CA2211458A1 - Azole compounds, their production and use - Google Patents
Azole compounds, their production and useInfo
- Publication number
- CA2211458A1 CA2211458A1 CA 2211458 CA2211458A CA2211458A1 CA 2211458 A1 CA2211458 A1 CA 2211458A1 CA 2211458 CA2211458 CA 2211458 CA 2211458 A CA2211458 A CA 2211458A CA 2211458 A1 CA2211458 A1 CA 2211458A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- compound
- phenyl
- triazol
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides an azole compound represented by formula (I), wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; 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
W O 96/2S410 P~N~G~
.
DESCRIPTION
Azole Compounds, Their Production and Use TECHNICAL FIELD
The present invention relates to a~ole 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, EPOi22056Al, EP03323B7Al, EP0122693Al and EP0567982A).
None of these azole compounds, however, is sari~factory as a pharmaceutical agent in terms of its antifungai activi-ty, antiiungal spectrum, side effect and in vivo ph~-~acokl-netics.
There has been a demand for a safer compound ~hich exhibits better absorption in vivo and higher antlfungal activity as an antifungal therapeutic agent.
DISCLOSURE OF INVENTION
The present invent,ion provides (1) a compound represented by the formula (I):
CHz--C--C--N\ / ~(CH2)n--Az Ar R2 CA 022114~8 1997-07-24 W O 96/2S410 PCT/JF9. 003~
wherein Ar is an optionally substituted phenyl group;
Rl and R2, the same or different, are a hydrogen atom or a lower alkyl group, or Rl 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 O to 2; and Az is an optionally substituted azolyl group, or a salt thereof, ~ 2) a process ~or preparing a compound of the formula (I) as defined in claim 1 or a salt thereof which comprises (i) reacting a compound represented by the formula (II):
~(CH2)n--Az H2C--C--f--N\ y ~ (:~) Ar R2 wherein the symbols have the same meanings as de~ined above;
or a salt thereof with a compound represented by the formula (III):
gNH ( ~:
N
W O96/25410 PCr~JF~
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):
~X~ / \ / ( ~ ) wherein the symbols have the same meanings as defined above;
or a salt thereof with a compound repres2nted by the formula (V'):
~ ~CH2)n ~
HN~ N ~/ (~
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 (I") x~ f ~ ~CH2)n--A~
~N - CH2 - C - C ~
wherein the symbols have the same meanings as defined above;
or a salt thereof, and, if necessary, followed by an acyla-CA 022114~8 1997-07-24 tion, (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) haloalkyisulfonyl 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 preferabiy from one ~o two.
Examples of Ar include halophenyl, lower (C1_4) haloal-kyiphenyl, lower (C1_4) haloalkoxyphenyl, lower (C1_4) alkylsulfonylphenyl, lower (C1_4) haloalkylsulfonylphenyl and the like.
Examples of the halophenyl groups include 2,4-difluoro-phenyl~ 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chioro-4-fluorophenyl, 2,4,6-trifluoropheny, 4-bromophenyl and the like.
Examples of the lower (C1_4) haloalkylphenyl groups include 4-trifluoromethylphenyl group and the like.
CA 022114~8 1997-07-24 W O 96/25410 PCT/JF96~0C~
Examples of the lower (Cl_4) haloalkoxyphenyl groups include 4-trifluoromethoxyphenyl, 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 (Cl_4) alkylsulfonylphenyl groups include 4-methanesulfonylphenyl and the like.
Examples of the lower (Cl_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 ~roups substituted with one to two halogen atoms such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl 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 Rl or R in the formula (I) include straight or branched Cl_4 ~ 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 Rl and R2 are hydrogen atoms or methyl CA 022114~8 1997-07-24 W O96/2S410 . PCT/JP96/00325 groups, or one of R1 and R2 is a hydrogen atom and the other is a methyl group.
Examples of the lower alkylene groups formed by the combination of R1 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 pre~erable that one of R1 and R2 is a hydrogen atom and the other is a C1_4 alkyl group such as a methyl group and the like.
Examples of the acyl groups represented by R3 in the formula (I) include acyl groups derived from organic carbox-ylic acids such as alkanoyl, preferably Cl_7 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl), more preferably C1_3 alkanoyl;
arylcarbonyl, preferably C7_15 arylcarbonyl (e.g., benzoyl and naphtalenecarbonyl), more preferably C7_11 arylcarbonyl group; alkoxycarbonyl, preferably C2_7 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopro-poxycarbonyl, butoxycarbonyl, isobutoxycarbonnyl, sec-bu-toxycarbonyl and tert-butoxycarbonyl), more preferably C2_4 alkoxycarbonyl; aryloxycarbonyl, preferably C7_15 aryloxy-carbonyl (e.g., phenoxycarbonyl), more preferably C7_11 ary-loxycarbonyl; aralkylcarbonyl group, preferably C8_20 aral-kylcarbonyl (e.g., benzylcarbonyl, phenetylcarbonyl) phenyl-propylcarbonyl and naphthylethylcarbonyl), more preferably CA 022114~8 1997-07-24 W O 9612S4~0 P ~/l~_.''G~-' C8_14 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 C1_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 substitute~
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 CA 022114~8 1997-07-24 W O96/25410 PCTN~
with a lower alkyl group" in the formula (I), examples of the lower alkyl groups include straight or branched Cl_4 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl, ethyl and the like arepreferable, and methyl and the like are more preferable.
Examples of the ethylene groups optionally substituted with a lower alkyl group represented by A include ethylene, l-methylethylene, l,l-dimethylethylene, 1,2-dimethyl-ethylene, l-ethylethylene, 1,2-diethylethylene and the like, among which ethylene and the likeare 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, among which -N=CH-, -CH=N-, -CH=CH-, -CH2-CH2- and the like are preferred.
In the formula (I), the groups represented by \A
are preferably N . N
N . N ~ N~l = = = = ~----CA 022114~8 1997-07-24 W O 9612S410 P~~l ~lr J C~
and the like, more preferably and the like, still more preferably and the like.
The integer from O to 2 represented by n is preferably O 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-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, iso~azolyl, furazanyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 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-l-yl, lH-imidazol-l-yl, lH-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, lH-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl, lH-tetrazol-l-yl, 2H-tetrazol-2-yl and the like, and further more pref-CA 022114~8 1997-07-24 W O96/2S410 ' PCT/J~9~00~
erably lH-pyrazol-l-yl, lH-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, lH-1,2,4-triazol-1-yl, lH-tetrazol-l-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, Cl_6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl), nitro group, amino group, acylamino group (e.g., Cl_10 alkanoylamino such as acetylamino, propionylamino and butyrylamino), mono-Cl_10 or di-Cl_lo alkylamino group (e.g., methylamino, dimethylamino, diethylamino and dibutylamino), Cl_6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl and hexyl), Cl_6 alkoxy group (e.g., methoxy, ethoxy and butoxy), halogen atom (e.g., fluorine, chlorine and bromine), Cl_6 haloalkyl group (e.g., trifluoromethyl, dichloromethyl, 2,2,2-trifluoroethyl and 2,2,3,3-tetrafluo-ropropyl), Cl_6 haloalkoxy group (e.g., trifluoromethoxy, 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, Cl_6 alkylthio group (e.g., methylthio, ethylthio and butylthio), Cl_6 alkylsul-fonyl group (e.g., methanesulfonyl, ethanesulfonyl and butanesulfonyl), Cl_10 alkanoyl group (e.g., acetyl, formyl, W O 96/2S410 . PCT/J1g~
propionyl and butylyl), phenyl group, Cl_6 alkylphenyl group (e.g., p-tolyl, mesityl and p-cumenyl), Cl_6 alkoxyphenyl group (e.g., 4-methoxyphenyl and 4-isopropoxyphenyl), halo-phenyl group (e.g., 4-chlorophenyl and 4-fluorophenyl, 2,4,-difluorophenyl?, Cl_6 haloalkylphenyl group (e.g., 4-trifluoromethylphenyl), Cl_6 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 ~roup and the number of the substituents is preferably one or two.
Specifically, Az are preferably diazolyl, triazolyl and tetrazolyl such as -~3 ~ N3 ' N~ ' and the like, more preferably N~
N
and the like. 11 CA 022114~8 1997-07-24 W O96/2S410 PCT/JPg6/00325 A preferred example of the compound (I) is a compound represented by the formula (I') N CH2 1 IH_ N N~Az (I') N I (R) I (R) Al ' (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 selected from the group consisting of an oxo group, a C1_6 alkyl group (e.g., methyl, ethyl, n-propyl, iso-propyl), a C1_6 haloalkyl group (e.g., trifluoromethyl, 2,2,2-trifluoroeth-yl, 2,2,3,3-tetrafluoropropyl) and a C1_6 haloalkyloxyphenyl group (e.g., 4-trifluoromethoxyphenyl, 4-(2,2,3,3-tetra-fluoropropoxyphenyl, 4-(1,1,2,2-tetrafluoroethoxyphenyl)) or a salt thereof. In the formula (I'), A' is preferably -CH2-CH2-, 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 CA 022114~8 1997-07-24 WO 9612S4~0 PCT~J~C.'OOi~
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 inventionj 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 R1 is hydrogen and R2 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 R2 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 b; the formula (II):
/o\ IR1 R ~ CH2)n--AZ
H2C--f--c--N\ /N ~d ~) Ar R2 (wherein the symbols have the same meanings as defined above) or a salt thereof CA 022114~8 1997-07-24 W O96/2S410 PCT/Jl~GIQ~
with a compound represented by the formula (III):
~X~
~ NH (~) (wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compound of the present invention in which R3 is a hydrogen atom.
The reaction can be 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-pyrrolidinone), 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., lithium carbonate, sodium bicarbonate, cesium carbonate, potassium CA 022114~8 1997-07-24 W O96/2S410 PC~JJP~6~0032S
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):
~ N- CH2- C/-\ / (~) (wherein the symbols have the same meanings as defined above) or a salt thereof with a compound represented by the formula (V'):
(CH2)n--Az \A~/ ~ (V') (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 compound represented by the formula (V"):
NQ /=v(CH2)n--Az H-- N ~ (V ) (wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compound of the present invention which A is Y-Z and R3 is hydrogen.
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.O.~ acetonitrile), aromatic hydrocar-CA 022114~8 1997-07-24 W 09612S4~0 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 CA 022114~8 1997-07-24 W O96/2S410 PCT/J~,G~
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, 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).
According to another embodiment, the compound of the present invention can be prepared by, for e~ample, reacting a compound represented by the formula (VI):
L--CH2 1 1 \ / ~(CH23n--Az Ar ~2 {wherein L is a leaving group [e.g., halogen atom (e.g., chlorine, bromine and iodine) OI' R4So3 (wherein R4 is 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):
CA 022114~8 1997-07-24 WO g6/2S410 PCT~J~, ,'5 ~37 ~X'NH ( ) (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 1-methyl-2-pyrrolidinone), 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 CA 022114~8 1997-07-24 W O 96/25410 PCTIJF9G;~3~
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 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 range 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 oftthe 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, but usually about 0 to about 150 C, preferably about 10 to about 120~C
The reaction time is about tens of minutes to tens of hours (e.g., from thirty minutes to fifty hours).
.
CA 022114~8 1997-07-24 ~V~ 961~541a PCT/3r~
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"):
X~ /~ CH2)n--A~
~N - CH2 - C - C
(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''')):
R30 Rl X~ I I ~ /=\~CH2)n--Az N - CH2 - C - C - ~ N ~ (I~) (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., CA 022114~8 1997-07-24 WO96/2S410 PCT/~6/00325 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 l50kg/cm2 at a temperature from room temperature up to about lO0 C.
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 R3 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 R3 is an acyl group, by treating it with an appropriate acylating agent of R3Ll [wherein R3 is an aliphatic or aromatic carboxylic acid residue (e.g., acetyl, propionyl, butylyl, ethoxycarbonyl, benzoyl, substituted benzoyl) and Ll 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 CA 022ll4~8 l997-07-24 W 096/2S410 PCT~JF9.'~
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 dimethylformamide, 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, recrystallization, 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, CA 022114~8 1997-07-24 W 096/25410 PCT/J~'G~~~
they can be separated into each isomer by the conventional separating method such as a method for producing a salt with an optically-active acid (e.g., camphorsulfonic acid and tartaric acid), various types of chromatographies, fraction-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 Rl is hydrogen, R2 is methyl, the carbon atom to which Ar is bonded is an (S)-configuration and the carbon atom to which R2 is bonded is an (R)-configu-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:
CH3 1 )Ph3P,PhCOOH
A~OH EtO2CN=NCO2Et ~5T 2)NaOMe/MeOH
Ar ~OH iso Pr2NEt ~OSO2CF3 Ar ( IX) CH2CI2 Ar ( x ) NàH CH~)n--Az N N ~CHz)n--AZ
DMF Ar (~nr) W O 961254tO PCT/J~
(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 dimethylforma-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:
O~THP
CH3 CO ~ ~ O ~
(Xl) Ar (Xlll) (CH ) S + ~ ~ ~N-TsOH
DMSO Ar (XIV) EtOH
~0~ /~< CH3 NO2 CH3 1)Cl-C~ ~ ~~~
(XV) 2)recrystallization ~ (XVI) N02 ÇH3 - OH ~ ~OH
Ar (Vlll) W O96/2S410 PcT/Jl~cto~
[wherein THP is tetrahydropyranyl group, Ts is p-toluenesulfonyl group, L2 is a halogen atom (e.g., chlorine, bromine, iodine), DMSO is dimethylsulfoxide, and the other symbols have the same meaings as defined above].
The intermediate compound (IX) can be synthesized, for example, by a method represented by the following reaction scheme:
02N>~
1 ) ~\ /~
CH3 ~, CH3 o /N02 ~OH EtO2CN=NC02Et ~ ~OC~) Ar 2)recrystallization ~
(XV) (XVII) 'N02 NaOMe/MeOH
Ar (IX~
(wherein the symbols have the same meanings as defined above).
The starting compound (IV) in the present invention wherein Rl is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded is in an (R)-configuration and the carbon atom to which R2 is bonded is in an (S)-configuration [i.e., a compound (XVIII)]:
CA 022114~8 1997-07-24 WO96t2S410 P~llJr~S/a~?~
(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 Rl 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 Rl 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)--conf igurat ion [i.e., a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the following reac-tion scheme:
lÇH~~N~ ~CH2)n--Az Q~s~ 0--S02--CF~ L~ \A/
~V) ÇH~ o ~ J~ ~(CH2)n--Az fH~ A
(CH~)2CH--O--Si--CH2 Md ~ \HzC= CH--MgL5 CH~ / \
\~
CH~ H0 ÇH~ ~ CH ) A H0 CH~ 0 (CH~)2CH 0 ~i C ~5)1 (R) \A/ ~ H2C cH(5~l (CR)H N\ / ~CH2)n--Az ()Wll) Ar H0 H~ ~
lÇ ~ /=\ ~(CH2)n--Az H0--CH2--~ H--N N
Ar oc~n R4So2L' R~S02--0--CH;~ (CR)H--N\ /~( base ~ C/H2--\C--CH ~CH2)n--Az OUX) ~1) WO 96/2S41~ PCTJJ~,G,'01~'7s [wherein each of L3, L4, L5 and L6 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:
CH~ HN/ \0 CH3 ¢~ ~ 3 oR5 ~ ~ (XXVIII) ~ ~ (XXIX) CH3 e~N ~ TsOH CH3 Ar MgL r (~OTHP ~ O~OH
Ar (XXX) Ar (X>CXI) (CF3SO2)0 o~ O--SO2--CF3 isoPr2NEt Ar (XX~
~ wherein R~ is a lower alkyl group, L7 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 W O96/2S410 ~ PCTIJ~C/0 Laid-Open No. HEI 5(1993)-230038.
CHs CHs o~ l PhCH2Br 0~ l (ChSO2)0 s)~OH K CO ~ s)~oH iSOr ~ t OH (~OOCII) OCH2Ph (~
N (CH2)n--Az CHs H~ ~ CH3 ~ O I \A/ (V) n 1 ~ /~(CH2)n--Az O--SO2--Ch NaH ' ~R)--N N ~) OCHzPh (XXXIV) OCH2Ph A (XXXV) H2/Pd-C 0~ N~(CH2)n--Az OH A
(XXXVI) (COCI)2 0 ~ ~ N ~ (CH2)n-Az (XXVI) (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, PBr3]
instead of (COCl)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 -CH2-CH2-[i.e., compounds (XXXVII), (XXXVIII) and (XXXIX) or salts thereof respectively] can be prepared, for example, by the W ~ 96125410 . PCT1JPg6/00325 method represented by the following reaction scheme:
H2N~CH2)~ ~l ~CH2)n--Az (XXXX
*~/
~"~ (EtO)2CHCH2NH2 ~R ~S~(CH2)n--Az ~ ~
H2NNHCNH~ > .~l ~ (CH2)n--Az \=/ (XXXXII) (EtO)2CHCH2NHCNH~
~ (XXXXIII) HN=CH-NH2 HCI/H20 (C1~12)n--Az (CH2)n--Az Hl~ ~ Hl~
(XXXVII) (XXXVIII) H2/Pd-C
~CH2)n--Az (XXXIX) (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:
CA 022114~8 1997-07-24 W 09612S410 . PCT/JP96100325 1 ) NaNO2 H2N~ 3) NaOH H2NNH~(CH2)n-AZ 1 ) OHCCOOH H~CH2)n~z 2) (PhO)2PON3 ~
()CXXX) / (XXXXV ()O~XXIV) Q~GG~/
~O HN=CH-NH2 ~ (CH2)n--Az 1) PhCHO CONH2 (CH2)n~Az H~ HzN-N--?~
,~rNH ~ 2) 1 kNNI I ~NO2 ~ ~XXXVII) (wherein the symbols have the same meanings as defined 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, recrystallization, column chromatography, thin layer chroma-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 toxicity and exhibits potent antifungal activity with broad antifun-gal spectrum against, for example, microorganisms cf genus CA 022114~8 1997-07-24 WO 9612S410 PCI~ 2'~
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, aspergillosis, 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 CA 022114~8 1997-07-24 W O96/2S410 PCT/JF~G~
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 which 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, polyvinylpyrrolidone and hydroxypro-pylcellulose), lubricants (e.g., talc, magnesium stearate and polyethylene glycol 6000) and the like, followed, if CA 022114~8 1997-07-24 W O 96/2S410 rCTJJl,.'l~ 5 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 microcrystalline 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), CA 022114~8 1997-07-24 W 096/2S410 . PCT/J~C/QO.~
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 compound of the present invention per gram using Vaseline (petroleum jelly) or lanolin as a base material.
