcium carbonate
  • binders e.g. , starch, arabic gum, carboxymethylcellulose, polyvinyIpyrrolidone and hydroxypro pylcellulose
  • lubricants
  • the coating agents are hydroxypropylmethylcellu- lose, ethylcellulose , hydroxymethycellulose, hydroxypropyl- cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudra- git (Rohm, West Germany; a copolymer of methacrylic acid with acrylic acid) and pigments such as titanium oxide and red iron oxide.
  • the compound of the present invention can be also used solid, semisolid or liquid preparations for external use.
  • solid external preparation the compound of the present invention is made into the form of powdered compositions as it is or in a mixture with filler (e.g. , glucose, mannitol, starch and microcrystal1ine cellu ⁇ lose), thickeners (e.g. , natural gum, cellulose derivatives and acrylic acid polymers) and the like.
  • filler e.g. , glucose, mannitol, starch and microcrystal1ine cellu ⁇ lose
  • thickeners e.g. , natural gum, cellulose derivatives and acrylic acid polymers
  • semisolid external preparation aqueous or oily gel prepara ⁇ tion or ointment is preferred.
  • liquid exter ⁇ nal preparation the procedures are nearly the same as those in the case of injections to give oily or aqueous suspen ⁇ sions.
  • pH Adjusting agents e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid and sodium hydroxide
  • antiseptics e.g. , p-hydroxybenzoates , chlorobutanol and benzalkonium chloride
  • it can be used for sterilization of disinfection of skin or mucous membrane as an ointment containing, for example, about 0.1 to lOOmg of the compoun of the present invention per gram using Vaseline (petroleu jelly) or lanolin as a base material.
  • the compound of the present invention can be made int oily or aqueous solid, semisolid or liquid suppositories.
  • oily base materials used therefor are high fatty acid glycerides [e.g. , cacao butter and Witepsols (Dynamite-Nobel)], medium fatty acids (e.g. , Migriols (Dynamite-Nobel)] or plant oil (e.g. , sesame oil, soybean oil and cotton seed oil) and the like.
  • the aqueous base materials are polyethylene glycols, propylene glycols, and those of the aqueous gel base materials are natural gums, cellulose derivatives, vinyl polymers, acryli acid polymers.
  • the dose of the compound of the present invention may vary depending upon the state of infection, the route of administration or the like. In the case of orally adminis trating it to an adult patient (weight: 50 kg) for the therapy of candidiasis, for example, it is about 0.01 to lOOmg/kg/day and, preferably about 0.1 to 50mg/kg/day, and more preferably about 1 to 20mg/kg/day.
  • a suitable liquid carrier e.g. , solvents
  • a suitable solid carrier e.g.
  • the amount of the compound of the present invention is, for example, about 25 to 150g, preferably about 40 to 80g per acre of irrigated rice field for prevention of rice blast diseases.
  • liquid carrier examples include water, alco ⁇ hols (e.g. , methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and ethylene glycol), ethers (e.g. , diox- ane , tetrahydrofran) , aliphatic hydrocarbons (e.g., kero ⁇ sene, lamp oil and fuel oil), aromatic hydrocarbons (e.g. , benzene and toluene), haloganated hydrocarbons (e.g. , meth- ylene chloride and chloroform), acid amides (e.g.
  • alco ⁇ hols e.g. , methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and ethylene glycol
  • ethers e.g. , diox- ane , tetrahydrofran
  • aliphatic hydrocarbons e.g., kero
  • esters e.g. , ethyl acetate and butyl acetate
  • nitrils e.g., acetonitrile and propionitrile
  • solid carriers examples include plant powder (e.g., soybean powder, tobacco powder and wheat flour), mineral powder (e.g. , kaolin and bentonite), alumina, sulf powder, activated charcoal and the like. They may be use either individually or as a mixture thereof in a suitable mixing ratio.
  • ⁇ H-NMR spectra were measured by a spectrometer of Varian Gemini 200 type (200MHz) using tetramethylsilane as an internal standard. All ⁇ values are given by ppm.
  • the figures given in ( ) are the mixi ratio of each of the solvents by volume. Unless otherwise specified, the symbol % means by weight. In the silica ge chromatography, the ratio of the solvents is a ratio of t mixed solvents by volume.
  • This compound (22.91 g) was dissolved in methanol (700 m1), to which an aqueous solution of lN-sodium hydroxide (146.5 ml) was added at ice-bath temperature. The mixture was stirred at room temperature for 1 hour. After lN-hydro chloric acid (85.5 ml) was added thereto, the solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (500 ml) and water (500 ml). The sepa ⁇ rated organic layer was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated.
  • Ferric chloride (0.2 g) and activated carbon (2.0 g) were added to a solution of l-(4-nitrophenyl)-3-[4-(2 ,2 , 3 , 3- tetrafluoropro ⁇ oxy)phenyl]-2 (lH,3H)-imidazolone (20.5 g) in methanol-tetrahydrofran (75 ml : 75 ml), to which hydrazine hydrate (8.0 ml) was added dropwise over the period of 10 minutes.
  • Phenyl 4-[5-oxo-4-[4-(2,2,3 , 3-tetrafluoropropoxy)- phenyl]-lH,4H-l ,2 ,4-triazol-l-y1]phenylcarbamate (5.6 g) was added to a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml). To the resulting mixture was added hydrazine hydrate (3 g) with stirring. The resultant was stirred at 80 C C for 2 hours and concentrated under reduce pressure to about 20 ml.
  • the precipitated crystals were collected by filtration and washed with water (100 ml).
  • the crystals were dried and dissolved in a mixture of tetrahydrofuran (300 ml) and ethyl acetate (600 ml) with warming.
  • the solution thus obtained was dried over anhydrous magnesium sulfate, filtrated and concentrated under reduced pressure.
  • the concentrated solution was subjected to flash column chroma ⁇ tography using silica gel and eluted with dichloromethane- hexane (1:1).
  • the desired fraction was concentrated to about 10 ml, and the residue was added at -14°C to a solu ⁇ tion prepared from 4-[4-[5-oxo-4-[4-(2 , 2, 3 , 3-tetrafluoropro ⁇ poxy)phenyl]-IH, 4H-1 ,2 ,4-triazol-l-y1]phenyl]-3 (2H,4H)- 1 ,2 ,4-triazolone (2.1 g) , dimethylformamide (40 ml) , dimeth ⁇ yl sulfoxide (50 ml) and sodium hydride (60% in oil: 180 mg) .
  • the resulting mixture was stirred at -14°C for 20 minutes and then at -5°C for 20 minutes.
  • the reaction solution was diluted with water (500 ml) and extracted with dichloromethane (300 ml X 2) .
  • the dichloromethane layer was washed with water (200 ml X 2) and a saturated aqueous solution of sodium chloride successively, dried over anhy ⁇ drous magnesium sulfate and distilled off under reduced pressure to give a colorless powder.
  • the resultant was diluted with hexane (25 ml), subjected to flash column chromatogra ⁇ phy using silica gel and eluted with dichloromethane-hexane (1:1) .
  • the desired fraction was concentrated to about 20 ml, and the residue was added to a solution prepared from l-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (1.14 g) , 1-methy1-2-pyrrolidone (30 ml) and 72% sodium hydride in oil (150 mg) at -30°C.
  • the reaction solution was stirred at -30°C for 15 minutes and then at -10°C for 15 minutes.
  • reaction solution was stirred at 30 to 35°C for 2 hours, it was cooled in an ice- bath.
  • a saturated aqueous solution of ammonium chloride (100 ml) was added thereto and the mixture was extracted with ethyl acetate (200 ml x 2, 100 ml).
  • the extract was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sul ⁇ fate, and distilled under reduced pressure to remove the solvent.
  • (2S)-2' ,4 '-Difluoro-2-hydroxypropiophenone (synthesized by the method disclosed in Japanese Unexamined Patent Publi ⁇ cation No. Hei 5 ( 1993)-230038 : 26.01 g) was dissolved in di ⁇ chloromethane (300 ml), to which diisopropylethylamine (19.90 g) was added at -60°C under a nitrogen atmosphere, and then trifluoromethanesulfonic anhydride (25.90 ml) was added thereto dropwise over the period of 20 minutes. After the reaction temperature was gradually raised to -30°C, the reaction solution was further stirred for 30 minutes.
  • X H-NMR (CDCl 3 ) ⁇ : 1.73 ( 3H , dd , J 7.0Hz , 1.6Hz ) , 5.93
  • (2S)-2 '-Fluoro-2-hydroxypropiophenone (synthesized by the method disclosed in Reference Example 76: 3.36 g) was dissolved in dichloromethane (30 ml). To the resultant was added diisopropylethylamine (4.18 ml) at -60 ⁇ C under a nitrogen atmosphere, and then trifluoromethanesulfonic anhy ⁇ dride (4.03 ml) was added dropwise to the mixture over the period of 2 minutes. After the reaction temperature was gradually raised to -25°C, the reaction solution was stirred for 30 minutes.
  • reaction solution was stirred at room temperature for 1 hour.
  • the reaction solution was cooled in an ice-bath and added dropwise over the period of 15 minutes to a solution of (2S)-2 '-fluoro-2-trifluoromethanesulfonyloxypropiophenone (4.7 g) in tetrahydrofuran (100 ml) which had been cooled to -20 ⁇ C.
  • the reaction tem ⁇ perature was raised to 10 ⁇ C over 30 minutes and the reaction solution was further stirred for 12 hours.
  • reaction solution was diluted with acetic acid (10 ml) and ethyl acetate (500 ml), washed with water (250 ml x 2), 0.5 hydro ⁇ chloric acid (250 ml x 2) and a saturated aqueous solution of sodium chloride (250 ml) successively, dried over anhy ⁇ drous magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • reaction solution was stirred at room temperature for 30 minutes.
  • the resultant was ice-cooled and added dropwise over the period of 10 minutes to a solution of (2S)-2' ⁇ fluoro-2-trifluoromethanesulfonyloxypropiophenone (1.57 g) in tetrahydrofuran (25 ml) which had been cooled to -10°C.
  • the reaction temperature was raised to 0 ⁇ C over 15 minutes and the reaction solution was stirred for 30 minutes.
  • reaction solution was diluted with acetic acid (3 ml) and ethyl acetate (100 ml), washed with water (50 ml x 2), 0.5 N-hydrochloric acid (50 ml x 2) and a saturated aqueous solution of sodium chloride (50 ml) successively, dried over anhydrous magnesium sulfat and distilled under reduced pressure to remove the solvent.
  • Chloromethylisopropoxydimethylsilane (2.14 g) and magnesium (for Grignard reaction, 313 mg) were added to tetrahydrofuran (15 ml), and the mixture was heated to 60°C. To the mixture was added magnesium in the form of turnings which had been activated by methyl iodide, and then the mixture was stirred in a bath at 60°C for 3 hours.
  • a cooled saturated aqueous solution of ammonium chloride (30 ml) and cooled water (100 ml) were added thereto at ice-bath temperature and the mixture was extracted with ethyl acetate (200 ml).
  • the extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concen ⁇ trated under reduced pressure.
  • the mixture was heated at 50°C for 4 hours, then cooled and extracted with ethyl acetate (100 ml).
  • the extract was washed with water (30 ml), an aqeous solution of Na 2 S 2 0 3 (30 ml x 2) and a satu ⁇ rated aqueous solution of sodium chloride (30 ml) successive ⁇ sively, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • reaction solution was stirred at 0°C for 30 minutes and washed with water (15 ml x 2) and a saturated aqueous solution of sodium chloride (15 ml) successively.
  • the organic layer was dried over magnesi ⁇ um sulfate and distilled under reduced pressure to remove the solvent.
  • the resultant was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and a saturated aqueous solution of sodium chloride (10 ml) successively.
  • the organic layer wa dried over magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • the resultant was diluted with ethyl acetate (150 ml) and tetrahydrofuran (50 ml) . Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml) , 1N- hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively.
  • Ice water 150 ml was added thereto to separate the ethyl acetate layer.
  • the aqueous layer was extracted with ethyl acetate (100 ml).
  • the ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride (50 ml) successively.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • reaction solution was dilut ⁇ ed with ethyl acetate (400 ml), and washed with water (100 ml), IN-hydrochloric acid (100 ml X 2) and a saturated - aqueous solution of sodium chloride (50 ml) successively.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • reaction solution was diluted with ethyl acetate (40 ml). Ice water (40 ml) was added thereto to separate the ethyl acetate layer.
  • the ethyl acetate layer was washed with 0.5N-sodium hydroxide (40 ml), IN-hydrochloric acid (40 ml) and a saturated aqueous solu ⁇ tion of sodium chloride (40 ml) successively.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • Ice water 200 ml was added thereto to separate the ethyl acetate layer.
  • the aqueous layer was extracted with ethyl acetate (100 ml).
  • the ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride (100 ml) successively.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • the reaction solution was cooled, diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer.
  • the aqueous layer was extracted with ethyl acetate (100 ml).
  • the combined ethyl acetate layers were washed with IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride (100 ml) successively.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • reaction solution was diluted with ethyl acetate (30 ml), washed with water (15 ml), IN-hydrochloric acid (15 ml x 2) and a saturated aque ⁇ ous solution of sodium chloride (15 ml).
  • the organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent.
  • the residue was purified by silica gel chromatography (eluent: ethyl acetate) .
  • Tables 10 to 14 show a group of preferred compounds belonging to the compound (I) of the present invention but the present invention is not limited to those compounds.
  • the compound 10. obtained in Working Example 10 and magnesium stearate were made into granules by using an aqueous solution of soluble starch, dried and mixed with lactose and corn starch. The mixture was molded under compression to form a tablet for the below prescription.
  • Test Method Five-week-old Crj : CDF- ⁇ mice were inoculated with the minimum lethal dose of Candida albi cans TA intrave ⁇ nously. The test compounds were administered orally once immediately after infection as a 30% HPCD (hydroxypropy1- ⁇ - cyclodextrin) solution. The activity was expressed in terms of EDg Q value calculated by the Reed and Muench method from the survival rate 7 days after infection. Result: Tables 15 and 16 shows the protective effects of the present compounds against Candida albicans infection in mice.
  • the present compounds or their salts have low toxicity and excellent antifungal activity. Therefore, they are useful in protection and treatment for fungal infections of mammals as antifungal preparations. In addition, they can serve as antifungal preparations for agricultural use.

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Abstract

The present invention provides an azole compound represented by formula (I), wherein Ar is an optionally substituted phenyl group; R?1 and R2¿, the same or different, are a hydrogen atom or a lower alkyl group, or R?1 and R2¿ may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Y=Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer from 0 to 2; and Az is an optionally substituted azolyl group, or its salt, which is useful for a prevention and therapy of a fungal infection of a mammal as an antifungal agent.

Description

DESCRIPTION Azole Compounds, Their Production and Use
TECHNICAL FIELD
The present invention relates to azole compounds useful as antifungal therapeutic agents, methods for producing the same and use thereof.
BACKGROUND ART
A variety of azole compounds have been reported exhib¬ iting antifungal activity (see, for example, EP0122056A1, EP0332387A1, EP0122693A1 and EP0567982A) .
None of these azole compounds, however, is satis actory as a pharmaceutical agent in terms of its antifungai activi¬ ty, antifungal spectrum, side effect and in vivo pharmacoki- netics .
There has been a demand for a safer compound which exhibits better absorption in vivo and higher antifungal activity as an antifungal therapeutic agent.
DISCLOSURE OF INVENTION
The present invention provides
(1) a compound represented by the formula (I):
Figure imgf000003_0001
wherein Ar is an optionally substituted phenyl group;
R-1- and R^, the same or different, are a hydrogen atom or a lower alkyl group, or R 1 and Rώ 9 may combine together to fo a lower alkylene group; R^ is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Y=Z ( and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer from 0 to 2; and Az is optionally substituted azolyl group, or a salt thereof,
(2) a process for preparing a compound of the formula as defined in claim 1 or a salt thereof which comprises
(i) reacting a compound represented by the formula
(II) :
Figure imgf000004_0001
wherein the symbols have the same meanings as defined abov or a salt thereof with a compound represented by the formula (III) :
(*)
Figure imgf000004_0002
wherein the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation;
(ii) reacting a compound represented by the formula (IV):
Figure imgf000005_0001
wherein the symbols have the same meanings as defined above; or a salt thereof with a compound represented by the formula (V):
Figure imgf000005_0002
wherein A" is -N=CH-, -CH=N- or -CH=CH-; the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acylation; or
(iii) reducing a compound represented by the formula d " )
Figure imgf000005_0003
wherein the symbols have the same meanings as defined above; or a salt thereof, and, if necessary, followed by an acyla- t i on ,
(3) a pharmaceutical composition to be an antifungal preparation containing a compound represented by the above formula (I) or a salt thereof.
Examples of the substituents for "optionally substitut ed phenyl group" represented by Ar in the formula (I) in¬ clude halogen atoms (e.g. , ■ fluorine, chlorine, bromide and iodine), lower (C1-4) haloalkyl , lower (C1-4) haloalkoxy, lower (C1-4) alkylsulfonyl , lower (C1-4) haloalkyisulfony1 and the like. Preferably, the substituent is halogen atoms (e.g. , fluorine, chlorine, bromine and iodine), and more preferably it is fluorine. The number of the substituents is preferably from one to three, more preferably from one t two .
Examples of Ar include halophenyl, lower (C^_4) haloal kyiphenyl, lower (C^_4) haloalkoxyphenyl , lower (C^_ ) alkyIsulfonylphenyl , lower (C^_4) haloalkylsulfonylphenyl and the like.
Examples of the halophenyl groups include 2 , 4-difluoro phenyl , 2 ,4-dichloropheny1 , 4-chlorophenyl , 4-fluorophenyl , 2-chloropheny1 , 2-fluorophenyl , 2-fluoro-4-chloropheny1 , 2- chioro-4-fluorophenyl , 2 ,4 , 6-trifluoropheny , 4-bromophenyl and the like.
Examples of the lower (C^_4) haloalkylphenyl groups include 4-trifluoromethylphenyl group and the like. Examples of the lower (C^_ ) haloalkoxyphenyl groups include 4-trifluoro ethoxypheny1 , 4-(1 , 1 , 2 , 2-tetrafluoro¬ ethoxy)phenyl , 4-(2 ,2 ,2-trifluoroethoxy)phenyl , 4-(2,2,3,3- tetrafluoropropoxy)phenyl , 4-(2 , 2 , 3 , 3 , 3-pentafluoro- propoxy)phenyl and the like.
Examples of the lower (C^_4) alkylsulfonylphenyl groups include 4-methanesulfonylphenyl and the like.
Examples of the lower (C^_4) haloalkylsulfonylphenyl groups include 4-(2 , 2 , 2-trifluoroethanesulfonyl)phenyl , 4- (2,2,3, 3-tetrafluoropropanesulfonyl )phenyl , 4-(2,2, 3,3,3- pentafluoropropanesulfonyl)phenyl and the like.
Specific examples of the phenyl groups of Ar are phenyl groups substituted with one to two halogen atoms such as 2 ,4-difluorophenyl , 2 ,4-dichloropheny1 , 4-chlorophenyl , 4- fluorophenyl , 2-chlorophenyl , 2-fluorophenyl , 2-fluoro-4- chlorophenyl , 2-chloro-4-fluorophenyl , 4-bromophen 1 and the like, among which phenyl groups substituted with one or two fluorine atoms such as 4-fluorophenyl , 2-fluorophenyl and 2 , 4-difluorophenyl are more preferable and 2-fluorophenyl and 2 ,4-difluorophenyl are most preferable.
Examples of the lower alkyl groups represented by R1 or R2 in the formula (I) include straight or branched C^_ alkyl groups such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, among which methyl is more preferable. It is particularly prefer¬ able that both of R1 and R2 are hydrogen atoms or methyl groups, or one of R 1 and Rώ ? is a hydrogen atom and the othe is a methyl group.
Examples of the lower alkylene groups formed by the combination of R and R2 include straight lower (C2_4) alkylene groups such as ethylene, propylene, butylene and the like, among which ethylene is preferred.
Among them, it is preferable that one of R and Rώ is hydrogen atom and the other is a C^_4 alkyl group such as a methyl group and the like.
Examples of the acyl groups represented by R° in the formula (I) include acyl groups derived from organic carbox ylic acids such as alkanoyl, preferably C1_γ alkanoyl (e.g. , formyl, acetyl , propionyl , butyryl , isobutyryl, pentanoyl , hexanoyl and heptanoyl) , more preferably C__ \ alkanoyl; arylcarbonyl, preferably
Figure imgf000008_0001
arylcarbonyl (e.g. , benzoyl and naphtalenecarbony1 ) , more preferably Cγ_^^ arylcarbonyl group; alkoxycarbonyl , preferably C2.-.7 alkoxycarbony1 (e.g. , methoxycarbonyl , ethoxycarbony1 , propoxycarbony1 , isopro- poxycarbonyl , butoxycarbony1 , isobutoxycarbonnyl , sec-bu- toxycarbonyl and tert-butoxycarbony1 ) , more preferably C _ alkoxycarbonyl; aryloxycarbonyl , preferably C7_15 aryloxy- carbonyl (e.g. , phenoxycarbony1 ) , more preferably C _^ ^ ary loxycarbonyl ; aralkylcarbonyl group, preferably CQ_2Q aral- kylcarbonyl (e.g. , benzylcarbonyl , phenetylcarbonyl , phenyl propylcarbonyl and naphthylethylcarbonyl) , more preferably Cg_1 aralkylcarbonyl ; and the like.
