Indian Patents
Title of Invention

TRIAZOLE DERIVATIVES HAVING ANTIFUNGAL ACTIVITY
Abstract A compound of the following formula (I) or a pharmaceuticalty acceptable salt or ester derivative thereof. wherein Ar is a phenyl group which may optionally be substituted from 1 to 3 substituents selected from the group consisting of halogen atoms and trifluoromethyl groups, in which ester derivative the hydroxyl group is protected to give an estar derivative which is capable of being cleaved in the body of a live animal to give the parent compound of formula (I) or a salt thereof.
Full Text TRIAZOLE DERIVATIVES HAVING ANTIFUNGAL ACTIVITY
The present invention relates to triazole derivatives having excellent activity
against a wide range of fungi, to certain of said derivatives in crystalline form, to a
pharmaceutical composition containing said derivatives, to the use of said derivatives
in treating and preventing fungal infections and to an intermediate useful in the
preparation of said derivatives.
Antifungal triazole derivatives having the following general formula are
disclosed in Japanese Patent Application (Kokai) Hei 8-333350 and EP-A-0841327:

wherein Ra represents a hydrogen atom or an alkyl group, Rb represents an alkyl
group. Ar1 and Ar2 can each represent an optionally substituted phenyl group, q and r
can each represent 1, and each of Rc, Rd, Rc and Rf can represent a hydrogen atom.
Similar compounds, in which the sulfur atom is replaced by a methylene group are
disclosed in Japanese Patent Application (Kokai) Hei 11-80135 and WO-A-99/02524.
These prior art compounds show good antifungal activity. There is, however,
a need for further compounds having improved antifungal activity, stability,
pharmacokinetics and safety.
It is therefore an object of the present invention to provide a series of new
compounds having antifungal activity.
Other objects and advantages of the present invention will become apparent as
the description proceeds.'


The compounds of the present invention are compounds of the following
formula (I), and pharmaceutically acceptable salts and ester derivatives thereof:

wherein Ar is a phenyl group which may optionally be substituted by from 1 to 3
substituents selected from the group consisting of halogen atoms and trifluoromethy]
groups.
The present invention also provides the compound (2R.3R)-3-[[trans-2-
((lE.3E)-4-(4-cyano-2-nuorophenyl)-1.3-butadien-l-yl]-1.3-dioxan-5-y)]thio]-2-(2.4-
difluorophenyl)-l-(lH-1.2.4-triazol-l-yl)-2-butanol [formula (lb) below] in crystalline
form:

The present invention also provides a pharmaceutical composition comprising
an effective amount of a pharmacologically active compound together with a
pharmaccutically acceptable diluent or carrier therefor, wherein said
pharmacologically active compound is a compound of formula (I) or a
pharmaceuticaHy acceptable salt or ester derivative thereof.
The present invention also provides a compound of formula (I) or a
pharmaceutically acceptable salt or ester derivative thereof for use as a medicament


and the use of a compound of formula (I) or a pharmaceutically acceptable salt or
ester derivative thereof in the manufacture of a medicament for the prophylaxis or
treatment of fungal infections.
Figure 1 shows the X-ray diffraction pattern of a first crystalline form of
(2R.3R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-1.3-
dioxan-5-yl]thio]-2-(2.4-difluorophenyl)-1 -(1H-1.2.4-triazol-1 -yl)-2-butanol. by me
powder method using the copper Kα-ray. X = 1.54 A. The vertical axis of the powder
X-ray diffraction pattern indicates diffraction intensity in units of counts/second (cps).
while the horizontal axis indicates the diffraction angle as the value 20.
Figure 2 shows the X-ray diffraction pattern of a second crystalline form of
(2R,3R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-1.3-
dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1 -(1H-1,2,4-triazol-1 -yl)-2-butanol. by the
powder method using the copper Kα-ray, X = 1.54 A. The vertical axis of the powder
X-ray diffraction pattern indicates diffraction intensity in units of counts/second (cps),
while the horizontal axis indicates the diffraction angle as the value 29.
Examples of the halogen atoms which are optional substituents on the group
Ar include fluorine, chlorine and bromine atoms. Fluorine and chlorine atoms are
preferred, and fluorine atoms are most preferred.
Examples of the substituent Ar include phenyl, dichlorophenyl.
difluorophenyl, dibromophenyl, chlorophenyl, fluorophenyl, bromophenyl.
trifluorophenyl, trichlorophenyl, tribromophenyl, (trifluoromethyl)phenyl,
bis(trifluoromethyl)phenyl, tris(trifluoromethyl)phenyl, fluoro(trifluoromethyl)phenyl
and chloro(trifluoromethyl)phenyl groups. Preferably, the group Ar is a phenyl
group which is substituted by 1 or 2 substituents selected from fluorine atoms,
chlorine atoms and trifluoromethyl groups. More preferably, the substituent Ar is a
phenyl group which is substituted with 1 or 2 fluorine atom(s). Still more preferably,
the substituent Ar is a 2-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-
difluorophenyl or 2,5-difluorophenyl group, particularly a 2-fluorophenyl or 2,4-
difluorophenyl group. Most preferably, the substituent Ar is a 2,4-difluorophenyl
group.


The compounds of formula (I) of the present invention can exist in the form of
stereoisomers and geometrical isomers. There are two asymmetric carbon atoms in
the compounds of formula (I) and each of said carbon atoms can therefore take the R
or S configuration. Preferably both of them are R configuration. These optical
isomers can be isolated by a conventional optical resolution method. Each of the four
possible optical isomers for any given compound of formula (I) can be prepared by
asymmetric synthesis. These optical isomers can also be isolated by conventional
techniques such as fractional crystallization and chromatography.
The compounds of formula (I) have a 2.5-disubstituted-1.3-dioxane ring.
Consequently, they can exist as cis or trans isomers with regard to the 2- and 5-
positions. The trans isomers are preferred. These cis and trans isomers can be
isolated by conventional techniques such as fractional crystallization and
chromatography.
The compounds of formula (I) have two double bonds. Consequently, they
exist as geometrical isomers in which each double bond has either the E or Z
configuration. The preferred geometrical isomers are those in which both of the
double bonds are E configuration. These geometrical isomers can be isolated by
conventional techniques such as fractional crystallization and chromatography.
The present invention includes each of the individual isomers described above
and mixtures of two or more thereof in any proportion, including racemic mixtures.
Of the possible isomers of the compounds of formula (I), the following isomer
of formula (la) is most preferred:


The present invention encompasses pharmaceutically acceptable ester
derivatives of the compounds of formula (I). These pharmaceutically acceptable ester
derivatives are so-called pro-drugs, in which a functional group (the hydroxy group)
in the compound of formula (I) is protected by a group which is capable of being
cleaved by a chemical or biological process (e.g. by hydrolysis) on administration of
the derivative to the body of a live animal to give the parent compound of formula (I)
or a salt thereof. Whether a derivative of a compound of formula (I) is
pharmaceutically acceptable can be easily determined. The ester derivative under
investigation is administered orally or intravenously to a test animal such as a mouse
or a rat and the body fluids of the test animal are thereafter studied. If the parent
compound of formula (I) or a salt thereof is detected in the body fluids of the test
animal, the ester derivative under investigation is judged to be a pharmaceutically
acceptable ester derivative of the compound of formula (I).
The group in the compounds of formula (I) which can be modified to give a
pharmaceutically acceptable ester derivative thereof is the hydroxyl group. Thus, the
pharmaceutically acceptable ester derivatives of the compounds of formula (I) are
those in which the hydroxyl group is protected to give an ester derivative which is
capable of being cleaved in the body of a live animal to give the parent compound of
formula (I) or a salt thereof.
Examples of pharmaceutically acceptable ester derivatives of the compounds
of formula (I) are those in which the hydroxy group is protected by an acyl group.
Examples of said acyl groups include aliphatic acyl groups^aromatic acyl groups,
alkoxycarbonyl groups, aralkyloxycarbonyl groups, aminoacyl groups and phosphoric
acid groups.
The aliphatic acyl groups have from 1 to 20 carbon atoms and can contain
from 1 to 3 double or triple bonds. Examples of such aliphatic acyl groups include
alkylcarbonyl groups having from 1 to 20 carbon atoms, alkenylcarbonyl groups
having from 3 to 20 carbon atoms and alkynylcarbonyl groups having from 3 to 20
"carbon atoms, said groups optionally being substituted by at least one substituent such
as a hydroxy group, an alkoxy group, a halogen atom, a phosphoric acid group and a
carboxy group.

Examples of the alkylcarbonyl groups having from 1 to 20 carbon atoms
include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl. isovaleryl.
octanoyl, nonanoyl, decanoyl. 3-methylnonanoyl. 8-methyl-nonanoyl. 3-
ethyloctanoyl, 3.7-dimethyloctanoyl. undecanoyl. dodecanoyl. tridecanoyl.
tetradecanoyl, pentadecanoyl, hexadecanoyl. 1 -methylpentadecanoyl. 14-
methylpentadecanoyl. 13.13-dimethyltetradecanoyl. heptadecanoyl. 15-methyl-
hexadecanoyl, octadecanoyl. 1-methylheptadecanoyl. nonadecanoyl. and eicosanoyl
groups.
Examples of the alkenylcarbonyl groups having from 3 to 20 carbon atoms
include acryloyl, methacryloyl, crotonoyl, isocrotonoyl and (E)-2-methyl-2-butenoyl
groups.
Examples of the alkynylcarbonyl groups having from 3 to 20 carbon atoms
include propioloyl groups.
The aromatic acyl groups are arylcarbonyl groups having from 7 to 11 carbon
atoms such as benzoyl, a-naphthoyl and P-naphthoyl groups. The aryl ring of these
aromatic acyl groups may optionally have at least one substituent such as an alkyl
group having from 1 to 4 carbon atoms, an aromatic acyl group (which may optionally
have at least one substituent such as an alkyl group having from 1 to 4 carbon atoms),
a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, a hydroxy group, a
carboxy group, an alkoxycarbonyl group wherein the alkoxy moiety has from 1 to 4
carbon atoms, a hydroxyalkyl group having from 1 to 4 carbon atoms, an alkyl group
having from 1 to 4 carbon atoms which is substituted by a phosphoric acid group or
an alkyl group having from 1 to 4 carbon atoms which is substituted by a carboxy
group.
The alkoxycarbonyl groups comprise a carbonyl group which is substituted by
an alkoxy group having from 1 to 20 carbon atoms, examples of which include groups
such as methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl and tert-
"butoxycarbonyl groups. The alkoxy moiety of these alkoxycarbonyl groups may
optionally have at least one substituent such as an alkyl group having from 1 to 4

carbon atoms, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, a
hydroxy group, a phosphoric acid group, a carboxy group, an alkoxycarbonyl group in
which the alkoxy moiety has from 1 to 4 carbon atoms, a hydroxyalkyl group having
from 1 to 4 carbon atoms, an alkyl group having from 1 to 4 carbon atoms which is
substituted by a phosphoric acid group or an alkyl group having from 1 to 4 carbon
atoms which is subtituted by a carboxy group.
The aralkyloxycarbonyl groups comprise a carbonyl group which is
substituted by an aralkyloxy group having from 8 to 20 carbon atoms, examples of
which include a benzyloxycarbonyl group. The aryl ring of these aralkyloxycarbonyl
groups may optionally have at least one substituent such as an alkyl group having
from 1 to 4 carbon atoms, a halogen atom, an alkoxy group having from 1 to 4 carbon
atoms, a hydroxy group, a phosphoric acid group, a carboxy group, an alkoxycarbonyl
group in which the alkoxy moiety has from 1 to 4 carbon atoms, a hydroxyalkyl group
having from 1 to 4 carbon atoms, an alkyl group having from 1 to 4 carbon atoms
which is substituted by a phosphoric acid group or an alkyl group having from 1 to 4
carbon atoms which is subtituted by a carboxy group.
The amino acyl group is an amino acid group such as glycyl. alanyl. leucyl.
phenylalanyl, glutamyl and asparaginyl groups or an aminoalkanoyl group having
from 1 to 10 carbon atoms such as P-alanyl, aminobutyryl and aminooctanoyl groups.
The phosporic acid group includes a phosporic acid group; a monoaikyl-
phosphonic acid group in which the alkyl moiety has from 1 to 20 carbon atoms,
examples of which include methylphosphate, ethyl phosphate, propyl phosphate, butyl
phosphate, decyl phosphate and octadecyl phosphate groups; and a dialkylphosphonic
acid group in which each alkyl moiety is the same or different and has from 1 to 20
carbons atoms, examples of which include dimethyl phosphate, diethyl phosphate,
dipropyl phosphate, dibutyl phosphate, didecyl phosphate and dioctadecyl phosphate
groups.
A pharmaceutically acceptable salt of a compound of formula (I) or a
pharmaceutically acceptable ester derivative thereof is a salt which has the same low