The compound of the present invention can be made into oily or aqueous solid, semisolid or liquid suppositories.
Examples of the oily base materials used therefor are higher 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, acrylic 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.
CA 022114~8 1997-07-24 WO 9612S410 PCr~J~9~ 0~
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 CA 022114~8 1997-07-24 WO96/2S410 PCT1~6/0032S
(e.g., soybean powder, tobacco powder and wheat flour), mineral powder (e.g., kaolin and bentonite), alumina, sulfur powder, activated charcoal and the like. They may be used 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 foliowing Reference Examples and Working Examples.
lH-NMR spectra were measured by a spectrometer of Varian Gemini 200 type (200MHz) using tetramethylsilane as an internal standard. All 8 values are given by ppm. In the mixing solvents, the figures given in ( ) are the mixing ratio of each of the solvents by volume. Unless otherwise specified, the symbol % means by weight. In the silica gel chromatography, the ratio of the solvents is a ratio of the 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; m: multiplet; br: broad;
J: coupling constant.
Reference Exam~le l 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 Publication CA 022114~8 1997-07-24 W O 96/25410 PCTJJ~ 3.
No. Hei 4(1992)-74168) and pyridinium p-toluenesulfonate (6.3 g) were dissolved in ethanol (600 ml), and the result-ant was stlrred 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)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (31.5 g) as a pale yellow oily substance.
lH-NMR (CDC13)~: 1.14-1.23 (3H,m), 1.77, 2.22 (lH), 2.80, 2.92 (lH), 3.27-3.32 (lH), 4.00-4.20 (lH,m), 6.75-6.94 (2H,m), 7.36-7.48 (lH,m) Reference Exam~le 2 (lR)-1-[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.
CA 022114~8 1997-07-24 W O96/2S410 PCT1JPg6/00325 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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]
.
DESCRIPTION
Azole Compounds, Their Production and Use TECHNICAL FIELD
The present invention relates to a~ole 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, EPOi22056Al, EP03323B7Al, EP0122693Al and EP0567982A).
None of these azole compounds, however, is sari~factory as a pharmaceutical agent in terms of its antifungai activi-ty, antiiungal spectrum, side effect and in vivo ph~-~acokl-netics.
There has been a demand for a safer compound ~hich exhibits better absorption in vivo and higher antlfungal activity as an antifungal therapeutic agent.
DISCLOSURE OF INVENTION
The present invent,ion provides (1) a compound represented by the formula (I):
CHz--C--C--N\ / ~(CH2)n--Az Ar R2 CA 022114~8 1997-07-24 W O 96/2S410 PCT/JF9. 003~
wherein Ar is an optionally substituted phenyl group;
Rl and R2, the same or different, are a hydrogen atom or a lower alkyl group, or Rl 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 O to 2; and Az is an optionally substituted azolyl group, or a salt thereof, ~ 2) a process ~or preparing a compound of the formula (I) as defined in claim 1 or a salt thereof which comprises (i) reacting a compound represented by the formula (II):
~(CH2)n--Az H2C--C--f--N\ y ~ (:~) Ar R2 wherein the symbols have the same meanings as de~ined above;
or a salt thereof with a compound represented by the formula (III):
gNH ( ~:
N
W O96/25410 PCr~JF~
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):
~X~ / \ / ( ~ ) wherein the symbols have the same meanings as defined above;
or a salt thereof with a compound repres2nted by the formula (V'):
~ ~CH2)n ~
HN~ N ~/ (~
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 (I") x~ f ~ ~CH2)n--A~
~N - CH2 - C - C ~
wherein the symbols have the same meanings as defined above;
or a salt thereof, and, if necessary, followed by an acyla-CA 022114~8 1997-07-24 tion, (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) haloalkyisulfonyl 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 preferabiy from one ~o two.
Examples of Ar include halophenyl, lower (C1_4) haloal-kyiphenyl, lower (C1_4) haloalkoxyphenyl, lower (C1_4) alkylsulfonylphenyl, lower (C1_4) haloalkylsulfonylphenyl and the like.
Examples of the halophenyl groups include 2,4-difluoro-phenyl~ 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chioro-4-fluorophenyl, 2,4,6-trifluoropheny, 4-bromophenyl and the like.
Examples of the lower (C1_4) haloalkylphenyl groups include 4-trifluoromethylphenyl group and the like.
CA 022114~8 1997-07-24 W O 96/25410 PCT/JF96~0C~
Examples of the lower (Cl_4) haloalkoxyphenyl groups include 4-trifluoromethoxyphenyl, 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 (Cl_4) alkylsulfonylphenyl groups include 4-methanesulfonylphenyl and the like.
Examples of the lower (Cl_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 ~roups substituted with one to two halogen atoms such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl 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 Rl or R in the formula (I) include straight or branched Cl_4 ~ 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 Rl and R2 are hydrogen atoms or methyl CA 022114~8 1997-07-24 W O96/2S410 . PCT/JP96/00325 groups, or one of R1 and R2 is a hydrogen atom and the other is a methyl group.
Examples of the lower alkylene groups formed by the combination of R1 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 pre~erable that one of R1 and R2 is a hydrogen atom and the other is a C1_4 alkyl group such as a methyl group and the like.
Examples of the acyl groups represented by R3 in the formula (I) include acyl groups derived from organic carbox-ylic acids such as alkanoyl, preferably Cl_7 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl), more preferably C1_3 alkanoyl;
arylcarbonyl, preferably C7_15 arylcarbonyl (e.g., benzoyl and naphtalenecarbonyl), more preferably C7_11 arylcarbonyl group; alkoxycarbonyl, preferably C2_7 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopro-poxycarbonyl, butoxycarbonyl, isobutoxycarbonnyl, sec-bu-toxycarbonyl and tert-butoxycarbonyl), more preferably C2_4 alkoxycarbonyl; aryloxycarbonyl, preferably C7_15 aryloxy-carbonyl (e.g., phenoxycarbonyl), more preferably C7_11 ary-loxycarbonyl; aralkylcarbonyl group, preferably C8_20 aral-kylcarbonyl (e.g., benzylcarbonyl, phenetylcarbonyl) phenyl-propylcarbonyl and naphthylethylcarbonyl), more preferably CA 022114~8 1997-07-24 W O 9612S4~0 P ~/l~_.''G~-' C8_14 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 C1_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 substitute~
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 CA 022114~8 1997-07-24 W O96/25410 PCTN~
with a lower alkyl group" in the formula (I), examples of the lower alkyl groups include straight or branched Cl_4 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl), among which methyl, ethyl and the like arepreferable, and methyl and the like are more preferable.
Examples of the ethylene groups optionally substituted with a lower alkyl group represented by A include ethylene, l-methylethylene, l,l-dimethylethylene, 1,2-dimethyl-ethylene, l-ethylethylene, 1,2-diethylethylene and the like, among which ethylene and the likeare 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, among which -N=CH-, -CH=N-, -CH=CH-, -CH2-CH2- and the like are preferred.
In the formula (I), the groups represented by \A
are preferably N . N
N . N ~ N~l = = = = ~----CA 022114~8 1997-07-24 W O 9612S410 P~~l ~lr J C~
and the like, more preferably and the like, still more preferably and the like.
The integer from O to 2 represented by n is preferably O 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-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, iso~azolyl, furazanyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 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-l-yl, lH-imidazol-l-yl, lH-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, lH-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl, lH-tetrazol-l-yl, 2H-tetrazol-2-yl and the like, and further more pref-CA 022114~8 1997-07-24 W O96/2S410 ' PCT/J~9~00~
erably lH-pyrazol-l-yl, lH-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, lH-1,2,4-triazol-1-yl, lH-tetrazol-l-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, Cl_6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl), nitro group, amino group, acylamino group (e.g., Cl_10 alkanoylamino such as acetylamino, propionylamino and butyrylamino), mono-Cl_10 or di-Cl_lo alkylamino group (e.g., methylamino, dimethylamino, diethylamino and dibutylamino), Cl_6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl and hexyl), Cl_6 alkoxy group (e.g., methoxy, ethoxy and butoxy), halogen atom (e.g., fluorine, chlorine and bromine), Cl_6 haloalkyl group (e.g., trifluoromethyl, dichloromethyl, 2,2,2-trifluoroethyl and 2,2,3,3-tetrafluo-ropropyl), Cl_6 haloalkoxy group (e.g., trifluoromethoxy, 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, Cl_6 alkylthio group (e.g., methylthio, ethylthio and butylthio), Cl_6 alkylsul-fonyl group (e.g., methanesulfonyl, ethanesulfonyl and butanesulfonyl), Cl_10 alkanoyl group (e.g., acetyl, formyl, W O 96/2S410 . PCT/J1g~
propionyl and butylyl), phenyl group, Cl_6 alkylphenyl group (e.g., p-tolyl, mesityl and p-cumenyl), Cl_6 alkoxyphenyl group (e.g., 4-methoxyphenyl and 4-isopropoxyphenyl), halo-phenyl group (e.g., 4-chlorophenyl and 4-fluorophenyl, 2,4,-difluorophenyl?, Cl_6 haloalkylphenyl group (e.g., 4-trifluoromethylphenyl), Cl_6 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 ~roup and the number of the substituents is preferably one or two.
Specifically, Az are preferably diazolyl, triazolyl and tetrazolyl such as -~3 ~ N3 ' N~ ' and the like, more preferably N~
N
and the like. 11 CA 022114~8 1997-07-24 W O96/2S410 PCT/JPg6/00325 A preferred example of the compound (I) is a compound represented by the formula (I') N CH2 1 IH_ N N~Az (I') N I (R) I (R) Al ' (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 selected from the group consisting of an oxo group, a C1_6 alkyl group (e.g., methyl, ethyl, n-propyl, iso-propyl), a C1_6 haloalkyl group (e.g., trifluoromethyl, 2,2,2-trifluoroeth-yl, 2,2,3,3-tetrafluoropropyl) and a C1_6 haloalkyloxyphenyl group (e.g., 4-trifluoromethoxyphenyl, 4-(2,2,3,3-tetra-fluoropropoxyphenyl, 4-(1,1,2,2-tetrafluoroethoxyphenyl)) or a salt thereof. In the formula (I'), A' is preferably -CH2-CH2-, 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 CA 022114~8 1997-07-24 WO 9612S4~0 PCT~J~C.'OOi~
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 inventionj 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 R1 is hydrogen and R2 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 R2 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 b; the formula (II):
/o\ IR1 R ~ CH2)n--AZ
H2C--f--c--N\ /N ~d ~) Ar R2 (wherein the symbols have the same meanings as defined above) or a salt thereof CA 022114~8 1997-07-24 W O96/2S410 PCT/Jl~GIQ~
with a compound represented by the formula (III):
~X~
~ NH (~) (wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compound of the present invention in which R3 is a hydrogen atom.
The reaction can be 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-pyrrolidinone), 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., lithium carbonate, sodium bicarbonate, cesium carbonate, potassium CA 022114~8 1997-07-24 W O96/2S410 PC~JJP~6~0032S
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):
~ N- CH2- C/-\ / (~) (wherein the symbols have the same meanings as defined above) or a salt thereof with a compound represented by the formula (V'):
(CH2)n--Az \A~/ ~ (V') (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 compound represented by the formula (V"):
NQ /=v(CH2)n--Az H-- N ~ (V ) (wherein the symbols have the same meanings as defined above) or a salt thereof. This reaction provides a compound of the present invention which A is Y-Z and R3 is hydrogen.
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.O.~ acetonitrile), aromatic hydrocar-CA 022114~8 1997-07-24 W 09612S4~0 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 CA 022114~8 1997-07-24 W O96/2S410 PCT/J~,G~
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, 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).
According to another embodiment, the compound of the present invention can be prepared by, for e~ample, reacting a compound represented by the formula (VI):
L--CH2 1 1 \ / ~(CH23n--Az Ar ~2 {wherein L is a leaving group [e.g., halogen atom (e.g., chlorine, bromine and iodine) OI' R4So3 (wherein R4 is 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):
CA 022114~8 1997-07-24 WO g6/2S410 PCT~J~, ,'5 ~37 ~X'NH ( ) (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 1-methyl-2-pyrrolidinone), 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 CA 022114~8 1997-07-24 W O 96/25410 PCTIJF9G;~3~
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 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 range 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 oftthe 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, but usually about 0 to about 150 C, preferably about 10 to about 120~C
The reaction time is about tens of minutes to tens of hours (e.g., from thirty minutes to fifty hours).
.
CA 022114~8 1997-07-24 ~V~ 961~541a PCT/3r~
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"):
X~ /~ CH2)n--A~
~N - CH2 - C - C
(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''')):
R30 Rl X~ I I ~ /=\~CH2)n--Az N - CH2 - C - C - ~ N ~ (I~) (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., CA 022114~8 1997-07-24 WO96/2S410 PCT/~6/00325 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 l50kg/cm2 at a temperature from room temperature up to about lO0 C.
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 R3 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 R3 is an acyl group, by treating it with an appropriate acylating agent of R3Ll [wherein R3 is an aliphatic or aromatic carboxylic acid residue (e.g., acetyl, propionyl, butylyl, ethoxycarbonyl, benzoyl, substituted benzoyl) and Ll 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 CA 022ll4~8 l997-07-24 W 096/2S410 PCT~JF9.'~
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 dimethylformamide, 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, recrystallization, 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, CA 022114~8 1997-07-24 W 096/25410 PCT/J~'G~~~
they can be separated into each isomer by the conventional separating method such as a method for producing a salt with an optically-active acid (e.g., camphorsulfonic acid and tartaric acid), various types of chromatographies, fraction-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 Rl is hydrogen, R2 is methyl, the carbon atom to which Ar is bonded is an (S)-configuration and the carbon atom to which R2 is bonded is an (R)-configu-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:
CH3 1 )Ph3P,PhCOOH
A~OH EtO2CN=NCO2Et ~5T 2)NaOMe/MeOH
Ar ~OH iso Pr2NEt ~OSO2CF3 Ar ( IX) CH2CI2 Ar ( x ) NàH CH~)n--Az N N ~CHz)n--AZ
DMF Ar (~nr) W O 961254tO PCT/J~
(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 dimethylforma-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:
O~THP
CH3 CO ~ ~ O ~
(Xl) Ar (Xlll) (CH ) S + ~ ~ ~N-TsOH
DMSO Ar (XIV) EtOH
~0~ /~< CH3 NO2 CH3 1)Cl-C~ ~ ~~~
(XV) 2)recrystallization ~ (XVI) N02 ÇH3 - OH ~ ~OH
Ar (Vlll) W O96/2S410 PcT/Jl~cto~
[wherein THP is tetrahydropyranyl group, Ts is p-toluenesulfonyl group, L2 is a halogen atom (e.g., chlorine, bromine, iodine), DMSO is dimethylsulfoxide, and the other symbols have the same meaings as defined above].
The intermediate compound (IX) can be synthesized, for example, by a method represented by the following reaction scheme:
02N>~
1 ) ~\ /~
CH3 ~, CH3 o /N02 ~OH EtO2CN=NC02Et ~ ~OC~) Ar 2)recrystallization ~
(XV) (XVII) 'N02 NaOMe/MeOH
Ar (IX~
(wherein the symbols have the same meanings as defined above).
The starting compound (IV) in the present invention wherein Rl is a hydrogen atom, R2 is a methyl group, the carbon atom to which Ar is bonded is in an (R)-configuration and the carbon atom to which R2 is bonded is in an (S)-configuration [i.e., a compound (XVIII)]:
CA 022114~8 1997-07-24 WO96t2S410 P~llJr~S/a~?~
(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 Rl 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 Rl 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)--conf igurat ion [i.e., a compound (VII) or a salt thereof] can be prepared, for example, by a method represented by the following reac-tion scheme:
lÇH~~N~ ~CH2)n--Az Q~s~ 0--S02--CF~ L~ \A/
~V) ÇH~ o ~ J~ ~(CH2)n--Az fH~ A
(CH~)2CH--O--Si--CH2 Md ~ \HzC= CH--MgL5 CH~ / \
\~
CH~ H0 ÇH~ ~ CH ) A H0 CH~ 0 (CH~)2CH 0 ~i C ~5)1 (R) \A/ ~ H2C cH(5~l (CR)H N\ / ~CH2)n--Az ()Wll) Ar H0 H~ ~
lÇ ~ /=\ ~(CH2)n--Az H0--CH2--~ H--N N
Ar oc~n R4So2L' R~S02--0--CH;~ (CR)H--N\ /~( base ~ C/H2--\C--CH ~CH2)n--Az OUX) ~1) WO 96/2S41~ PCTJJ~,G,'01~'7s [wherein each of L3, L4, L5 and L6 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:
CH~ HN/ \0 CH3 ¢~ ~ 3 oR5 ~ ~ (XXVIII) ~ ~ (XXIX) CH3 e~N ~ TsOH CH3 Ar MgL r (~OTHP ~ O~OH
Ar (XXX) Ar (X>CXI) (CF3SO2)0 o~ O--SO2--CF3 isoPr2NEt Ar (XX~
~ wherein R~ is a lower alkyl group, L7 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 W O96/2S410 ~ PCTIJ~C/0 Laid-Open No. HEI 5(1993)-230038.