Preferably, the above acyl groups are those being capable of hydrolyzing in vivo. Examples thereof are for- myl. acetyl, benzoyl, benzylcarbonyl and the like. Pre¬ ferred R3 is a hydrogen atom.
X in the general formula (I) is preferably a nitrogen atom.
Examples of the lower alkyl groups for "a methine group optionally substituted by a lower alkyl group" represented by Y or Z when A is Y=Z in the formula (I) include straight or branched C^_4 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl) , among which methyl is preferred.
Examples for the methine group optionally substituted with a lower alkyl group represented by Y or Z include me¬ thine, ethylidyne (-C(CH3)=) , propylidyne (-C(CH2CH3 )=) , butylidyne (-C(CH2CH2CH3)=) and the like, among which me¬ thine, ethylidyne and the like are preferable, and methine and the like are more preferable.
It is preferable that one of Y and Z is a nitrogen atom and the other is methine; that both are methine; that both are nitrogen atoms; and one is a nitrogen atom and the other is ethylidyne. It is particularly preferable that one of Y and Z is a nitrogen atom and the other is methine or both of Y and Z are methine.
When A is "an ethylene group optionally substituted with a lower alkyl group" in the formula (I), examples of the lower alkyl groups include straight or branched C^_4 alkyl groups (methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl, ethyl and the like are preferable , and methyl and the like are more preferable.
Examples of the ethylene groups optionally substitute with a lower alkyl group represented by A include ethylene 1-methylethylene , 1 , 1-dimethylethylene , 1 , 2-dimethy1- ethylene, 1-ethylethylene , 1 , 2-diethylethylene and the lik among which ethylene and the 1ike are preferred.
Specific examples of A are -N=CH-, -CH=N-, -CH=CH-, -N=N-, -N=C(CH3)-, -C(CH3)=N-, -CH2-CH2- and the like, amo which -N=CH-, -CH=N-, -CH=CH-, -CH2-CH2- and the like are preferred.
In the formula (I), the groups represented by
Figure imgf000010_0001
are preferably
Figure imgf000010_0002
and the like, more preferably
Figure imgf000011_0001
and the like, still more preferably
-ό ~
Figure imgf000011_0002
"(J and the like.
The integer from 0 to 2 represented by n is preferably 0 or 1, more preferably 0.
Examples of the azolyl groups for "an optionally sub¬ stituted azolyl group" represented by Az in the formula (I) include five-membered aromatic heterocyclic groups contain¬ ing one to four nitrogen atoms as ring-constituent atoms, which may further contain a hetero atom selected from sulfur or oxygen as a ring-constituent atom, such as pyrrolyl, pyrazolyl, imidazolyl, 1 , 2 ,3-triazolyl , 1 , 2 ,4-triazoly1 , tetrazolyl, thiazolyl, isothiazoly1 , oxazolyl, isoxazolyl, furazanyl, 1 , 3 ,4-thiadiazolyl , 1 ,2 ,3-thiadiazoly1 , 1,2,5- thiadiazolyl , 1 , 2 ,4-thiadiazolyl and the like.
In particular, the azolyl groups are preferably pyrazo¬ lyl, imidazolyl, 1 ,2 , 3-triazolyl , 1 ,2 ,4-triazolyl , tetrazo¬ lyl and the like, more preferably lH-pyrazol-1-yl , 1H- imidazol-1-yl , 1H-1 , 2 , 3-triazol-l-yl , 2H-1 ,2 , 3-triazol-2-y1 , 1H-1 , 2,4-triazol-l-yl , 4H-1 , 2 ,4-triazol-4-y1 , lH-tetrazol- 1-yl, 2H-tetrazol-2-y1 and the like, and further more pref- erably lH-pyrazol-1-yl , 1H-1 , 2 , 3-triazol-l-yl , 2H-1.2.3- triazol-2-yl , 1H-1 , 2 ,4-triazol-l-yl , lH-tetrazol-1-yl , 2H- tetrazol-2-yl and the like.
Examples of the substituents for "an optionally substi tuted azolyl group" represented by the above Az include hydroxyl group, optionally esterified carboxyl group (e.g. , carboxyl, C^_g alkoxycarbonyl such as methoxycarbonyl , ethoxycarbony1 and butoxycarbony1 ) , nitro group, a ino group, acylamino group (e.g. , C^.^Q alkanoylamino such as acetylamino, propionylamino and butyrylamino) , mono-C^- o o di-C^_^Q alkylamino group (e.g. , methylamino, dimethylamino diethylamino and dibutylamino) , C1_g alkyl group (e.g. , methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, sec- butyl, pentyl and hexyl), C^.g alkoxy group (e.g. , methoxy, ethoxy and butoxy) , halogen atom (e.g. , fluorine, chlorine and bromine) , C^_ haloalkyl group (e.g. , trifluoromethy1 , dichloromethyl, 2 , 2 , 2-trifluoroethy1 and 2 , 2 , 3 , 3-tetrafluo- ropropyl), C^_ haloalkoxy group (e.g. , trifluoro ethoxy , 1 , 1,2 ,2-tetrafluoroethoxy, 2 , 2 , 2-trifluoroethoxy , 2,2,3,3- tetrafluoropropoxy , 2,2,3,3, 3-pentafluoropropoxy, 2 , 2 , 3 , 3 , 4 , 4 , 5 , 5-octafluoropentoxy and 2-fluoroethoxy) , oxo group, thioxo group, mercapto group, C _g alkylthio group (e.g. , methylthio, ethylthio and butylthio), C1_6 alkylsul- fonyl group (e.g., methanesulfonyl , ethanesulfony1 and butanesulfonyl ) , C ±_ I Q alkanoyl group (e.g., acetyl, formyl propionyl and butylyl), phenyl group, C^_ alkylphenyl group (e.g. , p-tolyl, mesityl and p-cumenyl), C^_g alkoxyphenyl group (e.g., 4-methoxyphenyl and 4-isopropoxyphenyl) , halo¬ phenyl group (e.g. , 4-chlorophenyl and 4-fluorophenyl , 2 ,4,-difluorophenyl) , C^_ haloalkylphenyl group (e.g. , 4- trifluoromethylphenyl ) , Cj_g haloalkoxyphenyl group [e.g. , 4-trifluoromethoxyphenyl , 4-(2 ,2 , 3 ,3-tetrafluoropropoxy)- phenyl and 4-( 1 , 1 , 2 , 2-tetrafluoroethoxy)phenyl ] and the like. These substituents may be substituted on the ring- constituent carbon and/or nitrogen atom(s) of the azolyl group and the number of the substituents is preferably one or two.
Specifically, Az are preferably diazolyl, triazolyl and tetrazolyl such as
Figure imgf000013_0001
and the like, more preferably
Figure imgf000013_0002
and the like A preferred example of the compound (I) is a compound represented by the formula (I')
Figure imgf000014_0001
(wherein Ar' is a monofluorophenyl (e.g. , 2- fluorophenyl ) or difluorophenyl (e.g. , 2 ,4-difluorophenyl ) group; A' is -N=CH-, -CH=CH- or CH2-CH2-; and Az ' is an azolyl group selected from the group consisting of a diazo- lyl , triazolyl, tetrazolyl, thiazolyl or oxazolyl which are optionally substituted with one or two substituents selecte from the group consisting of an oxo group, a C^_g alkyl group (e.g. , methyl, ethyl, n-propyl , iso-propyl), a C1-6 haloalkyl group (e.g. , trifluoromethy1 , 2 , 2 , 2-trifluoroeth- yl , 2 , 2 , 3 , 3-tetrafluoropropy1 ) and a C^_ haloalkyloxypheny group (e.g. , 4-trifluoromethoxyphenyl , 4-(2 , 2 , 3 , 3-tetra- fluoropropoxypheny1 , 4-( 1 , 1 , 2 , 2-tetrafluoroethoxyphenyl ) ) o a salt thereof. In the formula (I'), A' is preferably -CH2-CH -, and Az ' is preferably a triazolyl group and a tetrazolyl group.
The compound represented by the formula (I), (I') may be used as a salt thereof. Examples of such salts are pharmacologically acceptable salts such as inorganic acid salts (e.g. , hydrochloride , hydrobromide , sulfate, nitrate and phosphorate), organic acid salts (e.g. , acetate, tarta- rate, citrate, fumarate, maleate, toluenesulfonate and methanesulfonate) . When carboxyl group is included in the formula (I) as a substituent, it may be an alkali methal (sodium, pottasium and the like) salt.
The compounds represented by the formula (I) or a salt thereof (hereinafter abbreviated as the compound of the present invention) have two or more stereoisomers thereof because of having one or more asymmetric carbon atom in their molecule. It should be understood that any of such stereoisomers as well as a mixture thereof is within a scope of the present invention. Among those, when R is hydrogen and Rώ is methyl, both the carbon atom to which the option¬ ally substituted phenyl group represented by Ar is bonded and the carbon atom to which R is bonded are preferred to be in (R)-configuration.
The compound of the present invention can be produced by, for example, reacting a compound represented by the formula (II ) :
Figure imgf000015_0001
(wherein the symbols have the same meanings as defined above) or a salt thereof with a compound represented by the formula (III)
Figure imgf000016_0001
(wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compoun of the present invention in which R^ is a hydrogen atom.
The reaction can be carried out in a solvent which doe not inhibit the reaction. Examples of the solvents are water, ketones (e.g. , acetone), sulfoxides (e.g. , dimethyl sulfoxide), ethers (e.g. , diethyl ether, tetrahydrofuran an dioxane), nitriles (e.g. , acetonitrile) , aromatic hydrocar¬ bons (e.g. , benzene, toluene and xylene) , halogenated hydro carbons (e.g., dichloromethane , chloroform and 1 ,2-dichloro ethane), esters (e.g. , ethyl acetate) , amides (e.g. , di eth ylformamide, acetamide, dimethylacetamide and l-methyl-2- pyrro1idinone) , ureylenes (e.g. , 1 , 3-dimety1-2-imidazo1idi- none) and the like. These solvents may be used either singly or as a mixture of two or more solvents in a suitabl mixing ratio.
Further, the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g. , potassium hydride and sodium hydride) , alkali metal carbonates (e.g. , lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate), alkali metal alcoholates (e.g. , sodium methylate, potassium tert-butylate and sodium tert- butylate), tetrabutylammonium fluoride, bis (tri-n-butylstan- nyl)oxide and the like.
Alternatively, the desired compound can also be pre¬ pared by the reaction in the above solvent using a metal salt (e.g., alkali metal salt such as sodium and potassium salt) of the compound (III) instead of the compound (III) .
The amount of the base used is usually about 0.01 to at 100 equivalents, preferably about 0.1 to about 50 equiva¬ lents per equivalent of the compound of formula (III) or a salt thereof.
The amount of the compound (III) or a salt thereof is about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (II) or a salt thereof.
The reaction temperature is not especially limited, but usually within the range of about 0 to about 150°C, prefera¬ bly about 10 to about 120°C.
The reaction time is usually within the range of about several minutes to tens of hours (e.g. , from five minutes to fifty hours) .
In another embodiment, the compound of the present invention can also be prepared by, for example, reacting a compound represented by the formula (IV):
(wherein the symbols have the same meanings as defined above) or a salt thereof with a compound represented by the formula (V):
Figure imgf000018_0002
(wherein A" is -N=CH-, -CH=N- or -CH=CH-, the other symbols have the same meanings as defined above) or a salt thereof. The compound of the formula (V) may be a compoun represented by the formula (V" ) :
Figure imgf000018_0003
(wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compoun of the present invention which A is Y=Z and RJ is hydrogen.
The reaction is usually carried out in a solvent which does not inhibit the reaction. Examples of the solvents ar water, ketones (e.g. , acetone), sulfoxides (e.g. , dimethyl sulfoxide), ethers (e.g. , diethyl ether, tetrahydrofuran an dioxane), nitriles (e.g. , acetonitrile) , aromatic hydrocar- bons (e.g. , benzene, toluene and xylene), halogenated hydro¬ carbons (e.g. , dichloromethane , chloroform and 1,2- dichloroethane) , esters (e.g., ethyl acetate), amides (e.g. , dimethylformamide , acetamide, dimethylacetamide and 1-meth- yl-2-pyrrolidinone) , ureylenes (e.g. , 1 , 3-dimetyl-2- imidazolidinone) and the like. These solvents may be used either singly or as a mixture of two or more solvents in a suitable mixing ratio.
Further, the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide, sodium hydroxide), alkali metal hydrides (e.g. , potassium hydride and sodium hydride), alkali metal carbonates (e.g. , lithium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate) , alkali metal alcoholates (e.g. , sodium methylate, potassium tert-butylate and sodium tert-butylate) , tetrabu¬ tylammonium fluoride, bis(tri-n-butylstannyl)oxide and the like.
Alternatively the desired compound can also be prepared by the reaction in the above solvent using a metal salt (e.g. , alkali metal salt such as sodium and potassium salt) of the compound (V) or (V") instead of the compound (V) or (V) .
The amount of the base used is usually about 0.01 to about 100 equivalents, preferably about 0.1 to about 50 equivalents per equivalent of the compound of formula (V)
or a salt thereof or (V") or a salt thereof.
The amount of compound (V) or (V") or a salt thereof is about 1 to about 100 equivalents, preferably about 1 to about 50 equivalents per equivalent of the compound of formula (IV) or a salt thereof.
The reaction temperature is not especially limited, bu usually within the range of about 0 to about 150°C, prefera bly about 10 to about 120°C.
The reaction time is usually within the range of about several minutes to tens of hours (e.g. , from five minutes t fifty hours) .
According to another embodiment, the compound of the present invention can be prepared by, for example, reacting a compound represented by the formula (VI) :
Figure imgf000020_0001
{wherein L is a leaving group [e.g. , halogen atom (e.g. , chlorine, bromine and iodine) or R S03 (wherein R4 i lower (C1-4) alkyl group or optionally substituted phenyl group)] and the other symbols have the same meaning as defined above} or a salt thereof with a compound represented by the formula (III):
Figure imgf000021_0001
(wherein the symbols have the same meaning as defined above) or a salt thereof. This reaction provides a compound of the formula (I) in which R3 is hydrogen.
Examples of the C1-4 lower alkyl group represented by R4 are methyl, ethyl, propyl, butyl and tert-butyl.
Examples of the optionally substituted phenyl group are the same as those of the optionally substituted phenyl group represented by Ar.
The reaction is usually carried out in a solvent which does not inhibit the reaction. Examples of the solvents are water, ketones (e.g. , acetone), sulfoxides (e.g. , dimethyl sulfoxide), ethers (e.g. , diethyl ether, tetrahydrofuran and dioxane), nitriles (e.g. , acetonitrile) , aromatic hydrocar¬ bons (e.g. , benzene, toluene and xylene), halogenated hydro¬ carbons (e.g. , dichloromethane , chloroform and 1 , 2-dichloro- ethane), esters (e.g. , ethyl acetate), amides (e.g. , dimeth¬ ylformamide, acetamide, dimethylacetamide and l-methyl-2- pyrrol idinone) , ureylenes (e.g. , 1 , 3-dimetyl-2-imidazolidi- none) and the like. These solvents may be used either singly or as a mixture of two or more solvents in a suitable mixing ratio.
Further, the reaction is preferably carried out in the presence of a base such as alkali metal hydroxides (e.g. , lithium hydroxide, potassium hydroxide and sodium hydroxide), alkali metal hydrides (e.g., potassium hydride and sodium hydride), alkali metal carbonates (e.g. , lithiu carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate and sodium carbonate), organic acid salts (e.g. , sodium acetate), alkali metal alcoholates (e.g. , sodium methylate, potassium tert-butylate and sodium tert- butylate), tetrabutylammonium fluoride, bis (tri-n-butylstan nyl)oxide and the like.
Alternatively the desired compound can be prepared by the reaction in the above solvent using a metal salt (e.g. , alkali metal salt such as sodium and potassium salt) of the compound (III) instead of the compound (III) .
The amount of the base used is usually within the rang of about 2 to about 100 equivalents, preferably about 2 to about 50 equivalents per equivalent of the compound of formula (III) or a salt thereof.
The amount of the compound (III) or a salt thereof is usually within the range of about 1 to about 100 equiva¬ lents, preferably about 1 to about 50 equivalents per equiv alent of the compound of formula (VI) or a salt thereof.
The reaction temperature is not especially limited, bu usually about 0 to about 150°C, preferably about 10 to abou 120°C.
The reaction time is about tens of minutes to tens of hours (e.g. , from thirty minutes to fifty hours) . The compound of the present invention wherein A is an ethylene group optionally substituted with a lower alkyl or salt thereof can be prepared by, for example, subjecting to a catalytic reduction a compound of the formula (I") :
Figure imgf000023_0001
(wherein the symbols have the same meaning as defined above) or a salt thereof, or the compound of the formula (I) wherein Y and Z are methine groups optionally substituted with lower alkyl (i.e. , a compound (I'' ')):
Figure imgf000023_0002
(wherein A' ' ' is a vinylene group optionally substitut¬ ed with lower alkyl group and the other symbols have the same meanings as defined above) or a salt thereof.
The above-mentioned reaction is usually carried out in the presence of a single or mixed solvent(s) such as water and organic solvents which do not inhibit the reaction such as ketones (e.g. , acetone and methylethyl ketone), alcohols (e.g. , methanol, ethanol, propanol, isopropyl alcohol and butanol), esters (e.g. , ethyl acetate), hydrocarbons (e.g. , benzene, toluene, hexane and xylene), organic carboxylic acids (e.g. , acetic acid and propionic acid) and the like. The reaction is usually carried out in the presence of catalyst. A suitable metal catalyst such as palladium- carbon is used as the catalyst. The reduction reaction is carried out at a pressure from atmospheric pressure up to about 150kg/cm2 at a temperature from room temperature up t about 100βC.
Examples of the salts of the above starting compounds (II), (IV), (VI), (I") and (I" ') are the same as those of the compounds (I) .
When a compound or a salt thereof of the present inven tion wherein R° is a hydrogen atom is obtained in the above reactions, the obtained compound or a salt thereof can be converted into by the conventional method to provide a compound of the formula (I) wherein R^ is an acyl group, by treating it with an appropriate acylating agent of R L [wherein R3 is an aliphatic or aromatic carboxylic acid residue (e.g. , acetyl, propionyl, butylyl, ethoxycarbony1 , benzoyl, substituted benzoyl) and L1 is group to be removed (e.g., a halogen atom such as chlorine, bromine and the like, an active ester)] in accordance with the conventional method.
The above-mentioned reaction is usually carried out in the presence or absence of a solvent which does not inhibit the reaction. Examples of such solvents are water, ketones such as acetone, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, aromatic hydrocarbons such as benzen, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1 , 2-dichloroethane , esters such as ethyl acetate, amides such as di ethylformamide , acetamide, dimethylacetamide, ureylenes such as 1,3-dimeth- yl-2-imidazolidinone , and the like. Also a base (e.g. , dimethylaminopyridine , pyridine, pyrroline and triethyla- mine) may be added to the reaction system for accelaration of the reaction. The amount of the base used is usually about 1 to about 100 equivalents per equivalent of the compound of formula (I) or a salt thereof.
The compound of the present invention obtained as above can be isolated and purified from the reaction mixture by a known procedure per se such as extraction, concentration, neutralization, filtration, recrystal1ization, column chromatography, thin layer chromatography and the like.
The compound of the present invention may have at least two stereoisomers as mentioned above. Such a stereoisomer can be separately prepared if desired. For example, a single isomer can be obtained by the above reaction using each single isomer cf the starting compounds (II), (IV), (VI), (I") and (I' " ') or salts thereof. Alternatively, when the obtained product is a mixture of two or more isomers, they can be separated into each isomer by the conventional separating method such as a method for producing a salt wi an optically-active acid (e.g., camphorsulfonic acid and tartaric acid), various types of chromatographies, fractio al recrystallization and the like.
The salt of the compound of the present invention can be prepared by a known method per se such as adding the aforesaid inorganic or organic acid to the compound (I) .
The starting compound (II) or a salt thereof in the present invention wherein R1 is hydrogen, R2 is methyl, th carbon atom to which Ar is bonded is an (S)-configuration and the carbon atom to which R2 is bonded is an (Reconfig ration [i.e. , a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the fol¬ lowing reaction scheme:
OPhaP.PhCOOH
Figure imgf000026_0001
2)NaOMe/MeOH
Figure imgf000026_0002
Figure imgf000026_0003
(wherein Me is methyl, Et is ethyl, Pr is propyl, Ph is phenyl, (R) and (S) denote the respectively symbolized configurations of the carbon atoms, DMF is dimethylf orma¬ mide, and the other symbols have the same meanings as de¬ fined above) .
The starting compound (VIII) in the reaction can be prepared, for example, by a method represented by the fol¬ lowing reaction scheme:
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0003
[wherein THP is tetrahydropyranyl group, Ts is p- toluenesulfonyl group, L2 is a halogen atom (e.g., chlorin bromine, iodine), DMSO is dimethylsulfoxide, and the other symbols have the same meaings as defined above] .