toxicity as, or is not significantly more toxic than, the compound of formula (I) or

dimensional structure and repeats the arrangement. The crystal is different from an
amorphous solid that has no regular arrangement of atoms in a three-dimensional
structure.
Different crystalline forms of the compound of formula (lb) of the present
invention can be produced depending upon the crystallization conditions used. These
different crystalline forms have different three-dimensional arrangements of the atom
and have different physicochemical properties.
The present invention encompasses these different crystalline forms and
mixtures of two or more of said crystalline forms.
One example of the compound of formula (lb) in crystalline form is a
crystalline form which has main peaks at lattice distances of 3.14. 3.39. 3.71. 3.75.
4.21,4.88, 5.28, 5.42, 5.89, 5.95, 6.79, 6.86. 8.03 and 8.41 A determined by X-ray
diffraction by the powder method using the copper KQ-ray, X = 1.54 A. A second
example of the compound of formula (lb) in crystalline form is a crystalline form
which has main peaks at lattice distances of 3.62, 3.96, 4.54,4.59, 4.79, 4.91, 5.32,
5.48, 6.18, 7.99 and 15.93 A determined by X-ray diffraction by the powder method
using the copper Ka-ray, X = 1.54 A. The main peaks are those having a diffraction
intensity of greater than 2000 counts per second (cps).
Preferred compounds of formula (I) and pharmaceutically acceptable salts and
ester derivatives thereof include:
(A) a compound of formula (I) or a pharmaceutically acceptable salt or ester
derivative thereof wherein Ar represents a 2,4-difluorophenyl group or a 2-
fluorophenyl group.
(B) a compound of formula (I) or a pharmaceutically acceptable salt or ester
derivative thereof wherein Ar is a 2,4-difluorophenyl group.
(C) a compound of formula (la) below or a pharmaceutically acceptable salt or
ester derivative thereof:


wherein Ar is a phenyl group or a phenyl group substituted with 1 to 3 substituents
selected from halogen atoms and trifluoromethyl groups.
(D) (2R.3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-
l,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2-butanol
(compound (lb)) or a pharmaceutically acceptable salt or ester derivative thereof.
More preferred are the following compounds of formula (I) and
pharmaceutically acceptable salts or ester derivatives thereof:
(2R,3R)-3-[[trans-2-[( 1 E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadien-1 -yl]-1,3-
dioxan-5-yl]thio]-2-(2-fluorophenyl)-1 -(1H-1,2,4-triazol-1 -yl)-2-butanol.
(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l,3-butadien-l-yl]-K3-
dioxan-5-yl]thio]-2-(4-fluorophenyl)-1 -(1H-1,2,4-triazol-l -yl)-2-butanol.
(2R,3R)-3-[[trans-2-[(l E,3E)-4-(4-cyano-2-fluoropheTryl)-l ,3-butadien-l -yl]-l ,3-
dioxan-5-yl]thio]-2-(2,3-difluorophenyl)- 1 -(1H-1,2,4-triazol-1 -yl)-2-butanol,
(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l ,3-butadien-l -yl]-l ,3-
dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1 -(1 H-l ,2,4-triazol-1 -yl)-2-butanol,
(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l ,3-butadien-l -yl]-l,3-
dioxan-5-yl]thio]-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2-butanol,
(2R,3R)-3-[[trans-2-[(l E,3E)-4-(4-cyano-2-fluorophenyl)-l ,3-butadien-1 -yl]-1,3-
dioxan-5-yl]thio]-2-(4-chlorophenyl)-1 -(1H-1,2,4-triazol-l -yl)-2-butanol,

(2R.3R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-1.3-
dioxan-5-yl]thio]-2-(2.4-dichlorophenyl)-l-(lH-L2.4-triazol-l-yl)-2-butanol. and
(2R.3R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-1.3-
dioxan-5-yl]thio]-2-[4-(trifluoromethyl)phenyl]-1 -(1H-1.2.4-triazol-1 -yl )-2-butanol.
Yet more preferred are the following compounds of formula (I) and
pharmaceutically acceptable salts and ester derivatives thereof:
(2R^R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-1.3-
dioxan-5-yl]thio]-2-(2-fluorophenyl)-l-(lH-L2,4-triazol-l-yl)-2-bmanoK
(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l,3-butadien-l-yl]-L3-
dioxan-5-yl]thio]-2-(4-fluorophenyl)-1 -(1H-1.2,4-triazol-1 -yl)-2-butanol,
(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-l-yl]-1.3-
dioxan-5-yl]thio]-2-(2,3-difluorophenyl)-l-(1 H-l.2,4-triazol-l-yl)-2-butanol.
(2R,3R)-3-[[trans-2-[(l E,3E)-4-(4-cyano-2-fluorophenyl)-1.3-butadien-1-yl]-1.3-
dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1 -(1H-1.2,4-triazol-1 -yl)-2-butanol, and
(2R,3R)-3-[[trans-2-[( 1 E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadien-1 -yl ]-1,3-
dioxan-5 -yl]thio]-2-(2,5-difluorophenyl)-1 -(1H-1,2,4-triazol-1 -yl )-2-butanol.
The most preferred compound of formula (I) is (2R,3R)-3-[[trans-2-[(lE,3E)-
4-(4-cyano-2-fluorophenyl)-1,3-butadien-l-yl]-l,3-dioxan-5-yl]thio]-2-(2,4-difluoro-
phenyl)-1 -(1H-1,2,4-triazol-1 -yl)-2-butanol.


In the above reaction scheme, the substituent Ar is as defined earlier.
The method A comprises the reaction of a compound of formula (V) with a
compound of formula (II) in the presence of an acetalization reagent in an inert
solvent, water produced during this reaction being removed from the reaction mixture
during said reaction.
In method A, a salt of the compound of formula (V) or the following
compound of formula (Va), can be used instead of the compound of formula the starting material:

wherein Ar is as defined above, and R4 is an alkyl group having from 1 to 6 carbon
atoms, an aryl group having from 6 to 10 carbon atoms or an indenyl group.
In the definition of substituent R4, the alkyl group having from 1 to 6 carbon
-atoms is a straight or branched alkyl group having from 1 to 6 carbon atoms,
examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl and hexyl groups. Straight or branched alkyl groups having from 1

to 4 carbon atoms are preferred. In the definition of substituent R4. the aryl group
having from 6 to 10 carbon atoms is an aromatic hydrocarbon group having from 6 to
10 carbon atoms such as a phenyl or naphthyl group, of which phenyl groups are
preferred. Compounds of formula (Va) in which R4 is a phenyl group are preferred.
Compounds of formula (V) can be prepared according to the method described
in Japanese Patent Application (Kokai) Hei 8-333350. or by a modified version
thereof. Compounds of formula (Va) can be obtained as an intermediate in the
process for preparing the compounds of formula (V) described in Japanese Patent
Application (Kokai) Hei 8-333350. Salts of the compounds of formula (V) can be
obtained by the removal of the acetal protecting group from the compounds of
formula (Va) using an acid.
In method A, an acetal derivative of the compound of formula (II) can be used
as an alternative starting material to the compound of formula (II). The compound of
formula (II) can be prepared by Method B described below, while the acetal
derivative of the compound of formula (II) can be obtained by using as the starting
material in method B an acetal derivative of the compound of formula (IV).
In method A, the amount of the compound of formula (II) or acetal derivative
thereof which is used is from 0.5 to 2 molar equivalents of the compound of formula
(V), and is preferably from 0.9 to 1.2 molar equivalents.
In method A, there is no particular limitation on the solvent used provided that
it has no adverse effect on the reaction and that it dissolves the starting materials at
least to some extent. Suitable solvents are aprotic solvents, for example halogenated
hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic
hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether or
tetrahydrofuran; or a mixture thereof. Halogenated hydrocarbons and ethers are
preferred, and dichloromethane or tetrahydrofuran are particularly preferred.

chloride; sulfonic acids such as methanesulfonic acid, benzenesul.fonic acid, p-
toluenesulfonic acid, camphorsulfonic acid or trifloromethanesulfonic acid;
carboxylic acids such as formic acid, acetic acid, trifiuoroacetic acid, oxalic acid or
citric acid; and silylating agents such as chlorotrimethylsilane or trimethylsilyl
trifluoromethanesulfonate. The preferred acetalization reagents are sulfonic acid
derivatives, and p-toluenesulfonic acid is particularly preferred.
In method A. the amount of the acetalization reagent used is from 0.5 to 3
molar equivalents of the amount of the compound of formula (V) used, and is
preferably from 1.0 to 1.4 molar equivalents.
Water produced during the reaction of Method A can be removed by
azeotropic distillation of the reaction solvent, by evaporation under reduced pressure
or by using a dehydrating reagent such as molecular sieves.
The reaction temperature employed in the reaction of method A depends upon
various factors such as the solvent, the starting materials and the acetalization reagent
used. However, it is usually from 0°C to the boiling point of the solvent used, and is
preferably from 5°C to 40°C.
The reaction time for the reaction of method A depends on a number of factors
such as the starting materials, the acetalization reagent, the solvent and the reaction
temperature. However, it is usually from 0.5 to 24 hours, and is preferably from 1 to
5 hours.
After the reaction of method A is complete, the reaction mixture is neutralized
with an aqueous sodium bicarbonate solution or the like and the desired compound is
then isolated using a conventional isolation technique. For example, the reaction
mixture or the residue of the reaction mixture obtained by evaporation of the solvent
from the reaction mixture is partitioned between an organic solvent and water,
washing the organic layer with water and then distilling off the solvent to give the
"desired product of formula (I).

The product thus obtained can. if necessary, be further purified using a
conventional technique such as recrystallization. reprecipitation or chromatography.
A pharmaceutically acceptable ester derivative of a compound of formula (I)
can be prepared in a conventional manner known to those skilled in the art (see. for
example. "Protective Groups in Organic Synthesis". Theodora W. Greene and Peter
G. M. Wuts, Second Edition, 1991. John Wiley & Sons. Inc.). Of these
pharmaceutically acceptable ester derivatives, acyl derivatives are prepared by
acylation of the hydroxy group according to procedures well known in the art.
The compound of formula (I) or ester derivative thereof thus obtained can be
converted to a salt thereof by the addition of a pharmaceutically acceptable acid or
base to a solution of said compound of formula (I) or ester derivative thereof.
The solvent used in preparing a salt of a compound of formula (I) or a
pharmaceutically acceptable ester derivative thereof is not particularly limited
provided that it has no adverse effect on the reaction and that it dissolves the starting
materials at least to some extent. Examples of suitable solvents include aromatic
hydrocarbons such as benzene or toluene; halogenated hydrocarbons such as
dichloromethane or chloroform; ethers such as diethyl ether, tetrahydrofuran or
dioxane; esters such as ethyl acetate; alcohols such as methanol or ethanol; ketones
such as acetone; nitriles such as acetonitrile; hydrocarbons such as hexane or
cyclohexane; or a mixture thereof.
The acid for preparing the pharmaceutically acceptable salt may be a
pharmaceutically acceptable acid, for example inorganic acids such as hydrochloric
acid, hydrogen bromide, sulfuric acid or nitric acid; carboxylic acids such acetic acid,
fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid or malic
acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid or toluenesulfonic acid; and amino acid derivatives such as
glutamic acid or aspartic acid. Inorganic acids and carboxylic acids are preferred, and
"hydrochloric acid, nitric acid, fumaric acid, maleic acid or oxalic acid are particularly
preferred.