CHs CHs o~ l PhCH2Br 0~ l (ChSO2)0 s)~OH K CO ~ s)~oH iSOr ~ t OH (~OOCII) OCH2Ph (~
N (CH2)n--Az CHs H~ ~ CH3 ~ O I \A/ (V) n 1 ~ /~(CH2)n--Az O--SO2--Ch NaH ' ~R)--N N ~) OCHzPh (XXXIV) OCH2Ph A (XXXV) H2/Pd-C 0~ N~(CH2)n--Az OH A
(XXXVI) (COCI)2 0 ~ ~ N ~ (CH2)n-Az (XXVI) (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, PBr3]
instead of (COCl)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 -CH2-CH2-[i.e., compounds (XXXVII), (XXXVIII) and (XXXIX) or salts thereof respectively] can be prepared, for example, by the W ~ 96125410 . PCT1JPg6/00325 method represented by the following reaction scheme:
H2N~CH2)~ ~l ~CH2)n--Az (XXXX
*~/
~"~ (EtO)2CHCH2NH2 ~R ~S~(CH2)n--Az ~ ~
H2NNHCNH~ > .~l ~ (CH2)n--Az \=/ (XXXXII) (EtO)2CHCH2NHCNH~
~ (XXXXIII) HN=CH-NH2 HCI/H20 (C1~12)n--Az (CH2)n--Az Hl~ ~ Hl~
(XXXVII) (XXXVIII) H2/Pd-C
~CH2)n--Az (XXXIX) (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:
CA 022114~8 1997-07-24 W 09612S410 . PCT/JP96100325 1 ) NaNO2 H2N~ 3) NaOH H2NNH~(CH2)n-AZ 1 ) OHCCOOH H~CH2)n~z 2) (PhO)2PON3 ~
()CXXX) / (XXXXV ()O~XXIV) Q~GG~/
~O HN=CH-NH2 ~ (CH2)n--Az 1) PhCHO CONH2 (CH2)n~Az H~ HzN-N--?~
,~rNH ~ 2) 1 kNNI I ~NO2 ~ ~XXXVII) (wherein the symbols have the same meanings as defined 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, recrystallization, column chromatography, thin layer chroma-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 toxicity and exhibits potent antifungal activity with broad antifun-gal spectrum against, for example, microorganisms cf genus CA 022114~8 1997-07-24 WO 9612S410 PCI~ 2'~
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, aspergillosis, 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 CA 022114~8 1997-07-24 W O96/2S410 PCT/JF~G~
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 which 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, polyvinylpyrrolidone and hydroxypro-pylcellulose), lubricants (e.g., talc, magnesium stearate and polyethylene glycol 6000) and the like, followed, if CA 022114~8 1997-07-24 W O 96/2S410 rCTJJl,.'l~ 5 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 microcrystalline 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), CA 022114~8 1997-07-24 W 096/2S410 . PCT/J~C/QO.~
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 compound of the present invention per gram using Vaseline (petroleum jelly) or lanolin as a base material.
The compound of the present invention can be made into oily or aqueous solid, semisolid or liquid suppositories.
Examples of the oily base materials used therefor are higher 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, acrylic 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.
CA 022114~8 1997-07-24 WO 9612S410 PCr~J~9~ 0~
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 CA 022114~8 1997-07-24 WO96/2S410 PCT1~6/0032S
(e.g., soybean powder, tobacco powder and wheat flour), mineral powder (e.g., kaolin and bentonite), alumina, sulfur powder, activated charcoal and the like. They may be used 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 foliowing Reference Examples and Working Examples.
lH-NMR spectra were measured by a spectrometer of Varian Gemini 200 type (200MHz) using tetramethylsilane as an internal standard. All 8 values are given by ppm. In the mixing solvents, the figures given in ( ) are the mixing ratio of each of the solvents by volume. Unless otherwise specified, the symbol % means by weight. In the silica gel chromatography, the ratio of the solvents is a ratio of the 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; m: multiplet; br: broad;
J: coupling constant.
Reference Exam~le l 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 Publication CA 022114~8 1997-07-24 W O 96/25410 PCTJJ~ 3.
No. Hei 4(1992)-74168) and pyridinium p-toluenesulfonate (6.3 g) were dissolved in ethanol (600 ml), and the result-ant was stlrred 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)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (31.5 g) as a pale yellow oily substance.
lH-NMR (CDC13)~: 1.14-1.23 (3H,m), 1.77, 2.22 (lH), 2.80, 2.92 (lH), 3.27-3.32 (lH), 4.00-4.20 (lH,m), 6.75-6.94 (2H,m), 7.36-7.48 (lH,m) Reference Exam~le 2 (lR)-1-[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.
CA 022114~8 1997-07-24 W O96/2S410 PCT1JPg6/00325 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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]
3,5-dinitrobenzoate (28.7 g) as colorless needles.
mp: 104-107~C (recrystallized from ethylacetate-hexane) H-NMR (CDCl3)~: 1.46 (3H,dd,J=6.6Hz,J=1.2Hz), 3.01 (lH,d,J=4.6Hz), 3.23 (lH,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 Exam~le 3 [(lR)-1-[(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-CA 022ll4~8 l997-07-24 W O96/2S410 PCT~3F~C~OC~
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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (25 g) as a pale yellow oily substance.
H-NMR (CDC13)o: 1.17 (3H,dd,J=6.6Hz,1.2Hz), 1.83 (lH,d,J=8Hz), 2.80 (lH,d,J=5.2Hz), 3.30 (lH,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)-1-[(ZR)-2-(2,4-di-fluorophenyl)-Z-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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl] benzoate (19.2 g) as a colorless oily substance.
1H-NMR (CDC13)~: 1.37 (3H,d,J=6.6Hz), 2.90 (lH,d,J=~.2Hz), 3.Z8 (lH,d,J=5.2Hz), 5.36 (lH,q,J=6.6Hz), 6.74-6.94 (2H,m), CA 022114~8 1997-07-24 W O 96/2S410 PCT/~G~
7.38-7.60 (4H,m), 7.94-8.01 (2H,m) IR ~maxneatcm~1: 1725, 1615, 1600, 1505, 1450, 1425 [(lS)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]-ethyl]
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) was added thereto, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatog-raphy (eluent: hexane/ethyl acetate = 6/1 to 2/1) to give (lS)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (9.7 g) as a colorless oily substance.
H-NMR (CDCl3)~: 1.20 (3H,dd,J-6.4Hz,lHz), 2.24 (lH,d,J=2Hz), 2.92 (lH,d,J=5Hz), 3.28 (lH,d,J=5Hz), 4.12 (lH,dq,J=6.4Hz,2Hz), 6.77-6.95 (2H,m), 7.32-7.44 (lH,m) IR ~maxneat cm 1 3420, 2980, 1615, 1600, 1500, 1425 Reference ExamPle 5 2-(Z-Fluorophenyl)-2-[(lR)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane (synthesized by the method dis-closed in EP0548553A) was converted into [(lR)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate by the method described in Reference Examples 1 and 2.
Colorless prisms (recrystallized from ethyl acetate) mp: 183-184~C
H-NMR (CDCl3)~: 1.47 (3H,dd,J=6.6Hz,1.6Hz), 3.03 W O 9612S410 PCTJJP96~DD~25 (lH,d,J=4.7Hz), 3,23 (lH,d,J=4.7Hz), 5.35 ~lH,q,J=6.6Hz), 7.09-7.59 (4H,m), 9.13 (2H,d,J=2.2Hz), 9.23 (lH,t,J=2.2Hz) [a]23D -24.7~C (c=l.O, in CHCl3) Elemental analysis for C17H13FN207 Calcd (%): C,54.26; H,3.48; N,7.44 Found (%): C,54.23; H,3.25; N,7.41 Reference ExamPle 6 [(lR)-1-[(2R)-2-(2-Fluorophenyl)-2-oxiranyl]ethyl]
3,5-dinitrobenzoate was converted into (lR)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol by the method described in Reference Example 3.
Colorless oily substance H-NMR (CDC13)~: 1.17 (3H,dd,J=6.6Hz,l.OHz), 1.78 (lH,d,J=8.2Hz), 2.81 (lH,d,J=5.3Hz), 3.32 (lH,d,J=5.3Hz), 4.09-4.23 (lH,m), 6.99-?.47 (4H,m) Reference Exam~le 7 (lR)-1-[(2R)-2-(2-Fluorophenyl)-2-oxiranyl]ethanol was converted into (lS)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]-ethanol by the method described in Reference Example 4.
Colorless oily substance H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 2.27 (lH,d,J=2Hz), 2.96 (lH,d,J=5Hz), 3.30 (lH,d,J=5Hz), 4.16 (lH,dq,J=7Hz,2Hz), ~ 7.03-7.44 (4H,m) Reference Exam~le 8 2-(2-Fluorophenyl)-2-[(lR)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl] oxirane (synthesized by the method de-CA 022114~8 1997-07-24 W O96/2S410 ' . PCT/JP96/00325 scribed in EP0548553A) was converted into (lR)-1-[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 an 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 [(lS)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate (23.15 g) as colorless needles.
H-NMR (CDC13)~: 1.47 (3H,d,J=7Hz), 2.97 (lH,d,J=5Hz), 3.29 (lH,d,J=5Hz), 5.43 (lH,q,J=7Hz), 7.02-7.56 (4H,m), 9.06 (2H,d,J=2Hz), 9.21 (lH,t,J=2Hz) This compound (22.91 g) was dissolved in methanol (700 ml), 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-CA 022114~8 1997-07-24 WO 96r2S410 PCr/J~C~OO~?~
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 (lS)-1-[(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 Exam~le 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-nitrophe-nyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,lH)-1,2,4-triazolone (5.5 g, 67%) as yellow crystalline powders.
W O96/2S410 PCTIJl~C
mp: 161-162~C
Reference Exam~les 10 to 14 The compounds shown in Table 1 as below were obtained in the same manner as in Reference Example 9.
Table 1 02N ~ Az Ex~mp;e No. ~2 yield (~) mp. (9~) --~ I ~ OCH2CF2CF2H 75 1 17-118 11 --~ ~ OCF2CF2H 70 143-145 12 --1~--CH2Ch 45 143-145 N
13 --~ q 83 198-199 14 --~1--CH2CF2CF2H 41 141-143 N
Reference ExamPle 15 4-Fluoronitrobenzene (21 g) was reacted with lH-1,2,3-triazole (12.4 g) in the same manner as in Reference Example 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and CA 022114~8 1997-07-24 W O 96/2S410 . P~Nl ,.','~
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-1,2,3-triazole (18.8 g) as pale yellow prisms.
mp: 183-184~C
lH-NMR (CDC13)~: 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 1-(4-nitro-phenyl)-lH-1,2,3-triazole (6.02 g) as pale yellow prisms.
mp: 205-206~C
H-NMR (CDCl3)8: 7.92 (lH,d,J=1.4Hz), 8.00 (2H,dt,J=9Hz,J=2.4Hz), 8.13 (lH,d,J=1.4Hz), 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)-1,2;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 W O9612S410 PCT/J~3cN~
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 Exam~les 17 to 21 The compounds shown in Table 2 as below were obtained in the same manner as in Reference Example 16.
Table 2 H2N ~ Az Roference E~mple No. Az yield (96) .
17 ~ --CH2CF~ 97 18 --~ 94 19 _~ 96 -~ 100 21 --~1--CH2CF2CF2H 95 N
Reference Exam~le 22 Ferric chloride (0.2 g) and activated carbon (2.0 g) CA 022114~8 1997-07-24 W O 96/2S410 PC~Jr~r'D~ S
were added to a solution of 1-(4-nitrophenyl)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,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(lH,3H)-imidazolone (18.1 g, 95%) as a pale yellow powder.
mp: 178-179~C
Elemental analysis for C18H15F4N3O2 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 1-(4-nitrophenyl)-3-[4-(1,1,2,2-tetrafluoroethoxy) phenyl]-2(lH,3H)-imidazolone, 1-(4-aminophenyl)-3-[4-CA 022114~8 1997-07-24 (1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone was obtained.
mp: 150-151~C
Elemental analysis for C17H13F4N302 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)-1,2,4-triazolone (4.6 g) and pyridine (1.43 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-1-yl]phenylcarbamate (5.6 g, 93%) as colorless scaly crystals.
mp: 204-206~C
Elemental analysis for C24H18F4N404 WO 961254~0 PCT~ 0 Calcd (%): C,57.37; H,3.61; N,11.15 Found (%): C,57.50; H,3.67; N,11.13 Reference Exam~les 25 to 31 The compounds shown in Table 3 as below were obtained in the same manner as in Reference Example 24.
Table 3 ~ OCNH ~Az Reference A2 yield(%) mp. (~) --~I~OCH2CF2CF2H 89 243-244 26 _~OCF2CF2H 95 208-211 27 --~--CH2CFs 87 183--184 N~
28 --~ 90 157-160 29 --~J 96 195-200 r~
--~N~ 89 143-144 31 --1~--CH2CF2CF2H 84 173-175 CA 022114~8 1997-07-24 W O96/2S410 PCT/JF9GI'~G325 Reference Exam~le 32 Phenyl 4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-lH,4H-1,2,4-triazol-1-yl~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 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 t~ 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 C18H16F4N6O3 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.
W 096/2S410 PCT~Jr3~DO~
Table 4 H2NNHCNH~Az Roforo~co A2 yield(~) mp. (~) 33 --I~I~OCH2CF2CF2H 95 >280 34 ~ OCF2CF2H 92 >250 --~1--CH2CF!~ 90 275-280 36 _N,Nq 95 228-232 37 --1~ 98 225-234 38 --~ 96 275-277 39 --~1--CH2CF2CF2H 95 265-274 Reference Exam~le 40 4-[4-t5-Oxo-4-t4-(2~2~3~3-tetrafluoropropoxy)phenyl]-lH,4H-l,Z,4-triazol-1-yl]phenyl]semicarbazide (4.75 g) was added to N,N-dimethylformamide (60 ml). To the mixture were -CA 022114~8 1997-07-24 W O96/25410 PCTIJ~C~
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 80~C 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)-phenyl]-lH,4H-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.4 g, 49%) as a white crystalline powder.
mp: 297-298~C
Elemental analysis for C1gH14F4N603 Calcd (%): C,50.67; H,3~.13; N,18.66 Found (%): C,50.49; H,3.20; N,18.50 Reference Exam~les 41 to 47 The compounds shown in Table 5 as below were obtained in the same manner as in Reference Example 40.
W O 96/2S410 PCT/J~ 3 Table 5 H ~ ~ Az a-~ r;nc A~ y~eld (%) mp.
41 - ~ ~ OCHzCFzCFzH 52 >260 42 - ~ ~ OCF2CF2H 49 >260 43 - ~ - CH~CF 71 >300 44 - ~ 40 >300 - ~ 58 >300 46 - ~ ~ 54 .281-283 47 - ~ - CHzCF2CF2H 52 Z46-248 ~eference Exzm~le 48 A mixture of phenyl 4-(lH-1,2,4-triazol-1-yl)phenylcar-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 WO 96/2S410 PCrlJ~ OD~
cooled and the precipitated crystals were washed with a mixture of diisopropyl ether and petroleum ether (1:1, 100 ml x 2) to give 1-(2,2-diethoxyethyl)-3-[4-(lH-1,2,4-tria-zol-l-yl)phenyl]urea (14.5 g) as a colorless crystalline powder.
mp: 139-140~C
lH-NMR (CDC13)~: 1.25 (6H,t,J=7.2Hz), 3.43 (2H,t,J=5Hz), 3.52-3.85 (4H,m), 4.57 (lH,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 Exam~les 49 to 50 The compounds shown in Table 6 as below were obtained in the same manner as in Reference Example 48.
Table 6 (CHsCH20)2CHCH2NHCNH~ Az R~eronce A2 yield (%) mP- (~) 49 - ~ 95 194-196 - ~ 84 175-176 W O 96/2S410 . P ~r~
Reference Exam~le 51 1-(2,2-Diethoxyethyl)-3-[4-(lH-1,2,4-triazol-1-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 1-[4-(lH 1,2,4-triazol-1-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 Exam~les 52 to 53 The compound shown in Table 7 as below were obtained in the same manner as in Reference Example 51.
Table 7 Ref erence E~ple Noi Azyield (g63 mP- (~C) 52 - ~ 86255-257 (~f ~C _ -sition) 53 - ~ 85 ~00 CA 022114~8 1997-07-24 W 096/2S410 PCT/Jl~G~
Reference Exam~le 54 To a solution of (lS)-1-[(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 tnen 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]-lH,4H-1,2,4-triazol-1-yl]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 W O96125410 . PCT1JPg6~0032~
acetate = 1/1 to 1/2) and crystallized from ethyl acetate-hexane to give 2-[(lR,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-l-methylpropyl]-4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoro-propoxy)phenyl]-lH-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (0.29 g) as colorless crystalline powders.
mp: 181-183~C
Elemental analysis for C29H22F6N604 Calcd (%): C,55.07; H,3.51; N,13.29 Found (%): C,55.12; H,3.34; N,13.24 Reference Exam~les 55 to 63 The compounds shown in Table 8 as below were obtained in the same manner as in Reference Example 40.
WO 96/2S410 PCr/J1 ,"~
Table 8 H~(CH2)n--Az ofor;nc n Az mp- (~C) 1 - ~ 249-250 56 0 - ~ 269-270 57 1 - ~ 201-205 58 0 - ~ 2~4-286 59 0 - ~ 245-248 1 - ~ 250-252 61 0 ~H3 282-284 62 0 ~H3 280-283 63 0 - ~ 243-248 W~ 961"54~0 PCr~JFg~ 0 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 Hl~ ~CH2)n--AZ
E~mp;- No. n Az mp. (~C) 64 0 - ~ 239-240 1 - ~ 170-171 66 1 - ~ 190-191 67 o - ~ 210-211 68 o - ~ 235-240 69 1 - ~ 213-215 o ~ 206-208 71 0 ~ 216-218 72 o - ~ 251-255 CA 022114~8 1997-07-24 WO96/25410 PCT/~610 Reference Exam~le 73 1-[4-(lH-1-Tetrazolyl)phenyl]-2(1H,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 1-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolidi-none (4.1 g) as colorless crystals.
mp: 237-240 C (dec.) lH-NMR (d6-DMS0)~: 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 C1OHlON6O
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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (1.20 g) in dichloromethane (26 ml) at -78 C 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).