The intermediate compound (IX) can be synthesized, fo example, by a method represented by the following reaction scheme :
Figure imgf000028_0001
NaOMe/MeOH
Figure imgf000028_0002
(wherein the symbols have the same meanings as define above) .
The starting compound (IV) in the present invention wherein R* is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded is in an (R)-configurati and the carbon atom to which R2 is bonded is in an (S)- configuration [i.e. , a compound (XVIII)]:
(Xvll
Figure imgf000028_0003
(wherein the symbols have the same meanings as defined above) can be synthesized, for example, by methods described in EP0421210A, EP0548553A or EP0567982A or by a method based thereon.
The starting compound (VI) or a salt thereof in the present invention wherein R-*- is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded in (S)- configuration, the carbon atom to which R2 is bonded in (R)-configuration, and L is a leaving group represented by R4S03 (wherein R4 has the same meaning as mentioned above) [i.e. , a compound (XIX) or a salt thereof], and the starting compound (II) or a salt thereof in the present invention wherein R1 is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded in (S)-configuration and the carbon atom to which R2 is bonded in (R)-configuration [i.e. , a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the following reac¬ tion scheme:
Figure imgf000030_0001
[wherein each of L , L , L5 and L is a halogen atom (e.g. , chlorine, bromine, iodine) and the other symbols have the same meanings as defined above] .
The starting compound (XX) or a salt thereof and the starting compound (XXI) or a salt thereof in the above reaction wherein L3 is a chlorine atom [i.e. , a compound (XXVI) or a salt thereof] can be each prepared, for example, by a method represented by the following reactions scheme:
Figure imgf000031_0001
(CFsSθ2)0». isoPreNEt
Figure imgf000031_0002
[wherein R is a lower alkyl group, L is a halogen atom (e.g. , chlorine, bromine, iodine) and the other symbols have the same meanings as defined above] .
A synthesizing method for a compound (XXXI) or a salt thereof in which Ar is 2, 4-difluorophenyl as mentioned in the above reaction scheme is described in Japanese Patent Laid-Open No . HEI 5 ( 1993 ) -230038
(CFsSCtejO isoPreNEt
Figure imgf000032_0001
(xxxiii)
Figure imgf000032_0002
(wherein H2/Pd-C denotes a catalytic reduction using palladium-carbon catalyst and the other symbols have the same meanings as defined above) .
A compound (XXI) or a salt thereof wherein L3 is a halogen atom except chlorine can be prepared using the corresponding halogenating agent [e.g. , (COBr)2, PBr ] instead of (C0C1)2 in a similar way to the above reaction.
The starting compounds (V) or a salt thereof in the present invention wherein A is -N=CH-, -CH=CH- or -CH -CH2- [i.e. , compounds (XXXVII), (XXXVIII) and (XXXIX) or salts thereof respectively] can be prepared, for example, by the method represented by the following reaction scheme
Figure imgf000033_0001
(wherein the symbols have the same meanings as defined above) .
Further, the starting compound (V) or a salt thereof wherein A is -CH=N- [i.e. , a compound (XXXXIV) or a salt thereof ] can be prepared, for example, by a method repre¬ sented by the reaction scheme:
Figure imgf000034_0001
H2)n-A2
Figure imgf000034_0002
(wherein the symbols have the same meanings as define above) .
The starting compounds or synthesized intermediate compounds above-obtained can be isolated and purified from the reaction mixtures by a known procedure per se such as extraction, concentration, neutralization, filtration, recrystal1ization, column chromatography, thin layer chrom tography and the like. Alternatively the reactant mixture itself can be used as a material in the next step without isolation.
The compound of the present invention has low toxicit and exhibits potent antifungal activity with broad antifun gal spectrum against, for example, microorganisms cf genus Candida (e.g., Candida albicans, Candida utilis, Candida grabrata, etc.), those of genus Histoplasma (e.g. , Histo- plasma capsulatum, etc.), those of genus Aspergillus (e.g. , Aspergillus niger, Aspergillus fumigatus, etc.), those of genus Cryptococcus (e.g. , Cryptococcus neoformans, etc.), those of genus Tricophyton (e.g., Trichophyton rubrum, Trichophyton mentagrophytes, etc.), those of genus Microspo- rum (e.g. , Microsporum gypseum, etc.), those of genus Malas- sezia (e.g. , Malassezia furfur, etc.) and the like. Accord¬ ingly, it can be used for prevention and treatment of the systemic fungal infection and dermatomycosis (e.g. , candid- iasis, histoplasmosis , aspergi1losis , cryptococcosis , tri- chophytosis and microsporumosis) of mammals (e.g. , human being, domestic animals and fowls) and further atopic derma¬ titis. Further, the compound of the invention can be used as an antifungal agent for agricultural use.
When the compound of the present invention is adminis¬ tered to a human being, it can be safely administered either orally or parenterally in the form of pharmaceutical compo¬ sitions such as oral administration preparations (e.g. , powders, granules, tablets, capsules), parenteral prepara¬ tions [e.g. , injections and external preparations (e.g. , nasal and dermatological ones), suppositories (e.g. , rectal and vaginal ones)] and the like in per se or in mixture with suitable pharmacologically-acceptable carriers, fillers or diluents. The content of the compound of the present inven tion in a whole pharmaceutical composition is usually 5 to 100 wt , preferably 20 to 100 wt% in an oral drug and 5 to 30 wt% in a parenteral drug.
Those preparations can be manufactured by methods whic are known per se and commonly used in the manufacture of pharmaceutical preparations.
For example, the compound of the present invention can be made into an injection such as aqueous injections togeth er with dispersing agents [e.g., Tween 80 (Atlas Powder, U.S.A.), HCO60 (Nikko Chemicals, Japan), carboxymethylcellu lose or sodium alginate], preservatives (e.g. , methylpara- ben, propylparaben, benzyl alcohol and chlorobutanol ) , iso- tonic agents (e.g. , sodium chloride, glycerol, sorbitol and glucose) and the like, or as oily injections by dissolving, suspending or emulsifying in a plant oil (e.g. , olive oil, sesame oil, peanut oil, cotton seed oil and corn oil), propylene glycol and the like.
In the manufacture of preparations for oral administra tion, the compound of the present invention is compression- molded together, for example, with fillers (e.g. , lactose, sugar and starch), disintegrating agents (e.g. , starch and calcium carbonate), binders (e.g. , starch, arabic gum, carboxymethylcellulose, polyvinyIpyrrolidone and hydroxypro pylcellulose) , lubricants (e.g. , talc, magnesium stearate and polyethylene glycol 6000) and the like, followed, if necessary, by coating in accordance with a known method per se with an object of taste-masking or of providing the preparation with enteric or sustained release property. Examples of the coating agents are hydroxypropylmethylcellu- lose, ethylcellulose , hydroxymethycellulose, hydroxypropyl- cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudra- git (Rohm, West Germany; a copolymer of methacrylic acid with acrylic acid) and pigments such as titanium oxide and red iron oxide.
The compound of the present invention can be also used solid, semisolid or liquid preparations for external use. For example, in the case of solid external preparation, the compound of the present invention is made into the form of powdered compositions as it is or in a mixture with filler (e.g. , glucose, mannitol, starch and microcrystal1ine cellu¬ lose), thickeners (e.g. , natural gum, cellulose derivatives and acrylic acid polymers) and the like. In the case of semisolid external preparation, aqueous or oily gel prepara¬ tion or ointment is preferred. In the case of liquid exter¬ nal preparation, the procedures are nearly the same as those in the case of injections to give oily or aqueous suspen¬ sions. pH Adjusting agents (e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid and sodium hydroxide) , antiseptics (e.g. , p-hydroxybenzoates , chlorobutanol and benzalkonium chloride) or the like can be added to the above-mentioned solid, semisolid or liquid preparations. More specifically, it can be used for sterilization of disinfection of skin or mucous membrane as an ointment containing, for example, about 0.1 to lOOmg of the compoun of the present invention per gram using Vaseline (petroleu jelly) or lanolin as a base material.
The compound of the present invention can be made int oily or aqueous solid, semisolid or liquid suppositories. Examples of the oily base materials used therefor are high fatty acid glycerides [e.g. , cacao butter and Witepsols (Dynamite-Nobel)], medium fatty acids (e.g. , Migriols (Dynamite-Nobel)] or plant oil (e.g. , sesame oil, soybean oil and cotton seed oil) and the like. Examples of the aqueous base materials are polyethylene glycols, propylene glycols, and those of the aqueous gel base materials are natural gums, cellulose derivatives, vinyl polymers, acryli acid polymers.
The dose of the compound of the present invention may vary depending upon the state of infection, the route of administration or the like. In the case of orally adminis trating it to an adult patient (weight: 50 kg) for the therapy of candidiasis, for example, it is about 0.01 to lOOmg/kg/day and, preferably about 0.1 to 50mg/kg/day, and more preferably about 1 to 20mg/kg/day. When the compound of the present invention is used as an agricultural antifungal agent, it may be dissolved or dispersed in a suitable liquid carrier (e.g. , solvents), or mixed or absorbed with a suitable solid carrier (e.g. , diluents and fillers), followed, if necessary, by addition of an emulsifier, suspending agent, spreader, penetrating agent, moisturizing agent, thickener, stabilizer, etc. to give the preparation a form such as emulsion, hydrating agent, powder, granules and the like. Such preparations can be prepared by known methods per se. The amount of the compound of the present invention is, for example, about 25 to 150g, preferably about 40 to 80g per acre of irrigated rice field for prevention of rice blast diseases.
Examples of the above liquid carrier are water, alco¬ hols (e.g. , methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and ethylene glycol), ethers (e.g. , diox- ane , tetrahydrofran) , aliphatic hydrocarbons (e.g., kero¬ sene, lamp oil and fuel oil), aromatic hydrocarbons (e.g. , benzene and toluene), haloganated hydrocarbons (e.g. , meth- ylene chloride and chloroform), acid amides (e.g. , dimethyl- formamide and dimethylacetamido) , esters ( e.g. , ethyl acetate and butyl acetate), nitrils (e.g., acetonitrile and propionitrile) and the like. They may be used either singly or as a mixture thereof in a suitable mixture ratio.
Examples of the above solid carriers are plant powder (e.g., soybean powder, tobacco powder and wheat flour), mineral powder (e.g. , kaolin and bentonite), alumina, sulf powder, activated charcoal and the like. They may be use either individually or as a mixture thereof in a suitable mixing ratio. BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is further described by way of the following Reference Examples and Working Examples.
^H-NMR spectra were measured by a spectrometer of Varian Gemini 200 type (200MHz) using tetramethylsilane as an internal standard. All δ values are given by ppm. In the mixing solvents, the figures given in ( ) are the mixi ratio of each of the solvents by volume. Unless otherwise specified, the symbol % means by weight. In the silica ge chromatography, the ratio of the solvents is a ratio of t mixed solvents by volume.
The symbols used in the examples have the following meanings . s: singlet; d: doublet; t: triplet; q: quartet; dd: double doublet; tt : triple triplet; : multiplet; br: bro J: coupling constant.
Reference Example 1
2-(2,4-Difluorophenyl )-2-[ ( lR)-l-(3 ,4 , 5 , 6-tetrahydro 2H-pyran-2-yl )oxyethyl]oxirane (82 g) (synthesized by the method disclosed in Japanese Unexamined Patent Publicatio No. Hei 4(1992)-74168) and pyridinium p-toluenesulfonate (6.3 g) were dissolved in ethanol (600 ml), and the result¬ ant was stirred at 55°C for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl ace¬ tate (1 lit.) and washed with water (200 ml x 2). The aque¬ ous layer was extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatog¬ raphy (eluent: hexane/ethyl acetate = 10/1 to 8/1 to 3/1) to give (lR)-l-[2-(2 ,4-difluorophenyl)-2-oxiranyl]ethanol (31.5 g) as a pale yellow oily substance.
1H-NMR (CDCl3)δ: 1.14-1.23 (3H,m), 1.77, 2.22 (1H), 2.80, 2.92 (1H), 3.27-3.32 (1H) , 4.00-4.20 (lH,m), 6.75-6.94 (2H,m), 7.36-7.48 (lH,m) Reference Example 2
(lR)-l-[2-(2 , 4-Difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 3 , 5-dinitrobenzoyl chloride (40 g) were dissolved in methylene chloride (500 ml), to which trimethylamine (24.1 ml) was added dropwise at ice-bath temperature. After the mixture was stirred at room temperature for 3.5 hours, it was washed with water (150 ml) and 5% sodium bicarbonate aqueous solution successively, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were filtrated and washed with methylene chloride. The mother liquor and the washings were combined and dis¬ tilled off under reduced pressure. Ethyl acetate (25 ml) and methanol (300 ml) were added to the residue, and the mixture was cooled in an ice bath. The precipitated crys¬ tals were collected by filtration and recrystallized from a mixture of ethyl acetate (25 ml) and methanol (250 ml) to give [ (lR)-l-[ (2R)-2-(2,4-difluorophenyl )-2-oxirany1]ethyl] 3 , 5-dinitrobenzoate (28.7 g) as colorless needles, mp: 104-107°C (recrystallized from ethylacetate-hexane) 1H-NMR (CDCl3)δ: 1.46 (3H,dd,J=6.6Hz ,J=l .2Hz) , 3.01 (lH,d,J=4.6Hz) , 3.23 (1H,d,J=4.6Hz) , 5.33 (lH,q,J=6.6Hz) , 6.85-7.07 (2H,m), 7.54 (lH,m), 9.13 (2H, d, J=2.2Hz) , 9.25 (lH,t,J=2.2Hz) Reference Example 3
[ (lR)-l-[ (2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]ethyl] 3 , 5-dinitrobenzoate (50 g) was dissolved in methanol (2 lit.), to which lN-sodium hydroxide (255 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and neutralized by an addition of 1 N-hydrochloric acid (127 ml) thereto. The resultant was concentrated under reduced pressure, to which ethyl acetate (1 lit.) and water (200 ml) were added. The mix¬ ture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride (200 ml), dried over magnesium sulfate and dis- tilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane = 1/3) to give (lR)-l-[ (2R)-2-(2,4- difluorophenyl)-2-oxiranyl]ethanol (25 g) as a pale yellow oily substance.
1H-NMR (CDC13)5: 1.17 (3H,dd,J=6.6Hz, 1.2Hz) , 1.83 (lH,d,J=8Hz) , 2.80 (1H,d,J=5.2Hz) , 3.30 (1H,d,J=5.2Hz) , 4.01-4.17 (lH,m), 6.75-6.93 (2H,m) 7.36-7.48 (lH,m) Reference Example 4
To an ice-cooled solution of (lR)-l-[ (2R)-2-(2 ,4-di- fluorophenyl)-2-oxiranyl]ethanol (16.1 g) in tetrahydrofuran (320 ml) were added triphenylphosphine (63.3 g) , benzoic acid (29.5 g) and diethyl azodicarboxylate (42.0 g) . The mixture was stirred at room temperature for 6 hours under an argon atmosphere. After ethyl acetate (800 ml) and water (500 ml) were added thereto, the separated aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were washed with water and a saturated aqueous solu¬ tion of sodium chloride successively, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 15/1 to 7/1) to give [(lS)-l-[ (2R)-2-(2 ,4-difluorophenyl)- 2-oxiranyl]ethyl] benzoate (19.2 g) as a colorless oily substance .
1H-NMR (CDCl3)δ: 1.37 (3H,d,J=6.6Hz) , 2.90 ( 1H,d,J=5.2Hz) , 3.28 (lH,d,J=5.2Hz) , 5.36 (1H,q,J=6.6Hz) , 6.74-6.94 (2H,m), 7.38-7.60 (4H,m), 7.94-8.01 (2H,m)
IR υ maxneatcm~1: 1725, 1615, 1600, 1505, 1450, 1425
[ (IS)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxirany1]-ethy benzoate (15.9 g) was dissolved in methanol (800 ml), to which 28% sodium methylate-methanol solution (12.9 ml) was added at ice-bath temperature and stirred at room tempera¬ ture for 6 hours. After lN-hydrochloric acid (63.2 ml) wa added thereto, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromato raphy (eluent: hexane/ethyl acetate = 6/1 to 2/1) to give ( lS)-l-[ (2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (9. g) as a colorless oily substance.
1H-NMR (CDCl3)δ: 1.20 (3H,dd,J=6.4Hz , 1Hz) , 2.24 (lH.d,J=2Hz) , 2.92 ( 1H,d,J=5Hz) , 3.28 ( 1H,d,J=5Hz) , 4.12 (lH.dq,J=6.4Hz,2Hz) , 6.77-6.95 (2H,m), 7.32-7.44 (lH,m) IR l/maxneat cm"1: 3420, 2980, 1615, 1600, 1500, 1425 Reference Example 5
2-(2-Fluorophenyl )-2-[ ( lR)-l-(3 ,4 , 5 , 6-tetrahydro-2H- pyran-2-yl)oxyethyl]oxirane (synthesized by the method dis closed in EP0548553A) was converted into [ ( lR)-l-[ ( 2R)- 2-(2-fluorophenyl )-2-oxiranyl ]ethyl] 3 , 5-dinitrobenzoate b the method described in Reference Examples 1 and 2. Colorless prisms (recrystallized from ethyl acetate) mp: 183-184°C ^-H-NMR (CDCl3)δ: 1.47 (3H,dd,J=6.6Hz , 1.6Hz) , 3.03 (lH,d,J=4.7Hz) , 3,23 (IH,d,J=4.7Hz) , 5.35 (IH,q,J=6.6Hz) , 7.09-7.59 (4H,m), 9.13 (2H,d,J=2.2Hz) , 9.23 (IH, t ,J=2.2Hz) [α]23 D -24.7βC (c=1.0, in CHC13) Elemental analysis for
Figure imgf000045_0001
Calcd (%) : C.54.26; H.3.48; N.7.44
Found (%) : C, 54.23; H.3.25; N.7.41 Reference Example 6
[ (lR)-l-[ (2R)-2-(2-Fluorophenyl)-2-oxiranyl]ethyl] 3 , 5-dinitrobenzoate was converted into (1R)-l-[ (2R)-2-(2- fluorophenyl )-2-oxiranyl ]ethanol by the method described in Reference Example 3. Colorless oily substance
1H-NMR (CDCl3)δ: 1.17 (3H,dd,J=6.6Hz, 1.0Hz) , 1.78 (lH,d,J=8.2Hz) , 2.81 ( IH,d,J=5.3Hz) , 3.32 ( IH,d,J=5.3Hz) , 4.09-4.23 (lH,m), 6.99-7.47 (4H,m) Reference Example 7
(lR)-l-[ (2R)-2-(2-Fluorophenyl)-2-oxiranyl]ethanol was converted into (IS)-l-[ (2R)-2-(2-fluorophenyl )-2-oxiranyl ]- ethanol by the method described in Reference Example 4. Colorless oily substance
XH-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 2.27 (IH,d,J=2Hz) , 2.96 (lH,d,J=5Hz) , 3.30 (lH,d,J=5Hz) , 4.16 (IH,dq,J=7Hz ,2Hz) , 7.03-7.44 (4H,m) Reference Example 8
2-(2-Fluorophenyl)-2-[(lR)-l-(3,4,5,6-tetrahydro-2H- pyran-2-yl)oxyethyl] oxirane (synthesized by the method de- scribed in EP0548553A) was converted into ( lR)-l-[2-(2- fluorophenyl )-2-oxiranyl]ethanol by the method described in Reference Example 1. To an ice-cooled solution of this compound (34.77 g) in tetrahydrofuran (600 ml) were added triphenylphosphine (127.21 g) , 3 , 5-dinitrobenzoic acid (102.88 g) and diethyl azodicarboxylate (84.47 g) . The mixture was stirred at room ..temperature for 7 hours under a argon atmosphere, and then ethyl acetate (600 ml), diisopro pyl ether (100 ml) and water (800 ml) were added. The separated aqueous layer was extracted with ethyl acetate (600 ml, 400 ml) . The organic layers were combined, washed with water and a saturated aqueous solution of sodium chlo¬ ride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 5/1) and recrystallized from ethyl acetate to give [ ( 1S)-1-[ (2R)- 2-(2-fluorophenyl)-2-oxiranyl]ethyl] 3 , 5-dinitrobenzoate (23.15 g) as colorless needles.
1H-NMR (CDCl3)δ: 1.47 (3H,d,J=7Hz) , 2.97 ( IH,d,J=5Hz) , 3.29 (lH.d,J=5Hz) , 5.43 ( IH,q,J=7Hz) , 7.02-7.56 (4H,m) , 9.06 (2H,d,J=2Hz) , 9.21 (IH,t ,J=2Hz)
This compound (22.91 g) was dissolved in methanol (700 m1), to which an aqueous solution of lN-sodium hydroxide (146.5 ml) was added at ice-bath temperature. The mixture was stirred at room temperature for 1 hour. After lN-hydro chloric acid (85.5 ml) was added thereto, the solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (500 ml) and water (500 ml). The sepa¬ rated organic layer was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 3/1) to give ( IS)-l-[ (2R)-2-(2-fluo¬ rophenyl )-2-oxiranyl ]ethanol (10.76 g) as a colorless oily substance. The product was identical with the compound obtained in Reference Example 7. Reference Example 9
A mixture of 4-fluoronitrobenzene (3.1 g) , 4-[4- (2,2,3, 3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1 ,2,4- triazolone (5.8 g) , potassium carbonate (13.8 g) and N,N- dimethylformamide (60 ml) was stirred at 80°C for 2 hours. The resultant was cooled and poured into water (500 ml) . The mixture was neutralized with hydrochloric acid and the precipitated crystals were collected by filtration. The crystals thus obtained were dissolved in ethyl acetate (300 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-(4-nι rophe- nyl)-4-[4-(2, 2,3,3-tetraf1uoropropoxy)phenyl]-3(2H,4H)- 1 , 2 ,4-triazolone (5.5 g, 67%) as yellow crystalline powders. mp : 161-162 ° C
Reference Examples 10 to 14
The compounds shown in Table 1 as below were obtained in the same manner as in Reference Example 9.