The base for preparing the pharmaceutically acceptable salt may be a
pharmaceutically acceptable base, for example alkali metal hydroxides or alkaline
earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium
hydroxide, calcium hydroxide or magnesium hydroxide; alkaline metal carbonates or
alkaline earth metal carbonates such as sodium carbonate, potassium carbonate,
lithium carbonate, calcium carbonate or magnesium carbonate: alkali metal
hydrogencarbonates such as sodium hydrogencarbonate. potassium
hydrogencarbonate or lithium hydrogencarbonate: other inorganic bases such as
ammonia; and amine salts such as t-octylamine. dibenzylamine. morpholine.
glucosamine, phenylglycine alkyl esters, ethylenediamine. methylglucamine.
guanidine, diethylamine. triethylamine, dicyclohexylamine. N.N'-dibenzylethyl-
enediamine, chloroprocaine, procaine, diethanolamine, benzylphenethylamine.
piperazine, tetramethylammonium and tris(hydroxymethyl)aminomethane.
The desired salt of the compound of formula (I) or pharmaceutically
acceptable ester derivative thereof is usually precipitated as crystals or a powder from
the reaction solution of said compound of formula (I) or pharmaceutically acceptable
derivative thereof with an acid or base. The desired salt can also be obtained as a
precipitate by the addition of a solvent which slightly dissolves the salt to the solution
of said salt, or by removal of the solvent from the solution containing the desired salt.
An acetal derivative of the compound of formula (II) or the compound of
formula (Ha) is a derivative in which the aldehyde group of said compound of formula
The compound of formula (II) or an acetal derivative thereof is particularly
suitable for the synthesis of the compounds of formula (I) of the present invention and
it therefore also forms a part of the present invention. The following compound of
formula (Ha) or an acetal derivative thereof is particularly preferred.


(II) or said compound of formula (TIa) is protected as a group of formula
CH(OR1)(OR2) wherein R1 and R2 are the same or different and each is independently
selected from the group consisting of hydrogen atoms and alkyl groups having from 1
to 4 carbon atoms, or R1 and R2 together form an alkylene group having from 1 to 4
carbon atoms.
In the definition of the substituents R1 and R: the alkyl groups having from 1
to 4 carbon atoms include methyl, ethyl, propyl, isopropyl. butyl, isobutyl. sec-butyl
and tert-butyl groups, of which methyl groups are preferred.
In the definition of the substituents R1 and R2. the alkylene groups having
from 1 to 4 carbon atoms include methylene, methylmethylene, ethylene, propylene,
trimethylene, tetramethylene, 1-methyltrimethylene. 2-methyltrimethylene and 3-
methyltrimethylene groups, of which ethylene groups are preferred.
The preferred acetal derivatives of the compounds of formulae (II) and (Ha)
are those having the acetal group -CH(OR')(OR2) in which each of R1 and R" is a
methyl group.
The compound of formula (II) and the acetal derivatives thereof have two
double bonds and they can therefore exist as.geometrical isomers in which each
double bond as the E or Z configuration. The present invention encompasses both the
individual geometrical isomers and mixtures of two or more of them. Among these
isomers, the compound of formula (Ha) and acetal derivatives thereof in which both
double bonds have the E configuration is preferred.
When the compound of formula (II) or an acetal derivative thereof is allowed
to stand so that it is open to the atmosphere, it may absorb water to form a hydrate.
The compound of formula (II) or an acetal derivative thereof may also absorb a
solvent to give a solvate. The present invention also encompasses these hydrates and
solvates.
The starting material of formula (II) can be prepared by Method B depicted in
the reaction scheme shown below.


In the above reaction scheme, X is a halogen atom (preferably a chlorine or
bromine atom) and R3 is an alkyl group having from 1 to 6 carbon atoms which may
optionally be substituted with at least one fluorine atom.
Method B involves the reaction of a 4-(halogenomethyl)-3-fluorobenzonitrile
compound of formula (VI) [which can, for example, be prepared according to the
process disclosed in J. Med. Chem., 40, 2064 (1997)] with a compound of formula
(VII) to afford a compound of formula (IN), followed by the reaction of said
compound of formula (III) with a compound of formula (IV) to give the desired
compound of formula (II).
In the definition of substituent R3, the alkyl group having from 1 to 6 carbon
atoms which is optionally substituted by at least fluorine atom is, for example, a
methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 1-fluoroethyl, 2-
fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl, 3-fluoropropyl,
butyl, isobutyl, sec-butyl, tert-butyl, 4-fluorobutyl, pentyl or hexyl group. Of these,
alkyl groups having from 1 to 4 carbon atoms which are optionally substituted by
from 1 to 3 fluorine atoms such as methyl, ethyl, propyl, butyl or 2,2,2-trifluoroethyl
groups are preferred, unsubstituted alkyl groups having from 1 to 4 carbon atoms are
"more preferred and ethyl.groups are most preferred.

In step Bl a compound of formula (III) is prepared by heating a 4-(halogeno-
methyl)-3-fluorobenzonitrile compound of formula (VI) [which can. for example, be
prepared according to the process disclosed in J. Med. Chem.. 40. 2064 (1997)] with a
compound of formula (VII) in the presence or absence of a solvent.
Examples of the compound of formula (IV) include 4-(chloromethyl)-3-
fluorobenzonitrile and 4-(bromomethyl)-3-fluorobenzonitrile. of which 4-
(bromomethyl)-3-fluorobenzonitrile is preferred.
Examples of the compound of formula (VII) include trialkyl phosphites, in
which each alkyl group is the same or different and is a primary alkyl group having
from 1 to 4 carbon atoms, such as trimethyl phosphite, triethyl phosphite, tripropyl
phosphite or tributyl phosphite; and tris(fluoroalkyl) phosphites, in which each
fluoroalkyl group is the same or different and is a primary alkyl group having from 1
to 4 carbon atoms which is substituted by at least one fluorine atom such as tris(2.2.2-
trifluoroethyl) phosphite. The preferred compounds of formula (VII) are the trialkyl
phosphites, of which triethyl phosphite is most preferred.
The amount of the compound of formula (VII) employed is from 1 and 5
molar equivalents of amount of the compound of formula (VI) used, and is preferably
from 1 to 1.5 molar equivalents of the compound of formula (VI).
Thesolvent employed in step Bl is not particularly limited provided that it has
no adverse effect on the reaction and dissolves the starting materials to at least some
extent. Suitable solvents are aprotic solvents, for example hydrocarbons such as
hexane, cyclohexane, heptane, octane, nonane, decaneor decalin; aromatic
hydrocarbons which may optionally be substituted with at least one alkyl group or
halogen atom such as benzene, toluene, xylene, mesitylene, ethylbenzene or
chlorobenzene; halogenated hydrocarbons such as chloroform or dichloroethane;
esters such as ethyl acetate or butyl acetate; ethers such as tetrahydrofuran,
dimethoxyethane or dioxane; nitriles such as acetonitrile; and amide derivatives such
"as dimethylformamide; or mixture thereof. Preferably step B1 is conducted in the
absence of a solvent.

The reaction temperature employed in step B1 depends upon various factors
such as the nature of the starting materials and. if used, the solvent, but is typically
between 80°C and 170°C and is preferably between 85°C and 150°C.
The reaction time employed in step B1 mainly depends on the reaction
temperature and the solvent, if one is used. It is usually from 0.5 to 24 hours, and is
preferably from 1 to 3 hours.
After the reaction of step Bl is complete, volatile substances such as excess
compound of formula (VII), by-products of the reaction and solvent are evaporated
off to afford the desired product of formula (III), which can be used in the following
step B2 without further purification.
The product of formula (III) can, if necessary, be purified using a conventional
technique such as recrystallization, reprecipitation or chromatography.
In step B2 a compound of formula (II) or an acetal derivative thereof can be
prepared by condensation of a compound of formula (III) with a compound of formula
(IV) or with an acetal derivative thereof in the presence of base in a solvent, if
necessary, followed by removal of the acetal protecting group if desired.
An acetal derivative of the compound of formula (IV) is a compound in which
one of the two aldehyde groups of the compound of formula (IV) is protected with
group of formula CH(OR')(OR2) wherein R1 and R2 are as defined above. Preferred
acetal derivatives of the compound of formula (IV) include the dimethyl acetal and
ethylene acetal derivatives, of which the dimethyl acetal derivative of the compound
of formula (IV) is most preferred.
The compound of formula (IV) or an acetal derivative thereof can be prepared
according to a procedure described in the literature [see, for example, Chem. Ber., 45,
1748 (1912); Tetrahedron Lett., 38,1121 (1997); Justus Liebigs Ann. Chem., 638,
"187 (1960); and J. Chem. Soc, Perkin Trans. 1, 1907 (1991)], or in a modified
version of such literature procedures.

The amount of the compound of formula (IV) or acetal derivative thereof
employed in Step B2 is usually from 0.5 to 1.5 molar equivalents of the amount of the
compound of formula (III) used, and is preferably from 0.9 to 1.2 molar equivalents.
The solvent employed in this condensation reaction is not particularly limited
provided that it has no adverse effect on the reaction and dissolves the starting
materials to at least some extent. Suitable solvents include ethers such as
tetrahydrofuran, dioxane or dimethoxyethane; hydrocarbons such as hexane.
cyclohexane, benzene or toluene; sulfoxides such as dimethyl sulfoxide; or a mixture
thereof. Ether solvents are preferred, of which tetrahydrofuran is particularly
preferred.
The base used in step B2 is not particularly limited provided that it can
abstract an active proton from the compound of formula (III). Suitable bases include
organolithium compounds such as methyllithium, butyllithium or phenyllithium;
metal hydrides such as lithium hydride, sodium hydride or potassium hydride;
alkoxides such as sodium methoxide or potassium tert-butoxide; and sulfoxides
metalated with an alkali metal such as dimesyl sodium. Of these, organolithium
compounds are preferred, and butyllithium is particularly preferred.
The amount of base used is from 0.9 to 1.5 molar equivalents of the amount of
the compound of formula (III), and is preferably from 1 to 1.1 molar equivalents.
The temperature of the condensation reaction mainly depends on the base
employed. It is usually from -78°C to ambient temperature, and is preferably from
-20°C to 10°C.
The reaction time for step B2 mainly depends on the reaction temperature and
the solvent employed. It is usually from 30 minutes to 24 hours, and is preferably
from 1 to 3 hours.

If an acetal protecting group is employed and the target compound is the free
aldehyde of formula (II). an acid is added to the reaction mixture after the
condensation reaction is complete, and the reaction mixture is then stirred to remove
the acetal protecting group so as to afford the compound of formula (II).
The acid used for the removal of the acetal protecting group is not particularly
limited provided that it does not affect any of the other substituents and it is one that is
usually used in organic synthetic processes. Suitable examples of the acid which can
be employed include inorganic acids such as hydrochloric acid, sulfuric acid or nitric
acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluene-
sulfonic acid, camphorsulfonic acid or trifluoromethanesulfonic acid: and carboxylic
acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid or citric acid.
Of these, inorganic acids are preferred, and hydrochloric acid is particularly preferred.
The amount of acid used in the deprotection reaction is not particularly
limited. Preferably, the amount of acid used is such that the resulting pH of the
reaction mixture is from -1 to 3, preferably from 0 to 1.
The temperature used in the deprotection reaction is usually between -10°C
and 40°C, and is preferably between 0°C and ambient temperature.
The reaction time of the deprotection reaction depends mainly on the pH of the
reaction mixture and the reaction temperature. It is usually from 0.2 to 3 hours, and is
preferably from 0.5 to 1.5 hours.
The reaction product of formula (II) or acetal derivative thereof can be isolated
using a conventional technique, for example by partitioning the reaction mixture
between an organic solvent and water, washing the organic layer with water, followed
by evaporation of the solvent.
The product of formula (II) or acetal derivative thereof obtained above can be
further purified by a conventional manner such as recrystallization, reprecipitation or
chromatography.

Alternatively, the compound of formula (II) may be produced according to the
method described in Japanese Patent Application (Kokai) Hei 8-333350 or by a
modified version of said method.
The compound of formula (la), which is an isomer of the compound of
formula (I), can be prepared according to Method A above using the compound of
formula (Vb) below and the compound of formula (Ha) above as the starting
materials.