CA 022114~8 1997-07-24 W O96/25410 - PCTJ~9GJ~ s The desired fraction was concentrated to about 20 ml, and the residue was added to a solution prepared from 1-[4-(lH-1-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 -30~C. The resulting mixture was stirred for 20 minutes at -30~C 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 t100 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 1-[(lR,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (0.13 g) and (2R)-2-(2,4-difluorophenyl)-2-[(lR)-1-[1-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolyl]oxy]ethyl]oxirane (0.05 g).
1-[(lR,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-meth-ylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazo-lone: colorless crystalline powder.
mp: 205-207~C
H-NMR (CDC13)8: 1.39(3H,d,J=7Hz), 2.73 (lH,d,J=5Hz), 2.83 (lH,d,J=5Hz), 5.09 (lH,q,J=7Hz), 6.52 (lH,d,J=3Hz), 6.66 CA 022114~8 1997-07-24 W O96/2S410 PCT/J~9-'00 (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)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol (1.21 g) in dichloromethane (25 mli 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 -30~C 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 1-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (1.14 g), l-methyl-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 CA 022114~8 1997-07-24 WO 9612S410 PCI'JJ~
l-[(lR,2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (0.39 g) and (2R)-2-(2-fluorophenyl)-2-[(lR)-1-[1-[4-(lH-l-tetrazo-~ lyl)phenyl]-2-imidazolyloxy]ethyl]oxirane (0.18 g).
l-[(lR,2S)-2-(2-Fluorophenyl)-2,3-epoxy-1-methylpro-pyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone:
colorless crystalline powder.
H-NMR (CDC13)ô: 1.39(3H,d,J=7Hz), 2.76 (lH,d,J=5Hz), 2.84 (lH,d,J=5Hz), 5.15 (lH,q,J=7Hz), 6.55 (lH,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 Exam~le 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 CA 022114~8 1997-07-24 W O9612S410 PCT/JPg6/00325 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-(3,4,5,6-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-CA 022114~8 1997-07-24 W O 961254~0 PCTJJF9CJOD~
yloxy)propiophenone t25 g) was dissolved in ethanol (200 ml), to which pyridinium p-toluenesulfonate (1.28 g) was added. The reaction solution was stirred at 55 C 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 H-NMR (CDCl3)8: 1.41(3H,dd,J=7Hz,J=1.4Hz), 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 Exam~le 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.
CA 022114~8 1997-07-24 W O96/2S410 PCT/JPg6/00325 H-NMR (CDC13)~: 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) [a]D23 + 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 -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. 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.
H-NMR (CDC13)~: 1.73(3H,dd,J=7Hz,J=1.6Hz), 6.49 (lH,q,J=7Hz), 7.15-7.38 (2H,m), 7.58-7.72 (lH,m), 7.97 (lH,dt,J=1.8Hz,J=7.6Hz) Reference Exam~le 79 1-[4-(lH-1,2,4-Triazol-l-yl)phenyl]-2(1H,3H)-imidazolone (3.39 g) was dissolved in 1-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 CA 022114~8 1997-07-24 W O9612S410 PCTJJ~ Q~3~s 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. After the addition was complete, the reaction tem-perature was raised to 10~C 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 1-[(lR)-2-fluorophenyl)-2-oxo-l-methylethyl]-3-[4-(lH-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone as a colorless crystalline powder.
lH-NMR (CDC13)~: 1.65(3H,d,J=7.2Hz), 5.82 (lH,q,J=7.2Hz), 6.64 (lH,d,J=3.2Hz), 6.70 (lH,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 Exam~le 80 1-[4-(lH-l-Tetrazolyl)phenyl]-2(1H,3H)-imidazolone (0.94 g) was dissolved in 1-methyl-2-pyrrolidone (25 ml), to which 72% sodium hydride in oil (0.126 g) was added. The CA 022ll4~8 l997-07-24 W O 96/2S410 PCTIJF9C~
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 0~C 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 sulfate 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-1-methylethyl]-3-[4-(lH-l-tetra-zolyl)phenyl]-2(lH,3H)-imidazolone (0.22 g) as a colorless crystalline powder.
mp: 162-164~C
lH-NMR (CDCl3)~: 1.66 (3H,d,J=7.2Hz), 5.83 (lH,q,J=7.2Hz), 6.67 (lH,d,J=3.2Hz), 6.74 (lH,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), 9.03 (lH,s) Reference ExamPle 81 Chloromethylisopropoxydimethylsilane (2.14 g) and W O 96t~5410 P~T/J~9CJOO.
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-1-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 ~odium 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-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (637 mg) as a color-less crytalline powder.
H-NMR (d6-DMSO)~: -0.30(3H,s), -0.28 (3H,s), 0.99-1.64 (llH,m), 3.83 (lH,quintet,J=6Hz), 4.81 (lH,q,J=7Hz), 5.21 (lH,br), 6.93-7.77 (6H,m), 8.05 (2H,d,J=9Hz), 8.17 CA 022114~8 1997-07-24 W O96/25410 PCT/JF9C/0~2 (2H,d,J=9Hz), 10.17 (lH,s) Reference ExamPle 82 l-[(lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxy dimethylsilyl)-l-methylpropyl]-3-[4-(lH-l-tetrazolyl)phe-nyl]-2(lH,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-1-methyl propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) as a colorless crystalline powder.
lH-NMR (CDC13)~: 1.17(3H,d,J=7Hz), 3.52-3.62 (lH,m), 4.05-4.18 (2H,m), 5.01 (lH,q,J=7Hz), 6.72 (lH,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-[(lR,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone CA 022114~8 1997-07-24 W 0961~54~0 PCT/~P~6/~032S
(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-[(lR, 2S) - 2 - (2 - f luorophenyl)-2-hydroxy-3-methanesulfonyloxy-l-methylpropyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (330 mg) as a colorless crystalline powder.
H-NMR (CDC13)~: 1.27(3H,d,J=7Hz), 2.87 (3H,s), 4.54 (lH,d,J=12Hz), 4.73-4.88 (2H,m), 6.63 (lH,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-l-tetrazolyl)phenyl]-2(1H,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 CA 022114~8 1997-07-24 W O 96/2S410 PCT/JF9G/00~
sodium chloride (10 ml) successively. 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: 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-1-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (58 mg) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.40 (3H,d,J=7Hz), 2.76 (lH,d,J=5Hz), 2.84 (lH,d,J=5Hz), 5.15 (lH,q,J=7Hz), 6.55 (lH,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) Workin~ Exam~le 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-1-methylpropyl]-4-[4-[5-oxo-4-[4-(2,Z,3,3-tetrafluoropropoxy)phenyl]-lH-1,2,4-triazol-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 added to the mixture. The separated aqueous layer was extracted CA 022ll4~8 l997-07-24 W O 96/25410 P~-lJJ~
with ethyl acetate twice. The combined ethyl acetate layers were washed with water and a saturated a~ueous 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-[(lR,2R)-2-(2,4-difluorophe-nyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-lH-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (Com-pound l; 0.21g) as a colorless powder.
[a]20D -16.9~ (c=1.0% in MeOH) Elemental analysis for C31H25F6NgO4-0.5H2O
Calcd (%): C,52.40; H,3.69; N.17.74 Found (%): C,52.59; H,3.67; N,17.69 Workin~ Exam~le 2 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-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)-1,2,4-triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N,N-dimethylforma-mide (50 ml), and the mixture was heated with stirring at 90 C 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 CA 022114~8 1997-07-24 W O96/25410 . PCT1JP96/0032S
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), lN-hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate 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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-lH,3H-imidazol-l-yl]phenyl]-3(2H,4H)-1,2,4-triazo-lone (Compound 2; 0.26g) as a colorless crystalline powder.
mp: 181-183~C
Elemental analysis for C32H26F6N8O4 Calcd (%): C,54.86; H,3.74; N.15.99 Found (%): C,54.58; H,3.75; N,15.71 [a]20D -18.9 (c=1.0% in MeOH) Workin~ Exam~le 3 2-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-lH,3H-imidazol-1-yl]
phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 3) was obtained in the same manner as in Working Example 2, CA 022114~8 1997-07-24 W O 96/2S410 PCTJJ~ D~
Colorless crystalline powder mp: 214-215~C
Elemental analysis for C31H24F6N8O4 Calcd (%): C,54.23; H,3.52; N,16.32 Found (%): C,54.05; H,3.37; N,16.32 [a]20D -19.0 (c=1.0% in MeOH) Workin~ Ex~m~le 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-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-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-(lH-1,2,4-triazol-1-yl)methyloxirane (1.0 g), and the mixture was stirred at 80 C 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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,2-trifluo-roethyl)-lH,4H-1,2,4-triazol-1-yl]phenyl~-3-(2H,4H)-1,2,4-triazolone (Compound 4; 0.46 g) as a pale yellow powder.
CA 022114~8 1997-07-24 W O96/2S410 PCT/J~3G;~
H-NMR (CDCl3)~: 1.31(3H,d,J=7Hz), 4.36 (2H,q,J=8.4Hz), 4.37 ~lH,d,J=14Hz), 5.03 (lH,d,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) Workin~ Exam~le 5 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4-(lH-1,2,4-triazol-1-yl)phenyl]-3(2H,4H)-1,2,4-triazolone (0.91 g) in the same manner as in Working Example 4 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-1,2,4-triazol-1-yl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 5; 0.54 g).
Colorless crystalline powder mp: 182-184~C
H-NMR (CDC13)~: 1.32(3H,d,J=7Hz), 4.40 (lH,d,J=14.4Hz), 5.03 (lH,d,J=14.4Hz), 5.11 (lH,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 (lH,s), 8.14(1H,s), 8.65 (lH,s) Elemental analysis for C22HlgF2N902 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~
CA 022114~8 1997-07-24 W 096t254~0 Workin~ Exam~le 6 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4-(lH-1,2,3-triazol-1-yl)phenyl3-3(2H,4H)-1,2,4-triazolone (1.09 g) in the same ~anner as in Working Example 4 to give 2-[(lR,2R)-2-(Z,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-1,2,3-triazol-1-yl) phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 6; 0.27 g).
Colorless crystalline powder mp: 219-220~C
lH-NMR (CDC13)~: 1.32(3H,d,J=7Hz), 4.40 (lH,d,J=14.2Hz), 5.03 (lH,d,J=14.2Hz), ~.10 (lH,q,J=7Hz), 5.38 (lH,s), 6.7~-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 C22HlgF2N902 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 Workin~ Exam~le 7 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4-(2H-1,2,3-triazol-2-yl)phenyl]-3(2H,4H)-1,2,4-triazolone (1.09 g) in the same manner as in Working Example 4 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl~-4-[4-(2H-1,2,3-triazol-2-CA 022114~8 1997-07-24 W O96/2S410 PCTIJ~3C/Q~
yl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 7; 0.65 g).
Pale yellow plates mp: 213-215~C
H-NMR (CDC13)~: 1.32(3H,d,J=7Hz), 4.38 (lH,d,J=14.2Hz), 5.04 (lH,d,J=14.2Hz), 5.11 (lH,q,J=7Hz), 5.42 (lH,s), 6.?5-6.90 (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 (lH,s), 8.25(2H,d,J=9Hz) Elemental analysis for C22HlgF2NgO2 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~
Workin~ ExamPle 8 2-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropyl)-lH,4H-1,2,4-triazol-1-yl]phenyl]-3-(2H,4H)-1,2,4-triazolone (Compound 8) was obtained in the same manner as in Working Example 4.
Pale yellow powder H-NMR (CDCl3)8: 1.31(3H,d,J=7Hz), 4.34 (2H,t,J=14Hz), 4.37 (lH,d,J=14Hz), 5.04 (lH,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) CA 022114~8 1997-07-24 W 096/2S4tO PC~rh.,~J5 ~2 Workin~ Exam~le 9 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.5 g), 1-[4-(lH-1,2,4-tria-zol-l-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and cesium carbonate (powder: 9.7 g) were added to N,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), lN-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 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-l-yl)phenyl]-2(1H,3H)-imidazolone (Compound 9; 1.03 g) as a pale yellow powder.
lH-NMR (CDC13)8: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14.2Hz), 5.01 (lH,q,J=7Hz), 5.12 (lH,d,J=14.2Hz), 5.50 (lH,br), 6.72 (lH,d,J=3.2Hz), 6.73-6.90 (2H,m), 6.83 (lH,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) CA 022114~8 1997-07-24 W O 96/2S410 PCTlJ~JG/O
IR(KBr): 3400, 3118, 1683, 1616, 1527, 1500cm~
Workin~ ExamDle 10 l-t(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-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 50 C 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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 10; 0.37 g) as a colorless crys-talline powder.
H-NMR (CDCl3)~: 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 (lH,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 C23H22F2NgO2 Calcd (%): C,57.50; H,4.62; N,23.32 Found (%): C,57.46; H,4.47; N,23.19 CA 022114~8 1997-07-24 wos6ns4l0 PCTJJ~C,'Or'~
IR(KBr): 3390, 3106, 1677, 1614, 1523, 1484cm~
Workin~ Exam~le 11 To a mixture of 1-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and 1-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-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100~C 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), lN-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-[(lR,2R)-2-(2 7 4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyi]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound ~1; 1.82 g) as a pale yellow crystal-line powder.
mp: 178-181~C
~ lH-NMR (CDC13)~: 1.22(3H,d,J=7Hz), 4.22 (lH,d,J=14.4Hz), 5.01 (lH,q,J=7Hz), 5.12 (lH,d,J=14.4Hz), 5.38 (lH,br), 6.70-6.88 (4H,m), 7.40-7.55 (lH,m), 7.76 (lH,s), 7.80-7.93 CA 022114~8 1997-07-24 (6H,m), 8.03 (lH,s) Elemental analysis for C23H20F2N8O2 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~
Workin~ Exam~le 12 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-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-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 12; 0.69 g).
Colorless crystalline powder H-NMR (CDC13)~: 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 (lH,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 C23H22F2N8O2 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~
CA 022114~8 1997-07-24 W O9612S410 PCT/J~C~. ~~ 5 Workin~ Exam~le 13 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.51 g) was reacted with 1-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2(lH,3H)-imidazolone (Compound 13; 1.41 g).
Pale yellow needles mp: 182-185~C
lH-NMR (CDCl3)8: 1.22(3H,d,J=7Hz), 4.22 (lH,d,J=14.4Hz), 4.99 (lH,q,J=7Hz), 5.0~ (lH,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 C23H20F2N802 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 Workin~ ExamPle 14 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl3-2(1H,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 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-8~
CA 022114~8 1997-07-24 W O 96/2S410 PCT/JPg6/00325 l-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2-imidazol-idinone (Compound 14; 0.70 g).
Colorless crystalline powder mp: 196-197~C
H-NMR (CDC13)~: 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 (lH,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 Workin~ ExamPle 15 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(lH-l-pyrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluoro-phenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-pyrazolyl)phenyl]-2(lH,3H)-imidazolone (Compound lH-NMR (CDC13)~: 1.21(3H,d,J=7Hz), 4.22 (lH,d,J=14.4Hz), 4.98 (lH,q,J=7Hz), 5.12 (lH,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 (lH,d,J=2.4Hz) Elemental analysis for C24H2lF2N7o2 Calcd (%): C,60.37; H,4.43; N,20.53 Found (%): C,60.29; H,4.42; N,20.50 CA 022114~8 1997-07-24 W~ 96~2S4~ PCT~JP9~0032S
Workin~ ExamPle 16 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-~4-(lH-l-pyrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 15) obtained in Working Example 15 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-1-methyl-3-(lH-1,2,4-triazol-1- yl)propyl]-3-[4-(lI~-l-pyrazolyl)phenyl]-2-imidazolidinone (Compound 16).
H-NMR (CDCl3)8: 1.08 (3H,d,J=7Hz), 3.65-4.10 (4H,m), 4.53 (lH,d,J=14.2Hz), 4.55-4.75(1H,m), 5.12 (lH,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,m), 7.60-7.75 (5H,m), 7.76 (lH,s), 7.88 (lH,s), 7.90 (lH,d,J=2.6Hz) Elemental analysis for C24H23F2N7O2 Calcd (%): C,60.12; H,4.83; N,20.45 Found (%): C,60.02; H,4.95; N,20.34 Workin~ ExamPle 17 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(lH-1,2,4-triazol-l-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-ylmethyl)phenyl]-2(lH,3H)-imidazolone (Compound 17).
lH-NMR (CDC13)~: 1.20 (3H,d,J=7Hz), 4.19 (lH,d,J=14.4Hz), CA 022114~8 1997-07-24 W O96/2S410 PCT/Jl ,CI'~f ~
4.97 (lH,q,J=7Hz), 5.10 (lH,d,J=14.4Hz), 5.37 (2H,s), 5.55 (lH,br), 6.65 tlH,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) Workin~ ExamPle 18 - (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methy1-3-(lH-1,2,4-triazol-l-yl)propyl]-4-[4-(lH-1,2,4-triazol-1-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 18).
lH-N~ (CDC13)~: 1.30 (3H,d,J=7.2Hz), 4.36 (lH,d,J=14.2Hz), 5.02 (lH,d,J=14.2Hz), 5.09 (lH,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) Workin~ ExamPle 19 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-l-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-l-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 19).
CA 022114~8 1997-07-24 WO96/2S410 PCT1~6~003~
lH-NMR (CDCl3)~: 1.32 (3H,d,J=7Hz), 4.38 (lH,d,J=14.4Hz), 5.05 (lH,d,J=14.4Hz), 5.11 (lH,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 (lH,d,J=2.6Hz) Workin~ Exam~le 20 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-t(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 20).
lH-NMR (CDC13)~: 1.19 (3H,d,J=7Hz), 4.17 (lH,d,J=14.4Hz), 4.95 (lH,q,J=7Hz), 5.09 (lH,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 (ZH,s), 7.64 (2H,d,J=8.6Hz), 7.73 (lH,s), 7.85 (lH,s) Workin~ ExamPle 21 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-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 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-4-[4-(2H-1,2,3-triazol-2-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 21).