Table 1
Figure imgf000048_0001
Reference Example No . Az yie ld {%) mp * ( )
Figure imgf000048_0002
14 — CH2CF2CF2H 41 141-143
Figure imgf000048_0003
Reference Example 15
4-Fluoronitrobenzene (21 g) was reacted with 1H-1,2,3- triazole (12.4 g) in the same manner as in Reference Exampl 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and purified by silica gel chromatography (eluent: dichlorometh- ane to dichloromethane/acetone = 8/1). The first eluted fraction was recrystallized from dichloromethane-diisopropyl ether to give 2-(4-nitrophenyl)-2H-l,2 , 3-triazole (18.8 g) as pale yellow prisms, mp: 183-184°C
1H-NMR (CDCl3)δ: 7.90 (2H,s), 8.28 (2H,dt ,J=9.4Hz ,J=2.4Hz) , 8.38 (2H,dt,J=9.4Hz,J=2.4Hz)
Further, the second eluated fraction was recrystallized from dichloromethane-diisopropyl ether to give l-(4-nitro- phenyl)-lH-l ,2,3-triazole (6.02 g) as pale yellow prisms, mp: 205-206βC
XH-NMR (CDCl3)δ: 7.92 ( IH,d,J=l .4Hz) , 8.00 (2H,dt,J=9Hz,J=2.4Hz) , 8.13 ( IH,d,J=l .4Hz) , 8.44 (2H,dt,J=9Hz,J=2.4Hz) Reference Example 16
2-(4-Nitrophenyl )-4-[4-(2,2,3, 3-tetrafluoropropoxy)- phenyl]-3(2H,4H)-l,2,4-triazolone (5.5 g) and 10% palladium—carbon (50% wet, 0.5 g) were added to methanol (200 ml). The mixture was subjected to catalytic hydroge- nation at ordinary temperature under ordinary pressure. When hydrogen absoption stopped, dichloromethane (200 ml) was added thereto and the catalyst was removed by filtra¬ tion. The catalyst was washed with dichloroethane (50 ml). The washings and the filtrate were combined and distilled under reduced pressure to give 2-(4-aminophenyl)-4-[4— (2,2,3, 3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1 , 2 ,4-triazo- lone (4.6 g, 90%) as a white solid. This compound was used for the next process, without purification. Reference Examples 17 to 21
The compounds shown in Table 2 as below were obtained in the same manner as in Reference Example 16.
Table 2
Figure imgf000050_0001
Reference Example No. Az yie ld ( %)
Figure imgf000050_0002
21 — i r l— CH2CF2CF2H 95
Reference Example 22
Ferric chloride (0.2 g) and activated carbon (2.0 g) were added to a solution of l-(4-nitrophenyl)-3-[4-(2 ,2 , 3 , 3- tetrafluoroproρoxy)phenyl]-2 (lH,3H)-imidazolone (20.5 g) in methanol-tetrahydrofran (75 ml : 75 ml), to which hydrazine hydrate (8.0 ml) was added dropwise over the period of 10 minutes. After the mixture was refluxed with stirring for 14 hours, ferric chloride (0.2 g) , activated carbon (2.0 g) and hydrazine hydrate (8.0 ml) were added thereto and the reaction mixture was refluxed with stirring for further 6 hours. The activated carbon was filtered off and washed with methanol (100 ml) . The filtrate and the washing were combined and distilled off under reduced pressure. The residue thus obtained was dissolved in ethyl acetate (700 ml). The ethyl acetate layer was washed with water (200 ml X 4), dried over anhydrous magnesium sulfate and distilled off under reduced pressure to give 1-(4-aminophenyl )-3-[4- (2,2,3, 3-tetrafluoropropoxy)phenyl ]-2( IH, 3H)-imidazolone (18.1 g, 95%) as a pale yellow powder, mp: 178-179βC Elemental analysis for
Figure imgf000051_0001
Calcd (%) : C.56.70; H.3.96; N, 11.02
Found (%) : C.56.58; H.3.93; N.11.21 Reference Example 23
In the same manner as in Reference Example 22, starting from l-(4-nitroρhenyl)-3-[4-(1,1,2,2-tetrafluoroethoxy) phenyl]-2(lH, 3H)-imidazolone , l-(4-aminophenyl)-3-[4- (1,1,2,2-tetrafluoroethoxy)phenyl]-2(IH, 3H)-imidazolone was obtained. mp: 150-151°C
Elemental analysis for C-LγHι3F4N 02
Calcd (%) : C.55.59; H.3.57; N, 11.44
Found (%) : C.55.74; H.3.40; N.11.49 Reference Example 24
2-(4-Aminophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-3(2H,4H)-l ,2,4-triazolone (4.6 g) and pyridine (1.4 g) were dissolved in ethyl acetate (200 ml) . To the result ant was added dropwise at room temperature a solution of phenyl chlorocarbonate (2.83 g) in ethyl acetate (20 ml) . After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Water (200 ml) , ethyl acetate (600 ml) and tetrahydrofuran (300 ml) were added thereto. The separated organic layer was washed with 5% phosphoric acid (200 ml X 2) and water (200 ml) succes¬ sively, dried over anhydrous magnesium sulfate and filtrat¬ ed. The filtrate was concentrated to about 50 ml and the precipitated crystals were collected by filtration. The crystals thus obtained were washed with diethyl ether and dried to give phenyl 4-[5-oxo-4-[4-(2,2 , 3 , 3-tetrafluoropro¬ poxy)phenyl]-lH,4H-1 ,2 ,4-triazol-l-yl]phenylcarbamate (5.6 g, 93%) as colorless scaly crystals, mp: 204-206°C Elemental analysis for C24H18F4N40 Calcd (%): C,57.37; H.3.61; N.11.15
Found (%): C.57.50; H.3.67; N.11.13 Reference Examples 25 to 31
The compounds shown in Table 3 as below were obtained in the same manner as in Reference Example 24.
Table 3
Figure imgf000053_0001
Reference Bx—ple Mo. Az y eld {%) »P- CC)
Figure imgf000053_0002
26 95 208-211
Figure imgf000053_0003
30 89 143-144
31 -A- -CH2CF2CF2H 84 173-175 Reference Example 32
Phenyl 4-[5-oxo-4-[4-(2,2,3 , 3-tetrafluoropropoxy)- phenyl]-lH,4H-l ,2 ,4-triazol-l-y1]phenylcarbamate (5.6 g) was added to a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml). To the resulting mixture was added hydrazine hydrate (3 g) with stirring. The resultant was stirred at 80CC for 2 hours and concentrated under reduce pressure to about 20 ml. After water (100 ml) was added, the precipi¬ tated crystals were collected by filtration, washed with ethanol and dried under reduced pressure to give 4-[4-[5- oxo-4-[4-(2,2,3, 3-tetrafluoropropoxy)phenyl]-lH,4H-1,2,4- triazol-1-yl]phenyl]semicarbazide (4.8 g, 98%) as colorless prisms . mp: >350°C
Elemental analysis for C18H16F4N6(^3
Calcd (%) : C.49.10; H.3.66; N.19.08
Found (%) : C.48.95; H.3.72; N, 19.20 Reference Examples 33 to 39
The compounds shown in Table 4 as below were obtained in the same manner as in Reference Example 32.
Table 4
Figure imgf000055_0001
Reference Ex— pie Mo. Az yield (Jg) »P- (X)
Figure imgf000055_0002
38 7? 96 275-277
Figure imgf000055_0003
Reference Example 40
4- [4- [5-OXO-4- [4- (2 , 2 , 3 , 3-tet raf luoropropoxy ) phenyl ]- IH, 4H-1 ,2,4-triazol-l-yl]phenyl]semicarbazide (4.75 g) was added to N.N-dimethylf ormamide (60 ml). To the mixture were added acetic acid (4 g) and formamidine acetate (6 g) , and the resulting mixture was stirred at room temperature for 3 hours and then at 80βC for 1.5 hours. After cooling, the reaction solution was diluted with water (30 ml) . The precipitated crystals were collected by filtration and washed with water (100 ml). The crystals were dried and dissolved in a mixture of tetrahydrofuran (300 ml) and ethyl acetate (600 ml) with warming. The solution thus obtained was dried over anhydrous magnesium sulfate, filtrated and concentrated under reduced pressure. Ethyl acetate (50 ml) was added to the residue and the precipitated crystals were collected by filtration and recrystallized from tetrahydrof- uran to give 4-[4-[5-oxo-4-[4-(2 , 2 , 3 , 3-tetrafluoropropoxy)- pheny1]-IH, 4H-1 , 2 ,4-triazo1-1-y1]phenyl ]-3 (2H,4H)-1 ,2 , 4- triazolone (2.4 g, 49%) as a white crystalline powder, mp: 297-298°C Elemental analysis for C^gH^ F4Ng0
Calcd (%) : C.50.67; H.3..13; N, 18.66
Found (%) : C.50.49; H.3.20; N.18.50 Reference Examples 41 to 47
The compounds shown in Table 5 as below were obtained in the same manner as in Reference Example 40. Tab l e 5
Figure imgf000057_0001
Reference Bx— ie Mo . Az yie ld (%) mp* (t)
Figure imgf000057_0002
46 -0 54 281-283
Figure imgf000057_0003
Reference Example 48
A mixture of phenyl 4-(1H-1 ,2 ,4-triazol-l-yl )ρhenylcar- bamate (13 g) , 2 ,2-diethoxyethyl amine (7.4 g) and pyridine (3.67 g) was heated at 50°C for 3 hours. The resultant was cooled and the precipitated crystals were washed with a mixture of diisopropyl ether and petroleum ether (1:1, 100 ml x 2) to give l-(2 , 2-diethoxyethyl)-3-[4-(1H-1 , 2 , 4-tria- zol-l-yl)phenyl]urea (14.5 g) as a colorless crystalline powder. mp: 139-140βC
1H-NMR (CDCl3)δ: 1.25 (6H,t ,J=7.2Hz) , 3.43 (2H, t ,J=5Hz) , 3.52-3.85 (4H,m), 4.57 ( IH, t ,J=5Hz) , 5.08-5.18 (lH,m) , 7.16
(lH.br), 7.49 (2H,d,J=9.4Hz) , 7.57 (2H,d,J=9.4Hz) , 8.08
(lH,s), 8.48 (lH.s) Reference Examples 49 to 50
The compounds shown in Table 6 as below were obtained in the same manner as in Reference Example 48.
Table 6
Figure imgf000058_0001
MiTSo . AZ yie ld <%) mp * (t)
Figure imgf000058_0002
Reference Example 51 l-(2,2-Diethoxyethyl)-3-[4-(lH-l,2,4-triazol-l- yl)phenyl]urea (14.5 g) was dissolved in a mixture of metha¬ nol (214 ml) and water (85 ml), to which diluted hydrochlor¬ ic acid (0.48 M, 104 ml) was added dropwise. After the reaction solution was stirred at room temperature for 14 hours, the precipitated crystals were collected by filtra¬ tion to give l-[4-(lH-l,2,4-triazol-l-yl)phenyl]-2- (lH,3H)-imidazolone (8.0 g) as a colorless crystalline powder. The filtrate was concentrated under reduced pres¬ sure to about 200 ml and the precipitated crystals were collected by filtration to give an additional amount (1.08 g) of the product, mp: 294-296"C Reference Examples 52 to 53
The compound shown in Table 7 as below were obtained in the same manner as in Reference Example 51.
Table 7
Figure imgf000059_0001
Reference Example No. Az yield (%) ">P - PC)
tion)
Figure imgf000059_0002
Reference Example 54
To a solution of (lS)-l-[ (2R)-2-(2 , 4-difluorophenyl )-2- oxiranyl]ethanol (1.0 g) in dichloromethane (14 ml) was added diisopropylethylamine (0.96 ml) at -78°C in a nitrogen atmosphere, to which trifluoromethanesulfonic anhydride (0.93 ml) was added dropwise over the period of 5 minutes. After the reaction solution was stirred at -78*C for 20 minutes and then at -25°C for 25 minutes, the reaction solution was concentrated at -10°C to about 10 ml. The concentrated solution was subjected to flash column chroma¬ tography using silica gel and eluted with dichloromethane- hexane (1:1). The desired fraction was concentrated to about 10 ml, and the residue was added at -14°C to a solu¬ tion prepared from 4-[4-[5-oxo-4-[4-(2 , 2, 3 , 3-tetrafluoropro¬ poxy)phenyl]-IH, 4H-1 ,2 ,4-triazol-l-y1]phenyl]-3 (2H,4H)- 1 ,2 ,4-triazolone (2.1 g) , dimethylformamide (40 ml) , dimeth¬ yl sulfoxide (50 ml) and sodium hydride (60% in oil: 180 mg) . The resulting mixture was stirred at -14°C for 20 minutes and then at -5°C for 20 minutes. The reaction solution was diluted with water (500 ml) and extracted with dichloromethane (300 ml X 2) . The dichloromethane layer was washed with water (200 ml X 2) and a saturated aqueous solution of sodium chloride successively, dried over anhy¬ drous magnesium sulfate and distilled off under reduced pressure to give a colorless powder. The product was puri¬ fied by silica gel chromatography (eluent: hexane/ethyl acetate = 1/1 to 1/2) and crystallized from ethyl acetate- hexane to give 2-[ ( 1R, 2S)-2-(2 ,4-difluorophenyl )-2 , 3- epoxy-l-methylpropyl]-4-[4-[5-oxo-4-[4-(2,2 ,3 ,3-tetraf1uoro- propoxy)phenyl]-lH-l,2,4-triazol-l-y1]phenyl]-3(2H.4H)-1,2,4- triazolone (0.29 g) as colorless crystalline powders. mp: 181-183βC
Elemental analysis for C2gH2 F Ng0
Calcd (%) : C,55.07; H.3.51; N.13.29
Found (%): C,55.12; H.3.34; N, 13.24 Reference Examples 55 to 63
The compounds shown in Table 8 as below were obtained in the same manner as in Reference Example 40.
Table 8
Figure imgf000062_0001
Reference Exanple Ho. Az ■p* CC)
55 *V*1 249-250
Figure imgf000062_0002
63 0 —N T 243-248 Reference Examples 64 to 72
The compounds shown in Table 9 as below were obtained in the same manner as in Reference Example 51.
Table 9
Figure imgf000063_0001
Reference Example No. Az mp . <£
64 -0 239-240
65 -V-1 170-171
66 - 190-191
Figure imgf000063_0002
Reference Example 73 l-[4-(lH-l-Tetrazolyl)phenyl]-2(lH,3H)-imidazolone (5.0 g) was dissolved in acetic acid (500 ml) and 10% palladium- carbon (50% wet, 5.0 g) was added. The resulting mixture was stirred at 40°C for 4 hours under a hydrogen atmosphere. The catalyst was filtered and washed with acetic acid. The filtrate and the washings were combined and distilled off under reduced pressure. The residue was crystallized from ethanol to give l-[4-( lH-1-tetrazolyl )phenyl]-2-imidazolidi- none (4.1 g) as colorless crystals, mp: 237-240°C (dec.)
1H-NMR (dg-DMSO)δ: 3.45 (2H, t ,J=7Hz) , 3.93 (2H, t ,J=7Hz) , 7.20 (lH.s), 7.82 (4H,s), 10.02 (lH.s) Elemental analysis for C-^QH-^Q O
Calcd (%) : C.52.17; H.4.38; N.36.50
Found (%) : C.51.99; H.4.33; N, 36.41 Reference Example 74
Diisopropylethylamine (1.15 ml) was added to a solution of (lS)-l-[ (2R)-2-(2,4-difluorophenyl )-2-oxiranyl]ethanol (1.20 g) in dichloromethane (26 ml) at -78βC under a nitro¬ gen atmosphere, to which trifluoromethanesulfonic anhydride (1.10 ml) was added dropwise over the period of 5 minutes. The mixture was stirred at -78°C for 20 minutes and then at -30°C for 15 minutes. After addition of hexane (26 ml), the mixture was subjected to flash column chromatography using silica gel and eluted with dichloromethane-hexane (1:1). The desired fraction was concentrated to about 20 ml, and the residue was added to a solution prepared from l-[4- (lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (940 mg) , dimethylformamide (20 ml), dimethyl sulfoxide (10 ml), tetrahydrofuran (10 ml) and sodium hydride (72% in oil: 126 mg) at -30βC. The resulting mixture was stirred for 20 minutes at -30βC and then for 40 minutes at ice-bath temper¬ ature. Water (100 ml) was added and the mixture was ex¬ tracted with ethyl acetate (150 ml). The ethyl acetate layer was washed with water (100 ml X 2) and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and distilled off under reduced pressure to give a colorless powder. The product was puri¬ fied by silica gel chromatography (eluent: hexane/ethyl acetate = 1/3) to give l-[ (1R,2S)-2-(2 ,4-difluorophenyl )- 2 , 3-epoxy-l-methylpropyl]-3-[4-(lH-l-tetrazolyl )phenyl ]- 2(lH,3H)-imidazolone (0.13 g) and (2R)-2-(2,4- difluorophenyl)-2-[(lR)-l-[l-[4-(lH-l-tetrazolyl)phenyl]-2- imidazolyl]oxy]ethyl ]oxirane (0.05 g) . l-[ (lR,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-l-meth- ylpropyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazo- lone: colorless crystalline powder, mp: 205-207°C
XH-NMR (CDCl3)δ: 1.39 (3H,d,J=7Hz) , 2.73 (IH,d,J=5Hz) , 2.83 (lH.d,J=5Hz) , 5.09 (IH,q,J=7Hz) , 6.52 (IH,d,J=3Hz) , 6.66 (lH,d,J=3Hz) , 6.81-6.96 (2H,m), 7.36-7.48 (lH.m), 7.78 (2H,d,J=9Hz) , 7.94 (2H,d,J=9Hz) , 9.02 (lH.s) SIMS (MH+): 411 Reference Example 75
Diisopropylethylamine (1.27 ml) was added to a solution of (lS)-l-[ (2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol (1.21 g) in dichloromethane (25 ml) at -78°C under a nitrogen atmosphere, to which trifluoromethanesulfonic anhydride (1.22 ml) was added dropwise over a period of 5 minutes. The reaction solution was stirred at -78°C for 15 minutes and then at -30βC for 15 minutes. The resultant was diluted with hexane (25 ml), subjected to flash column chromatogra¬ phy using silica gel and eluted with dichloromethane-hexane (1:1) . The desired fraction was concentrated to about 20 ml, and the residue was added to a solution prepared from l-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (1.14 g) , 1-methy1-2-pyrrolidone (30 ml) and 72% sodium hydride in oil (150 mg) at -30°C. The reaction solution was stirred at -30°C for 15 minutes and then at -10°C for 15 minutes. Water (100 ml) was added and the mixture was extracted with ethyl acetate (150 ml). The ethyl acetate layer was washed with water (100 ml) and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and distilled off under reduced pressure to give a colorless powder. The product was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 1/3) to give l-[ (lR,2S)-2-(2-fluorophenyl)-2,3-epoxy-l-methylpropyl]-3- [4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (0.39 g) and (2R)-2-(2-fluorophenyl )-2-[ ( lR)-l-[ l-[4-( lH-1-tetrazo- lyl )phenyl]-2-imidazolyloxy]ethyl ]oxirane (0.18 g) . l-[ (1R.2S)-2-(2-Fluorophenyl)-2,3-epoxy-l-meth lpro¬ pyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2 (1H.3H)-imidazolone: colorless crystalline powder.
XH-NMR (CDCl3)δ: 1.39(3H, d,J=7Hz) , 2.76 (IH,d,J=5Hz) , 2.84 (lH.d,J=5Hz) , 5.15 (IH,q,J=7Hz) , 6.55 (IH,d,J=3Hz) , 6.67 (lH,d,J=3Hz) , 7.06-7.49 (4H,m) , 7.79 (2H,d,J=9Hz) , 7.96 (2H,d,J=9Hz) , 9.04 (lH,s) Reference Example 76
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80°C for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate = 4/1 to ethyl acetate) to give 4-[ (S)-2-hydroxypropionyl]- morpholine (69.4 g) as a pale yellow oily substance. p- Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[ (S)-2-hydroxypropionyl ]morpholine (69.4 g) in dichloromethane (300 ml), to which 3 ,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0°C for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate = 8/1 to ethyl acetate) to give 4-[ (2S)-2-(3 , , 5 , 6-tetrahy- dro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance. l-Bromo-2-fluorobenzene (15 g) and 4-[ (2S)-2-(3 , 4 , 5 , 6- tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (40 g) were dissolved in tetrahydrofuran (200 ml), to which magnesium (turnings: 4.4 g) was added. The mixture was stirred vigor¬ ously. The reaction flask was cooled when the temperature of the reaction solution reached to 35°C, and l-bromo-2- fluorobenzene (16.7 g) was added thereto over the period of 10 minutes while the temperature of the reaction solution was kept at 35 to 37°C. After the reaction solution was stirred at 30 to 35°C for 2 hours, it was cooled in an ice- bath. A saturated aqueous solution of ammonium chloride (100 ml) was added thereto and the mixture was extracted with ethyl acetate (200 ml x 2, 100 ml). The extract was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sul¬ fate, and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel chromatog¬ raphy (eluent: hexane/ethyl acetate = 10/1 to 5/1) to give (2S)-2 '-fluoro-2-(3 ,4,5 , 6-tetrahydro-2H-pyran-2-yloxy)- propiophenone (22.4 g) as a pale yellow oily substance.