In this procedure a mixture of cis and trans isomers concerning the substituents
at the 2- and 5- position on the 1,3-dioxane ring are obtained. The trans isomer of
formula (la) can be isolated from the mixture of cis and trans isomers by
chromatography or recrystallization. When water produced during the reaction in
method A is removed under reduced pressure, the trans isomer is predominantly
obtained.
The compound of formula (Vb) can be prepared according to the method
described in Japanese Patent Application (Kokai) Hei 8-333350 or by a modified
version of said method. The compound of formula (Ila) can be produced by the
process of Method B using fumaraldehyde mono-dimethyl acetal as the starting
material in Step B2.
Crystals of the compound of formula (lb) or a salt thereof can be obtained
from a supersaturated solution thereof. The supersaturated solution can be obtained in
conventional manner such as through concentration of a solution of said compound of
formula (lb) or salt thereof, through the cooling of a solution of said compound of
formula (lb) or salt thereof or by adding a solvent in which said compound of formula
(lb) or salt thereof is sparingly soluble to a solution of said compound of formula (lb)

or salt thereof in which it is readily soluble. Precipitation of the crystals can take
place spontaneously in the reaction vessel or it can be accelerated by the addition of a
crystalline seed to the supersaturated solution of the compound of formula (lb) or salt
thereof, by mechanical stimulation such as through the use of ultrasonic waxes or by
scratching the inside of the reaction vessel.
A product of formula (lb) isolated according to Method A or a crude reaction
product containing the compound of formula (lb) can be crystallized.
Where the supersaturated solution of the compound of formula (lb) or salt
thereof is to he obtained by concentration of a solution thereof, this can be conducted
using a rotary evaporator or the like at atmospheric pressure or under reduced pressure
with heating.
Where the supersaturated solution of the compound of formula (lb) or salt
thereof is to be obtained by cooling a solution thereof, the temperature used to cool
the solution depends on the solvent employed and usually ranges from 0° to ambient
temperature.
Where the supersaturated solution of the compound of formula (lb) or salt
thereof is to be obtained by adding a solvent in which said compound of formula (lb)
or salt thereof is sparingly soluble to a solution of said compound of formula (lb) or
salt thereof in which it is readily soluble, this can be conducted by first dissolving said
compound of formula (lb) or salt thereof in a solvent in which it is readily soluble and
then adding the second solvent in which it is only slightly soluble and. if necessary,
cooling the solution to afford crystals of the compound of formula (lb).
Solvents in which the compound of formula (lb) is readily soluble include
acetates such as ethyl acetate; ketones such as acetone or 2-butanone; primary
alcohols such as methanol, ethanol, propanol or butanol; cyclic ethers such as
tetrahydrofuran; amides such as dimethylformamide or dimethylacetamide; sulfoxides
"such as dimethyl sulfoxide; nitriles such as acetonitrile; and halogenated

hydrocarbons such as dichloromethane or chloroform. Of these, ethyl acetate, acetone
or ethanol are preferred.
The solvents in which the compound of formula (lb) is sparingly soluble
depend on the nature of the solvent in which the compound of formula (lb) is readily
soluble. Suitable solvents include aliphatic hydrocarbons such as petroleum ether,
pentane, hexane or heptane: non-cyclic ethers such as diethyl ether or diisopropyl
ether; aromatic hydrocarbons such as benzene or toluene; secondary or tertian
alcohols such as 2-propanol or 2-methyl-2-propanol; and water. Of these, hexane.
heptane, diisopropyl ether. 2-propanol or water are preferred.
The two preferred crystalline forms of the compound of formula (lb) of the
present invention are preferably produced through the addition of hexane to a solution
of the compound of formula (lb) in ethyl acetate or by dissolving the compound of
formula (lb) in a heated mixture of 2-propanol and ethyl acetate followed, if
necessary, by cooling the solution.
The compounds of formula (I) and pharmaceutically acceptable salts and ester
derivatives thereof exhibit excellent activity against many eumycetes. Examples of
eumycetes include Candida species, Aspergillus species. Cryptococcus species,
Mucor species, Histoplasma species, Blastomyces species, Coccidioides species,
Paracoccidioides species, Trichophyton species, Epidermophyton species.
Microsporum species, Malassezia species, Pseudallescheria species, Sporothrix
species, Rhinosporidium species, Fonsecaea species, Wangiella species. Phialophora
species, Exophiala species, Cladosporiutn species, Alternaria species. Aureobasidium
species, Chaetomium species, Curvularia species, Drechslera species,
Mycocentrospora species, Phoma species, Hendersonula species, Scytalidium species,
Corynespora species, Leptospheria species, Madurella species, Neotestudina species,
Scedosporium species, Pyrenochaeta species, Geotrichum species, Trichosporon
species, Chrysosporium species, Coprinus species, Schizophyllum species,
Pneumocystis species, Conidiobolus species, Basidiobolus species, Paecilomyces
"species, Penicillium species, Acremonium species, Fusarium species, Scopulariopsis
species, Saccharomyces species, Cephalosporium species, Loboa species, Rhizopus
species, Rhizomucor species and Absidia species.

As a result of this excellent antifungal activity, compounds of formula (I) and
pharmaceutically acceptable salts and ester derivatives thereof can be used as a
medicament, preferably as an antifungal agent.
The compound of formula (I) or a pharmaceutically acceptable salt or ester
derivative thereof can be administered by itself or as a mixture of the compound of
formula (I) or a pharmaceutically acceptable salt or ester derivative thereof with a
pharmaceutically acceptable excipient(s) or diluent(s). Compositions according to the
present invention can be in unit dosage form such as tablets, capsules, granules,
powders or syrups for oral administration or as injectable, topical, vaginal or
percutaneous formulations or suppositories for parenteral administration or
formulations suitable for inhalation (orally or intanasally).
The pharmaceutical compositions can be prepared in a known manner by
using additives such as excipients, binders, disintegrants. lubricants, stabilizers,
corrigents, suspending agents, diluents and solvents.
Examples of suitable excipients includes sugar derivatives such as lactose,
sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato
starch, a-starch, dextrin or carboxymethylstarch; cellulose derivatives such as
crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropyl-
methylcellulose, carboxymethylcellulose or internally-cross-linked sodium
carboxymethylceilutose; gum arabic; dextran; pullulan; silicate derivatives such as
light silicic acid anhydride, synthetic aluminum silicate or magnesium aluminate
metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives
such as calcium carbonate; sulfate derivatives such as calcium sulfate; glycols; and
colloidal silica.
Examples of suitable binders include starch derivatives and cellulose
derivatives such as those described above, gelatin, polyvinylpyrrolidone and
"Macrogol.

Examples of suitable disintegrants include starch derivatives and cellulose
derivatives such as those described above, a chemically modified starch or cellulose
derivative such as sodium cross-carmelose. sodium carboxymethylstarch and cross-
linked polyvinylpyrrolidone.
Examples of suitable lubricants include talc: stearic acid: metal stearate
derivatives such as calcium stearate or magnesium stearate: waxes such as bee's wax
or spermaceti; glycols: carboxylic acids such as fumaric acid: sulfates such as calcium
sulfate; leucine; silicic acid derivatives such as silicic acid anhydride or silicic acid
hydrate; and starch derivatives such as those described above for excipients.
Examples of stabilizers include para-hydroxybenzoic acid ester derivatives
such as methylparaben or propylparaben; alcohols such as chlorobutanol. benzyl
alcohol or phenethyl alcohol; benzalkonium chloride; phenol derivatives such as
phenol or cresol; thimerosal; acetic anhydride; sorbic acid; boric acid; adipic acid:
sodium carboxylates such as sodium benzoate; lauryl sulfates such as sodium lauryl
sulfate or magnesium lauryl sulfate; antioxidants such as retinol, tocoferol or sodium
ascorbate; and synthetic hydrotalcite.
Examples of corrigents includes sweeteners, souring agents and flavoring
agents commonly used for the purpose.
Examples of suspending agents include polysorbate 80 and sodium
carboxymethylcellulose.
Examples of suitable solvents for the preparation of formulations for
parenteral administration include water, ethanol, glycerin, physiological saline,
glucose solution, water containing α-, β- or -cyclodextrin having 2 to 11
hydroxypropyl groups per molecule of cyclodextrin, propylene glycol, polyethylene
glycol 200 and polyethylene glycol 400.
The dose of the compound of formula (I) or pharmaceutically acceptable salt
or ester derivative thereof will vary depending on a variety of factors such as the age
and symptoms of the patient and the route of administration. A suitable dosage level

for oral administration is from 1 mg (preferably 5 mg) per day as a lower limit to 2000
mg (preferably 1000 mg) per day as an upper limit for an adult. A suitable dosage
level for intravenous administration is from 0.1 mg (preferably 0.5 mg) per day as a
lower limit to 600 mg (preferably 500 mg) per day as an upper limit for an adult. The
compound of formula (I) or a pharmaceutically acceptable salt or ester derivative
thereof can be administered either as a single unit dosage or. if desired, the dosage
may be divided into convenient sub-units administered from one to six times
throughout the day depending on the symptoms of the patient.

The following examples, reference examples, test examples and formulation
examples are intended to further illustrate the present invention and are not intended
to limit the scope of the invention in any way.

l(i) Diethyl 4-cvano-2-fluorobenzylphosphonate
A mixture of 1.5 g (7.0 mmol) of 4-(bromomethyl)-3-fluorobenzonitrile [ref.
J.Med.Chem., 40, 2064 (1997)] and 1.4 g (8.4 mmol) of triethyl phosphite was heated
at 150°C for 2 hours. At the end of this time, the reaction mixture was concentrated
under reduced pressure. Volatile materials in the residue thus obtained were removed
by heating said residue at 100°C in vacuo for 1 hour to afford 1.97 g (quantitative
yield) of the title compound as an oil which solidified in the freezer. This oily product
was used in the next step without further purification.
'H-Nuclear magnetic resonance spectrum (270 MHz, CDC13) 8 ppm:
1.27 (6H, triplet, J=7.1 Hz);
3.24 (2H, doublet, J=22.3 Hz);
4.00-4.05 (4H, multiplet);
7.37 (1H, doublet, J=9.2 Hz);
- 7.43 (1H, doublet, J=7.9 Hz);
7.51 (1H, triplet of doublets, J,=9.2 Hz, Jd=2.6 Hz).

IR spectrum vmax (CHC13) cm-1: 2237. 1262. 1054. 1029.
Mass spectrum m/z (EI): 27l(M^). 139. 109(100%). 93.
1 (ii) 3-Fluoro-4-|"( 1 E.3E)-5-oxo-1 3-pentadienvllbenzonitrile
0.5 ml (0.77 mmol) of a 1.53 N hexane solution of butyllithium were added
dropwise to a solution of 209 mg (0.77 mmol) of diethyl 4-cyano-2-fiuorobenzyl-
phosphonate [which was obtained in Step l(i) above] in 4 ml of anhydrous
tetrahydrofuran at -78°C with stirring. The mixture was stirred at -78°C for 30
minutes. At the end of this time, a solution of 100 mg (0.77 mmol) of commercially
available fumaraldeyde mono-dimethylacetal in 2 ml of anhydrous tetrahydrofuran
was added to the mixture, and the resulting mixture was stirred at -78°C for 2 hours.
The cooling bath was then removed and the mixture was stirred in an ice bath for a
further 15 minutes. 3.9 ml (0.39 mmol) of 0.1 N hydrochloric acid were added to the
reaction mixture and the mixture was then stirred for 30 minutes in the ice bath and
then for 1 hour at ambient temperature. At the end of this time, a saturated aqueous
sodium hydrogen carbonate solution was added to the mixture in an ice bath. The
resulting mixture was partitioned between ethyl acetate and water, the organic layer
was washed with water and with aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate and then concentrated under reduced pressure. The
crystalline residue thus obtained was recrystallized from a mixture of ethyl acetate
and hexane to afford 127 mg (yield 87%) of the title compound as pale yellow
crystals.
mp: 174-177°C
'H-Nuclear magnetic resonance spectrum (270 MHz, CDCI3) 5 ppm:
6.36 (1H, doublet of doublets, J=15, 8 Hz);
7.14 (1H, doublet-like, J=3 Hz);
7.16 (1H, doublet, J=8 Hz);
7.28 (1H, double doublet .of doublets, J=15, 8, 3 Hz);
7.40 (1H, doublet of doublets, J=10,1 Hz);