H-NMR (CDCl3)~: 1.29 (3H,d,J=7Hz), 4.34 (lH,d,J=14.4Hz), CA 022114~8 1997-07-24 5.02 (lH,d,J=14.4Hz), 5.08 (lH,q,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 (lH,s), 7.78 (lH,s), 7.94 (lH,s) Elemental analysis for C23H21F2N902 Calcd (%): C,55.98; H,4.29; N,25.55 Found (%): C,55.87; H,4.18; N,25.42 Workin~ ExamPle 22 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-l-imidazolyl)phenyl~-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-l-imidazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 22).
H-NMR (CDC13)~: 1.32 (3H,d,J=7Hz), 4.40 (lH,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 (lH,s), 7.33 (lH,s), 7.51-7.65 (lH,m), 7.57 (2H,d,J=9Hz), 7.71 (lH,s), 7.76 (2H,d,J=9Hz), 7.86 (lH,s), 7.91 (lH,s), 7.95 (lH,s) Workin~ ExamPle 23 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-~4-(lH-l-imidazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-CA 022114~8 1997-07-24 W O 96/2S410 PCr/JP9~/00325 difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-imidazolyl)phenyl]-2(1H,3H)-imidazo-- lone (Compound 23).
H-NMR (CDC13)ô: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.00 (lH,q,J=7Hz), 5.12 (lH,d,J=14Hz), 5.56 (lH,br), 6.70 (lH,d,J=3Hz), 6.76-6.~6 (3H,m), 7.23 (lH,s), 7.30 (lH,s), 7.42-7.54 (lH,m), 7.49 t2H,d,J=8HZ), 7.75 (lH,s), 7.78 (lH,s), 7.84 (2H,d,J=~Hz), 7.86 (lH,s) Workin~ ExamPle 24 l-{(lR,2R)-2-(2,~-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-imidazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 23) obtained in Working Example 23 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-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-l-imidazolyl)phenyl]-2-imidazolidinone (Compound 24).
H-NMR (CDC13)8: 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 (lH,d,J=14Hz), 5.40 (lH,br), 6.73-6.84 (2H,m), 7.20 (lH,s), 7.26 (lH,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) Workin~ ExamPle 25 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same CA 022114~8 1997-07-24 W O96/2S410 PCT1J~9C/00~
manner as in Working Example 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 25).
H-NMR (CDCl3)~: 1.33 (3H,d,J=7Hz), 4.40 (lH,d,J=14Hz), 5.04 (lH,d,J=14Hz), 5.11 (lH,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 C21H18F2N10O2 Calcd (%): C,52.50; H,3.78; N,29.15 Found (%): C,52.36; H,3.85; N,29.02 Workin~ ExamPle 26 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(lH,3H)-imidazo-lone (Compound 26).
H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.02 (lH,q,J=7Hz), 5.12 (lH,d,J=14Hz), 5.49 (lH,br), 6.75 (lH,d,J=3Hz), 6.75-6.85 (2H,m), 6.85 (lH,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) CA 022114~8 1997-07-24 WO g6/2S410 PCTJJ~G~ 4 Workin~ Exam~le 27 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl) phenyl]-2(1H,3H)-imidazolone (Compound 26) obtained in Working Example 26 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-1-methyl-3-(lH-1,2,4-tri-azol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2-imidazolidinone (Compound 27).
lH-NMR (CDC13)~: 1.08 (3H,d,J=7Hz), 3.69-3.81 (lH,m), 3.94-4.10 (3H,m), 4.52 (lH,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), ? 77 (lH,s), 7.80 (2H,d,J=9Hz), 7.86 (lH,s), 8.13 (2H,d,J=9Hz), 8.64 (lH,s) Workin~ Exam~le 28 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(lH-1,2,3-triazol-l-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working E~ample 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-ylmethyl)phenyl]-2(lH,3H)-imidazolone (Compound 28).
H-NMR (CDC13)~: 1.20 (3H,d,J=7Hz), 4.19 (lH,d,J=14Hz), 4.97 (lH,q,J=7Hz), 5.09 (lH,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) CA 022114~8 1997-07-24 W O96/2S410 PCT/JPg6/00325 Workin~ ExamPle 29 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-1,2,3-triazol-l-ylmethyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-4-[4-(lH-1,2,3-triazol-1-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 29).
H-NMR (CDC13)8: 1.30 (3H,d,J=7Hz), 4.36 (lH,d,J=14Hz), 5.00 (lH,d,J=14Hz), 5.08 (lH,q,J=7Hz), 5.41 (lH,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) Workin~ ExamPle 30 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(2-methyl-4-thiazolyl)phenyl]-2(lH,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2-methyl-4-thiazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 30).
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 2.78 (3H,s), 4.22 (lH,d,J=14Hz), 4.98 (lH,q,J=7Hz), 5.12 (lH,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) CA 022114~8 1997-07-24 W O 96125410 PCTJ~ 5 Workin~ Exam~le 31 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(2-methyl-4-thiazolyl)phenyl]-3(ZH,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-thiazolyl)phe-nyl]-3(2H,4H)-1,2,4-triazolone (Compound 31).
H-NMR (CDCl3)~: 1.31 (3H,d,J=7Hz), 2.79 (3H,s), 4.37 (lH,d,J=14Hz), 5.04 (lH,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) Workina Exam~le 32 (2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 1-[4-(lH-1,2,3-triazol-l-yl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2-fluorophe-nyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 32).
l-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14.2Hz), 5.08 (lH,q,J=7Hz), 5.17 (lH,d,J=14.2Hz), 5.36 (lH,br), 6.73 (lH,d,J=3.2Hz), 6.86 (lH,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 C23H21FN8O2 Calcd (%): C,59.99; H,4.60; N,24.23 CA 022114~8 1997-07-24 Found (%): C,59.62; H,4.61; N,24.13 Workin~ ExamPle 33 (2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 1-[4-(2H-1,2,3-triazol-2-yl)propyl]-2(lH,3H)-imidazolone to give l-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propoxy]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2(lH,3H)-imidazolone (Compound 33).
H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14Hz), 5.07 (lH,q,J=7Hz), 5.18 (lH,d,J=14Hz), 5.37 (lH,br), 6.70 (lH,d,J=3.2Hz), 6.83 (lH,d,J=3.2Hz), 6.98-7.08 (2H,m), 7.19-7.51 (2H,m), 7.73 (lH,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 C23H21FNgO2 Calcd (%): C,59.99; H,4.60; N,24.33 Found (%): C,59.80; H,4.58; N,23.87 Workin~ Exam~le 34 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (compound 32) obtained in Working Example 32 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 34).
_ 96 CA 022114~8 1997-07-24 W O96/2S410 PC~/JP~/00~2S
H-NMR (CDC13)o: 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 (lH,d,J=14.2Hz), .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 C23H23FN8O2 Calcd (%): C,59.73; H,~.01; N,24.23 Found (%): C,59.32; H,4.99; N,24.00 Workin~ ExamPle 35 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,3-triazol-1-yl)propyl]-3-[4-(2H-l,Z,3-triazol-2-yl)phe-nyl]-2(1H,3H)-imidazolone (Compound 33) obtained in Working Example 33 was subjected to catalytic hydrogenation in the same manner as in Working Example lQ to ~ive l-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2-imidazoli-dinone (Compound 35).
mp.: 178-179~C
H-NMR (CDCl3)o: 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 (lH,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 C23H23FNgO2 Calcd (%): C,59.73; H,5.01; N,24.23 Found (%): C,59.49; H,5.23; N,24.01 CA 022114~8 1997-07-24 W O96/2S410 PCTIJ~3C
Workin~ Exam~le 36 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (0.50 g), 4-[4-(2-methyl-4-oxazolyl)phenyl]-3(2H,4H)-1,2,4-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 O.SN-sodium hydroxide (40 ml), lN-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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-oxazolyl)phe-nyl]-3(2H,4H)-1,2,4-triazolone (Compound 36, 0.33 g).
H-NMR (CDC13)~: 1.31 (3H,d,J=7Hz), 2.54 (3H,s), 4.36 (lH,d,J=14Hz), 5.04 (lH,d,J=14Hz), 5.10 (lH,q,J=7Hz), 5.47 (lH,s), 6.77-6.88 (2H,m), 7.51-7.69 (4H,m), 7.85 (lH,s), 7.86 (2H,d,J=8Hz), 7.88 (lH,s), 7.96 (lH,s) CA 022114~8 1997-07-24 WO 96/2S410 PCT1JPg6JOD325 Workin~ ExamPle 37 (2R,3S)-Z-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 1-[4-(2-methyl-4-oxazolyl)phenyl]-2(lH,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(2-methyl-4-oxazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 37).
H-NMR (CDC13)o: 1.21 (3H,d,J=7Hz), 2.53 (3H,s), 4.21 (lH,d,J=14Hz), 4.97 (lH,q,J=7Hz), 5.12 (lH,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) Workin~ Exam~le 38 (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.24 g), 1-[4-(lH-1,2,4-tria-zol-l-yl)phenyl]-2(1H,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 O.~N-sodium hydroxide (100 ml), lN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride CA 022114~8 1997-07-24 (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 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-tlH-1,2,4-triazol-l-yl)phenyl]-2(lH,3H) imidazolone (Compound 38; 0.45 g)-H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14Hz), 5.02 (lH,q,J=7Hz), 5.17 (lH,d,J=14Hz), 5.37 (lH,br), 6.71 (lH,d,J=3.2Hz), 6.86 (lH,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) Workin~ ExamPle 39 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-l-yl)phenyl]-2(lH,3H)-imidazolone (Compound 38) 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-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 39).
H-NMR (CDC13)~: 1.08 (3H,d,J=7Hz), 3.72-4.10 (4H,m), 4.53 (lH,d,J=14.2Hz), 4.76-4.79(1H,m), 5.17 (lH,d,J=14.2Hz), 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 (lH,s), 8.52 (lH,s) CA 022114~8 1997-07-24 W O 96125410 PCT~JFg. ~. 5 Elemental analysis for C23H23FN8~2 Calcd t%): C,59.73; H,6.01; N,24.23 Found (X): C,59.33; H,5.03; N,23.98 Workin~ Exam~le 40 (2R,3S)-2-t2-Fluorophenyl)-3-methyl-2-(lH-1,2,4-tria-zol-l-yl)methyloxirane (2.34 g), 1-[4-(2H-2-tetrazolyl)-phenyl]-2(1H,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrroli done (100 ml), and the mixture was heated at 80~C 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 lN-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-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 40;
0.494 g) as a colorless crystalline powder.
H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14Hz), 5.10 (lH,q,J=7Hz), 5.19 (lH,d,J=14Hz), 5.34 (lH,br), 6.75 (lH,d,J=3.2Hz), 6.88 (lH,d,J=3.2Hz), 6.99-7.09 (2H,m), CA 022114~8 1997-07-24 W O96/25410 PCT1J~6/0 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 C22H20FNgO2 Calcd (%): C,57.26; H,4.37; N,27.32 Found (%): C,57.19; H,4.29; N,27.07 Workin~ Exam~le 41 l-[(lR,2R)-2-(2-Fluoropkenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phe-nyl]-2(lH,3H)-imidazolone (Compound 40) obtained in Working Example 40 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-tria-zol-l-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2-imidazolidinone (Compound 41) as a colorless crystalline powder.
lH-NMR (CDCl3)~: 1.08 (3H,d,J=7Hz), 3.74-3.81 (lH,m), 3.94-4.13 (3H,m), 4.53 (lH,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 (lH,s) Elemental analysis for C22H22FNgO2 Calcd (%): C,57.01; H,4.78; N,27.20 Found (%): C,56.96; H,4.86; N,26.84 Wor~in~ Exam~le 42 72% sodium hydride in oil (17 mg) was dispersed in CA 022114~8 1997-07-24 W O96/25410 P~J1~6~0~32S
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 l-[(lR, 2S)-2-(2,4-difluorophe-nyl)-2,3-epoxy-1-methylpropyl]-3-[4-[(lH-l-tetrazolyl)phe-nyl]-2H(lH,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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 42; 0.15g) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.03 (lH,q,J=7Hz), 5.13 (lH,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 42) 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-CA 022114~8 1997-07-24 W O96/2S410 PCT/JP9G~
ate.
Workin~ ExamPle 43 l-t(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-tetrazolyl)phe-nyl]-2(1H,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-[(lR,2R)-2-(2,4- difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-tria-zol-l-yl)propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2-imidazoli-dinone (compound 43) as a colorless crystalline powder.
H-NMR (CDC13)~: 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 (lH,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 (lH,s), 7.82 (2H,d,J=9Hz), 7.87 (lH,s), 8.98 (lH,s) Workin~ 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 l-[(lR, 2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-[(lH-l-tetrazolyl)phenyl]-2H(lH,3H)-imidazolone (0.82 g) in dimethylformamide (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 CA 022114~8 1997-07-24 W O96J25410 PCTJJr,.'~0~
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 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 44; 0.30 g) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14H7), 5.10 (lH,q,J=7Hz), 5.18 (lH,d,J=14Hz), 5.31 (lH,br), 6.75 (lH,d,J=3Hz), 6.90 (lH,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) Workin~ Exam~le 45 1-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1-tetrazolyl)phe-nyl]-2(1H,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 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolidinone (Compound 45).
H-NMR (CDC13)~: 1.08 (3H,d,J=7Hz), 3.70-4.19 (4H,m), 4.53 CA 022114~8 1997-07-24 W O 96/2S410 PCT/J~G~
(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 (lH,s), 7.83 (2H,d,J=9Hz), 8.97 (lH,s) Workin~ Example 46 1-[(lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methane-sulfonyloxy-1-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (200 mg) was dissolved in dimethylfor-mamide (10 ml), to which lH-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 mi), washed with water (15 ml), lN-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-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl-3-[4-(lH-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 44, 65 mg) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.11 (lH,q,J=7Hz), 5.18 (lH,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 CA 022ll458 l997-07-24 W O96~2S410 PCT/Jl,-'~0~
(lH,m), 7.75 (lH,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.
W O96/25410 PCT/J~3G~
Table 10 HO CH~
I~N--CH2~ CR)--Q
D
Compo~nd No. D Q
2,4-F2 --h~ ~OCH2CF2CF2H
O O
2 2,4-F2 ~ 3 OCH2CF2CF2H
O ' O
3 2,4-F2 --~ ~OCF2CF2H
4 2,4--F2 --1~ ~--CH2CF3 2,4-F2 _~ ~N'~
6 2,4-F2 --2,4-F2 --~
2,4-F2 --~ CH2CF2CF2H
2,4-F2 _~
2,4--F2 - --~ N~
WO 9612S410 PCI'~Jr~C,'00 Table 11 Compound No. D Q
11 2,4-F
12 2,4-F2 13 2,4-F2 --1 4 2,4-F2 2,4-F2 16 2,4-F2 --1 17 2,4--F2 --~CH2--18 2,4-F2 --~I~CH2--1 19 2,4--F2 --~Q 2,4-F2 ~ ~H2--1 W O96/2S410 PCTlJ~_''vC3 Table 12 Compound No. D Q
2,4-Fz --~I~CH2--1 22 2,4-F2 --t~
23 2,4-F2 24 2,4-F2 2,4-F2 26 2,4-F2 --1 27 ~,4-F2 --2,4-F2 --I~I~CH2--1 29 2,4-F2 --~I~CH2--1 2,4-F2 --~ ~CH3 WC~ 9612S410 PCr/JP96/00325 Table 13 ComPound No. D Q
3 l 2,4-F2 ~ WH3 33 2--F --t~
2-F ~
36 2,4-F2 --~ /cH3 37 2,4-F2 --~H3 39 2-F --~
W O96t2S410 PCT/JF~6/00 Table 14 Compound No. D Q
42 2,4-F2 43 2,4-F2 --Formulation Exam~le 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.
CA 022114~8 1997-07-24 WO 96/2S410 PCT/Jr~C/~ 7~;
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 lO 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 1050 mg Lactose 65 mg Corn Starch 30 mg Soluble Starch 35 mg Magnesium Stearate 20 mg Total 200 mg Ex~eriment ExamPle 1 Test Method: Five-week-old Crj: CDF1 mice were inoculated with the minimum lethal dose of Candida al bicans TA intrave-nously. The test compounds were administered orally once immediately after infection as a 30% HPCD (hydroxypropyl-~-cyclodextrin) solution. The activity was expressed in terms of ED50 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. ED~(mg/~) PO
0.22 6 0.35 7 0.096 0.16 0 0.32 1 1 0.45 13 0.18 4 0.32 19 0.39 0.088 26 O.t6 0.18 34 0.80 0.71 PO: oral ~rini~tration CA 022ll458 l997-07-24 W0 961'~S41~ PC'r~J
Table 16 Compound No. ED~(mg/kg) PO
38 s ~' 39 0.5 0.35 41 0.80 42 0.22 43 0.89 44 0.39 0.45 P0: oral ~ ni~tration - .
W 096t2S410 PCTIJ~CI~C~
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 m~mm~lS as antifungal preparations. In addition, they can serve as antifungal preparations for agricultural use.
mp: 104-107~C (recrystallized from ethylacetate-hexane) H-NMR (CDCl3)~: 1.46 (3H,dd,J=6.6Hz,J=1.2Hz), 3.01 (lH,d,J=4.6Hz), 3.23 (lH,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 Exam~le 3 [(lR)-1-[(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-CA 022ll4~8 l997-07-24 W O96/2S410 PCT~3F~C~OC~
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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (25 g) as a pale yellow oily substance.
H-NMR (CDC13)o: 1.17 (3H,dd,J=6.6Hz,1.2Hz), 1.83 (lH,d,J=8Hz), 2.80 (lH,d,J=5.2Hz), 3.30 (lH,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)-1-[(ZR)-2-(2,4-di-fluorophenyl)-Z-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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl] benzoate (19.2 g) as a colorless oily substance.