(2S)-2 '-Fluoro-2-(3 ,4,5, 6-tetrahydro-2H-pyran-2- yloxy)propiophenone (25 g) was dissolved in ethanol (200 ml), to which pyridinium p-toluenesulfonate (1.28 g) was added. The reaction solution was stirred at 55βC for 2.5 hours and then concentrated. The residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate =
9/1 to 5/1) to give (2S)-2 '-fluoro-2-hydroxypropiophenone
(16.4 g) as a colorless oily substance.
IR(neat): 1690 (C=0) cm-1
1H-NMR (CDCl3)δ: 1.41(3H,dd,J=7Hz ,J=l .4Hz) , 3.78
(lH.d,J=6Hz) , 4.98-5.15 (lH.m), 7.12-7.36 (2H,m), 7.54-7.68
(lH.m), 7.90-8.00 (lH,m)
Reference Example 77
(2S)-2' ,4 '-Difluoro-2-hydroxypropiophenone (synthesized by the method disclosed in Japanese Unexamined Patent Publi¬ cation No. Hei 5 ( 1993)-230038 : 26.01 g) was dissolved in di¬ chloromethane (300 ml), to which diisopropylethylamine (19.90 g) was added at -60°C under a nitrogen atmosphere, and then trifluoromethanesulfonic anhydride (25.90 ml) was added thereto dropwise over the period of 20 minutes. After the reaction temperature was gradually raised to -30°C, the reaction solution was further stirred for 30 minutes. The reaction solution was purified by silica gel chromatography (silica gel 400 g, eluent: dichloromethane/hexane = 1/1) to give (2S)-2* ,4 '-difluoro-2-trifluoromethanesulfonyloxypro- piophenone (39.21 g) as a pale yellow oily substance. XH-NMR (CDCl3)δ: 1.73 ( 3H , dd , J=7.0Hz , 1.6Hz ) , 5.93
(lH,q,J=7.0Hz) , 6.90-7.12 (2H,m) , 8.03
(lH,dt,J=6.4Hz,8.6Hz)
[α]D 23 + 29.2° (c=1.12, in MeOH)
Reference Example 78
(2S)-2 '-Fluoro-2-hydroxypropiophenone (synthesized by the method disclosed in Reference Example 76: 3.36 g) was dissolved in dichloromethane (30 ml). To the resultant was added diisopropylethylamine (4.18 ml) at -60βC under a nitrogen atmosphere, and then trifluoromethanesulfonic anhy¬ dride (4.03 ml) was added dropwise to the mixture over the period of 2 minutes. After the reaction temperature was gradually raised to -25°C, the reaction solution was stirred for 30 minutes. The reaction solution was purified by silica gel chromatography (silica gel 60 g, eluent: dichlo- romethane/hexane = 1/1) to give (2S)-2 '-fluoro-2- trifluoromethanesulfonyloxypropiophenone (5.30 g) as a pale yellow oily substance.
1H-NMR (CDCl3)δ: 1.73 (3H,dd,J=7Hz,J=l .6Hz) , 6.49 (lH,q,J=7Hz) , 7.15-7.38 (2H,m), 7.58-7.72 (lH.m), 7.97 ( IH,dt ,J=l .8Hz ,J=7.6Hz) Reference Example 79 l-[4-(lH-l,2,4-Triazol-l-yl)phenyl]-2(lH,3H)- imidazolone (3.39 g) was dissolved in l-methyl-2-pyrrolidone (220 ml), to which 72% sodium hydride in oil (528 mg) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was cooled in an ice-bath and added dropwise over the period of 15 minutes to a solution of (2S)-2 '-fluoro-2-trifluoromethanesulfonyloxypropiophenone (4.7 g) in tetrahydrofuran (100 ml) which had been cooled to -20βC. After the addition was complete, the reaction tem¬ perature was raised to 10βC over 30 minutes and the reaction solution was further stirred for 12 hours. The reaction solution was diluted with acetic acid (10 ml) and ethyl acetate (500 ml), washed with water (250 ml x 2), 0.5 hydro¬ chloric acid (250 ml x 2) and a saturated aqueous solution of sodium chloride (250 ml) successively, dried over anhy¬ drous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (silica gel, eluent: hexane/ethyl ace¬ tate/acetic acid = 1/4/0.06) and recrystallized from diiso¬ propyl ether (25 ml) to give l-[ ( 1R)-2-fluorophenyl )-2-oxo- l-methylethyl]-3-[4-(lH-l,2,4-triazol-l-yl)phenyl]-2(lH,3H)- imidazolone as a colorless crystalline powder. *H-NMR (CDC13)6: 1.65(3H,d,J=7.2Hz) , 5.82 (lH.q,J=7.2Hz) , 6.64 (lH.d,J=3.2Hz) , 6.70 (IH,d,J=3.2Hz) , 7.14-7.31 (2H,m), 7.53-7.94 (6H,m), 8.11 (lH.s), 8.56 (lH.s) Reference Example 80 l-[4-(lH-l-Tetrazolyl)phenyl]-2(lH,3H)-imidazolone (0.94 g) was dissolved in l-methyl-2-pyrrolidone (25 ml), to which 72% sodium hydride in oil (0.126 g) was added. The reaction solution was stirred at room temperature for 30 minutes. The resultant was ice-cooled and added dropwise over the period of 10 minutes to a solution of (2S)-2'~ fluoro-2-trifluoromethanesulfonyloxypropiophenone (1.57 g) in tetrahydrofuran (25 ml) which had been cooled to -10°C. After the addition was complete, the reaction temperature was raised to 0βC over 15 minutes and the reaction solution was stirred for 30 minutes. The reaction solution was diluted with acetic acid (3 ml) and ethyl acetate (100 ml), washed with water (50 ml x 2), 0.5 N-hydrochloric acid (50 ml x 2) and a saturated aqueous solution of sodium chloride (50 ml) successively, dried over anhydrous magnesium sulfat and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate/acetic acid = 1/3/0.05) and recrystallized from diisopropyl ether (20 ml) to give 1- [ (lR)-2-fluorophenyl)-2-oxo-l-methylethy1]-3-[4-(lH-1-tetra zolyl)phenyl]-2(lH, 3H)-imidazolone (0.22 g) as a colorless crystalline powder, mp: 162-164βC
1H-NMR (CDCl3)δ: 1.66 (3H,d,J=7.2Hz) , 5.83 (IH,q,J=7.2Hz) , 6.67 (lH,d,J=3.2Hz) , 6.74 ( IH,d,J=3.2Hz) , 7.16-7.33 (2H,m), 7.54-7.98 (2H,m), 7.77 (2H,d,J=9Hz) , 7.91 (2H,d,J=9Hz) , 9.0 (lH.s) Reference Example 81
Chloromethylisopropoxydimethylsilane (2.14 g) and magnesium (for Grignard reaction, 313 mg) were added to tetrahydrofuran (15 ml), and the mixture was heated to 60°C. To the mixture was added magnesium in the form of turnings which had been activated by methyl iodide, and then the mixture was stirred in a bath at 60°C for 3 hours.
The solution of the Grignard reagent thus obtained was added dropwise to a solution of l-[ (lR)-2-(2-fluorophenyl)- 2-oxo-l-methylethyl]-3-[4-(lH-l-tetrazolyl)phenyl-2(lH,3H)- imidazolone (1 g) in tetrahydrofuran (150 ml) over the period of 10 minutes at ice-bath temperature, and the mix¬ ture was stirred for 30 minutes. A cooled saturated aqueous solution of ammonium chloride (30 ml) and cooled water (100 ml) were added thereto at ice-bath temperature and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concen¬ trated under reduced pressure. The residue was recrystal¬ lized from a mixture of diisopropyl ether and ethyl acetate to give l-[ (lR,2S)-2-(2-fluorophenyl)-2-hydroxy-3- ( isopropoxydimethylsilyl)-l-methylpropyl]-3-[4-(1H-1- tetrazolyl)phenyl]-2(lH,3H)-imidazolone (637 mg) as a color¬ less crytalline powder.
1H-NMR (dg-DMSO)δ: -0.30(3H,s), -0.28 (3H,s), 0.99-1.64 (llH.m), 3.83 (IH,quintet ,J=6Hz) , 4.81 (IH, ,J=7Hz) , 5.21 (lH.br), 6.93-7.77 (6H,m), 8.05 (2H,d,J=9Hz) , 8.17 (2H,d,J=9Hz) , 10.17 ( IH, s) Reference Example 82 l-[ (lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-( isopropoxy dimethylsilyl)-l-methylpropyl]-3-[4-(lH-1-tetrazolyl)phe¬ nyl ]-2( IH,3H)-imidazolone (1 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which an 30% aqueous solution of hydrogen peroxide (2 ml) and sodium bicarbonate (157 mg) were added. The mixture was heated at 50°C for 4 hours, then cooled and extracted with ethyl acetate (100 ml). The extract was washed with water (30 ml), an aqeous solution of Na2S203 (30 ml x 2) and a satu¬ rated aqueous solution of sodium chloride (30 ml) succes¬ sively, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 1/4) and recrystallized from diethyl ether (20 ml) to give l-[ (lR,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-l-methyl propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (440 mg) as a colorless crystalline powder. XH-NMR (CDCl3)δ: 1.17(3H,d,J=7Hz) , 3.52-3.62 (lH,m), 4.05- 4.18 (2H,m), 5.01 (IH,q,J=7Hz) , 6.72 (IH,d,J=3.2Hz) , 6.82 (lH,d,J=3.2Hz) , 7.01-7.33 (3H,m), 7.70-7.78 (lH,m), 7.90 (2H,d,J=9Hz) , 7.99 (2H,d,J=9Hz) , 9.55 (lH.s) Reference Example 83 l-[ (1R, 2S)-2-(2-Fluorophenyl)-2, 3-dihydroxy-l-methyl propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (440 mg) was dissolved in a mixture of ethyl acetate and tetrahydrofuran (1:2, 30 ml), to which methanesulfonyl chloride (0.18 g) and triethylamine (0.16 g) were added dropwise at ice-bath temperature. The reaction solution was stirred at 0°C for 30 minutes and washed with water (15 ml x 2) and a saturated aqueous solution of sodium chloride (15 ml) successively. The organic layer was dried over magnesi¬ um sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chroma¬ tography (eluent: hexane/ethyl acetate = 1/4) to give 1- [ (1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy- l-methylpropyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)- imidazolone (330 mg) as a colorless crystalline powder. XH-NMR (CDCl3)δ: 1.27(3H,d,J=7Hz) , 2.87 (3H,s), 4.54 (lH,d,J=12Hz) , 4.73-4.88 (2H,m), 6.63 (IH,d,J=3.2Hz) , 6.72 (lH.d,J=3.2Hz) , 7.09-7.39 (3H,m), 7.75-7.94 (lH,m), 7.81 (2H,d,J=9Hz) , 7.93 (2H,d,J=9Hz) , 9.04 (lH.s) Reference Example 84 l-[ (lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfo- nyloxy-l-methylpropyl]-3-[4-( lH-1-tetrazolyl)phenyl]- 2(IH, 3H)-imidazolone (100 mg) was dissolved in dimethylfor- mamide (4 ml), to which potassium carbonate (42 mg) was added, and the mixture was heated at 40"C for 1 hour. The resultant was diluted with ethyl acetate (20 ml) and washed with water (10 ml) and a saturated aqueous solution of sodium chloride (10 ml) successively. The organic layer wa dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified b silica gel chromatography (eluent: hexane/ethyl acetate = 1/4) . The desired fraction was concentrated and the residue was recrystallized from diisopropyl ether to give 1- [ (lR,2S)-2-(2-fluorophenyl)-2,3-epoxy-l-methylpropyl]-3-[4- ( lH-1-tetrazolyl )phenyl]-2( IH, 3H)-imidazolone (58 mg) as a colorless crystalline powder.
1H-NMR (CDCl3)δ: 1.40 (3H,d,J=7Hz) , 2.76 (IH,d,J=5Hz) , 2.84 (lH.d,J=5Hz) , 5.15 (lH,q,J=7Hz) , 6.55 (IH,d,J=3.2Hz) , 6.67 (lH,d,J=3.2Hz) , 7.07-7.48 (4H,m), 7.79 (2H,d,J=9Hz) , 7.95 (2H,d,J=9Hz) , 9.05 (lH.s)
Working Example 1
60% sodium hydride in oil (108 mg) was dispersed in dimethylformamide (4 ml), to which 1 , 2 ,4-triazole (207 mg) was added at ice-bath temperature, and the mixture was stirred at room temperature for 10 minutes. To the result¬ ant was added a solution of 2-[(lR, 2S)-2-(2 ,4-difluorophe¬ nyl)-2,3-epoxy-l-methylpropyl]-4-[4-[5-oxo-4-[4-(2 , 2,3,3- tetrafluoropropoxy)phenyl]-lH-l , 2 ,4-triazo1-1-yl]phenyl]- 3(2H,4H)-1 , 2 ,4-triazolone (560 mg) in dimethylformamide (2 ml) , and the mixture was heated at 60°C for 11 hours. After cooling, water (40 ml) and ethyl acetate (40 ml) were adde to the mixture. The separated aqueous layer was extracted with ethyl acetate twice. The combined ethyl acetate layers were washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatog¬ raphy (eluent: ethyl acetate/hexane = 19/1 to ethyl acetate) and then by reverse phase chromatography (eluent: ethanol/water = 4/1) to give 2-[ (1R,2R)-2-(2 , 4-difluorophe¬ nyl )-2-h droxy-1-methyl-3-(1H-1 ,2 ,4-triazol-l-yl)propyl ]-4- [4-[5-oxo-4-[4-(2 ,2,3, 3-tetrafluoropropoxy)phenyl ]-lH- 1 ,2,4-triazol-l-yl]phenyl]-3(2H,4H)-l ,2 ,4-triazolone (Com¬ pound __; 0.21g) as a colorless powder. [α]20 D -16.9° (c=1.0% in MeOH) Elemental analysis for C31H 5F Ng04 • 0.5H20
Calcd (%): C, 52.40; H.3.69; N.17.74
Found (%) : C.52.59; H.3.67; N.17.69 Working Example 2
(2R,3S)-2-(2,4-Difluorophenyl)-3-meth 1-2-(1H-1,2,4- triazol-l-yl)methyloxirane (1.2g), 4-[4-[2-oxo-3-[4- (2,2,3,3-tetrafluoropropoxy)phenyl]-lH,3H-imidazol-l- yl]phenyl]-3(2H,4H)-l ,2 ,4-triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N, -dimethylforma¬ mide (50 ml), and the mixture was heated with stirring at 90βC for 42 hours. After cooling, the resultant was diluted with ethyl acetate (150 ml) and tetrahydrofuran (50 ml) . Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml) , 1N- hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetat layer was dried over anhydrous magnesium sulfate and dis¬ tilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (elute:ethyl acetate/acetone = 10/1) and crystallized from tetrahydrofuran-diisopropyl ether to give 2-[ (IR,2R)-2-(2 ,4 difluorophenyl)-2-hydroxy-l-methy1-3-( 1H-1 , 2 ,4-triazol-l- yl)propyl]-4-[4-[2-oxo-3-[4-( , 2, 3 ,3-tetrafluoropropoxy)- pheny1]-1H,3H-imidazol-l-yl]phenyl]-3 (2H.4H)-1,2,4-triazo- lone (Compound __; 0.26g) as a colorless crystalline powder, mp: 181-183βC Elemental analysis for C32H2gF N8θ4
Calcd (%) : C.54.86; H.3.74; N.15.99
Found (%) : C.54.58; H.3.75; N, 15.71 [α]20 D -18.9° (c=1.0% in MeOH) Working Example 3
2-[ (lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-l-methy1- 3-(lH-l,2,4-triazol-l-yl)propyl]-4-[4-[2-oxo-3-[4- (1 , 1,2,2-tetrafluoroethoxy)pheny1]-lH,3H-imidazo1-1-yl] phenyl]-3(2H,4H)-1, 2,4-triazolone (Compound 3.) was obtained in the same manner as in Working Example 2, Colorless crystalline powder mp: 214-215βC
Elemental analysis for C3jH24Fg β0
Calcd (%): C.54.23; H.3.52; N, 16.32
Found (%): C, 54.05; H.3.37; N, 16.32 [α]20 D -19.0° (c=1.0% in MeOH) Working Example 4
A mixture of 60% sodium hydride in oil (0.24 g) and di¬ methyl sulfoxide (60 ml) was stirred at 80°C for 30 minutes. To the mixture was added 4-[4-[5-oxo-4-(2,2 , 2-trifluoroeth- yl)-lH,4H-l,2,4-triazol-l-yl]phenyl]-3(2H,4H)-l,2,4-triazo- lone (1.94 g) , and the mixture was stirred for 5 minutes. To the resultant was added (2R,3S)-2-(2 ,4-difluorophenyl )-3- methyl-2-(1H-1 ,2 ,4-triazol-l-yl)methyloxirane (1.0 g), and the mixture was stirred at 80βC for 24 hours under an argon atmosphere. The reaction solution was cooled, diluted with ethyl acetate (300 ml) and washed with water (50 ml X 2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resi¬ due was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 1/2 to ethyl acetate) to give 2- [ (1R.2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methy1-3-(1H- 1, 2,4-triazol-l-yl)propyl]-4-[4-[5-oxo-4-[4-(2 ,2 ,2-trifluo¬ roethy1)-lH,4H-1 ,2,4-triazol-l-yl]pheny1]-3-(2H,4H)-1 ,2 ,4- triazolone (Compound 4_; 0.46 g) as a pale yellow powder. ^•H-NMR (CDCl3)δ: 1.31(3H,d,J=7Hz) , 4.36 (2H,q,J=8.4Hz) , 4.37 (lH,d,J=14Hz) , 5.03 ( IH, ,J=14Hz) , 5.10 (lH,q,J=7Hz) , 5.44 (lH,s), 6.75-6.88 (2H,m), 7.48-7.65 (lH,m), 7.67 (2H,d,J=9Hz) , 7.68 (lH,s), 7.69 (lH.s), 7.83 (lH.s), 7.94 (lH.s), 8.16 (2H,d,J=9Hz) Working Example 5
(2R,3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1, 2,4- triazol-1-yl)methyloxirane (1.0 g) was reacted with 4-[4- (lH-l,2,4-triazol-l-yl)phenyl]-3(2H,4H)-l,2,4-triazolone (0.91 g) in the same manner as in Working Example 4 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methy1-3-( 1H- l,2,4-triazol-l-yl)propyl]-4-[4-(lH-l,2,4-triazol-l- yl)phenyl]-3(2H,4H)-l , 2 , 4-triazolone (Compound 5.; 0.54 g). Colorless crystalline powder mp: 182-184βC
XH-NMR (CDCl3)δ: 1.32(3H,d,J=7Hz) , 4.40 (IH,d,J=14.4Hz) , 5.03 (lH,d,J=14.4Hz) , 5.11 ( IH,q,J=7Hz) , 5.41 (lH.s) , 6.75- 6.90 (2H,m), 7.50-7.65 (lH.m), 7.69 (lH.s), 7.79 (2H,d,J=9Hz) , 7.88 (2H,d,J=9Hz) , 7.92 (lH,s), 7.96 ( IH, s) , 8.14(lH,s), 8.65 (lH.s) Elemental analysis for
Figure imgf000080_0001
Calcd (%) : C.55.11; H.3.99; N.26.29
Found (%): C.55.05; H.4.01; N.26.14 IR(KBr): 1714, 1618, 1556, 1527, 1394cm-1 Working Example 6
(2R.3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4- (lH-l,2,3-triazol-l-yl)phenyl]-3(2H,4H)-l,2,4-triazolone (1.09 g) in the same manner as in Working Example 4 to give 2-[ ( IR,2R)-2-(2 ,4-difluorophenyl )-2-hydroxy-l-methy1-3-( 1H- 1,2,4-triazol-l-yl )propyl]-4-[4-(1H-1 , 2 ,3-triazol-l-yl ) phenyl]-3(2H,4H)-l, 2,4-triazolone (Compound 6.; 0.27 g) . Colorless crystalline powder mp: 219-220'C
XH-NMR (CDCl3)δ: 1.32(3H,d,J=7Hz) , 4.40 (IH,d,J=14.2Hz) , 5.03 (lH,d,J=14.2Hz) , 5.10 ( IH,q,J=7Hz) , 5.38 (lH,s), 6.75- 6.90 (2H,m), 7.50-7.65 (lH,m), 7.70 (lH.s), 7.82 (2H,d,J=9Hz) , 7.88 (lH,s), 7.90 (lH.s), 7.94 (2H,d,J=9Hz) , 7.94 (lH,s), 8.05 (lH,s) Elemental analysis for C2 H^gF2Ng0
Calcd (%) : C.55.11; H,3.99; N.26.29
Found (%) : C,54.91; H.3.97; N.26.26 IR(KBr): 1700, 1675, 1618, 1556, 1527, 1502cm-1 Working Example 7
(2R.3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4- (2H-l,2,3-triazol-2-yl)phenyl]-3(2H,4H)-l,2,4-triazolone (1.09 g) in the same manner as in Working Example 4 to give 2-[(1R.2R)-2-(2,4-difluorophenyl )-2-hydroxy-l-methy1-3-(1H- l,2,4-triazol-l-yl)propyl]-4-[4-(2H-l,2,3-triazol-2- yl)phenyl]-3(2H,4H)-l , 2 ,4-triazolone (Compound 1; 0.65 g) .