7.47 (1H. doublet of doublets, J=8. 1 Hz):
7.67 (1H. triplet, J=8 Hz);
9.68 (1H. doublet. J=8 Hz).
IR spectrum vmax (KBr) cm'1: 2230. 1681. 1672. 1621. 1421. 1159. 1124.
Mass spectrum m/z(EI): 201 (NT), 172(100%). 158. 145.
Anal, calculated for C,2HgFNO : C. 71.64; H, 4.01; N, 6.96.
Found: C, 71.84; H. 4.27; N. 6.83.
1(iii) (2R.3R)-3-rrtrans-2-[(1E.3E)-4-(4-Cvano-2-fluorophenvl)-1.3-butadien-l-vl-

A mixture of 4.63 g (23.0 mmol) of 3-fluoro-4-[(lE.3E)-5-oxo-1.3-
pentadienyl]benzonitrile [produced as described in Step l(ii) above], 8.73 g (24.3
mmolof(2R,3R)-2-(2,4-difluorophenyl)-3-[[l-(hydroxymethyl)-2-
hydroxyethyl]thio]-l-(lH-l,2,4-triazol-l-yl)-2-butanol [produced as described in
Japanese Patent Application (Kokai) Hei 8-333350)], 5.07 g (26.7 mmol) of p-
toluenesulfonic acid monohydrate and 200 ml of anhydrous tetrahydrofuran was
allowed to stand at ambient temperature for 30 minutes. At the end of this time, the
reaction mixture was concentrated using a rotary evaporator and dried in vacuo. The
resulting residue was dissolved in 150 ml of anhydrous tetrahydrofuran and the
resulting mixture was then evaporated to dryness in vacuo using a rotary evaporator.
This procedure was repeated twice more. A solution of Ac resulting residue in 150
ml of anhydrous tetrahydrofuran was poured into a saturated aqueous sodium
hydrogen carbonate solution with stirring. The product was then extracted with ethyl
acetate and the organic layer was washed with aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residual oil was purified by chromatography on a silica gel (500 g)
column using a 2:1 mixture of ethyl acetate and hexane as the eluant to give 9.35 g
"-(yield 74%) of the title compound as a yellow amorphous solid.
'H-Nuclear magnetic resonance spectrum (400MHz, CDC13) 6 ppm:
_

1.19 (3H. doublet. J=7 Hz):
3.33 (1H. quartet. J=7 Hz);
3.40 (1H. triplet of triplets, 'J= 11. 5 Hz);
3.62 (1H. triplet. J=ll Hz);
3.64 (1H, triplet. J= 11 Hz);
4.30 (1H. double doublet of doublets. J=l 1. 5. 2 Hz):
4.43 (1H. double doublet of doublets. J=l 1. 5. 2 Hz):
4.83 (1H, doublet. J= 14 Hz):
5.01 (lH,s);
5.03 (1H, doublet. J= 14 Hz);
5.07 (1H, doublet, J=4 Hz);
5.90 (1H. doublet of doublets. J=15.4 Hz);
6.62 (1H, doublet of doublets. J=15. 11 Hz);
6.7-6.8 (2H, multiplet);
6.73 (1H, doublet, J= 16 Hz);
6.95 (1H, doublet of doublets, J=16, 11 Hz);
7.3-7.4 (1H, multiplet);
7.34 (1H, doublet, J=9 Hz);
7.40 (1H, doublet. J=8 Hz);
7.58 (1H, triplet, J=8 Hz);
7.79 (2H, singlet).
IR spectrum vmax(KBr) cm'1: 2232,1616,1499, 1418, 1140.
Mass spectrum m/z (FAB): 543(M++1).
Specific rotation: [a]D25 -76.6° (c = 1.00 , CHC13).

Example 2
Crystalline (2R.3RV3-rrtrans-2-raE.3E)-4-(4-cvano-2-fluorophenvn-1.3-butadien-l-
yl]-1.3-dioxan-5-vllthio1-2-(2.4-difluorophenvl 1-1-flH-l .2.4-triazol-1 -vl )-2-butanol
(2R.3R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-fluoropheny])-1.3-butadien-l-yl]-
1.3-dioxan-5-yl]thio]-2-(2.4-difluorophenyl)-1 -(1H-1.2.4-triazol-1 -yl )-2-butanol.
prepared as described in Example 1. was dissolved in a hot 9:1 mixture of 2-propanol
and ethyl acetate. The resulting solution was then irradiated with ultrasonic waves in
an ultrasonic bath to afford a powdery form of the title compound, which was
collected by filtration.
Melting Point: 111 - 112°C
IR spectrum vmax (KBr) cm-1: 2232, 1616, 1499, 1419. 1141.
A powder X ray diffraction pattern of the crystalline product, illustrated in
Figure 1, was obtained by irradiation of the crystalline product using the copper Kα,
ray. The vertical axis of the powder X ray diffraction pattern indicates the diffraction
intensity in units of counts/second (cps). The horizontal axis indicates the diffraction
angle as the value 26. The spacing of the lattice planes d can be calculated using the
equation 2d sin θ = nX in which n is 1.
Example 3
Crystalline r2R.3R)-3-rr-trans-2-rflE,3E)-4-(4-cvano-2-fluorophenvl)-1.3-butadien-l-
vll-1.3-dioxan-5-vnthio1-2-(2.4-difluorophen vl)-1 -(1H-1.2.4-triazol-1 -vl )-2-butanol
(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l,3-butadien-l-yl]-
1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1 -(1H-1,2,4-triazoI-1 -yl )-2-butanol,
obtained as described in Example 1, was dissolved in ethyl acetate and then the same
amount of hexane as that of the ethyl acetate was added to the solution to precipitate
crystals of the title compound.

Melting Point: 127-128°C
IR spectrum vmax (KBr) cm;): 2232. 1616. 1499. 1419. 1140.
A powder X ray diffraction pattern of the crystalline product, illustrated in Figure
2. was obtained by irradiation of the crystalline product using the copper Kα ray. The
vertical axis of the powder X ray diffraction partem indicates the diffraction intensity
in units of counts/second (cps). The horizontal axis indicates the diffraction angle as
the value 29. The spacing of the lattice planes d can be calculated using the equation
2d sin 9 = nk in which n is 1.
Example 4
(2R.3R)-3-rrtrans-2-rnE.3E)-4-(4-Cvano-2-fluorophenvn-1.3-butadien-l-vn-1.3-
dioxan-5-vnthiol-2-f 2.4-difluorophenvl)-1 -(1H-1.2.4-triazol-1 -vl)-2-butanol
(Synthesis by dehydration using molecular sieves)

791 mg (4.16 mmol) of p-toluenesulfonic acid monohydrate were added to a
solution of 760 mg (3.77 mmol) of 3-fluoro-4-[(lE,3E)-5-oxo-l,3-pentadienyl]-
benzonitrile [obtained as described in Example l(ii) above] and 1.36 g (3.77 mmol) of
(2R,3R)-2-(2,4-difluorophenyl)-3-[[ 1 -(hydroxymethyl)-2-hydroxyethyl]thio]-1 -(1H-
_l,2,4-triazol-l-yl)-2-butanol [prepared as described in Japanese Patent Application
(Kokai) Hei 8-333350] in-13 ml of dichloromethane. The resulting mixture was
concentrated using a rotary evaporator. 13 ml of dichloromethane and 13 g of 4 A

molecular sieves were added to the resulting residue and the mixture was then stirred
at ambient temperature overnight. At the end of this time, an aqueous sodium
hydrogen carbonate solution was added to the reaction mixture. The molecular sieves
were removed by filtration and the filtrate was partitioned between ethyl acetate and
water. The organic layer was dried and concentrated under reduced pressure. The
resulting oily residue was purified by chromatography on a silica gel (20 g) column
using a 1:1 mxiture of ethyl acetate and hexane as the eluant to afford 1.42 g (yield
69%) of the title compound as an amorphous solid. The spectral data were identical
to those of the title compound of Example 1.
Example 5
R.3RV3-rftrans-2-r(lE.3E1-4-(4-Cvano-2-fluorophenvn-1.3-butadien-l-vll-1.3-
dioxan-S-vllthiol^^-fluorophenvn-l-H-l.2-4-trazol-l-yl)-butanol

5(i) (2R.3R)-2-(2-Fluorophenvn-3-r(trans-2-phenvl-1.3-dioxan-5-vnthiol-l-(lH-
1,2,4-triazol-1 -vl)-2-butanol
0.12 ml (0.59 mmol) of a 4.9 M methanolic solution of sodium methoxide
were added to a solution of 0.93 g (4.0 mmol) of (2R,3S)-2-(2-fluorophenyl)-3-
methyl-2-[(lH-l,2,4-triazol-l-yl)methyl]oxirane [prepared as described in Chem.
Pharm. Bull., 43,441-449 (1995)] and 1.14 g (4.8 mmol) of trans-5-(acetylthio)-2-
phenyl-l,3-dioxane [prepared as described in Japanese Patent Application (Kokai)
Hei 8-333350] in 15 ml of ethanol. The resulting mixture was stirred at 87°C for 13
hours. After cooling, the reaction mixture was partitioned between ethyl acetate and
.an aqueous ammonium chloride solution. The organic solution was washed with
saturated aqueous sodium chloride solution and then concentrated under reduced
pressure. The resulting oily residue was purified by chromatography on a silica gel

(75 g) column using a 3:2 mixture of ethyl acetate and hexane as the eluant to afford
0.68 g (yield 40%) of the title compound as a non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400MHz. CDC13) 5 ppm:
1.21 (3H, doublet. 5=1 Hz);
3.42 (1R quartet. J=7 Hz);
3.49 (1H, triplet of triplets. J=l 1, 5 Hz);
3.75 (2H, triplet, J= 11 Hz);
3.72 (2H, triplet, J= 11 Hz);
4.41 (1H, double doublet of doublets. J=l 1, 5,2 Hz);
4.52 (1H, double doublet of doublets, J=l 1, 5, 2 Hz);
4.89 (1H, doublet, J=14 Hz);
4.92 (1H, doublet, J=l Hz);
5.07 (1H, doublet, J=14 Hz);
5.49 (1H, singlet);
6.94-7.03 (2H, multiplet);
7.17-7.23 (1H, multiplet);
7.33-7.41 (3H, multiplet);
7.49 (2H, doublet of doublets, J=7,2 Hz);
7.75 (1H, singlet);
7.77 (1H, singlet).
IR spectrum vmflx(CHCl3) cm'1: 3131, 1732, 1376, 1140.
Mass spectrum m/z (FAB): 430 (NT+1).
5(ii) (2R.3R)-2-('2-FluoroDhenvn-3-rri-fhvdroxvmethvn-2-hvdroxvethvllthio1-l-
(1H-1.2.4-triazol-1 -vl)-2-butanol
110 ml (110 mmol) of 1 N hydrochloric acid were added to a solution of 13 g
(30.3mmol)of(2R,3R)-2r(2-fluorophenyl)-3-[(trans-2-phenyl-l,3-dioxan-5-yl)thio]-
l-(lH-l,2,4-triazol-l-yl)-2-butanol [prepared as described in Step 5(i) above] in 80 ml
of toluene. The resulting mixture was heated at 50°C for 2.5 hours. At the end of this

time, the water layer was separated and the oily layer was extracted twice with
hydrochloric acid and then with an aqueous sodium chloride solution. The aquous
layers were combined and sodium hydrogen carbonate was carefully added ther
small portions until bubbles of carbon dioxide were no longer detected. The res
mixture was extracted with ethyl acetate and the extract was then concentrated
reduced pressure to afford a solid residue. This residue was collected by filtratino
then washed with a small amount of ethyl acetate to afford 5.57 g (yield 55%) o
title compound as a pale brown solid.
Melting Point: 121 - 123°C
'H-Nuclear magnetic resonance spectrum (400MHz, CDCI3) 5 ppm:
1.21 (3H, doublet, 5=1 Hz);
2.47 (1H, triplet, J=6 Hz);
2.78 (1H, triplet, J=6 Hz);
3.24 (1H, quintet, J=6 Hz);
3.50 (1H, quartet, J=7 Hz);
3.7-4.0 (4H, multiplet);
4.92 (1H, doublet, J=14 Hz);
5.14 (1H, doublet, J=14 Hz);
5.16 (1H, singlet);
6.97 (1H, double doublet of doublets, J=12, 8, 1 Hz);
7.02 (1H, triplet of doublets, J=8, 1 Hz);
7.22 (1H, triple doublet of doublets, J=8, 5,2 Hz);
7.39 (1H, triplet of doublets, J=8, 2 Hz);
7.765 (1H, singlet);
7.770 (1H, singlet).
IR spectrum vmax(KBr) cm-1: 1513, 1485, 1451, 1275, 1209, 1136, 1072, 1054.
Mass spectrum m/z (FAB): 342 (M++l).
Specific rotation: [α]D25 -78.2° (c = 1.16, CHCI3).