1H-NMR (CDC13)~: 1.37 (3H,d,J=6.6Hz), 2.90 (lH,d,J=~.2Hz), 3.Z8 (lH,d,J=5.2Hz), 5.36 (lH,q,J=6.6Hz), 6.74-6.94 (2H,m), CA 022114~8 1997-07-24 W O 96/2S410 PCT/~G~
7.38-7.60 (4H,m), 7.94-8.01 (2H,m) IR ~maxneatcm~1: 1725, 1615, 1600, 1505, 1450, 1425 [(lS)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]-ethyl]
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) was added thereto, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatog-raphy (eluent: hexane/ethyl acetate = 6/1 to 2/1) to give (lS)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (9.7 g) as a colorless oily substance.
H-NMR (CDCl3)~: 1.20 (3H,dd,J-6.4Hz,lHz), 2.24 (lH,d,J=2Hz), 2.92 (lH,d,J=5Hz), 3.28 (lH,d,J=5Hz), 4.12 (lH,dq,J=6.4Hz,2Hz), 6.77-6.95 (2H,m), 7.32-7.44 (lH,m) IR ~maxneat cm 1 3420, 2980, 1615, 1600, 1500, 1425 Reference ExamPle 5 2-(Z-Fluorophenyl)-2-[(lR)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl]oxirane (synthesized by the method dis-closed in EP0548553A) was converted into [(lR)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate by the method described in Reference Examples 1 and 2.
Colorless prisms (recrystallized from ethyl acetate) mp: 183-184~C
H-NMR (CDCl3)~: 1.47 (3H,dd,J=6.6Hz,1.6Hz), 3.03 W O 9612S410 PCTJJP96~DD~25 (lH,d,J=4.7Hz), 3,23 (lH,d,J=4.7Hz), 5.35 ~lH,q,J=6.6Hz), 7.09-7.59 (4H,m), 9.13 (2H,d,J=2.2Hz), 9.23 (lH,t,J=2.2Hz) [a]23D -24.7~C (c=l.O, in CHCl3) Elemental analysis for C17H13FN207 Calcd (%): C,54.26; H,3.48; N,7.44 Found (%): C,54.23; H,3.25; N,7.41 Reference ExamPle 6 [(lR)-1-[(2R)-2-(2-Fluorophenyl)-2-oxiranyl]ethyl]
3,5-dinitrobenzoate was converted into (lR)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol by the method described in Reference Example 3.
Colorless oily substance H-NMR (CDC13)~: 1.17 (3H,dd,J=6.6Hz,l.OHz), 1.78 (lH,d,J=8.2Hz), 2.81 (lH,d,J=5.3Hz), 3.32 (lH,d,J=5.3Hz), 4.09-4.23 (lH,m), 6.99-?.47 (4H,m) Reference Exam~le 7 (lR)-1-[(2R)-2-(2-Fluorophenyl)-2-oxiranyl]ethanol was converted into (lS)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]-ethanol by the method described in Reference Example 4.
Colorless oily substance H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 2.27 (lH,d,J=2Hz), 2.96 (lH,d,J=5Hz), 3.30 (lH,d,J=5Hz), 4.16 (lH,dq,J=7Hz,2Hz), ~ 7.03-7.44 (4H,m) Reference Exam~le 8 2-(2-Fluorophenyl)-2-[(lR)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxyethyl] oxirane (synthesized by the method de-CA 022114~8 1997-07-24 W O96/2S410 ' . PCT/JP96/00325 scribed in EP0548553A) was converted into (lR)-1-[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 an 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 [(lS)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethyl] 3,5-dinitrobenzoate (23.15 g) as colorless needles.
H-NMR (CDC13)~: 1.47 (3H,d,J=7Hz), 2.97 (lH,d,J=5Hz), 3.29 (lH,d,J=5Hz), 5.43 (lH,q,J=7Hz), 7.02-7.56 (4H,m), 9.06 (2H,d,J=2Hz), 9.21 (lH,t,J=2Hz) This compound (22.91 g) was dissolved in methanol (700 ml), 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-CA 022114~8 1997-07-24 WO 96r2S410 PCr/J~C~OO~?~
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 (lS)-1-[(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 Exam~le 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-nitrophe-nyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,lH)-1,2,4-triazolone (5.5 g, 67%) as yellow crystalline powders.
W O96/2S410 PCTIJl~C
mp: 161-162~C
Reference Exam~les 10 to 14 The compounds shown in Table 1 as below were obtained in the same manner as in Reference Example 9.
Table 1 02N ~ Az Ex~mp;e No. ~2 yield (~) mp. (9~) --~ I ~ OCH2CF2CF2H 75 1 17-118 11 --~ ~ OCF2CF2H 70 143-145 12 --1~--CH2Ch 45 143-145 N
13 --~ q 83 198-199 14 --~1--CH2CF2CF2H 41 141-143 N
Reference ExamPle 15 4-Fluoronitrobenzene (21 g) was reacted with lH-1,2,3-triazole (12.4 g) in the same manner as in Reference Example 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and CA 022114~8 1997-07-24 W O 96/2S410 . P~Nl ,.','~
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-1,2,3-triazole (18.8 g) as pale yellow prisms.
mp: 183-184~C
lH-NMR (CDC13)~: 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 1-(4-nitro-phenyl)-lH-1,2,3-triazole (6.02 g) as pale yellow prisms.
mp: 205-206~C
H-NMR (CDCl3)8: 7.92 (lH,d,J=1.4Hz), 8.00 (2H,dt,J=9Hz,J=2.4Hz), 8.13 (lH,d,J=1.4Hz), 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)-1,2;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 W O9612S410 PCT/J~3cN~
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 Exam~les 17 to 21 The compounds shown in Table 2 as below were obtained in the same manner as in Reference Example 16.
Table 2 H2N ~ Az Roference E~mple No. Az yield (96) .
17 ~ --CH2CF~ 97 18 --~ 94 19 _~ 96 -~ 100 21 --~1--CH2CF2CF2H 95 N
Reference Exam~le 22 Ferric chloride (0.2 g) and activated carbon (2.0 g) CA 022114~8 1997-07-24 W O 96/2S410 PC~Jr~r'D~ S
were added to a solution of 1-(4-nitrophenyl)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,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(lH,3H)-imidazolone (18.1 g, 95%) as a pale yellow powder.
mp: 178-179~C
Elemental analysis for C18H15F4N3O2 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 1-(4-nitrophenyl)-3-[4-(1,1,2,2-tetrafluoroethoxy) phenyl]-2(lH,3H)-imidazolone, 1-(4-aminophenyl)-3-[4-CA 022114~8 1997-07-24 (1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone was obtained.
mp: 150-151~C
Elemental analysis for C17H13F4N302 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)-1,2,4-triazolone (4.6 g) and pyridine (1.43 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-1-yl]phenylcarbamate (5.6 g, 93%) as colorless scaly crystals.
mp: 204-206~C
Elemental analysis for C24H18F4N404 WO 961254~0 PCT~ 0 Calcd (%): C,57.37; H,3.61; N,11.15 Found (%): C,57.50; H,3.67; N,11.13 Reference Exam~les 25 to 31 The compounds shown in Table 3 as below were obtained in the same manner as in Reference Example 24.
Table 3 ~ OCNH ~Az Reference A2 yield(%) mp. (~) --~I~OCH2CF2CF2H 89 243-244 26 _~OCF2CF2H 95 208-211 27 --~--CH2CFs 87 183--184 N~
28 --~ 90 157-160 29 --~J 96 195-200 r~
--~N~ 89 143-144 31 --1~--CH2CF2CF2H 84 173-175 CA 022114~8 1997-07-24 W O96/2S410 PCT/JF9GI'~G325 Reference Exam~le 32 Phenyl 4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-lH,4H-1,2,4-triazol-1-yl~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 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 t~ 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 C18H16F4N6O3 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.
W 096/2S410 PCT~Jr3~DO~
Table 4 H2NNHCNH~Az Roforo~co A2 yield(~) mp. (~) 33 --I~I~OCH2CF2CF2H 95 >280 34 ~ OCF2CF2H 92 >250 --~1--CH2CF!~ 90 275-280 36 _N,Nq 95 228-232 37 --1~ 98 225-234 38 --~ 96 275-277 39 --~1--CH2CF2CF2H 95 265-274 Reference Exam~le 40 4-[4-t5-Oxo-4-t4-(2~2~3~3-tetrafluoropropoxy)phenyl]-lH,4H-l,Z,4-triazol-1-yl]phenyl]semicarbazide (4.75 g) was added to N,N-dimethylformamide (60 ml). To the mixture were -CA 022114~8 1997-07-24 W O96/25410 PCTIJ~C~
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 80~C 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)-phenyl]-lH,4H-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.4 g, 49%) as a white crystalline powder.
mp: 297-298~C
Elemental analysis for C1gH14F4N603 Calcd (%): C,50.67; H,3~.13; N,18.66 Found (%): C,50.49; H,3.20; N,18.50 Reference Exam~les 41 to 47 The compounds shown in Table 5 as below were obtained in the same manner as in Reference Example 40.
W O 96/2S410 PCT/J~ 3 Table 5 H ~ ~ Az a-~ r;nc A~ y~eld (%) mp.
41 - ~ ~ OCHzCFzCFzH 52 >260 42 - ~ ~ OCF2CF2H 49 >260 43 - ~ - CH~CF 71 >300 44 - ~ 40 >300 - ~ 58 >300 46 - ~ ~ 54 .281-283 47 - ~ - CHzCF2CF2H 52 Z46-248 ~eference Exzm~le 48 A mixture of phenyl 4-(lH-1,2,4-triazol-1-yl)phenylcar-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 WO 96/2S410 PCrlJ~ OD~
cooled and the precipitated crystals were washed with a mixture of diisopropyl ether and petroleum ether (1:1, 100 ml x 2) to give 1-(2,2-diethoxyethyl)-3-[4-(lH-1,2,4-tria-zol-l-yl)phenyl]urea (14.5 g) as a colorless crystalline powder.
mp: 139-140~C
lH-NMR (CDC13)~: 1.25 (6H,t,J=7.2Hz), 3.43 (2H,t,J=5Hz), 3.52-3.85 (4H,m), 4.57 (lH,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 Exam~les 49 to 50 The compounds shown in Table 6 as below were obtained in the same manner as in Reference Example 48.
Table 6 (CHsCH20)2CHCH2NHCNH~ Az R~eronce A2 yield (%) mP- (~) 49 - ~ 95 194-196 - ~ 84 175-176 W O 96/2S410 . P ~r~
Reference Exam~le 51 1-(2,2-Diethoxyethyl)-3-[4-(lH-1,2,4-triazol-1-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 1-[4-(lH 1,2,4-triazol-1-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 Exam~les 52 to 53 The compound shown in Table 7 as below were obtained in the same manner as in Reference Example 51.
Table 7 Ref erence E~ple Noi Azyield (g63 mP- (~C) 52 - ~ 86255-257 (~f ~C _ -sition) 53 - ~ 85 ~00 CA 022114~8 1997-07-24 W 096/2S410 PCT/Jl~G~
Reference Exam~le 54 To a solution of (lS)-1-[(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 tnen 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]-lH,4H-1,2,4-triazol-1-yl]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 W O96125410 . PCT1JPg6~0032~
acetate = 1/1 to 1/2) and crystallized from ethyl acetate-hexane to give 2-[(lR,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-l-methylpropyl]-4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoro-propoxy)phenyl]-lH-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (0.29 g) as colorless crystalline powders.
mp: 181-183~C
Elemental analysis for C29H22F6N604 Calcd (%): C,55.07; H,3.51; N,13.29 Found (%): C,55.12; H,3.34; N,13.24 Reference Exam~les 55 to 63 The compounds shown in Table 8 as below were obtained in the same manner as in Reference Example 40.
WO 96/2S410 PCr/J1 ,"~
Table 8 H~(CH2)n--Az ofor;nc n Az mp- (~C) 1 - ~ 249-250 56 0 - ~ 269-270 57 1 - ~ 201-205 58 0 - ~ 2~4-286 59 0 - ~ 245-248 1 - ~ 250-252 61 0 ~H3 282-284 62 0 ~H3 280-283 63 0 - ~ 243-248 W~ 961"54~0 PCr~JFg~ 0 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 Hl~ ~CH2)n--AZ
E~mp;- No. n Az mp. (~C) 64 0 - ~ 239-240 1 - ~ 170-171 66 1 - ~ 190-191 67 o - ~ 210-211 68 o - ~ 235-240 69 1 - ~ 213-215 o ~ 206-208 71 0 ~ 216-218 72 o - ~ 251-255 CA 022114~8 1997-07-24 WO96/25410 PCT/~610 Reference Exam~le 73 1-[4-(lH-1-Tetrazolyl)phenyl]-2(1H,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 1-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolidi-none (4.1 g) as colorless crystals.
mp: 237-240 C (dec.) lH-NMR (d6-DMS0)~: 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 C1OHlON6O
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)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (1.20 g) in dichloromethane (26 ml) at -78 C 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).
CA 022114~8 1997-07-24 W O96/25410 - PCTJ~9GJ~ s The desired fraction was concentrated to about 20 ml, and the residue was added to a solution prepared from 1-[4-(lH-1-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 -30~C. The resulting mixture was stirred for 20 minutes at -30~C 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 t100 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 1-[(lR,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (0.13 g) and (2R)-2-(2,4-difluorophenyl)-2-[(lR)-1-[1-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolyl]oxy]ethyl]oxirane (0.05 g).
1-[(lR,2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-meth-ylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazo-lone: colorless crystalline powder.
mp: 205-207~C
H-NMR (CDC13)8: 1.39(3H,d,J=7Hz), 2.73 (lH,d,J=5Hz), 2.83 (lH,d,J=5Hz), 5.09 (lH,q,J=7Hz), 6.52 (lH,d,J=3Hz), 6.66 CA 022114~8 1997-07-24 W O96/2S410 PCT/J~9-'00 (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)-1-[(2R)-2-(2-fluorophenyl)-2-oxiranyl]ethanol (1.21 g) in dichloromethane (25 mli 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 -30~C 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 1-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (1.14 g), l-methyl-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 CA 022114~8 1997-07-24 WO 9612S410 PCI'JJ~
l-[(lR,2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (0.39 g) and (2R)-2-(2-fluorophenyl)-2-[(lR)-1-[1-[4-(lH-l-tetrazo-~ lyl)phenyl]-2-imidazolyloxy]ethyl]oxirane (0.18 g).
l-[(lR,2S)-2-(2-Fluorophenyl)-2,3-epoxy-1-methylpro-pyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone:
colorless crystalline powder.
H-NMR (CDC13)ô: 1.39(3H,d,J=7Hz), 2.76 (lH,d,J=5Hz), 2.84 (lH,d,J=5Hz), 5.15 (lH,q,J=7Hz), 6.55 (lH,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 Exam~le 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 CA 022114~8 1997-07-24 W O9612S410 PCT/JPg6/00325 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-(3,4,5,6-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-CA 022114~8 1997-07-24 W O 961254~0 PCTJJF9CJOD~
yloxy)propiophenone t25 g) was dissolved in ethanol (200 ml), to which pyridinium p-toluenesulfonate (1.28 g) was added. The reaction solution was stirred at 55 C 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 H-NMR (CDCl3)8: 1.41(3H,dd,J=7Hz,J=1.4Hz), 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 Exam~le 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.
CA 022114~8 1997-07-24 W O96/2S410 PCT/JPg6/00325 H-NMR (CDC13)~: 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) [a]D23 + 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 -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. 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.
H-NMR (CDC13)~: 1.73(3H,dd,J=7Hz,J=1.6Hz), 6.49 (lH,q,J=7Hz), 7.15-7.38 (2H,m), 7.58-7.72 (lH,m), 7.97 (lH,dt,J=1.8Hz,J=7.6Hz) Reference Exam~le 79 1-[4-(lH-1,2,4-Triazol-l-yl)phenyl]-2(1H,3H)-imidazolone (3.39 g) was dissolved in 1-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 CA 022114~8 1997-07-24 W O9612S410 PCTJJ~ Q~3~s 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. After the addition was complete, the reaction tem-perature was raised to 10~C 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 1-[(lR)-2-fluorophenyl)-2-oxo-l-methylethyl]-3-[4-(lH-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone as a colorless crystalline powder.
lH-NMR (CDC13)~: 1.65(3H,d,J=7.2Hz), 5.82 (lH,q,J=7.2Hz), 6.64 (lH,d,J=3.2Hz), 6.70 (lH,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 Exam~le 80 1-[4-(lH-l-Tetrazolyl)phenyl]-2(1H,3H)-imidazolone (0.94 g) was dissolved in 1-methyl-2-pyrrolidone (25 ml), to which 72% sodium hydride in oil (0.126 g) was added. The CA 022ll4~8 l997-07-24 W O 96/2S410 PCTIJF9C~
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 0~C 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 sulfate 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-1-methylethyl]-3-[4-(lH-l-tetra-zolyl)phenyl]-2(lH,3H)-imidazolone (0.22 g) as a colorless crystalline powder.
mp: 162-164~C
lH-NMR (CDCl3)~: 1.66 (3H,d,J=7.2Hz), 5.83 (lH,q,J=7.2Hz), 6.67 (lH,d,J=3.2Hz), 6.74 (lH,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), 9.03 (lH,s) Reference ExamPle 81 Chloromethylisopropoxydimethylsilane (2.14 g) and W O 96t~5410 P~T/J~9CJOO.
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-1-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 ~odium 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-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (637 mg) as a color-less crytalline powder.
H-NMR (d6-DMSO)~: -0.30(3H,s), -0.28 (3H,s), 0.99-1.64 (llH,m), 3.83 (lH,quintet,J=6Hz), 4.81 (lH,q,J=7Hz), 5.21 (lH,br), 6.93-7.77 (6H,m), 8.05 (2H,d,J=9Hz), 8.17 CA 022114~8 1997-07-24 W O96/25410 PCT/JF9C/0~2 (2H,d,J=9Hz), 10.17 (lH,s) Reference ExamPle 82 l-[(lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxy dimethylsilyl)-l-methylpropyl]-3-[4-(lH-l-tetrazolyl)phe-nyl]-2(lH,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-1-methyl propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) as a colorless crystalline powder.
lH-NMR (CDC13)~: 1.17(3H,d,J=7Hz), 3.52-3.62 (lH,m), 4.05-4.18 (2H,m), 5.01 (lH,q,J=7Hz), 6.72 (lH,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-[(lR,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone CA 022114~8 1997-07-24 W 0961~54~0 PCT/~P~6/~032S
(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-[(lR, 2S) - 2 - (2 - f luorophenyl)-2-hydroxy-3-methanesulfonyloxy-l-methylpropyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (330 mg) as a colorless crystalline powder.