Pale yellow plates mp: 213-215βC
1H-NMR (CDCl3)δ: 1.32(3H,d,J=7Hz) , 4.38 ( IH, ,J=14.2Hz) ,
5.04 (lH,d,J=14.2Hz) , 5.11 (lH,q,J=7Hz) , 5.42 (lH.s), 6.75-
6.90 (2H,m), 7.50-7.64 (lH,m), 7.69 (lH.s), 7.74
(2H,d,J=9Hz) , 7.85 (2H,s), 7.86 (lH,s), 7.95 (IH, s) ,
8.25(2H,d,J=9Hz)
Elemental analysis for C 2H-^gF2Ng0
Calcd (%) : C.55.11; H,3.99; N.26.29
Found (%) : C.54.97; H.3.96; N.26.29 IR(KBr): 1697, 1623, 1602, 1564, 1519, 1510cm-1 Working Example 8
2-[ ( lR,2R)-2-(2 ,4-Difluorophenyl )-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,3,3- tetrafluoropropyl )-lH,4H-1 ,2 ,4-triazol-l-yllphenyl ]-3- (2H,4H)-1,2 ,4-triazolone (Compound 8.) was obtained in the same manner as in Working Example 4. Pale yellow powder
XH-NMR (CDC13)6: 1.31(3H,d,J=7Hz) , 4.34 (2H, t ,J=14Hz) , 4.37 (lH,d,J=14Hz) , 5.04 ( IH,d,J=14Hz) , 5.10 ( lH.q,J=7Hz) , 5.46 (lH,s), 5.98 (lH,tt,J=53Hz,J=2.4Hz) , 6.75-6.90 (2H,m), 7.50-7.65 (lH.m), 7.67 (2H,d,J=9Hz) , 7.68 (lH.s), 7.72 (lH.s), 7.86 (lH.s), 7.96 (lH,s), 8.16 (2H,d,J=9Hz) Working Example 9
(2R.3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-l-yl)methyloxirane (2.5 g) , l-[4-(1H-1,2 ,4-tria- zol-l-yl)phenyl]-2(lH,3H)-imidazolone (2.72 g) and cesium carbonate (powder: 9.7 g) were added to N, -dimethylforma¬ mide (150 ml), and the mixture was heated at 80*C with stirring for 9.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (400 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate/acetone = 2/1) to give l-[ (lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l- methyl-3-(1H-1 , 2 ,4-triazol-l-yl)ρropyl]-3-[4-(1H-1 ,2,4- triazol-l-yl)phenyl]-2(lH, 3H)-imidazolone (Compound ; 1.03 g) as a pale yellow powder.
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 (IH,d,J=14.2Hz) , 5.01 (lH,q,J=7Hz) , 5.12 (IH,d,J=14.2Hz) , 5.50 (lH.br), 6.72 (lH,d,J=3.2Hz) , 6.73-6.90 (2H,m), 6.83 (IH,d,J=3.2Hz) , 7.40-7.55 (lH.m), 7.75 (lH.s), 7.78 (2H,d,J=9.4Hz) , 7.86 (lH.s), 7.86 (2H,d,J=9.4Hz) , 8.13 (lH.s), 8.59 (lH.s) IR(KBr): 3400, 3118, 1683, 1616, 1527, 1500cm-1 Working Example 10
1-[ (IR, 2R)-2-(2,4-Difluoropheny1)-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l,2,4-triazol-l- yl)phenyl]-2(lH, 3H)-imidazolone (0.50 g) obtained in Working Example 9 was dissolved in acetic acid (25 ml), to which 10% palladium-carbon (200 mg) was added. The resultant was stirred under a hydrogen atmosphere at room temperature for 3 hours and then at 50βC for 3 hours. After the catalyst was filtered off, the filtrate was concentrated. The resi¬ due was purified by silica gel chromatography (eluent: ethyl acetate/acetone = 5/1 to 2/1) and recrystallized from ethyl acetate-diisopropyl ether to give l-[ (IR,2R)-2-(2,4- difluorophenyl )-2-hydroxy-l-methy1-3-( 1H-1 , 2 ,4-triazol-l- yl)propyl]-3-[4-(lH-l,2,4-triazol-l-yl)phenyl]-2- imidazolidinone (Compound __0_ 0.37 g) as a colorless crys¬ talline powder.
XH-NMR (CDCl3)δ: 1.08(3H,d,J=7.2Hz) , 3.68-4.18 (4H,m), 4.52 (lH,d,J=14Hz) , 4.58-4.80 (lH.m), 5.12 (IH,d,J=14Hz) , 5.38 (lH.br), 6.70-6.86 (2H,m), 7.35-7.50 (lH.m), 7.66 (2H,dt,J=9.4Hz,J=2.4Hz) , 7.75 (2H,dt ,J=9.4Hz,J=2.4Hz) , 7.77 (lH,s), 7.87 (lH.s), 8.11 (lH,s), 8.53 (lH.s)
Elemental analysis for
Figure imgf000084_0001
Calcd (%) : C.57.50; H.4.62; N.23.32 Found (%) : C, 57.46; H.4.47; N.23.19 IR(KBr): 3390, 3106, 1677, 1614, 1523, 1484cm-1 Working Example 11
To a mixture of l-[4-(1H-1 ,2 ,3-triazol-l-yl)phenyl ]- 2(lH,3H)-imidazolone (2.72 g) and l-methyl-2-pyrrolidone (100 ml) was added sodium hydride (70% in oil, 0.40 g) , and the mixture was stirred at room temperature for 1 hour. (2R.3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-1-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100βC for 8 hours under an argon atmosphere. After cooling, the reaction solution was dilut¬ ed with ethyl acetate (400 ml), and washed with water (100 ml), IN-hydrochloric acid (100 ml X 2) and a saturated - aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resi¬ due was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate/acetone = 5/1) and recrystallized from ethyl acetate-diisopropyl ether to give l-[ (IR, 2R)-2- (2 ,4-difluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 ,2,4-triazol- l-yl)propyl]-3-[4-(lH-l,2,3-triazol-l-yl)phenyl]-2(lH,3H)- imidazolone (Compound 1_L; 1.82 g) as a pale yellow crystal¬ line powder, mp: 178-181'C
-■■H-NMR (CDCl3)δ: 1.22(3H,d,J=7Hz) , 4.22 (IH,d,J=14.4Hz) , 5.01 (lH,q,J=7Hz) , 5.12 (IH,d,J=14.4Hz) , 5.38 (lH.br), 6.70-6.88 (4H,m), 7.40-7.55 (lH.m), 7.76 (IH, s) , 7.80-7.93 ( 6H , m ) , 8 . 03 ( lH . s )
Elemental analysis for
Figure imgf000086_0001
Calcd (%) : C.57.74; H.4.21; N.23.42
Found (%): C.57.46; H.4.25; N.23.30 IR(KBr): 1691, 1656, 1619, 1527, 1502, 1430cm-1 Working Example 12 l-[ (lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l,2,3-triazol- l-yl)phenyl]-2(lH,3H)-imidazolone (0.80 g) obtained in Working Example 11 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1- [ (lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methy1-3-( 1H- l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l,2,3-triazol-l- yl )phenyl]-2-imidazolidinone (Compound 12.; 0.69 g) . Colorless crystalline powder
1H-NMR (CDCl3)δ: 1.08(3H,d,J=7Hz) , 3.70-4.14 (4H,m) , 4.52 (lH,d,J=14.2Hz) , 4.60-4.78 (lH.m), 5.12 (IH,d,J=14.2Hz) , 5.38 (lH.br), 6.70-6.86 (2H,m) , 7.35-7.50 (lH.m), 7.68-7.82 (4H,m), 7.77 (lH.s), 7.86 (2H,s), 7.97 (lH.s) Elemental analysis for C23H22F Ng02
Calcd (%) : C.57.50; H.4.62; N.23.32
Found (%): C, 57.38; H.4.59; N.23.41 IR(KBr): 1697, 1664, 1618, 1527, 1502, 1427cm-1 Working Example 13
(2R,3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-1-yl)methyloxirane (2.51 g) was reacted with l-[4- (2H-l,2,3-triazol-2-yl)phenyl]-2(lH,3H)-imidazolone (2.72 g) in the same manner as in Working Example 11 to give 1- [ ( IR, 2R)-2-(2 ,4-difluorophenyl )-2-hydroxy-l-methy1-3-( 1H- l,2,4-triazol-l-yl)propyl]-3-[4-(2H-l,2,3-triazol-2- yl )phenyl]-2(lH,3H)-imidazolone (Compound H; 1.41 g) . Pale yellow needles mp: 182-185βC
1H-NMR (CDCl3)δ: 1.22(3H,d,J=7Hz) , 4.22 (IH,d,J=14.4Hz) , 4.99 (lH,q,J=7Hz) , 5.01 ( IH,d,J=14.4Hz) , 5.13 (lH.br), 6.70-6.88 (4H,m), 7.40-7.56 (lH.m), 7.75 (lH,s), 7.81 (2H,d,J=9.2Hz) , 7.84 (2H,s), 7.86 (lH.s), 8.18 (2H,d,J=9.2Hz) Elemental analysis for C2 H2QF2NQ0
Calcd (%) : C.57.74; H.4.21; N,23.42
Found (%) : C, 57.67; H.4.20; N.23.59 IR(KBr): 3328, 1664, 1614, 1519, 1430, 1384cm-1 Working Example 14 l-[ (lR,2R)-2-(2,4-Difluorophenyl )-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(2H-l,2,3-triazol-2- yl)phenyl]-2(lH,3H)-imidazolone (0.80 g) obtained in Working Example 13 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give l-[ (IR,2R)-2- (2 ,4-difluorophenyl )-2-hydroxy-l-methy1-3-(1H-1 , 2 ,4-triazol- l-yl)propyl]-3-[4-(2H-l,2,3-triazol-2-yl)phenyl]-2-imidazol- idinone (Compound JL_4_; 0.70 g) .
Colorless crystalline powder mp: 196-197°C
1H-NMR (CDCl3)δ: 1.08(3H,d,J=7.4Hz) , 3.68-4.12 (4H,m), 4.53
(lH,d,J=14Hz) , 4.58-4.76 (lH.m), 5.13 ( IH,d,J=14Hz) , 5.42
(lH.br), 6.70-6.85 (2H,m), 7.36-7.50 (lH,m), 7.71
(2H,d,J=9Hz) , 7.76 (lH,s), 7.81 (2H,s), 7.87.(lH,s), 8.07
(2H,d,J=9Hz)
IR(KBr): 3426, 1687, 1658, 1616, 1517, 1484cm-1
Working Example 15
(2R, 3S)-2-(2, 4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-1-yl )methyloxirane was reacted with l-[4-(lH-l- pyrazolyl )pheny1 ]-2( IH, 3H)-imidazolone in the same manner as in Working Example 11 to give l-[ ( IR, 2R)-2-(2 ,4-difluoro¬ phenyl )-2-hydroxy-l-methyl-3-( 1H-1 , 2 ,4-triazo1-1-yl )propyl ]- 3-[4-( lH-1-pyrazolyl)phenyl ]-2 (IH,3H)-imidazolone (Compound iό) *
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 (IH,d,J=14.4Hz) ,
4.98 (lH,q,J=7Hz) , 5.12 ( IH,d,J=14.4Hz) , 5.56 (lH.br) ,
6.47-6.54 (lH.m) , 6.68-6.88 (4H,m) , 7.40-7.56 (lH.m) , 7.70-
7.85 (6H,m), 7.85 (lH.s), 7.94 (IH,d,J=2.4Hz)
Elemental analysis for C24H21F2Nγ02
Calcd (%) : C.60.37; H.4.43; N.20.53
Found (%) : C.60.29; H.4.42; N.20.50 Working Example 16
1-[(1R.2R)-2-(2,4-Difluorophenyl )-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l-pyrazolyl)phenyl]- 2 (lH,3H)-imidazolone (Compound JJ5.) obtained in Working Example 15 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give l-[ (IR, 2R)-2- (2,4-difluorophenyl )-2-hydroxy-l-methy1-3-(1H-1 , 2,4-triazol- 1- yl )propyl]-3-[4-(lH-1-pyrazolyl)phenyl ]-2-imidazolidinone (Compound __§_) . iH-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.65-4.10 (4H,m), 4.53 (lH,d,J=14.2Hz) , 4.55-4.75(lH,m) , 5.12 (IH,d,J=14.2Hz) , 5.45 (lH.br), 6.46-6.48 (lH,m), 6.70-6.85 (2H,m), 7.35-7.50 (lH,τι), 7.60-7.75 (5H,m), 7.76 (lH.s), 7.88 (lH,s), 7.90 (lH.d,J=2.6Hz) Elemental analysis for C24H F2Nγ02
Calcd (%) : C.60.12; H.4.83; N.20.45
Found (%) : C.60.02; H.4.95; N.20.34 Working Example 17
(2R,3S)-2-(2, 4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-l-yl)methyloxirane was reacted with l-[4-(1H-1 , 2 ,4- triazol-1-ylmethyl )phenyl ]-2 (IH, 3H)-imidazolone in the same manner as in Working Example 11 to give l-[ (IR,2R)-2-(2 ,4- difluorophenyl)-2-hydroxy-l-methyl-3-(1H-1 ,2,4-triazol-l- yl)propyl]-3-[4-(lH-l, 2 , 4-triazol-l-ylmethyl )phenyl]- 2(1H, 3H)-imidazolone (Compound 17) . 1H-NMR (CDCl3)δ: 1.20 (3H,d,J=7Hz) , 4.19 ( IH,d,J=14.4Hz) , 4.97 (lH,q,J=7Hz) , 5.10 ( IH,d,J=14.4Hz) , 5.37 (2H,s), 5.55 (lH.br), 6.65 ( IH,d,J=3.2Hz) , 6.70-6.90 (3H,m) , 7.37 (2H,d,J=8.6Hz) , 7.35-7.55 (lH.m), 7.69 (2H,d,J=8.6Hz) , 7.74 (lH.s), 7.85 (lH.s), 7.99 (lH.s), 8.10 (lH.s) Working Example 18
(2R, 3S)-2-(2,4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-1-yl)methyloxirane was reacted with 4-[4-( 1H-1 , 2 , 4— triazol-l-ylmethyl)phenyl]-3 (2H,4H)-1 , 2 ,4-triazolone in the same manner as in Working Example 11 to give 2-[ ( IR,2R)-2- (2 ,4-difluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 ,2,4- triazol-l-yl)propyl]-4-[4-(1H-1 , 2 , 4-triazol-l-ylmethy1)- phenyl]-3(2H,4H)-l,2 ,4-triazolone (Compound 18) . 1H-NMR (CDCl3)δ: 1.30 (3H,d,J=7.2Hz) , 4.36 (IH,d,J=14.2Hz) , 5.02 (lH,d,J=14.2Hz) , 5.09 ( IH,q,J=7.2Hz) , 5.42 (2H,s), 5.43 (lH.s) , 6.75-6.90 (2H,m), 7.43 (2H, d,J=8.6Hz) , 7.50-7.67 (lH.m), 7.63 (2H,d,J=8.6Hz) , 7.69 (lH.s), 7.82 (lH.s), 7.94 (lH.s), 8.01 (lH.s), 8.15 (lH.s) Working Example 19
(2R,3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1, 2,4- triazol-1-yl)methyloxirane was reacted with 4-[4-(lH-l- pyrazoly1)phenyl]-3(2H,4H)-1 , 2,4-triazolone in the same manner as in Working Example 11 to give 2-[ ( IR, 2R)-2-(2 ,4- difluorophenyl)-2-hydroxy-l-methyl-3-( 1H-1 , 2 , 4-triazol-l- yl)propyl]-4-[4-( lH-1-pyrazolyl)pheny1]-3(2H,4H)-1,2,4- triazolone (Compound U.) . 1H-NMR (CDCl3)δ: 1.32 (3H,d,J=7Hz) , 4.38 (IH,d,J=14.4Hz) , 5.05 (lH,d,J=14.4Hz) , 5.11 ( IH,q,J=7Hz) , 5.45 (lH,s), 6.52- 6.54 (lH.m), 6.76-6.90 (2H,m), 7.50-7.65 (lH.m), 7.65-7.93 (7H,m), 7.96 (lH.s), 7.98 ( IH,d,J=2.6Hz) Working Example 20
(2R.3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-1-yl)methyloxirane was reacted with l-[4-(2H-l ,2 , 3- triazol-2-ylmethyl )phenyl ]-2 ( lH,3H)-imidazolone in the same manner as in Working Example 11 to give l-[ (IR, 2R)-2-(2 , 4- difluorophenyl )-2-hydroxy-l-methyl-3-(1H-1 , 2 ,4-triazol-l- yl)propyl]-3-[4-(2H-l, 2 ,3-triazol-2-ylmethy1)pheny1]- 2(1H, 3H)-imidazolone (Compound 20) .
1H-NMR (CDCl3)δ: 1.19 (3H,d,J=7Hz) , 4.17 (IH,d,J=14.4Hz) , 4.95 (lH.q,J=7Hz) , 5.09 ( IH, d,J=14.4Hz) , 5.55 (lH.br) , 5.63 (2H,s), 6.63 (lH,d,J=3.2Hz) , 6.70-6.86 (3H,m), 7.40-7.55 (lH,m), 7.42 (2H,d,J=8.6Hz) , 7.64 (2H,s), 7.64 (2H,d,J=8.6Hz) , 7.73 (lH,s), 7.85 (lH,s) Working Example 21
(2R,3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-1-yl)methyloxirane was reacted with 4-[4-(2H-1 , 2, 3- triazol-2-ylmethyl)phenyl]-3 (2H,4H)-1,2 ,4-triazolone in the same manner as in Working Example li to give 2-[ (IR, 2R)-2- (2 , 4-difluorophenyl)-2-hydroxy-l-methyl-3-( 1H-1 ,2,4- triazol-l-yl)propyl]-4-[4-(2H-l,2,3-triazol-2-ylmethyl)- phenyl]-3(2H,4H)-l,2,4-triazolone (Compound 21) . 1H-NMR (CDCl3)δ: 1.29 (3H,d,J=7Hz) , 4.34 (IH,d,J=14.4Hz) , 5.02 (lH,d,J=14.4Hz) , 5.08 ( IH, ,J=7Hz) , 5.44 (lH.s), 5.66 (2H,s), 6.73-6.87 (2H,m), 7.46 (2H,d,J=8.6Hz) , 7.50-7.62 (lH,m) , 7.58 (2H,d,J=8.6Hz) , 7.66 (2H,s), 7.68 ( IH, s) , 7.78 (lH.s) , 7.94 (lH.s) Elemental analysis for C 3H -^F2Ng0
Calcd (%) : C.55.98; H.4.29; N.25.55
Found (%) : C.55.87; H.4.18; N, 25.42 Working Example 22
(2R, 3S)-2-(2,4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-1-yl)methyloxirane was reacted with 4-[4-(lH-l- imidazolyl)phenyl]-3(2H,4H)-l , 2,4-triazolone in the same manner as in Working Example 11 to give 2-[ ( IR, 2R)-2-(2 ,4- difluorophenyl )-2-hydroxy-l-methyl-3-( lH-l,2,4-triazol-l- yl)propyl]-4-[4-(lH-l-imidazolyl)phenyl]-3(2H,4H)-l,2,4- triazolone (Compound 2_2_) .
1H-NMR (CDCl3)δ: 1.32 (3H,d,J=7Hz) , 4.40 (IH, d,J=14Hz) , 5.03 (lH.d,J=14Hz) , 5.11 ( lH,q,J=7Hz) , 5.42 (lH.s) , 6.73-6.88 (2H,m) , 7.26 ( IH, s) , 7.33 (lH.s), 7.51-7.65 (lH,m), 7.57 (2H,d,J=9Hz) , 7.71 ( IH, s) , 7.76 (2H,d,J=9Hz) , 7.86 (lH.s), 7.91 (lH,s), 7.95 (lH,s) Working Example 23
(2R,3S)-2-(2,4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-1-yl)methyloxirane was reacted with l-[4-(lH-l- imidazolyl)phenyl]-2( IH, 3H)-imidazolone in the same manner as in Working Example 11 to give l-[ ( IR, 2R)-2-(2 ,4- difluorophenyl)-2-hydroxy-l-methyl-3-(1H-1 ,2,4-triazol-l- yl)propyl]-3-[4-(lH-l-imidazolyl)phenyl]-2(lH,3H)-imidazo- lone (Compound 22.) .