Anal, calculated for C15H20F2N4O3S: C. 52.77: H. 5.91: N. 12.31.
Found: C, 52.74; H. 5.95: N. 12.24.
5(iii) (2R.3R)-3-rrtrans-2-r( 1 E.3E)-4-(4-Cvano-2-fluorophenvl)-1.3-butadien-1 -vl|-
1.3-dioxan-5-vnthio1-2-(2-fluoroDhenvn-1 -(1H-1.2.4-triazol-1 -vl )-2-butanol
The crude title compound was obtained as an oil in a similar manner to that
described in Example l(iii) above using 510.7 mg (1.50 mmol) of (2R.3R)-2-(2-
fluorophenyl)-3-[[l-(hydroxymethyl)-2-hydroxyethyl]thio]-2-butanol [prepared as
described in step 5(ii) above], 300 mg (1.5 mmol) of 3-fluoro-4-[(lE.3E)-5-oxo-1.3-
pentadienyljbenzonitrile [prepared as described in Example l(ii) above] and 283.1 mg
(1.64 mmol) of p-toluenesulfonic acid monohydrate. The oil was purified by
chromatography on a column silica gel (50 g) using a 1:1 mixture of ethyl acetate and
hexane as the eluant to give 431 mg (yield 55%) of the title compound as a colorless
non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz. CDCI3) 5 ppm:
1.19 (3H, doublet, J=7 Hz);
3.39 (1H, quartet, J=7 Hz);
3.38-3.45 (lH,multiplet);
3.62 (1H, triplet, J= 11 Hz);
3.65 (1H, triplet, J=11 Hz);
4.31 (1H, double doublet of doublets, J=l 1, 5, 2 Hz);
4.44 (1H, double doublet of doublets, J=l 1, 5, 2 Hz);
4.87 (1H, doublet, J=14 Hz);
4.92 (1H, singlet);
5.04 (1H, doublet, J=14 Hz);
5.07 (1H, doublet, J=4 Hz);
5.90 (1H, doublet of doublets, J=15,4 Hz);
6.62 (1H, doublet of doublets, J=15, 11 Hz);
6.75 (1H, doublet, J=l5 Hz);
6.98 (1H, doublet of doublets, J=15, 11 Hz);
6.92-7.02 (2H, multiplet);
7.18-7.23 (lH,multiplet);

7.32-7.36 (2H. multiplet);
7.41 (1H. doublet of doublets. J=8. 1 Hz);
7.58 (1H. triplet, J=8 Hz);
7.75 (1H, singlet);
7.77 (1H, singlet).
IR spectrum vmax (KBr) cm"1: 3426. 2852. 2231. 1141.
Mass spectrum m/z (FAB): 525 (M++l).
Example 6
(2R.3R)-3-rrtrans-2-[( 1 E.3EV4-(4-Cvano-2-fluorophenvl)-1.3-butadien-1 -vl]-1.3-
dioxan-5-yl]thio1-2-(4-fluorophenvl)-1 -(1H-1,2.4-triazol-1 -vl )-2-butanol

6(i) cis-5-(Acetvlthio)-2-phenyl-l ,3-dioxane
A mixture of 30 g (90 mmol) of trans-2-phenyl-5-(p-toluenesulfonyloxy)-l,3-
dioxane (prepared as described in Tetrahedron, 48, 5941 - 5950), 15.3 g (134 mmol)
of potassium thioacetate, 240 ml of toluene and 60 ml of N,N-dimethylacetamide was
stirred at 100°C for 3 hours and then at 110 - 120°C for 7 hours. After cooling, the
reaction mixture was partitioned between toluene and water. The organic layer was
then washed with water, dried over anhydrous magnesium sulfate and concentrated.
The resulting oily residue was purified by chromatography on a silica gel (200 g)
column using a 1:4 mixture of ethyl acetate and hexane as the eluant to afford the
crude title compound as a solid. This solid was recrystallized from a mixture of ethyl

acetate and hexane to afford 10 g (yield 47 %) of the title compound as brown needle-
like crystals.
Melting Point: 94 - 95°C.
'H-Nuclear magnetic resonance spectrum (270 MHz. CDCI3) 5 ppm:
2.39 (3H, singlet);
3.71 (1H, broad singlet);
4.19 (2H, broad doublet, J=12 Hz);
4.38 (2H, broad doublet, J=12 Hz);
5.55 (1H, singlet);
7.30-7.42 (3H, multiple!);
7.42-7.55 (2H, multiplet).
IR spectrum vmax (KBr) cm"1: 1676, 1402, 1130.
Mass spectrum m/z (EI): 238 (M+), 237. 178, 107, 105. 43 (100%).
6fii) f2R.3R)-2-(4-Fluorophenvn-S-f(cis-2-phenvl-l ,3-dioxan-5-vnthiol-l -(1 H-l .2,4-
triazol-1 -vl)-2-butanol
1 ml (0.59 mmol) of a 4.8 M methanolic solution of sodium methoxide was added
to a solution of 2.33 g (10 mmol) of (2R,3S)-2-(4-fluorophenyl)-3-methyl-2-[(lH-
l,2,4-triazol-l-yl)methyl]oxirane [prepared as described in Chem. Pharm. Bull., 43,
441 - 449 (1995)] and 2.38 g (10 mmol) of cis-5-(acetylthio)-2-phenyl-l,3-dioxane
[prepared as descripted in Step 6(i) above] in 40 ml of ethanol. The resulting mixture
was stirred at 80°C for 5 hours. After cooling, the reaction mixture was partitioned
between ethyl acetate and water. The organic layer was separated and washed with
saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel (50 g) column using a 2:1 mixture of ethyl acetate and
hexane as the eluant to afford 3.1 g (yield 72%) of the title compound as a brown
foamy solid.

'H-Nuclear magnetic resonance spectrum (270 MHz. CDCI3) 6 ppm:
1.29 (3H, doublet, J=7 Hz);
2.97 (1H, multiplet);
3.50 (1H. quartet, J=7 Hz);
4.26 (1H, doublet-like. J=12 Hz);
4.36 (1H, doublet of doublets, J=12, 3 Hz);
4.36 (1H, doublet of doublets, J=12. 2 Hz);
4.42 (1H, doublet of doublets, J=12, 3 Hz);
4.56 (1H, singlet);
4.57 (1H, doublet, J=l4 Hz);
5.10 (1H, doublet, J=14 Hz);
5.61 (1H, singlet);
6.89 (2H, triplet, J=9 Hz);
7.16 (1H, doublet of doublets, J=9, 5 Hz);
7.3-7.5 (3H, multiplet);
7.4-7.6 (2H, multiplet);
7.69 (1H, singlet);
7.80 (1H, singlet).
IR spectrum vmax(CHCl3) cm"1: 1732, 1605, 1509, 1278, 1135.
Mass spectrum m/z (FAB): 430 (M++l).
Specific rotation: [ct]D25 -59.8° (c = 1.29, CHC13).
6(iii)(2R.3RV2-('4-fluoroDhenvn-3-rfWhvdroxvmethvn-2-hvdroxvethvnthio1-l-nH-
1.2.4-triazol-l -vn-2-butanol
1 ml (12 mmol) of 12 N hydrochloric acid were added to a solution of 3.1 g
(7.2mmol)of(2R,3R)-2-(4-fluorophenyl)-3-[(cis-2-phenyl-l,3-dioxan-5-yl)thio]-l-
(lH-l,2,4-triazol-l-yl)-2-butanol (prepared as described in Step 6(ii) above] in 39 ml
of methanol. The resulting mixture was stirred at ambient temperature for 16 hours.

At the end of this time, an aqueous sodium hydrogen carbonate solution was carefull;
added to the reaction mixture until the solution became weakly alkaline. Most of the
methanol was evaporated from the mixture under reduced pressure. The resulting
residue was then partitioned between ethyl acetate and aqueous sodium chloride
solution. The organic layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was purified by
chromatography on a silica gel (30 g) column using a 1:9 mixture of methanol and
ethyl acetate as the eluant to afford 2.15 g (yield 87%) of the title compound as a
hygroscopic pale brown foamy solid.
'H-Nuclear magnetic resonance spectrum (270 MHz, CDCI3) 8 ppm:
1.26 (3H, doublet, J=7 Hz);
2.6-2.8 (2H, broad);
3.16 (1H, quintet, J=6 Hz);
3.27 (1H, quartet, J= 7 Hz);
3.6-4.0 (4H, multiplet);
4.66 (1H, doublet, J= 14 Hz);
4.92 (1H, singlet);
4.94 (1H, doublet, J= 14 Hz);
6.99 (2H, triplet, J=9 Hz);
7.25 (2H, doublet of doublets, J=9, 5 Hz);
7.75 (1H, singlet);
7.84 (1H, singlet).
IR spectrum vmax(CHCl3) cm'1: 1605, 1510, 1277.
Mass spectrum m/z (FAB): 342 (M++l).
Specific rotation: [ 6(iv) (2R,3RV3-rrtrans-2-r(lE.3E)-4-(4-Cvano-2-fluorophenvn-1.3-butadien-l-vn-
1.3 -dioxan-5-vnthio)-2-(4-fluorophenvl)-1 -(1H-1.2.4-triazol-1 -vl)-2-butanol

The crude title compound was obtained as an oil in a similar manner to that
described in Example l(iii) above using 510.7 mg (1.50 mmol) of (2R.3R)-2-(4-
fluorophenyl)-3-[[l-(hydroxymethyl)-2-hydroxyethyl]thio]-2-butanol [prepared as
described in Step 6(iii) above], 301 mg (1.5 mmol) of 3-fluoro-4-[(lE.3E)-5-oxo-1.3-
pentadienyljbenzonitrile [prepared as described in Example l(ii) above] and 283 mg
(1.64 mmol) of p-toluenesulfonic acid monohydrate. The oil was purified by
chromatography on a silica gel column using a 1:1 mixture of ethyl acetate and
hexane as the eluant to give 214 mg (yield 27%) of the title compound as a colorless
non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 8 ppm:
1.21 (3H, doublet, J=7 Hz);
3.13 (1H, quartet, J=7 Hz);
3.33 (1H, triplet of triplets, J= 11,5 Hz);
3.58 (1H, triplet, J= 11 Hz);
3.60 (1H, triplet, J= 11 Hz);
4.26 (1H, double doublet of doublets, J=l 1. 5. 2 Hz);
4.37 (1H, double doublet of doublets, J=l 1, 5. 2 Hz);
4.52 (1H, doublet, J=14 Hz);
4.60 (1H, singlet);
4.98 (1H, doublet, J= 14 Hz);
5.04 (1H, doublet, J=4 Hz);
5.89 (1H, doublet of doublets, J=15,4 Hz);
6.60 (1H, doublet of doublets, J=15, 10 Hz);
6.74 (1H, doublet, J= 16 Hz);
6.94 (1H, doublet of doublets, J=16, 10 Hz);
6.95-6.99 (2H, multiplet);
7.21-7.24 (2H, multiplet);
7.34 (1H, doublet of doublets, J=10, 1 Hz);
7.40 (1H, doublet of doublets, J=8, 1 Hz);
7.58 (1H, triplet, J=8 Hz);
7.71 (1H, singlet);
7.83 (1H, singlet).