H-NMR (CDC13)~: 1.27(3H,d,J=7Hz), 2.87 (3H,s), 4.54 (lH,d,J=12Hz), 4.73-4.88 (2H,m), 6.63 (lH,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-l-tetrazolyl)phenyl]-2(1H,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 CA 022114~8 1997-07-24 W O 96/2S410 PCT/JF9G/00~
sodium chloride (10 ml) successively. 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: 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-1-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(lH,3H)-imidazolone (58 mg) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.40 (3H,d,J=7Hz), 2.76 (lH,d,J=5Hz), 2.84 (lH,d,J=5Hz), 5.15 (lH,q,J=7Hz), 6.55 (lH,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) Workin~ Exam~le 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-1-methylpropyl]-4-[4-[5-oxo-4-[4-(2,Z,3,3-tetrafluoropropoxy)phenyl]-lH-1,2,4-triazol-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 added to the mixture. The separated aqueous layer was extracted CA 022ll4~8 l997-07-24 W O 96/25410 P~-lJJ~
with ethyl acetate twice. The combined ethyl acetate layers were washed with water and a saturated a~ueous 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-[(lR,2R)-2-(2,4-difluorophe-nyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-lH-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (Com-pound l; 0.21g) as a colorless powder.
[a]20D -16.9~ (c=1.0% in MeOH) Elemental analysis for C31H25F6NgO4-0.5H2O
Calcd (%): C,52.40; H,3.69; N.17.74 Found (%): C,52.59; H,3.67; N,17.69 Workin~ Exam~le 2 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-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)-1,2,4-triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N,N-dimethylforma-mide (50 ml), and the mixture was heated with stirring at 90 C 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 CA 022114~8 1997-07-24 W O96/25410 . PCT1JP96/0032S
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), lN-hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate 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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-lH,3H-imidazol-l-yl]phenyl]-3(2H,4H)-1,2,4-triazo-lone (Compound 2; 0.26g) as a colorless crystalline powder.
mp: 181-183~C
Elemental analysis for C32H26F6N8O4 Calcd (%): C,54.86; H,3.74; N.15.99 Found (%): C,54.58; H,3.75; N,15.71 [a]20D -18.9 (c=1.0% in MeOH) Workin~ Exam~le 3 2-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-lH,3H-imidazol-1-yl]
phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 3) was obtained in the same manner as in Working Example 2, CA 022114~8 1997-07-24 W O 96/2S410 PCTJJ~ D~
Colorless crystalline powder mp: 214-215~C
Elemental analysis for C31H24F6N8O4 Calcd (%): C,54.23; H,3.52; N,16.32 Found (%): C,54.05; H,3.37; N,16.32 [a]20D -19.0 (c=1.0% in MeOH) Workin~ Ex~m~le 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-1,2,4-triazol-1-yl]phenyl]-3(2H,4H)-1,2,4-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-(lH-1,2,4-triazol-1-yl)methyloxirane (1.0 g), and the mixture was stirred at 80 C 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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,2-trifluo-roethyl)-lH,4H-1,2,4-triazol-1-yl]phenyl~-3-(2H,4H)-1,2,4-triazolone (Compound 4; 0.46 g) as a pale yellow powder.
CA 022114~8 1997-07-24 W O96/2S410 PCT/J~3G;~
H-NMR (CDCl3)~: 1.31(3H,d,J=7Hz), 4.36 (2H,q,J=8.4Hz), 4.37 ~lH,d,J=14Hz), 5.03 (lH,d,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) Workin~ Exam~le 5 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4-(lH-1,2,4-triazol-1-yl)phenyl]-3(2H,4H)-1,2,4-triazolone (0.91 g) in the same manner as in Working Example 4 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-1,2,4-triazol-1-yl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 5; 0.54 g).
Colorless crystalline powder mp: 182-184~C
H-NMR (CDC13)~: 1.32(3H,d,J=7Hz), 4.40 (lH,d,J=14.4Hz), 5.03 (lH,d,J=14.4Hz), 5.11 (lH,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 (lH,s), 8.14(1H,s), 8.65 (lH,s) Elemental analysis for C22HlgF2N902 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~
CA 022114~8 1997-07-24 W 096t254~0 Workin~ Exam~le 6 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4-(lH-1,2,3-triazol-1-yl)phenyl3-3(2H,4H)-1,2,4-triazolone (1.09 g) in the same ~anner as in Working Example 4 to give 2-[(lR,2R)-2-(Z,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-1,2,3-triazol-1-yl) phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 6; 0.27 g).
Colorless crystalline powder mp: 219-220~C
lH-NMR (CDC13)~: 1.32(3H,d,J=7Hz), 4.40 (lH,d,J=14.2Hz), 5.03 (lH,d,J=14.2Hz), ~.10 (lH,q,J=7Hz), 5.38 (lH,s), 6.7~-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 C22HlgF2N902 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 Workin~ Exam~le 7 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (1.0 g) was reacted with 4-[4-(2H-1,2,3-triazol-2-yl)phenyl]-3(2H,4H)-1,2,4-triazolone (1.09 g) in the same manner as in Working Example 4 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl~-4-[4-(2H-1,2,3-triazol-2-CA 022114~8 1997-07-24 W O96/2S410 PCTIJ~3C/Q~
yl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 7; 0.65 g).
Pale yellow plates mp: 213-215~C
H-NMR (CDC13)~: 1.32(3H,d,J=7Hz), 4.38 (lH,d,J=14.2Hz), 5.04 (lH,d,J=14.2Hz), 5.11 (lH,q,J=7Hz), 5.42 (lH,s), 6.?5-6.90 (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 (lH,s), 8.25(2H,d,J=9Hz) Elemental analysis for C22HlgF2NgO2 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~
Workin~ ExamPle 8 2-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropyl)-lH,4H-1,2,4-triazol-1-yl]phenyl]-3-(2H,4H)-1,2,4-triazolone (Compound 8) was obtained in the same manner as in Working Example 4.
Pale yellow powder H-NMR (CDCl3)8: 1.31(3H,d,J=7Hz), 4.34 (2H,t,J=14Hz), 4.37 (lH,d,J=14Hz), 5.04 (lH,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) CA 022114~8 1997-07-24 W 096/2S4tO PC~rh.,~J5 ~2 Workin~ Exam~le 9 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.5 g), 1-[4-(lH-1,2,4-tria-zol-l-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and cesium carbonate (powder: 9.7 g) were added to N,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), lN-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 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-l-yl)phenyl]-2(1H,3H)-imidazolone (Compound 9; 1.03 g) as a pale yellow powder.
lH-NMR (CDC13)8: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14.2Hz), 5.01 (lH,q,J=7Hz), 5.12 (lH,d,J=14.2Hz), 5.50 (lH,br), 6.72 (lH,d,J=3.2Hz), 6.73-6.90 (2H,m), 6.83 (lH,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) CA 022114~8 1997-07-24 W O 96/2S410 PCTlJ~JG/O
IR(KBr): 3400, 3118, 1683, 1616, 1527, 1500cm~
Workin~ ExamDle 10 l-t(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-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 50 C 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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 10; 0.37 g) as a colorless crys-talline powder.
H-NMR (CDCl3)~: 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 (lH,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 C23H22F2NgO2 Calcd (%): C,57.50; H,4.62; N,23.32 Found (%): C,57.46; H,4.47; N,23.19 CA 022114~8 1997-07-24 wos6ns4l0 PCTJJ~C,'Or'~
IR(KBr): 3390, 3106, 1677, 1614, 1523, 1484cm~
Workin~ Exam~le 11 To a mixture of 1-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and 1-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-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100~C 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), lN-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-[(lR,2R)-2-(2 7 4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyi]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound ~1; 1.82 g) as a pale yellow crystal-line powder.
mp: 178-181~C
~ lH-NMR (CDC13)~: 1.22(3H,d,J=7Hz), 4.22 (lH,d,J=14.4Hz), 5.01 (lH,q,J=7Hz), 5.12 (lH,d,J=14.4Hz), 5.38 (lH,br), 6.70-6.88 (4H,m), 7.40-7.55 (lH,m), 7.76 (lH,s), 7.80-7.93 CA 022114~8 1997-07-24 (6H,m), 8.03 (lH,s) Elemental analysis for C23H20F2N8O2 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~
Workin~ Exam~le 12 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-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-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 12; 0.69 g).
Colorless crystalline powder H-NMR (CDC13)~: 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 (lH,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 C23H22F2N8O2 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~
CA 022114~8 1997-07-24 W O9612S410 PCT/J~C~. ~~ 5 Workin~ Exam~le 13 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.51 g) was reacted with 1-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2(lH,3H)-imidazolone (Compound 13; 1.41 g).
Pale yellow needles mp: 182-185~C
lH-NMR (CDCl3)8: 1.22(3H,d,J=7Hz), 4.22 (lH,d,J=14.4Hz), 4.99 (lH,q,J=7Hz), 5.0~ (lH,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 C23H20F2N802 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 Workin~ ExamPle 14 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl3-2(1H,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 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-8~
CA 022114~8 1997-07-24 W O 96/2S410 PCT/JPg6/00325 l-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2-imidazol-idinone (Compound 14; 0.70 g).
Colorless crystalline powder mp: 196-197~C
H-NMR (CDC13)~: 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 (lH,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 Workin~ ExamPle 15 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(lH-l-pyrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluoro-phenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-pyrazolyl)phenyl]-2(lH,3H)-imidazolone (Compound lH-NMR (CDC13)~: 1.21(3H,d,J=7Hz), 4.22 (lH,d,J=14.4Hz), 4.98 (lH,q,J=7Hz), 5.12 (lH,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 (lH,d,J=2.4Hz) Elemental analysis for C24H2lF2N7o2 Calcd (%): C,60.37; H,4.43; N,20.53 Found (%): C,60.29; H,4.42; N,20.50 CA 022114~8 1997-07-24 W~ 96~2S4~ PCT~JP9~0032S
Workin~ ExamPle 16 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-~4-(lH-l-pyrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 15) obtained in Working Example 15 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-1-methyl-3-(lH-1,2,4-triazol-1- yl)propyl]-3-[4-(lI~-l-pyrazolyl)phenyl]-2-imidazolidinone (Compound 16).
H-NMR (CDCl3)8: 1.08 (3H,d,J=7Hz), 3.65-4.10 (4H,m), 4.53 (lH,d,J=14.2Hz), 4.55-4.75(1H,m), 5.12 (lH,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,m), 7.60-7.75 (5H,m), 7.76 (lH,s), 7.88 (lH,s), 7.90 (lH,d,J=2.6Hz) Elemental analysis for C24H23F2N7O2 Calcd (%): C,60.12; H,4.83; N,20.45 Found (%): C,60.02; H,4.95; N,20.34 Workin~ ExamPle 17 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(lH-1,2,4-triazol-l-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-ylmethyl)phenyl]-2(lH,3H)-imidazolone (Compound 17).
lH-NMR (CDC13)~: 1.20 (3H,d,J=7Hz), 4.19 (lH,d,J=14.4Hz), CA 022114~8 1997-07-24 W O96/2S410 PCT/Jl ,CI'~f ~
4.97 (lH,q,J=7Hz), 5.10 (lH,d,J=14.4Hz), 5.37 (2H,s), 5.55 (lH,br), 6.65 tlH,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) Workin~ ExamPle 18 - (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methy1-3-(lH-1,2,4-triazol-l-yl)propyl]-4-[4-(lH-1,2,4-triazol-1-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 18).
lH-N~ (CDC13)~: 1.30 (3H,d,J=7.2Hz), 4.36 (lH,d,J=14.2Hz), 5.02 (lH,d,J=14.2Hz), 5.09 (lH,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) Workin~ ExamPle 19 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-l-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-l-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 19).
CA 022114~8 1997-07-24 WO96/2S410 PCT1~6~003~
lH-NMR (CDCl3)~: 1.32 (3H,d,J=7Hz), 4.38 (lH,d,J=14.4Hz), 5.05 (lH,d,J=14.4Hz), 5.11 (lH,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 (lH,d,J=2.6Hz) Workin~ Exam~le 20 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-t(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 20).
lH-NMR (CDC13)~: 1.19 (3H,d,J=7Hz), 4.17 (lH,d,J=14.4Hz), 4.95 (lH,q,J=7Hz), 5.09 (lH,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 (ZH,s), 7.64 (2H,d,J=8.6Hz), 7.73 (lH,s), 7.85 (lH,s) Workin~ ExamPle 21 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-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 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-4-[4-(2H-1,2,3-triazol-2-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 21).
H-NMR (CDCl3)~: 1.29 (3H,d,J=7Hz), 4.34 (lH,d,J=14.4Hz), CA 022114~8 1997-07-24 5.02 (lH,d,J=14.4Hz), 5.08 (lH,q,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 (lH,s), 7.78 (lH,s), 7.94 (lH,s) Elemental analysis for C23H21F2N902 Calcd (%): C,55.98; H,4.29; N,25.55 Found (%): C,55.87; H,4.18; N,25.42 Workin~ ExamPle 22 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-l-imidazolyl)phenyl~-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(lH-l-imidazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 22).
H-NMR (CDC13)~: 1.32 (3H,d,J=7Hz), 4.40 (lH,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 (lH,s), 7.33 (lH,s), 7.51-7.65 (lH,m), 7.57 (2H,d,J=9Hz), 7.71 (lH,s), 7.76 (2H,d,J=9Hz), 7.86 (lH,s), 7.91 (lH,s), 7.95 (lH,s) Workin~ ExamPle 23 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-~4-(lH-l-imidazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-CA 022114~8 1997-07-24 W O 96/2S410 PCr/JP9~/00325 difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-imidazolyl)phenyl]-2(1H,3H)-imidazo-- lone (Compound 23).
H-NMR (CDC13)ô: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.00 (lH,q,J=7Hz), 5.12 (lH,d,J=14Hz), 5.56 (lH,br), 6.70 (lH,d,J=3Hz), 6.76-6.~6 (3H,m), 7.23 (lH,s), 7.30 (lH,s), 7.42-7.54 (lH,m), 7.49 t2H,d,J=8HZ), 7.75 (lH,s), 7.78 (lH,s), 7.84 (2H,d,J=~Hz), 7.86 (lH,s) Workin~ ExamPle 24 l-{(lR,2R)-2-(2,~-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-imidazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 23) obtained in Working Example 23 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-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-l-imidazolyl)phenyl]-2-imidazolidinone (Compound 24).
H-NMR (CDC13)8: 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 (lH,d,J=14Hz), 5.40 (lH,br), 6.73-6.84 (2H,m), 7.20 (lH,s), 7.26 (lH,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) Workin~ ExamPle 25 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same CA 022114~8 1997-07-24 W O96/2S410 PCT1J~9C/00~
manner as in Working Example 11 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 25).
H-NMR (CDCl3)~: 1.33 (3H,d,J=7Hz), 4.40 (lH,d,J=14Hz), 5.04 (lH,d,J=14Hz), 5.11 (lH,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 C21H18F2N10O2 Calcd (%): C,52.50; H,3.78; N,29.15 Found (%): C,52.36; H,3.85; N,29.02 Workin~ ExamPle 26 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(lH,3H)-imidazo-lone (Compound 26).
H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.02 (lH,q,J=7Hz), 5.12 (lH,d,J=14Hz), 5.49 (lH,br), 6.75 (lH,d,J=3Hz), 6.75-6.85 (2H,m), 6.85 (lH,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) CA 022114~8 1997-07-24 WO g6/2S410 PCTJJ~G~ 4 Workin~ Exam~le 27 l-[(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl) phenyl]-2(1H,3H)-imidazolone (Compound 26) obtained in Working Example 26 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-1-methyl-3-(lH-1,2,4-tri-azol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2-imidazolidinone (Compound 27).
lH-NMR (CDC13)~: 1.08 (3H,d,J=7Hz), 3.69-3.81 (lH,m), 3.94-4.10 (3H,m), 4.52 (lH,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), ? 77 (lH,s), 7.80 (2H,d,J=9Hz), 7.86 (lH,s), 8.13 (2H,d,J=9Hz), 8.64 (lH,s) Workin~ Exam~le 28 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(lH-1,2,3-triazol-l-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working E~ample 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-ylmethyl)phenyl]-2(lH,3H)-imidazolone (Compound 28).
H-NMR (CDC13)~: 1.20 (3H,d,J=7Hz), 4.19 (lH,d,J=14Hz), 4.97 (lH,q,J=7Hz), 5.09 (lH,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) CA 022114~8 1997-07-24 W O96/2S410 PCT/JPg6/00325 Workin~ ExamPle 29 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(lH-1,2,3-triazol-l-ylmethyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-4-[4-(lH-1,2,3-triazol-1-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 29).
H-NMR (CDC13)8: 1.30 (3H,d,J=7Hz), 4.36 (lH,d,J=14Hz), 5.00 (lH,d,J=14Hz), 5.08 (lH,q,J=7Hz), 5.41 (lH,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) Workin~ ExamPle 30 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with l-[4-(2-methyl-4-thiazolyl)phenyl]-2(lH,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2-methyl-4-thiazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 30).
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 2.78 (3H,s), 4.22 (lH,d,J=14Hz), 4.98 (lH,q,J=7Hz), 5.12 (lH,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) CA 022114~8 1997-07-24 W O 96125410 PCTJ~ 5 Workin~ Exam~le 31 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 4-[4-(2-methyl-4-thiazolyl)phenyl]-3(ZH,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-thiazolyl)phe-nyl]-3(2H,4H)-1,2,4-triazolone (Compound 31).