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 (IH,d,J=14Hz) , 5.00 (lH,q,J=7Hz) , 5.12 (IH,d,J=14Hz) . 5.56 (lH,br), 6.70 (lH,d,J=3Hz) , 6.76-6.86 (3H,m), 7.23 (lH,s), 7.30 (IH, s) , 7.42-7.54 (lH,m), 7.49 (2H,d,J=8Hz) , 7.75 (lH,s), 7.78 (lH.s), 7.84 (2H,d,J=8Hz) , 7.86 (lH.s) Working Example 24 l-[ (lR,2R)-2-(2,4-Difluorophenyl )-2-hydroxy-l-methy1-3- ( 1H-1,2,4-triazol-1-yl)propyl]-3-[4-(IH-imidazolyl)phenyl]- 2(IH, 3H)-imidazolone (Compound 2__7) obtained in Working Example 23 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1-[ (IR, 2R)-2- (2 ,4-difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l,2,4-triazol- l-yl)propyl]-3-[4-(lH-1-imidazolyl )phenyl]-2-imidazolidinone (Compound .24.) .
1H-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.70-4.08 (4H,m), 4.52 (lH,d,J=14Hz) , 4.55-4.76 (lH.m), 5.11 ( IH,d,J=14Hz) , 5.40 (lH.br), 6.73-6.84 (2H,m), 7.20 (lH.s), 7.26 ( IH, s) , 7.36- 7.50 (lH.m), 7.39 (2H,d,J=9Hz) , 7.69 (2H,d,J=9Hz) , 7.76 (lH,s), 7.82 (lH.s), 7.87 (lH,s) Working Example 25
(2R,3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1,2,4- triazol-1-yl)methyloxirane was reacted with 4-[4-(2H-2- tetrazolyl)phenyl]-3 (2H,4H)-1 ,2 ,4-triazolone in the same manner as in Working Example 11 to give 2-[ (IR,2R)-2-(2 ,4- difluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 , ,4-triazol-l- yl)propyl]-4-[4-(2H-2-tetrazolyl)phenyl]-3(2H.4H)-l,2,4- triazolone (Compound .25.) .
1H-NMR (CDCl3)δ: 1.33 (3H, d,J=7Hz) , 4.40 (IH,d,J=14Hz) , 5.04 (lH,d,J=14Hz) , 5.11 (IH,q,J=7Hz) , 5.37 (lH,s), 6.77-6.88 (2H,m) , 7.52-7.64 (lH.m) , 7.71 (lH.s), 7.87 (2H,d,J=9Hz) , 7.92 (lH.s), 7.95 (lH.s), 8.34 (2H,d,J=9Hz) , 8.71 (lH,s) Elemental analysis for C2^H^QF2N^Q02
Calcd (%) : C,52.50; H.3.78; N.29.15 Found (%) : C.52.36; H.3.85; N, 29.02 Working Example 26
(2R,3S)-2-(2,4-difluorophenyl)-3-methy1-2-(IH-1,2,4- triazol-1-yl )methyloxirane was reacted with l-[4-(2H-2- tetrazolyl)phenyl]-2( IH, 3H)-imidazolone in the same manner as in Working Example 11 to give l-[ (IR,2R)-2-(2 ,4- difluorophenyl)-2-hydroxy-l-methyl-3-(1H-1 , 2 ,4-triazol-l- yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(lH,3H)-imidazo- lone (Compound 2_6) .
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 ( IH,d,J=14Hz) , 5.02 (lH,q,J=7Hz) , 5.12 (IH,d,J=14Hz) , 5.49 (lH.br), 6.75 (lH.d,J=3Hz) , 6.75-6.85 (2H,m) , 6.85 (IH,d,J=3Hz) , 7.42-7.54 (lH.m), 7.76 (lH.s), 7.85 (lH.s), 7.93 (2H,d,J=9Hz) , 8.25 (2H,d,J=9Hz) , 8.68 (lH,s) Working Example 27 l-[ ( 1R.2R)-2-(2,4-Difluorophenyl )-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(2H-2-tetrazolyl) phenyl]-2(lH,3H)-imidazolone (Compound 6.) obtained in Working Example 26 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1- [ (1R.2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methy1-3-(1H- l,2,4-tri-azol-l-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]- 2-imidazolidinone (Compound 27) .
1H-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.69-3.81 (lH,m), 3.94- 4.10 (3H,m), 4.52 ( IH,d,J=14Hz) , 4.62-4.80 (lH,m), 5.13 (lH.d,J=14Hz) , 5.25-5.50 (lH.br), 6.72-6.84 (2H.m), 7.36- 7.49 (lH.m), 7.77 (lH,s), 7.80 (2H,d,J=9Hz) , 7.86 ( IH, s) , 8.13 (2H,d,J=9Hz) , 8.64 (lH,s) Working Example 28
(2R,3S)-2-(2,4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-1-yl )methyloxirane was reacted with l-[4-( 1H-1 ,2 , 3- triazol-l-ylmethyl)phenyl]-2(lH,3H)-imidazolone in the same manner as in Working Example 11 to give l-[ (IR,2R)-2-(2 ,4- difluorophenyl )-2-hydroxy-l-methyl-3-(1H-1 ,2,4-triazol-l- yl)propyl]-3-[4-(lH-l,2,3-triazol-l-ylmethyl)phenyl]- 2 ( IH,3H)-imidazolone (Compound 28) .
XH-NMR (CDCl3)δ: 1.20 (3H,d,J=7Hz) , 4.19 (IH,d,J=14Hz) , 4.97 (lH,q,J=7Hz) , 5.09 (IH,d,J=14Hz) , 5.55 (lH.br), 5.59 (2H,s), 6.65 (lH,d,J=3.2Hz) , 6.75-6.90 (3H,m), 7.35-7.55 (4H,m), 7.66-7.75 (4H,m), 7.84 (lH.s) Working Example 29
(2R,3S)-2-(2,4-Difluorophenyl )-3-methy1-2-(1H-1,2,4- triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1 ,2 , 3- triazol-l-ylmethyl)phenyl]-3(2H,4H)-l ,2,4-triazolone in the same manner as in Working Example 2 to give 2-[ ( IR,2R)-2- (2 ,4-difluorophenyl )-2-hydroxy-l-me hy1-3-( 1H-1 ,2,4- triazol-l-yl)propyl]-4-[4-(lH-l,2,3-triazol-l-ylmethyl)- phenyl]-3 (2H,4H)-1 , 2 ,4-triazolone (Compound 29) * 1H-NMR (CDCl3)δ: 1.30 (3H,d,J=7Hz) , 4.36 ( IH,d,J=14Hz) , 5.00 (lH.d,J=14Hz) , 5.08 ( IH,q,J=7Hz) , 5.41 ( IH, s) , 5.63 (2H,s), 6.75-6.90 (2H,m), 7.40-7.64 (6H,m), 7.69 (lH,s), 7.76 (lH,s), 7.80 (lH.s), 7.94 (lH.s) Working Example 30
(2R, 3S)-2-(2, 4-Difluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-1-yl)methyloxirane was reacted with l-[4-(2-methy1- 4-thiazolyl)phenyl]-2 ( IH, 3H)-imidazolone in the same manner as in Working Example 11 to give l-[ ( IR, 2R)-2-(2 , 4- difluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 ,2 ,4-triazol-l- yl)propyl]-3-[4-(2-methyl-4-thiazolyl)phenyl]-2(lH,3H)- imidazolone (Compound 30) .
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 2.78 (3H,s) , 4.22 (lH,d,J=14Hz) , 4.98 ( IH,q,J=7Hz) , 5.12 ( IH,d,J=14Hz) , 5.60 (lH.br), 6.70-6.85 (4H,m), 7.33 (lH,s), 7.40-7.55 (lH,m) , 7.69-8.00 (6H,m) Working Example 31
(2R,3S)-2-(2 ,4-Difluorophenyl)-3-methy1-2-( 1H-1 ,2,4- triazol-l-yl)methyloxirane was reacted with 4-[4-(2- methy1-4-thiazoly1)pheny1]-3 (2H.4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[ (1R.2R)-2-(2,4-difluorophenyl )-2-hydroxy-l-methy1-3-(1H- 1 , 2 ,4-triazol-l-yl)propyl ]-4-[4-(2-methyl-4-thiazolyl )phe¬ nyl ]-3 (2H,4H)-1 ,2 ,4-triazolone (Compound 31) . XH-NMR (CDCl3)δ: 1.31 (3H,d,J=7Hz) . 2.79 (3H,s), 4.37 (lH,d,J=14Hz) , 5.04 (IH,d,J=14Hz) , 5.11 (lH.q,J=7Hz) , 5.47 (lH.s), 6.77-6.90 (2H,m), 7.39 (lH.s), 7.50-7.70 (4H,m), 7.85-8.05 (4H,m) Working Example 32
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(lH-l,2,4- triazol-1-yl )methyloxirane was reacted with l-[4-(1H-1 , 2 , 3- triazol-l-yl)phenyl]-2 (IH,3H)-imidazolone in the same manner as in Working Example 11 to give l-[ (IR,2R)-2-(2-fluorophe¬ nyl)-2-hydroxy-l-methy1-3-(1H-1 ,2 ,4-triazol-l-yl )propyl ]-3- [4-(lH-l,2,3-triazol-l-yl)phenyl]-2(lH,3H)-imidazolone (Compound 3_2 .
1-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.23 ( IH,d,J=14.2Hz) , 5.08 (lH,q,J=7Hz) , 5.17 ( IH,d,J=14.2Hz) , 5.36 (lH.br), 6.73 (lH,d,J=3.2Hz) , 6.86 ( IH,d,J=3.2Hz) , 6.99-7.09 (2H,m), 7.19-7.52 (2H,m), 7.51-7.92 (6H,m), 7.80 (lH,s), 8.03 (lH.s) Elemental analysis for C 3H2^FNg0
Calcd (%) : C.59.99; H.4.60; N.24.23 Found (%) : C, 59.62; H.4.61; N.24.13 Working Example 33
(2R.3S)-2-(2-Fluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-l-yl)methyloxirane was reacted with l-[4-(2H-l , 2 , 3- triazol-2-yl)propyl]-2(IH, 3H)-imidazolone to give 1-[(1R.2R)-2-(2-fluorophenyl)-2-hydroxy-l-methy1-3-(1H- 1 ,2 ,4-triazol-l-yl)propoxy]-3-[4-(2H-l,2,3-triazol-2- yl )phenyl]-2( IH, 3H)-imidazolone (Compound 33) . XH-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.23 ( IH,d,J=14Hz) , 5.07 (lH,q,J=7Hz) , 5.18 ( IH,d,J=14Hz) , 5.37 (lH.br), 6.70 (lH,d,J=3.2Hz) , 6.83 (IH,d,J=3.2Hz) , 6.98-7.08 (2H,m), 7.19-7.51 (2H,m), 7.73 (IH, s) , 7.75 (2H,d,J=9.2Hz) , 7.83 (2H,s) , 7.85 (lH,s) , 8.17 (2H,d,J=9.2Hz) Elemental analysis for C23H2-^FNg02
Calcd (%) : C,59.99; H.4.60; N.24.33
Found (%) : C.59.80; H.4.58; N.23.87 Working Example 34 l-[ (1R.2R)-2-(2-Fluorophenyl )-2-hydroxy-l-methy1-3-( 1H- 1.2.4-triazol-l-yl)propyl]-3-[4-(lH-l,2,3-triazol-l- yl )phenyl]-2(lH, 3H)-imidazolone (compound 3_2J obtained in Working Example 32 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1- [ ( IR, 2R)-2-(2-fluorophenyl)-2-hydroxy-l-methy1-3-( 1H-1 ,2,4- triazol-l-yl)ρropyl]-3-[4-(lH-l,2,3-triazol-l-yl)phenyl]-2- imidazolidinone (Compound 34) . XH-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.72-4.14 (4H,m), 4.54 (lH.d,J=14.2Hz) , 4.70-4.84 (lH.m), 5.17 (IH,d,J=14.2Hz) , 5.30 (lH.br), 6.96-7.08 (2H,m) , 7.18-7.50 (2H,m), 7.68-7.78 (4H,m), 7.75 (lH,s), 7.84 (2H,s), 7.98 (lH,s) Elemental analysis for C23H23FNg0
Calcd (%): C,59.73; H.5.01; N.24.23
Found (%): C.59.32; H.4.99; N.24.00 Working Example 35 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-l-methyl-3-(lH- l,2,3-triazol-l-yl)propyl]-3-[4-(2H-l,2,3- riazol-2-yl)phe- nyl]-2 ( IH, 3H)-imidazolone (Compound 3_3_) obtained in Working Example 33 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give l-[ ( IR, 2R)-2- (2-fluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 ,2 ,4-triazol-l- yl)propyl]-3-[4-(2H-l ,2 ,3-triazol-2-yl )pheny1]-2-imidazoli- dinone (Compound 3_5) . mp. : 178-179βC
XH-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.71-4.07 (4H,m), 4.54 (lH.d,J=14Hz) , 4.74-4.77 (lH.m), 5.18 (IH,d,J=14Hz) , 5.38 (lH.br). 6.96-7.06 (2H,m), 7.16-7.51 (2H,m), 7.71 (2H,d,J=9Hz) , 7.74 (lH,s), 7.80 (2H,s), 7.83 (lH.s), 8.07 (2H,d,J=9Hz) Elemental analysis for C23H 3FNg02
Calcd (%): C.59.73; H.5.01; N.24.23
Found (%): C.59.49; H.5.23; N.24.01 Working Example 36
(2R.3S)-2-(2,4-Difluorophenyl)-3-methy1-2-(1H-1, 2,4- triazol-l-yl)methyloxirane (0.50 g) , 4-[4-(2-methyl-4- oxazolyl)phenyl]-3(2H,4H)-l,2,4-triazolone (0.56 g) and potassium carbonate (powder: 1.38 g) were added to a mixture of l-methyl-2-pyrrolidone (5 ml) and N.N-dimethylformamide(4 ml) , and the mixture was heated with stirring at 90°C for 20 hours. After cooling, the reaction solution was diluted with ethyl acetate (40 ml). Ice water (40 ml) was added thereto to separate the ethyl acetate layer. The ethyl acetate layer was washed with 0.5N-sodium hydroxide (40 ml), IN-hydrochloric acid (40 ml) and a saturated aqueous solu¬ tion of sodium chloride (40 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate/methanol = 9/1) and crystal¬ lized from ethyl acetate-diisopropyl ether to give 2- [ (1R.2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methy1-3-(1H- 1 , 2 ,4-triazol-l-yl )propyl]-4-[4-(2-methyl-4-oxazolyl)phe¬ ny1]-3 (2H,4H)-1 ,2,4-triazolone (Compound 3_6, 0.33 g) . 1H-NMR (CDCl3)δ: 1.31 (3H,d,J=7Hz) , 2.54 (3H,s), 4.36 (lH,d,J=14Hz) , 5.04 (IH,d,J=14Hz) , 5.10 (IH,q,J=7Hz) , 5.47 (lH.s), 6.77-6.88 (2H,m), 7.51-7.69 (4H,m), 7.85 (IH, s) , 7.86 (2H,d,J=8Hz) , 7.88 (lH.s), 7.96 (lH.s) Working Example 37
(2R.3S)-2-(2,4-Difluorophenyl )-3-methy1-2-(1H-1,2,4- triazol-1-yl )methyloxirane was reacted with l-[4-(2-methyl- 4-oxazolyl)phenyl]-2(lH,3H)-imidazolone in the same manner as in Working Example 11 to give l-[ (IR,2R)-2-(2 ,4- difluorophenyl)-2-hydroxy-l-methyl-3-(1H-1 , 2 ,4-triazol- l-yl)proρyl]-3-[4-(2-methyl-4-oxazolyl)phenyl]-2(lH,3H)- imidazolone (Compound 3_7) .
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 2.53 (3H,s), 4.21 (lH,d,J=14Hz) , 4.97 (lH.q,J=7Hz) , 5.12 (IH,d,J=14Hz) , 5.60 (lH.br), 6.69-6.86 (4H,m), 7.42-7.55 (lH.m), 7.69 (2H,d,J=9Hz) , 7.73 (lH.s), 7.80 (2H,d,J=9Hz) , 7.84 (lH.s), 7.86 (lH.s) Working Example 38
(2R.3S)-2-(2-fluorophenyl )-3-methy1-2-(1H-1, 2,4- triazol-l-yl)methyloxirane (2.24 g) , l-[4-(1H-1 , 2 ,4-tria- zol-l-yl)phenyl]-2( lH,3H)-imidazolone (2.17 g) and cesium carbonate (powder: 7.76 g) were added to dimethylsulfoxide (100 ml), and the mixture was heated with stirring at 100°C for 17 hours. After being cooled, the reaction solution was diluted with ethyl acetate (200 ml). Ice water (200 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate/acetone = 4/1) to give l-[ (lR,2R)-2-(2-fluorophenyl)-2-hydroxy-l- methyl-3-(lH-l,2,4-triazol-l-yl)propyl]-3-[4-[lH-l,2,4- triazol-1-yl )phenyl]-2(IH, 3H)-imidazolone (Compound 3_8_; 0.45 g).
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.23 (IH,d,J=14Hz) , 5.02 (lH.q,J=7Hz) , 5.17 ( IH,d,J=14Hz) , 5.37 (lH.br), 6.71 (lH,d,J=3.2Hz) , 6.86 (IH,d,J=3.2Hz) , 6.99-7.10 (2H,m), 7.20-7.52 (2H,m), 7.70-7.89 (6H,m), 8.13 (lH.s) , 8.58 (lH,s) Working Example 39 l-[ (1R.2R)-2-(2-Fluorophenyl)-2-hydroxy-l-methy1- 3-(lH-l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l,2,4-triazol- 1-yl )phenyl]-2 ( IH,3H)-imidazolone (Compound 3_8_) obtained in Working Example 38 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1- [ (lR,2R)-2-(2-fluorophenyl)-2-hydroxy-l-methyl-3-(lH-l, 2 ,4- triazol-l-yl)propyl]-3-[4-(lH-l,2,4-triazol-l-yl)phenyl]-2- imidazolidinone (Compound 39) .
1H-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.72-4.10 (4H.m). 4.53 (lH,d,J=14.2Hz) . 4.76-4.79(lH,m) , 5.17 ( IH,d,J=1 .2Hz) , 5.19 (lH.br), 6.97-7.09 (2H,m), 7.17-7.46 (2H,m), 7.63-7.77 (5H,m), 7.82 (lH.s), 8.10 ( IH, s) , 8.52 (lH,s) Elemental analysis for C23H 3FNg02
Calcd (%): C.59.73; H.5.01; N, 24.23
Found (%) : C.59.33; H.5.03; N.23.98 Working Example 40
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(lH-l,2,4-tria- zol-l-yl)methyloxirane (2.34 g) , l-[4-(2H-2-tetrazolyl )- phenyl]-2(lH,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to l-methyl-2-pyrroli done (100 ml), and the mixture was heated at 80βC for 18 hours with stirring. The reaction solution was cooled, diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/acetone = 1/1) to give l-[ (lR,2R)-2-(2-fluorophenyl)-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-
(2H-2-tetrazolyl)phenyl]-2( lH,3H)-imidazolone (Compound 40 : 0.494 g) as a colorless crystalline powder.
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.23 (IH,d,J=14Hz) , 5.10 (lH,q,J=7Hz) , 5.19 (IH,d,J=14Hz) , 5.34 (lH.br), 6.75 (lH,d,J=3.2Hz) , 6.88 (IH,d,J=3.2Hz) , 6.99-7.09 (2H,m), 7.20-7.51 (2H,m), 7.75 (lH,s), 7.81. (lH,s), 7.94 (2H,d,J=9Hz) , 8.25 (2H,d,J=9Hz) , 8.68 (lH.s) Elemental analysis for C2 H2QF g02
Calcd (%): C,57.26; H.4.37; N.27.32
Found (%): C.57.19; H.4.29; N.27.07 Working Example 41 l-[ ( 1R,2R)-2-(2-Fluorophenyl)-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(2H-2-tetrazolyl)phe- nyl]-2(IH,3H)-imidazolone (Compound 4_0) obtained in Working Example 40 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1-[(1R,2R)- 2-(2-fluorophenyl )-2-hydroxy-l-methyl-3-( 1H-1 , 2 ,4-tria- zol-l-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2- imidazolidinone (Compound 4J.) a*s a colorless crystalline powder.