Example 7
(2R.3R)-3-ITtrans-2-rn E.3E)-4-(4-Cvano-2-fluorophenvl)-l .3-butadien-1 -vll-1.3-
dioxan-5-vllthio1-2-C2.3-difluorophenvn-1 -f 1H-1.2.4-triazol-1 -vl )-2-butanol

7(i)(2R)-2'.3'-Difluoro-2-f3.4.5.6-tetrahvdro-2H-pvran-2-yloxv)prapiophenone
A mixture of 0.5 g (2.6 mmol) of 1-bromo-2,3-difluorobenzene. 0.681 g (28
mmol) of metallic magnesium and 40 ml of tetrahydrofuran was heated to initiate
generation of a Grignard reagent. When the reaction had started, the mixture was
cooled to 0°C. A solution of 4.5 g (23 mmol) of l-bromo-2.3-difluorobenzene in 30
ml of tetrahydrofuran was added to the mixture over a period of 05 hours. At the end
of this time, the mixture was then stirred at ambient temperature for 1.5 hours. The
mixture was cooled to -30°C and a solution of 4.87 g (20 mmol) of 4-[(2R)-2-
(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (prepared as described in
Chem. Pharm. Bull., 41., 1035-1042 (1993)] in 30 ml of tetrahydrofuran was added
dropwise to the mixture over a period of 20 minutes. The resulting mixture was then
stirred at ambient temperature for 2 hours, after which the reaction was stopped by the
addition of a saturated aqueous ammonium chloride solution. The reaction product
was extracted with ethyl acetate and the organic layer was washed with aqueous
sodium chloride solution and then concentrated under reduced pressure. The oily
- residue thus obtained was purified by chromatography on a silica gel (75 g) column
using a 1:9 mixture of ethyl acetate and hexane as the eluant to afford 4.80 g (yield
89%) as a colorless oil.

'H-Nuclear magnetic resonance spectrum (400 MHz. CDCh) 6 ppm:
1.44 [(3/2)R doublet of doublets, J=7,1 Hz];
1.49 [(3/2)H, doublet of doublets, J=7, 1 Hz];
1.49-1.90 (6H, multiplet);
3.33-3.38 [(1/2)H. multiplet];
3.50-3.55 [(1/2)H, multiplet];
3.68-3.74 [(1/2)H. multiple];
3.87-3.93 [(1/2)H, multiplet];
4.66 [(1/2)H, triplet, J=4 Hz];
4.75 [(1/2)H, triplet, J=4 Hz];
4.85 [(1/2)H, quartet of doublets, J=7,2 Hz];
5.10 [(1/2)H, quartet of doublets, J=7, 2 Hz];
7.14-7.21 (1H, multiplet);
7.30-7.39 (1H, multiplet);
7.54-7.58 (1H, multiplet).
1R spectrum vmax (CHCI3) cm"1: 1700,1481,1273.
Mass spectrum m/z (FAB): 271 (M++l).
7(ii) (2R,3RV2-(23-Difluorophenvl)-1,2.3-butanetriol
(Dimethylisopropoxysilyl)methylmagnesium chloride was prepared from a
solution of 5.74 g (34.4 mmol) of chloromethyldimethylisopropoxysilane in 40 ml
tetrahydrofuran and 0.84 g (34.4 mmol) of metallic magnesium. A solution of 4.65 g
(17.2 mmol) of (2R)-2\3'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-
yloxy)propiophenone [prepared as described in Step 7(i) above] in 20 ml of
tetrahydrofuran was added to the solution of the Grignard reagent at 0°C with stirring.
The resulting mixture was stirred at ambient temperature for 30 minutes, after which
the reaction was stopped by the addition of a saturated aqueous ammonium chloride
solution to the reaction mixture. The reaction product was extracted with ethyl
acetate. The organic layer was washed with aqueous sodium chloride solution and

concentrated to afford 8.1 g of crude (2S.3R)-2-(2.3-difluorophenyl)-l-
(isopropoxydimethylsilyl)-3-(3.4.5.6-tetrahydro-2H-pyran-2-yloxy)-2-butanolasan
oil.
1.4 g (17 mmol) of sodium hydrogen carbonate and 16 ml of a 31% aqueous
hydrogen peroxide solution were added to a solution of the crude oil in a mixture of
40 ml of methanol and 40 ml of tetrahydrofuran. The resulting mixture was stirred at
80°C for 40 minutes. After cooling the reaction mixture, the reaction product was
extracted with ethyl acetate. The organic layer was washed with aqueous sodium
chloride solution and concentrated to afford lOg of crude (2R,3R)-2-(2.3-
difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-l,2-butanediol as an oil.
0.20 g (1.05 mmol) of p-toluenesulfonic acid monohydrate were added to a
solution of the oil in 40 ml of methanol. The resulting mixture was stirred at ambient
temperature for 1 hour. At the end of this time, the reaction mixture was concentrated
under reduced pressure. The resulting residue was purified by chromatography on a
silica gel (125 g) column using a 1:1 mixture of ethyl acetate and hexane to afford
3.74 g (quantitative yield) of the title compound as an oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 5 ppm:
0.96 (3H, doublet, J=6 Hz);
3.80 (1H, doublet, J=12 Hz);
3.94 (1H, singlet);
4.32 (1H, doublet of doublets, J= 12, 2 Hz);
4.53 (1H, quartet of doublets, J= 6, 3 Hz);
7.09-7.13 (2H, multiplet);
7.46-7.50 (lH,multiplet).
IR spectrum vmax(KBr) cm"1: 3402,3174, 1481, 1272, 1104.
Mass spectrum m/z (FAB): 219 (M++l).
"7(iii) (2R.3R)-2-a.3-DifluoroDhenvn-1.3-bis(methanesulfonvloxv)-2-butanol

5.7lg (50 mmol) of methanesulfonyl chloride were added to a solution of
3.51 g (16.1 mmol)of(2RJR)-2-(2.3-difluorophenyI)-1.2.3-butanetriol [obtained as
described in Step 7(ii) above] in 18 ml of pyridine at 0°C. After stirring the resulting
mixture for 0.5 hours, saturated aqueous sodium hydrogen carbonate solution was
added to the reaction mixture and the product was extracted with ethyl acetate. The
organic layer was washed with dilute hydrochloric acid and then washed with aqueous
sodium chloride solution and then concentrated under reduced pressure. The resulting
residue was purified by chromatography on a silica gel (100 g) column using a 1:1
mixture of ethyl acetate and hexane as the eluant to afford 5.04g (yield 84%) of the
title compound as a colorless oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 8 ppm:
1.28 (3H, doublet, J= 7 Hz):
2.99 (3H, singlet);
3.10 (3H, singlet);
3.41 (1H, singlet);
4,75 (2H, doublet, J=l Hz);
5.31 (1H, quartet, J=7 Hz);
7.16-7.23 (2H, multiplet);
7.46-7.50 (1H, multiple!).
IR spectrum vmax (KBr) cm"1: 3486, 1485. 1350. 1344, 1171.
Mass spectrum m/z (FAB): 375 (M++l).
7(iv)(2R.3SV2-(2.3-Difluorophenvl)-3-methvl-2-r(lH-1.2.4-triazol-l-
vDmethvnoxirane
3.32 g (48.1 mmol) of lH-l,2,4-triazole were added to a suspension of 1.84g
(41.1 mmol) of a 55% dispersion of sodium hydride in oil in 30 ml of N,N-
dimethylformamide at 0°C with stirring. After the evolution of hydrogen gas had
" ceased, a solution of 4.50g (12 mmol) of (2R,3R)-2-(2,3-difluorophenyl)-l,3-
bis(methanesulfonyloxy)-2-butanol [prepared as described in Step 7 (iii) above] in 13

ml of N,N-dimethylformamide was added to the above reaction mixture. This
resulting mixture was stirred at 70°C for 1.5 hours. After cooling, a saturated aqueous
ammonium chloride solution was added to the reaction mixture. The reaction product
was extracted with ethyl acetate and the organic layer was washed with water three
times and with aqueous sodium chloride solution once and then concentrated under
reduced pressure. The resulting residue was purified by chromatography on a silica
gel (100 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to
afford 1.80 g (yield 59%) of the title compound as an oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 6 ppm:
1.66 (3H, doublet, J=6 Hz);
3.23 (1H, quartet, J=6 Hz);
4.46 (1H. doublet, J= 15 Hz);
4.91 (1H, doublet, J= 15 Hz);
6.79 (1H, double doublet of doublets. J=8. 6, 1 Hz);
6.93 (1H, triple doublet of doublets, J=8. 6, 1 Hz);
7.08 (1H, quartet of doublets, J= 8, 1 Hz);
7.82 (1H, singlet);
7.98 (1H, singlet).
IR spectrum vmax (KBr) cm'1: 3111, 1486, 1273, 1136.
Mass spectrum m/z (EI): 251 (M+), 236, 188, 153, 141, 96 (100%).
7rv)(2R,3RV2-(2.3-DifTuorophenvl)-3-f(trans-2-phenvl-1.3-dioxan-5-vl)thiol-l-(lH-
1,2.4-triazol-1 -vl)-2-butanol
0.29 ml (1.4 mmol) of a 4.9 M solution of sodium methoxide in methanol were
added to a solution of 1.77 g (7.1 mmol) of (2R,3S)-2-(2,3-difluorophenyl)-3-methyl-
2-[(lH-l,2,4-triazol-l-yl)methyl]oxirane [prepared as described in Step 7(iv) above]
and 2.20g (9.2 mmol) of trans-5-(acetylthio)-2-phenyl-l,3-dioxane [prepared as
-described in Japanese Patent Application (Kokai) Hei 8-333350] in 20 ml of ethanol.
The resulting mixture was then heated under reflux for 7 hours. After cooling the
reaction mixture, it was partitioned between ethyl acetate and an aqueous ammonium

chloride solution. The organic layer was washed with saturated aqueous sodium
chloride solution and concentrated under reduced pressure to afford 3.65 g of the
crude title compound. An aliquot (0.28g) of the crude residue was purified by
chromatography on a silica gel (15g) column using a 2:5 mixture of ethyl acetate and
hexane as eluent to afford 0.2 lg of the title compound.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCb) 5 ppm:
1.23 (3H. doublet, 5=1 Hz);
3.39 (1H, quartet, J=7 Hz);
3.50 (1H, triplet of triplets, J=l 1, 5 Hz);
3.75 (1H, triplet, J=ll Hz);
3.77 (1H, triplet, J=ll Hz);
4.40 (1H. double doublet of doublets. J=l I, 5. 2 Hz);
4.52 (1H. double doublet of doublets. J=l 1, 5, 2 Hz);
4.87 (1H, doublet, J=14, 6 Hz);
5.08 (1H, doublet, J=14 Hz);
5.12 (1H, doublet, J=l Hz);
5.49 (1H, singlet);
6.92-6.98 (1H, multiplet);
7.05 (1H, quartet of doublets, J=8, 1 Hz);
7.11-7.16 (lH,multiplet);
7.34-7.41 (3H, multiplef);
7.49 (2H, doublet of doublets, J=7. 3 Hz);
7.79 (1H, singlet);
7.82 (1H, singlet).
IR spectrum vmjut (KBr) cm"1: 3405, 1480, 1275, 1140, 1075.
Mass spectrum m/z (FAB): 448 (M++l).

7(vi) (2R.3RV2-(2.3-difluoropfaenvl)-3-rr 1 -(hvdroxvmethvl)-2-hvdroxvethvnthio1-1 -
riH-1.2.4-triazol-l -vn-2-bmanol
30 ml (30 mmol) of 1 N hydrochloric acid were added to a solution of 3.35 g
of crude (2R,3R)-2-(2.3-difluorophenyl)-3-[(trans-2-phenyl-1.3-dioxan-5-yl)thio]-1 -
(lH-1.2.4-triazol-l-yl)-2-butanol [prepared as described in Step 7(v) above] in 45 ml
of toluene. The resulting mixture was heated at 50°C for 6 hours. At the end of this
time, the aqueous layer was separated. The oily layer was then extracted twice with a
dilute hydrochloric acid solution. The aqueous layers were then combined and
sodium hydrogen carbonate was carefully added in small portions to the solution until
the evolution of carbon dioxide gas had ceased. The reaction mixture was then
extracted with ethyl acetate and the extract was concentrated under reduced pressure
to afford the title compound as a solid. The solid was washed with a 2:1 mixture of
ethyl acetate and hexane and 1.54 g [overall yield from Step 7(v) 61%] of the title
compound were collected by filtration.
'H-Nuclear magnetic resonance spectrum (400 MHz, DMSO) 5 ppm:
1.06 (3H, doublet, J=7 Hz);
2.85 (1H, quintet, J=6 Hz);
3.55-3.68 (5H, multiplet);
4.80 (1H, doublet, J=15 Hz);
4.85 (1H, triplet, J=5 Hz);
5.04 (1H, triplet, J=5 Hz);
5.10 (1H, doublet, J=15 Hz);
6.01 (1H, singlet);
6.97-7.01 (2H, multiplet);
7.23-7.30 (1H, multiplet);
7.62 (1H, singlet);
8.31 (1H, singlet).
IR spectrum vmax (KBr) cm'1: 3238, 1480, 1272, 1206, 1138.
Mass spectrum m/z (FAB): 360 (frf+1).