H-NMR (CDCl3)~: 1.31 (3H,d,J=7Hz), 2.79 (3H,s), 4.37 (lH,d,J=14Hz), 5.04 (lH,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) Workina Exam~le 32 (2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 1-[4-(lH-1,2,3-triazol-l-yl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2-fluorophe-nyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 32).
l-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14.2Hz), 5.08 (lH,q,J=7Hz), 5.17 (lH,d,J=14.2Hz), 5.36 (lH,br), 6.73 (lH,d,J=3.2Hz), 6.86 (lH,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 C23H21FN8O2 Calcd (%): C,59.99; H,4.60; N,24.23 CA 022114~8 1997-07-24 Found (%): C,59.62; H,4.61; N,24.13 Workin~ ExamPle 33 (2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 1-[4-(2H-1,2,3-triazol-2-yl)propyl]-2(lH,3H)-imidazolone to give l-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propoxy]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2(lH,3H)-imidazolone (Compound 33).
H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14Hz), 5.07 (lH,q,J=7Hz), 5.18 (lH,d,J=14Hz), 5.37 (lH,br), 6.70 (lH,d,J=3.2Hz), 6.83 (lH,d,J=3.2Hz), 6.98-7.08 (2H,m), 7.19-7.51 (2H,m), 7.73 (lH,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 C23H21FNgO2 Calcd (%): C,59.99; H,4.60; N,24.33 Found (%): C,59.80; H,4.58; N,23.87 Workin~ Exam~le 34 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (compound 32) obtained in Working Example 32 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 34).
_ 96 CA 022114~8 1997-07-24 W O96/2S410 PC~/JP~/00~2S
H-NMR (CDC13)o: 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 (lH,d,J=14.2Hz), .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 C23H23FN8O2 Calcd (%): C,59.73; H,~.01; N,24.23 Found (%): C,59.32; H,4.99; N,24.00 Workin~ ExamPle 35 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,3-triazol-1-yl)propyl]-3-[4-(2H-l,Z,3-triazol-2-yl)phe-nyl]-2(1H,3H)-imidazolone (Compound 33) obtained in Working Example 33 was subjected to catalytic hydrogenation in the same manner as in Working Example lQ to ~ive l-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-yl)phenyl]-2-imidazoli-dinone (Compound 35).
mp.: 178-179~C
H-NMR (CDCl3)o: 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 (lH,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 C23H23FNgO2 Calcd (%): C,59.73; H,5.01; N,24.23 Found (%): C,59.49; H,5.23; N,24.01 CA 022114~8 1997-07-24 W O96/2S410 PCTIJ~3C
Workin~ Exam~le 36 (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (0.50 g), 4-[4-(2-methyl-4-oxazolyl)phenyl]-3(2H,4H)-1,2,4-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 O.SN-sodium hydroxide (40 ml), lN-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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-4-[4-(2-methyl-4-oxazolyl)phe-nyl]-3(2H,4H)-1,2,4-triazolone (Compound 36, 0.33 g).
H-NMR (CDC13)~: 1.31 (3H,d,J=7Hz), 2.54 (3H,s), 4.36 (lH,d,J=14Hz), 5.04 (lH,d,J=14Hz), 5.10 (lH,q,J=7Hz), 5.47 (lH,s), 6.77-6.88 (2H,m), 7.51-7.69 (4H,m), 7.85 (lH,s), 7.86 (2H,d,J=8Hz), 7.88 (lH,s), 7.96 (lH,s) CA 022114~8 1997-07-24 WO 96/2S410 PCT1JPg6JOD325 Workin~ ExamPle 37 (2R,3S)-Z-(2,4-Difluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane was reacted with 1-[4-(2-methyl-4-oxazolyl)phenyl]-2(lH,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(2-methyl-4-oxazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 37).
H-NMR (CDC13)o: 1.21 (3H,d,J=7Hz), 2.53 (3H,s), 4.21 (lH,d,J=14Hz), 4.97 (lH,q,J=7Hz), 5.12 (lH,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) Workin~ Exam~le 38 (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-(lH-1,2,4-triazol-l-yl)methyloxirane (2.24 g), 1-[4-(lH-1,2,4-tria-zol-l-yl)phenyl]-2(1H,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 O.~N-sodium hydroxide (100 ml), lN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium chloride CA 022114~8 1997-07-24 (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 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-tlH-1,2,4-triazol-l-yl)phenyl]-2(lH,3H) imidazolone (Compound 38; 0.45 g)-H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14Hz), 5.02 (lH,q,J=7Hz), 5.17 (lH,d,J=14Hz), 5.37 (lH,br), 6.71 (lH,d,J=3.2Hz), 6.86 (lH,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) Workin~ ExamPle 39 l-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1,2,4-triazol-l-yl)phenyl]-2(lH,3H)-imidazolone (Compound 38) 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-1-methyl-3-(lH-1,2,4-triazol-l-yl)propyl]-3-[4-(lH-1,2,4-triazol-1-yl)phenyl]-2-imidazolidinone (Compound 39).
H-NMR (CDC13)~: 1.08 (3H,d,J=7Hz), 3.72-4.10 (4H,m), 4.53 (lH,d,J=14.2Hz), 4.76-4.79(1H,m), 5.17 (lH,d,J=14.2Hz), 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 (lH,s), 8.52 (lH,s) CA 022114~8 1997-07-24 W O 96125410 PCT~JFg. ~. 5 Elemental analysis for C23H23FN8~2 Calcd t%): C,59.73; H,6.01; N,24.23 Found (X): C,59.33; H,5.03; N,23.98 Workin~ Exam~le 40 (2R,3S)-2-t2-Fluorophenyl)-3-methyl-2-(lH-1,2,4-tria-zol-l-yl)methyloxirane (2.34 g), 1-[4-(2H-2-tetrazolyl)-phenyl]-2(1H,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrroli done (100 ml), and the mixture was heated at 80~C 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 lN-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-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 40;
0.494 g) as a colorless crystalline powder.
H-NMR (CDC13)~: 1.21 (3H,d,J=7Hz), 4.23 (lH,d,J=14Hz), 5.10 (lH,q,J=7Hz), 5.19 (lH,d,J=14Hz), 5.34 (lH,br), 6.75 (lH,d,J=3.2Hz), 6.88 (lH,d,J=3.2Hz), 6.99-7.09 (2H,m), CA 022114~8 1997-07-24 W O96/25410 PCT1J~6/0 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 C22H20FNgO2 Calcd (%): C,57.26; H,4.37; N,27.32 Found (%): C,57.19; H,4.29; N,27.07 Workin~ Exam~le 41 l-[(lR,2R)-2-(2-Fluoropkenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phe-nyl]-2(lH,3H)-imidazolone (Compound 40) obtained in Working Example 40 was subjected to catalytic hydrogenation in the same manner as in Working Example 10 to give 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-tria-zol-l-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2-imidazolidinone (Compound 41) as a colorless crystalline powder.
lH-NMR (CDCl3)~: 1.08 (3H,d,J=7Hz), 3.74-3.81 (lH,m), 3.94-4.13 (3H,m), 4.53 (lH,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 (lH,s) Elemental analysis for C22H22FNgO2 Calcd (%): C,57.01; H,4.78; N,27.20 Found (%): C,56.96; H,4.86; N,26.84 Wor~in~ Exam~le 42 72% sodium hydride in oil (17 mg) was dispersed in CA 022114~8 1997-07-24 W O96/25410 P~J1~6~0~32S
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 l-[(lR, 2S)-2-(2,4-difluorophe-nyl)-2,3-epoxy-1-methylpropyl]-3-[4-[(lH-l-tetrazolyl)phe-nyl]-2H(lH,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-[(lR,2R)-2-(2,4-difluorophenyl)-2-hydroxy-l-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 42; 0.15g) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.03 (lH,q,J=7Hz), 5.13 (lH,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 42) 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-CA 022114~8 1997-07-24 W O96/2S410 PCT/JP9G~
ate.
Workin~ ExamPle 43 l-t(lR,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-l-tetrazolyl)phe-nyl]-2(1H,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-[(lR,2R)-2-(2,4- difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-tria-zol-l-yl)propyl]-3-[4-(lH-l-tetrazolyl)phenyl]-2-imidazoli-dinone (compound 43) as a colorless crystalline powder.
H-NMR (CDC13)~: 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 (lH,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 (lH,s), 7.82 (2H,d,J=9Hz), 7.87 (lH,s), 8.98 (lH,s) Workin~ 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 l-[(lR, 2S)-2-(2-fluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-[(lH-l-tetrazolyl)phenyl]-2H(lH,3H)-imidazolone (0.82 g) in dimethylformamide (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 CA 022114~8 1997-07-24 W O96J25410 PCTJJr,.'~0~
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 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 44; 0.30 g) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14H7), 5.10 (lH,q,J=7Hz), 5.18 (lH,d,J=14Hz), 5.31 (lH,br), 6.75 (lH,d,J=3Hz), 6.90 (lH,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) Workin~ Exam~le 45 1-[(lR,2R)-2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1-tetrazolyl)phe-nyl]-2(1H,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 1-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2-imidazolidinone (Compound 45).
H-NMR (CDC13)~: 1.08 (3H,d,J=7Hz), 3.70-4.19 (4H,m), 4.53 CA 022114~8 1997-07-24 W O 96/2S410 PCT/J~G~
(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 (lH,s), 7.83 (2H,d,J=9Hz), 8.97 (lH,s) Workin~ Example 46 1-[(lR,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methane-sulfonyloxy-1-methylpropyl]-3-[4-(lH-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (200 mg) was dissolved in dimethylfor-mamide (10 ml), to which lH-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 mi), washed with water (15 ml), lN-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-[(lR,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl-3-[4-(lH-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 44, 65 mg) as a colorless crystalline powder.
H-NMR (CDCl3)~: 1.21 (3H,d,J=7Hz), 4.22 (lH,d,J=14Hz), 5.11 (lH,q,J=7Hz), 5.18 (lH,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 CA 022ll458 l997-07-24 W O96~2S410 PCT/Jl,-'~0~
(lH,m), 7.75 (lH,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.
W O96/25410 PCT/J~3G~
Table 10 HO CH~
I~N--CH2~ CR)--Q
D
Compo~nd No. D Q
2,4-F2 --h~ ~OCH2CF2CF2H
O O
2 2,4-F2 ~ 3 OCH2CF2CF2H
O ' O
3 2,4-F2 --~ ~OCF2CF2H
4 2,4--F2 --1~ ~--CH2CF3 2,4-F2 _~ ~N'~
6 2,4-F2 --2,4-F2 --~
2,4-F2 --~ CH2CF2CF2H
2,4-F2 _~
2,4--F2 - --~ N~
WO 9612S410 PCI'~Jr~C,'00 Table 11 Compound No. D Q
11 2,4-F
12 2,4-F2 13 2,4-F2 --1 4 2,4-F2 2,4-F2 16 2,4-F2 --1 17 2,4--F2 --~CH2--18 2,4-F2 --~I~CH2--1 19 2,4--F2 --~Q 2,4-F2 ~ ~H2--1 W O96/2S410 PCTlJ~_''vC3 Table 12 Compound No. D Q
2,4-Fz --~I~CH2--1 22 2,4-F2 --t~
23 2,4-F2 24 2,4-F2 2,4-F2 26 2,4-F2 --1 27 ~,4-F2 --2,4-F2 --I~I~CH2--1 29 2,4-F2 --~I~CH2--1 2,4-F2 --~ ~CH3 WC~ 9612S410 PCr/JP96/00325 Table 13 ComPound No. D Q
3 l 2,4-F2 ~ WH3 33 2--F --t~
2-F ~
36 2,4-F2 --~ /cH3 37 2,4-F2 --~H3 39 2-F --~
W O96t2S410 PCT/JF~6/00 Table 14 Compound No. D Q
42 2,4-F2 43 2,4-F2 --Formulation Exam~le 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.
CA 022114~8 1997-07-24 WO 96/2S410 PCT/Jr~C/~ 7~;
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 lO 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 1050 mg Lactose 65 mg Corn Starch 30 mg Soluble Starch 35 mg Magnesium Stearate 20 mg Total 200 mg Ex~eriment ExamPle 1 Test Method: Five-week-old Crj: CDF1 mice were inoculated with the minimum lethal dose of Candida al bicans TA intrave-nously. The test compounds were administered orally once immediately after infection as a 30% HPCD (hydroxypropyl-~-cyclodextrin) solution. The activity was expressed in terms of ED50 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. ED~(mg/~) PO
0.22 6 0.35 7 0.096 0.16 0 0.32 1 1 0.45 13 0.18 4 0.32 19 0.39 0.088 26 O.t6 0.18 34 0.80 0.71 PO: oral ~rini~tration CA 022ll458 l997-07-24 W0 961'~S41~ PC'r~J
Table 16 Compound No. ED~(mg/kg) PO
38 s ~' 39 0.5 0.35 41 0.80 42 0.22 43 0.89 44 0.39 0.45 P0: oral ~ ni~tration - .
W 096t2S410 PCTIJ~CI~C~
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 m~mm~lS as antifungal preparations. In addition, they can serve as antifungal preparations for agricultural use.
Claims (24)
1. A compound represented by the formula (I):
(I) wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; 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.
(I) wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; 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 selected from the group consisting of a halogen atom, a C1-4 haloalkyl group, a C1-4 haloalkoxy group, a C1-4 alkylsulfonyl group and a C1-4 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 C2-4 alkylene group; R3 is a hydrogen atom, a C1-7 alkanoyl group, a C7-15 arylcarbonyl group, a C2-7 alkoxycarbonyl group, a C7-15 aryloxycarbonyl group or a C8-20 aralkylcarbonyl group; A is Y=Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a C1-4 alkyl group) or an ethylene group optionally substituted with a C1-4 alkyl group; and Az is an azolyl group optionally substituted with one or two substituents selected from the group consisting of an oxo group, a hydroxyl group, a carboxyl group, an optionally esterified carboxyl group, a nitro group, an amino group, a C1-10 alkanoyl amino group, a mono-C1-10 alkylamino group, a di-C1-10 alkylamino group, a C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a thioxo group, a mercapto group, a C1-6 alkylthio group, a C1-6 alkylsulfonyl group, a C1-10 alkanoyl group, a phenyl group, a C1-6 alkylphenyl group, a C1-6 alkoxyphenyl group, a halophenyl group, a C1-6 haloalkylphenyl group and a C1-6 haloalkoxyphenyl group.
3. A compound of claim 1 in which an azolyl group of Az is 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-constituent atom.
4. A compound of claim 1 in which one of R1 and R2 is a hydrogen atom and the other is a C1-4 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 C1-6 alkyl group, a C1-6 haloalkyl group and a C1-6 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'):
( I') 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 C1-6 alkyl group, a C1-6 haloalkyl group and a C1-6 haloalkyloxyphenyl group, or a salt thereof.
( I') 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 C1-6 alkyl group, a C1-6 haloalkyl group and a C1-6 haloalkyloxyphenyl 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-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,4-triazol-1-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-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-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-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)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):
(II) wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; 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, with a compound represented by the formula (III):
(III) 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 (IV):
(IV) wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; and X is a nitrogen atom or a methine group; or a salt thereof, with a compound represented by the formula (V'):
(V') 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") (I") wherein Ar is an optionally substituted phenyl group; R1 and R2, 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 R3 is not hydrogen.
(II) wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; 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, with a compound represented by the formula (III):
(III) 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 (IV):
(IV) wherein Ar is an optionally substituted phenyl group; R1 and R2, 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; and X is a nitrogen atom or a methine group; or a salt thereof, with a compound represented by the formula (V'):
(V') 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") (I") wherein Ar is an optionally substituted phenyl group; R1 and R2, 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 R3 is not hydrogen.
22. A pharmaceutical composition which comprises a pharmacologically 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 pharmacologically 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.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7/29579 | 1995-02-17 | ||
| JP2957995 | 1995-02-17 | ||
| JP28531895 | 1995-11-01 | ||
| JP7/285318 | 1995-11-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2211458A1 true CA2211458A1 (en) | 1996-08-22 |
Family
ID=26367799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2211458 Abandoned CA2211458A1 (en) | 1995-02-17 | 1996-02-15 | Azole compounds, their production and use |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU4675596A (en) |
| CA (1) | CA2211458A1 (en) |
| WO (1) | WO1996025410A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010005792A (en) * | 1997-03-31 | 2001-01-15 | 다케다 야쿠힌 고교 가부시키가이샤 | Azole compounds, their production and their use |
| 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 |
| GB9808447D0 (en) * | 1998-04-18 | 1998-06-17 | Zeneca Ltd | Process |
| WO2000034267A1 (en) * | 1998-12-04 | 2000-06-15 | Takeda Chemical Industries, Ltd. | Process for producing cyclic amide compound |
| US6319933B1 (en) * | 2000-04-17 | 2001-11-20 | Basilea Pharmaceutica Ag | Azole derivatives |
| IN192526B (en) * | 2001-09-25 | 2004-04-24 | Ranbaxy Lab | |
| US6884892B2 (en) * | 2002-06-20 | 2005-04-26 | Sumitomo Chemical Company, Limited | Production methods of 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 |
| DE10233817A1 (en) * | 2002-07-25 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Substituted diaryl heterocycles, process for their preparation and their use as medicaments |
| KR102457933B1 (en) | 2016-05-27 | 2022-10-24 | 브리스톨-마이어스 스큅 컴퍼니 | Triazolones and Tetrazolones as Inhibitors of ROCK |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW212798B (en) * | 1991-11-25 | 1993-09-11 | Takeda Pharm Industry Co Ltd | |
| TW218017B (en) * | 1992-04-28 | 1993-12-21 | Takeda Pharm Industry Co Ltd | |
| TW297813B (en) * | 1993-09-24 | 1997-02-11 | Takeda Pharm Industry Co Ltd |
-
1996
- 1996-02-15 WO PCT/JP1996/000325 patent/WO1996025410A1/en not_active Application Discontinuation
- 1996-02-15 CA CA 2211458 patent/CA2211458A1/en not_active Abandoned
- 1996-02-15 AU AU46755/96A patent/AU4675596A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996025410A1 (en) | 1996-08-22 |
| AU4675596A (en) | 1996-09-04 |
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