1H-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.74-3.81 (lH.m), 3.94- 4.13 (3H,m), 4.53 ( IH,d,J=14Hz) , 4.63-4.81 (lH.m), 5.13 (lH,d,J=14Hz) , 5.15-5.30 (lH.br), 6.97-7.07 (2H,m), 7.17- 7.45 (2H,m), 7.78 (lH.s), 7.79 (2H,d,J=9Hz) , 7.83 (lH,s), 8.13 (2H,d,J=9Hz) , 8.65 (IH, s) Elemental analysis for
Figure imgf000104_0001
Calcd (%) : C.57.01; H.4.78; N.27.20
Found (%) : C,56.96; H.4.86; N, 26.84 Working Example 42
72% sodium hydride in oil (17 mg) was dispersed in dimethylformamide (3 ml), to which 1 , 2 , 4-triazole (42 mg) was added at ice-bath temperature, and the mixture was stirred at room temperature for 40 minutes. To the result¬ ant was added a solution of 1-[(1R, 2S)-2-(2,4-difluorophe¬ nyl )-2, 3-epoxy-l-methylpropyl]-3-[4-[ (lH-1-tetrazolyl )phe¬ nyl]-2H(IH,3H)-imidazolone (0.205 g) in dimethylformamide (2 ml), and the mixture was heated at 50°C for 6 hours. After the mixture was cooled, cold water (30 ml) and ethyl acetate (30 ml) were added thereto. The separated aqueous layer was extracted with ethyl acetate twice. The combined ethyl acetate layers were washed with water and a saturated aque¬ ous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to give l-[ (1R.2R)-2-(2,4-difluorophenyl )-2-hydroxy-l-methy1-3-(1H- 1 , 2,4-triazol-l-yl)propyl]-3-[4-(lH-l-tetrazolyl)phenyl]- 2(IH,3H)-imidazolone (Compound ____; 0.15g) as a colorless crystalline powder.
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 (IH,d,J=14Hz) , 5.03 (lH,q,J=7Hz) , 5.13 (IH,d,J=14Hz) , 5.45 (lH.br), 6.74-6.88 (4H,m), 7.42-7.55 (lH.m), 7.77 (lH.s), 7.82 (2H,d,J=9Hz) , 7.86 (lH,s), 7.96 (2H,d,J=9Hz) , 9.06 (lH,s)
The same product (Compound __2_) was obtained when a reaction was carried out in the same manner as in the above except that sodium hydride was replaced by potassium carbon- ate .
Working Example 43 l-[ (IR,2R)-2-(2, 4-Difluorophenyl )-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l-tetrazolyl)phe- nyl]-2(IH, 3H)-imidazolone (compound 42.) obtained in Working Example 42 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give l-[ ( IR, 2R)-2- (2,4- difluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 ,2 ,4-tria- zol-l-yl )propyl]-3-[4-( lH-1-tetrazoly1 )phenyl]-2-imidazol i- dinone (compound ___.) as a colorless crystalline powder. 1H-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.69-4.14 (4H,m), 4.52 (lH.d,J=14Hz) , 4.65-4.80 (lH,m), 5.12 ( IH,d,J=14Hz) , 5.35 (lH.br), 6.74-6.84 (2H,m), 7.36-7.49 (lH.m), 7.68 (2H,d,J=9Hz) , 7.77 ( IH, s) , 7.82 (2H,d,J=9Hz) , 7.87 ( IH, s) , 8.98 (lH.s) Working Example 44
72% sodium hydride in oil (120 mg) was dispersed in di¬ methylformamide (10 ml), to which 1 , 2,4-triazole (290 mg) was added at ice-bath temperature, and the mixture was stirred at room temperature for 30 minutes. To the result¬ ant was added a solution of 1-[(1R, 2S)-2-(2-fluorophenyl)- 2 ,3-epoxy-l-methylpropyl]-3-[4-[ (lH-1-tetrazoly1)pheny1]- 2H(1H, 3H)-imidazolone (0.82 g) in dimethyIformamide (5 ml), and the mixture was heated at 50°C for 5 hours. After the reaction solution was cooled, cold water (30 ml) and ethyl acetate (40 ml) were added. The separated aqueous layer was extracted with ethyl acetate twice. The ethyl acetate layers were combined, washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to give l-[ ( IR, 2R)-2-(2-fluorophenyl)-2-hydroxy-l-methyl-3-(lH- 1 ,2 ,4-triazol-l-yl)propyl]-3-[4-(lH-l-tetrazolyl)phenyl]- 2 ( IH, 3H)-imidazolone (Compound 44; 0.30 g) as a colorless crystalline powder.
1H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 ( IH,d,J=14Hz) , 5.10 (lH,q,J=7Hz) , 5.18 ( IH,d,J=14Hz) , 5.31 (IH.br), 6.75 (lH,d,J=3Hz) , 6.90 ( IH, d,J=3Hz) , 6.99-7.32 (3H,m), 7.43-7.51 (lH.m), 7.75 (lH.s), 7.80-7.85 (3H,m), 7.97 (2H,d,J=9Hz) , 9.07 (lH,s) Working Example 45 l-[ ( 1R.2R)-2-(2-Fluorophenyl)-2-hydroxy-l-methy1-3- (lH-l,2,4-triazol-l-yl)propyl]-3-[4-(lH-l-tetrazolyl)phe- nyl]-2( IH, 3H)-imidazolone (compound 44) obtained in Working Example 44 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give l-[ (IR, 2R)-2- (2-fluorophenyl)-2-hydroxy-l-methy1-3-(1H-1,2 ,4-triazol-l- yl)propyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolidinone (Compound £__.) . 1H-NMR (CDCl3)δ: 1.08 (3H,d,J=7Hz) , 3.70-4.19 (4H,m) , 4.53 (lH,d,J=14Hz) , 4.72-4.88 (lH,m), 5.10-5.26 (2H,m), 6.97-7.45 (4H,m), 7.68 (2H,d,J=9Hz) , 7.76 (lH.s), 7.82 ( IH, s) , 7.83 (2H,d,J=9Hz) , 8.97 (lH.s) Working Example 46 l-[ (lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methane- sulfonyloxy-l-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]- 2(IH, 3H)-imidazolone (200 mg) was dissolved in dimethylfor- mamide (10 ml), to which 1H-1 ,2 ,4-triazole (83 mg) and potassium carbonate (168 mg) were added, and the mixture was heated at 50°C for 20 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (15 ml), IN-hydrochloric acid (15 ml x 2) and a saturated aque¬ ous solution of sodium chloride (15 ml). The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate) . The desired fraction was concentrated and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1- [ (IR, 2R)-2-(2-fluorophenyl)-2-hydroxy-l-methy1-3-(1H-1 ,2,4- triazol-l-yl)propyl-3-[4-(lH-l-tetrazolyl)phenyl]-2(lH,3H)- imidazolone (Compound 44., 65 mg) as a colorless crystalline powder.
:H-NMR (CDCl3)δ: 1.21 (3H,d,J=7Hz) , 4.22 ( lH.d,J=14Hz) , 5.11 (lH,q,J=7Hz) , 5.18 (IH,d,J=14Hz) , 5.32 (lH.br), 6.75 (lH,d,J=3Hz) , 6.90 (lH,d,J=3Hz) , 7.00-7.27 (3H,m) , 7.43-7.51 (lH.m) , 7.75 ( IH , s ) , 7.80-7.84 (3H,m) . 7.97 ( 2H, d, J=9Hz ) , 9.06 (lH.s)
Tables 10 to 14 show a group of preferred compounds belonging to the compound (I) of the present invention but the present invention is not limited to those compounds.
Table 10
Figure imgf000110_0001
Compound No .
Figure imgf000110_0002
Figure imgf000110_0003
Table 11
Compound No .
Figure imgf000111_0001
13 2.4-F2 tϊrOC.
Figure imgf000111_0002
Table 12
Compound No .
Figure imgf000112_0001
23 2.4-F2
Figure imgf000112_0002
29 2.4-F2
Figure imgf000112_0003
Table 13
Compound No .
Figure imgf000113_0001
32 2-F
33 2-F
Figure imgf000113_0002
36 2.4-F2
Figure imgf000113_0003
23 2-F
39 2-F - 0-C.
Ill Tab l e 14
Compound No
4Ω 2-F -Λ^
Figure imgf000114_0001
2 2.4-F2
Figure imgf000114_0002
Formulation Example 1
All the components for the below prescription using the Compound 7. obtained in Working Example 7 were mixed, and filled into gelatine capsules to prepare capsuled drugs each containing Compound 7. in the amount of 50 mg. Compound 7. in Working Example 7 50 mg
Lactose 100 mg
Corn Starch 40 mg
Magnesium Stearate 10 mg
Total 200 mg
Formulation Example 2
The compound 10. obtained in Working Example 10 and magnesium stearate were made into granules by using an aqueous solution of soluble starch, dried and mixed with lactose and corn starch. The mixture was molded under compression to form a tablet for the below prescription. Compound 10. of Working Example 10 50 mg
Lactose 65 mg
Corn Starch 30 mg
Soluble Starch 35 mg
Magnesium Stearate 20 mg
Total 200 mg
Experiment Example 1
Test Method: Five-week-old Crj : CDF-^ mice were inoculated with the minimum lethal dose of Candida albi cans TA intrave¬ nously. The test compounds were administered orally once immediately after infection as a 30% HPCD (hydroxypropy1-β- cyclodextrin) solution. The activity was expressed in terms of EDgQ value calculated by the Reed and Muench method from the survival rate 7 days after infection. Result: Tables 15 and 16 shows the protective effects of the present compounds against Candida albicans infection in mice.
Table 15
Compound No . EDso (mg/kg) PO
_5_ 0.22
_6_ 0.35
_7_ 0.096
9_ 0.16
10 0.32
1 0.45
12 0.71
13 0.18
14 0.32
9 0.39
25 0.088
26 0.16
27 0.18
34 0.80
___ 0.71
PO: oral administration Table 16
Compound No . EDso (mg/kg) PO
23 0.5
39 0.5
40 0.35
l 0.80
42 0.22
43 0.89
44 0.39
4§ 0.45
PO: oral administration
INDUSTRIAL APPLICABILITY
The present compounds or their salts have low toxicity and excellent antifungal activity. Therefore, they are useful in protection and treatment for fungal infections of mammals as antifungal preparations. In addition, they can serve as antifungal preparations for agricultural use.

Claims

1. A compound represented by the formula (I):
Figure imgf000119_0001
wherein Ar is an optionally substituted phenyl group; R1 and R , the same or different, are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; RJ is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Y=Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer from 0 to 2 ; and Az is an optionally substituted azolyl group, or a salt thereof.
2. A compound of claim 1 in which Ar is a phenyl group optionally substituted with one to three substituents se¬ lected from the group consisting of a halogen atom, a ^_^ haloalkyl group, a C__^ haloalkoxy group, a C1-4 alkylsulfo- nyl group and a C__^ haloalkylsulfonyl group; R1 and R2 , the same or different, are a hydrogen atom or a C1-4 alkyl group, or R1 and R2 may combine together to from a C _4 alkylene group; R^ is a hydrogen atom, a C^_γ alkanoyl group, a Cγ_15 arylcarbonyl group, a C2_7 alkoxycarbonyl group, a C _-_ζ aryloxycarbonyl group or a Cg_20 aralkylcar- bonyl group; A is Y=Z (Y and Z, the same or different, are nitrogen atom or a methine group optionally substituted wit a C1-.4 alkyl group) or an ethylene group optionally substi¬ tuted with a C;L_ alkyl group; and Az is an azolyl group optionally substituted with one or two substituents selecte from the group consisting of an oxo group, a hydroxyl group, a carboxyl group, an optionally esterified carboxyl group, nitro group, an amino group, a C^_^Q alkanoyl amino group, mono-C*L_*Lg alkylamino group, a i-C^_^Q alkylamino group, a C -Q alkyl group, a C^_g alkoxy group, a halogen atom, a C*L_g haloalkyl group, a C-^.g haloalkoxy group, a thioxo group, a mercapto group, a C^_g alkylthio group, a C^_g alkylsulfonyl group, a C1-10 alkanoyl group, a phenyl group, a C^ alkylphenyl group, a <A_g alkoxyphenyl group, a halophenyl group, a C^.g haloalkylphenyl group and a C1-6 haloalkoxyphenyl group.
3. A compound of claim 1 in which an azolyl group of Az i a five-membered aromatic heterocyclic group which contains one to four nitrogen atoms as ring-constituent atom(s) and may further contain a sulfur or oxygen atom as a ring-con¬ stituent atom.
4. A compound of claim 1 in which one of R1 and R2ώ is a hydrogen atom and the other is a C-^_4 alkyl group.
5. A compound of claim 4 in which the carbon atom to which Ar is bonded is an (R)-configuration and the carbon atom to which R2 is bonded is an (R)-configuration.
6. A compound of claim 1 in which R3 is a hydrogen atom.
7. A compound of claim 1 in which X is a nitrogen atom.
8. A compound of claim 1 in which Ar is a halophenyl group.
9. A compound of claim 8 in which Ar is a phenyl group substituted with one or two fluorine atoms.
10. A compound of claim 9 in which Ar is a 2-fluorophenyl group or a 2 ,4-difluorophenyl group.
11. A compound of claim 1 in which A is -CH2-CH2-.
12. A compound of claim 1 in which A is -N=CH-, -CH=N- or -CH=CH-.
13. A compound of claim 1 in which n is 0.
14. A compound of claim 1 in which Az is a diazolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl group, which is optionally substituted with one or two substituents selected from the group consisting of an oxo group, a C^g alkyl group, a C*L_g haloalkyl group and a C^_ haloalkyloxy-phenyl group.
15. A compound of claim 1 in which Az is a triazolyl group or a tetrazolyl group.
16. A compound of claim 1 which is represented by the formula (I ' ) :
Figure imgf000122_0001
wherein Ar' is a monofluorophenyl or difluorophenyl group; A' is -N=CH-, -CH=CH- or -CH2-CH2-; and Az' is a diazolyl , triazolyl, tetrazolyl, thiazolyl or oxazolyl group which is optionally substituted with one or two substituents selected from the group consisting of an oxo group, a C^_g alkyl group, a C^_g haloalkyl group and a C^_ haloalkyloxypheny1 group, or a salt thereof.
17. A compound of claim 16 in which A' is -CH2-CH2-; and Az is triazolyl group or a tetrazolyl group.
18. A compound of claim 1 which is 1-[(1R, 2R)-2-(2 ,4-di- fluorophenyl)-2-hydroxy-l-methy1-3-( 1H-1 ,2,4-triazol-l- yl)propyl]-3-[4-(lH-l,2,4-triazol-l-yl)phenyl]-2- imidazolidinone or a salt thereof.
19. A compound of claim 1 which is 1-[(1R, 2R)-2-(2 ,4-di- fluorophenyl )-2-hydroxy-l-methyl-3-(1H-1 , 2 ,4-triazol-l- yl)propyl]-3-[4-(lH-l,2,3-triazol-l-yl)phenyl]-2- imidazolidinone or a salt thereof.
20. A compound of claim 1 which is 1-[(1R, 2R)-2-(2 ,4-di- fluorophenyl )-2-hydroxy-l-methyl-3-(1H-1 , 2 ,4-triazol-l- yl)propyl]-3-[4-(2H-2-tetrazoly1 )phenyl]-2-imidazolidinone or a salt thereof.
21. A process for preparing a compound of the formula (I) as defined in claim 1 or a salt thereof which comprises (1) reacting a compound represented by the formula
(II):
Figure imgf000123_0001
wherein Ar is an optionally substituted phenyl group; R1 and p
Rώ , the same or different, are a hydrogen atom or a lower alkyl group, or R1 1, and Rώ? may combine together to form a lower alkylene group; A is Y=Z (Y and Z, the same or differ¬ ent, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer from 0 to 2; and Az is an optionally substituted azolyl group; or a salt thereof, with a compound represented by the formula (III):
Figure imgf000124_0001
wherein X is a nitrogen atom or a methine group, or a salt thereof, and, optionally followed by an acylation if R3 is not hydrogen;
(2) reacting a compound represented by the formula
Figure imgf000124_0002
wherein Ar is an optionally substituted phenyl group; R and R2 , the same or different, are a hydrogen atom or a lower
1 p alkyl group, or R1 and Rώ may combine together to form a lower alkylene group; and X is a nitrogen atom or a methine group; or a salt thereof, with a compound represented by the formula (V ) :
Figure imgf000124_0003
wherein A" is -N=CH-, -CH=N- or -CH=CH-; n is an integer from 0 to 2; and Az is an optionally substituted azolyl group; or a salt thereof, and, optionally followed by an acylation if R3 is not hydrogen; or
(3) reducing a compound represented by the formula (I")
Figure imgf000125_0001
wherein Ar is an optionally substituted phenyl group; R1 and p
RA the same or different, are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; n is an integer from 0 to 2; and Az is an optionally substituted azolyl group, or a salt thereof, and, optionally followed by an acylation if R° is not hydrogen.
22. A pharmaceutical composition which comprises a pharma¬ cologically effective amount of a compound of the formula (I) as defined in claim 1 or its pharmaceutically acceptable salt and one or more of a carrier and diluent.
23. A method for a prevention or treatment of a fungal infection which comprises administration of a pharmacologi¬ cally effective amount of a compound of the formula (I) as defined in claim 1 or its pharmaceutically acceptable salt.
24. Use of a compound of the formula (I) as defined in claim 1 or pharmaceutically acceptable salt thereof, as an active ingredient for the preparation of an antifungal agent which comprises the compound of the formula (I) or a salt thereof.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043970A1 (en) * 1997-03-31 1998-10-08 Takeda Chemical Industries, Ltd. Azole compounds, their production and their use
EP0884311A2 (en) * 1997-06-06 1998-12-16 Takeda Chemical Industries, Ltd. Triazole Derivatives and their production
WO1999054272A1 (en) * 1998-04-18 1999-10-28 Avecia Limited Process for the preparation of 2-hydroxyalkyl halophenones
WO2000034267A1 (en) * 1998-12-04 2000-06-15 Takeda Chemical Industries, Ltd. Process for producing cyclic amide compound
US6133485A (en) * 1998-04-15 2000-10-17 Synphar Laboratories, Inc. Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols
WO2001079196A2 (en) * 2000-04-17 2001-10-25 Basilea Pharmaceutica Ag 1-(h-1,2,4-triazol-1-yl)butan-2-ol derivatives
WO2003027103A1 (en) * 2001-09-25 2003-04-03 Ranbaxy Laboratories Limited Synthesis of key azole-antifungal intermediates
WO2004011438A1 (en) * 2002-07-25 2004-02-05 Aventis Pharma Deutschland Gmbh Diaryl-substituted cyclic urea derivatives having an mch-modulatory effect
EP1535914A1 (en) * 2002-06-20 2005-06-01 Sumitomo Chemical Company, Limited Processes for producing epoxytriazole derivative and intermediate therefor
US7141561B2 (en) 2002-07-25 2006-11-28 Sanofi-Aventis Deutschland Gmbh Substituted diaryl heterocycles, process for their preparation and their use as medicaments
US10562887B2 (en) 2016-05-27 2020-02-18 Bristol-Myers Squibb Company Triazolones and tetrazolones as inhibitors of ROCK

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407129B1 (en) 1997-03-31 2002-06-18 Takeda Chemical Industries, Ltd. Azole compounds, their production and their use
WO1998043970A1 (en) * 1997-03-31 1998-10-08 Takeda Chemical Industries, Ltd. Azole compounds, their production and their use
EP0884311A2 (en) * 1997-06-06 1998-12-16 Takeda Chemical Industries, Ltd. Triazole Derivatives and their production
EP0884311A3 (en) * 1997-06-06 1999-01-27 Takeda Chemical Industries, Ltd. Triazole Derivatives and their production
US6133485A (en) * 1998-04-15 2000-10-17 Synphar Laboratories, Inc. Asymmetric synthesis of 2-(2,4-difluorophenyl)-1-heterocycl-1-yl butan-2,3-diols
US6362376B1 (en) 1998-04-18 2002-03-26 Avecia Limited Process for the preparation of 2-hydroxyalkyl halophenones
WO1999054272A1 (en) * 1998-04-18 1999-10-28 Avecia Limited Process for the preparation of 2-hydroxyalkyl halophenones
US6300522B1 (en) 1998-04-18 2001-10-09 Avecia Limited Process for the preparation of 2-hydroxyalkyl halophenones
WO2000034267A1 (en) * 1998-12-04 2000-06-15 Takeda Chemical Industries, Ltd. Process for producing cyclic amide compound
WO2001079196A3 (en) * 2000-04-17 2002-02-21 Basilea Pharmaceutica Ag 1-(h-1,2,4-triazol-1-yl)butan-2-ol derivatives
WO2001079196A2 (en) * 2000-04-17 2001-10-25 Basilea Pharmaceutica Ag 1-(h-1,2,4-triazol-1-yl)butan-2-ol derivatives
WO2003027103A1 (en) * 2001-09-25 2003-04-03 Ranbaxy Laboratories Limited Synthesis of key azole-antifungal intermediates
EP1535914A1 (en) * 2002-06-20 2005-06-01 Sumitomo Chemical Company, Limited Processes for producing epoxytriazole derivative and intermediate therefor
EP1535914A4 (en) * 2002-06-20 2006-05-24 Sumitomo Chemical Co Processes for producing epoxytriazole derivative and intermediate therefor
US7297802B2 (en) 2002-06-20 2007-11-20 Sumitomo Chemical Company, Limited Production methods of epoxytriazole derivative and intermediate therefor
WO2004011438A1 (en) * 2002-07-25 2004-02-05 Aventis Pharma Deutschland Gmbh Diaryl-substituted cyclic urea derivatives having an mch-modulatory effect
US7141561B2 (en) 2002-07-25 2006-11-28 Sanofi-Aventis Deutschland Gmbh Substituted diaryl heterocycles, process for their preparation and their use as medicaments
US10562887B2 (en) 2016-05-27 2020-02-18 Bristol-Myers Squibb Company Triazolones and tetrazolones as inhibitors of ROCK

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