7-4-(4-Cvano-2-fluorophenvn-1.3-biitadien-l-vl1-
1.3-dioxan-5-vnthiol-2-(2.3-difluorophenvn-l-nH-1.2.4-triazol-l-vl)-2-butanol
Crude title compound was obtained as an oil in a similar manner to that
described in Example l(iii) above using 643.3 mg (1.80 mmol) of (2R.3R)-2-(2.3-
difluorophenyl)-3-[[ 1 -(hydroxymethyl)-2-hydroxyethyl]thio]-1 -(1H-1.2.4-triazol-1 -
yl)-2-butanol [prepared as described in Step 7(vi) above]. 361.8mg (1.80 mmol) of 3-
fluoro-4-[(lE.3E)-5-oxo-l,3-pentadienyl]-benzonitrile [prepared as described in
Example l(ii) above] and 376.3 mg (1.98 mmol) of p-toluenesulfonic acid
monohydrate. The oil was purified by chromatography on a silica gel (50 g) column
using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 533.7 mg (yield
55%) of the title compound as a colorless non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 5 ppm
1.21 (3H, doublet, J=7 Hz);
3.36 (1H, quartet, 5=1 Hz);
3.43 (1H, triplet of triplets, J=l 1, 5 Hz);
3.62 (1H, triplet, J= 11 Hz);
3.64 (1H, triplet, J=ll Hz);
4.32 (1H, double doublet of doublets, J=l 1, 5, 2 Hz);
4.43 (1H, double doublet of doublets, J=l 1, 5,2 Hz);
4.85 (1H, doublet, J=14 Hz);
5.6 (1H, doublet, J=14 Hz);
5.7 (1H, doublet, J=4 Hz);
5.12 (1H, singlet);
5.90 (1H, doublet of doublets, J=15,4 Hz);
6.62 (1H, doublet of doublets, J=15, 10 Hz);
6.75 (1H, doublet, J=16 Hz);
6.92-6.99 (2H, multiplet);
7.01-7.08 (lH,multiplet);
7.10-7.14 (1H, multiplet);
"-7.34 (1H, doublet of doublets, J=10, 1 Hz);
7.41 (1H, doublet of doublets, J=8,1 Hz);
7.58 (1H, triplet, J=8 Hz);

7.79 (1H. singlet);
7.82 (1H. singlet).
IR spectrum vmax (KBr) cm"': 3406. 2231. 1480. 1275. 1140.
Mass spectrum m/z (FAB): 543 (M"+l).
Example 8
(2R.3RV3-rrtrans-2-[(lE.3E)-4-(4-Cvano-2-fliiorophenvn-1.3-butadien-l-vn-1.3-
dioxan-5-vnthiol-2-(2.5-difluorophenvn-1 -(1H-1,2.4-triazol-1 -vn-2-butanol

8(0 (2R)-2'.5'-Difluoro-2-(3.4.5.6-tetrahvdro-2H-pyran-2-vloxv)propiophenone
6.50 g (yield 98%) of the title compound were obtained as an oil according to
the reaction and treatment described in Example 7(i) above using 7.04g (36.5 mmol)
of l-bromo-2,5-difluorobenzene and 6.0 g (25 mmol) of 4-[(2R)-2-(3.4.5.6-
tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine [prepared as described in Chem.
Pharm. Bull., 41,1035-1042 (1993)].
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 8 ppm:
1.43 [(3/2)H, doublet of doublets, J=6, 1 Hz];
1.48 [(3/2)H, doublet of doublets, J=7, 1 Hz];
1.50-1.89 (6H, multiplet);
3.36 [(1/2)H, doublet of triplets, J=12,4 Hz];
3.53 [(1/2)H, doublet of triplets, J=12, 4 Hz];
3.73 [(1/2)H, doublet of triplets, J=12, 4 Hz];
-3.90 [(1/2)H, doublet of triplets, J=l 1,4 Hz];
4.66 [(1/2)H, triplet, J=4 Hz];

4.75 [(1/2)H, triplet, J=4 Hz];
4.87 [(1/2)H, quartet of doublets, J=7. 1 Hz]:
5.12 [(1/2)H, quartet of doublets. J=7, 2 Hz);
7.08-7.15 (lH,multiplet);
7.17-7.25 (lH,multiplet);
7.50-7.54 (lH,multiplet).
IR spectrum vmax (CHC13) cm'1: 1698. 1491. 1417. 1257.
Mass spectrum m/z (FAB); 271 (M*+l).
8fii) (2R.3RV2-f2.5-Difluorophenvl)-l .2.3-butanetriol
4.90 g (yield 95%) of the title compound were obtained as an oil according to
the reaction of Example 7(ii) above using 6.40 g (23.7 mmol) of (2R)-2'.5'-difluoro-2-
(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone [prepared as described in Step
8(i) above] and 7.90 g (47.4 mmol) of (dirnethylisopropoxysilyl)methylmagnesium
chloride in the first step of the reaction. 22ml of a 31% solution of hydrogen peroxide
and 1.8 g (21 mmol) of sodium hydrogen carbonate in the second step and 0.3 g (1.57
mmol) of p-toluensulfonic acid monohydrate in the third step of the reaction followed
by purification of the reaction product by chromatography on a silica gel (lOOg)
column using a 1:2 to 1:0 mixture of ethyl acetate and hexane as the eluant.
lH-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 5 ppm:
0.95 (3H, doublet, J=6 Hz);
3.77 (1H, doublet, J=ll Hz);
4.31 (1H, doublet of doublets, J=l 1,2 Hz);
4.52 (1H, quartet of doublets, J= 6, 3 Hz);
6.94-7.00 (2H, multiplet);
7.44-7.48 (lH,multiplet).
IR spectrum vmax (KBr) cm'1: 3422, 1487, 1142, 1065.
Mass spectrum m/z (FAB): 219 (M*+l).

R(iiiU2R.3R)-2-(,2.S-Difluorophenvl)-1.3-bis(methanesulfonvn-2-butanol
In the same manner as that described in Example 7(fii) above. 4.80 g (10.1
mmol) of (2R.3R)-2-(2.5-difluorophenyl)-1.2.3-butanetriol [prepared as described in
Step 8(ii) above] were reacted with 7.75 g (67.8 mmol) of methanesulfonyl chloride
and the resulting product was purified by chromatography on a silica gel (110 g)
column using a 1:2 to 1:1 mixture of ethyl acetate and hexane as the eluant to afford
7.56 g (yield 92%) of the title compound as a colorless oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 5 ppm:
1.27 (3H. doublet, J=6 Hz);
2.99 (3H, singlet):
3.11 (3H. singlet);
3.36 (1H. singlet);
4.73 (2H. singlet);
5.32 (1H, quartet, J=7 Hz);
7.03-7.26 (2H, multiplet);
7.43-7.47 (1H, multiple!).
IR spectrum vmax (KBr) cm"1: 3484, 1492, 1346, 1169.
Mass spectrum m/z (FAB): 375 (M++l).
8 (iv) (2R.3SV2-(2.5-Difluorophenvl)-3-methvl-2-r( 1H-1.2,4-triazol 1 -
vDmethylloxirane
In the same manner as that described in Example 7(iv) above, 7.00g (18.7
mmol) of (2R,3R)-2-(2,5-difluorophenyl)-l ,3-bis(methanesulfonyl)-2-butanol
[prepared as described in Step 8(iii) above] were reacted with lH-l,2,4-triazole and
the reaction product was purified by chromatography on a silica gel (100 g) column
using a 1:1 to 3:2 mixture of ethyl acetate and hexane as the eluant to afford 2.65 g
-(yield 56%) of the title compound as an oil.

'H-Nuclear magnetic resonance spectrum (400 MHz. CDCI3) 5 ppm:
1.64 (3H, doublet, J=6 Hz);
3.20 (1H. quartet, J=6 Hz);
4.42 (1H, doublet, J= 15 Hz);
4.97 (1H, doublet, J=l 5 Hz);
6.76-6.81 (1H, multiplet);
6.89-6.96 (lH,multiplet);
6.99 (1H, doublet of triplets. J=9, 4 Hz);
7.83 (1H, singlet);
7.99 (1H, singlet).
IR spectrum vmax (KBr) cm"1: 3110.1500, 1490,1184,1135.
Mass spectrum m/z (EI): 251 (M+).
8fv)f2R.3RV2-f2.5-DifluorophenvlV3-rftrans-2-phenyl-l.3-dioxan-5-vl)thio1-1-(lH-
1.2.4-triazol-1 -vl)-2-butanol
In the same manner as that described in Example 7(v) above, 2.59g (10.3
mmol)of(2R,3S)-2-(2,5-difluorophenyl)-3-methyl-2-[(lH-l,2,4-triazol-l-
yI)methyl]oxirane [prepared as described in Step 8(iv) above] were reacted with 3.19g
(13.4 mmol) of trans-5-(acetylthio)-2-phenyl-l,3-dioxane [prepared as described in
Japanese Patent Application (Kokai) Hei 8-333350] to afford 5.36 g of the crude title
compound. 0.27g of the purified title compound were obtained as a non-crystalline
solid by chromatography of 0.36 g of the crude product on a silica gel (20g) column
using a 1:1 mixture of ethyl acetate and hexane as the eluant.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 6 ppm:
1.22 (3H, doublet, J=7 Hz);
3.38 (1H, quartet, J=7 Hz);
3.49 (1H, triplet of triplets, J=12,5 Hz);
"-3.75 (1H, triplet, J=12 Hz);
3.77 (1H, triplet, J=12 Hz);
4.41 (1H, double doublet of doublets, J=12, 5, 2 Hz);

4.52 (1H, double doublet of doublets. J=12. 5. 2 Hz):
4.88 (1H, doublet, J=14 Hz);
5.06 (1H. doublet, J=14 Hz);
5.08 (1H. doublet, J=l Hz);
5.49 (1H, singlet);
6.85-6.91 (lH,multiplet);
6.95 (1H. doublet of triplets. J=9,4 Hz);
7.08-7.13 (3H. multiplet);
7.36-7.41 (2H, multiplet);
7.49 (1H, doublet of doublets. 5=1, 2 Hz);
7.80 (1H, singlet);
7.82 (1H, singlet).
IR spectrum vmax (KBr) cm'1: 3405, 1487, 1140, 1074.
Mass spectrum m/z (FAB): 448 (M++l).
8(vi)(2R.3RV2-(2.5-Difluorophenvn-3-rri-(hvdroxvmethvlV2-hvdroxvethvllthiol-l-
(1H-1,2.4-triazol-1 -vl)-2-butanol
In the same manner as that described in Example 7(vi) above, 5.0g of crude
(2R,3R)-2-(2,5-difluorophenyl)-3-[(trans-2-phenyl-l,3-dioxan-5-yl)thio]-l-(lH-l,2,4-
triazol-l-yl)-2-butanol [prepared as described in Step 8(v) above] were treated with
hydrochloric acid and the product obtained was purified by chromatography on a
silica gel (50 g) column using a 3:100 mixture of methanol and ethyl acetate as the
eluant to afford 3.17 g (overall yield from Step 8(v) 83%] of the of the title compound
as an oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCb) 8 ppm:
1.22 (3H, doublet, J=7 Hz);
3.27 (1H, quintet, J=6 Hz);
: 3.50 (1H, quartet, J=7 Hz);
3.75 (1H, doublet of doublets, J=ll, 6 Hz);
3.78-3.86 (2H, multiplet);

3.96 (1H. doublet of doublets. J=ll. 6 Hz);
4.89 (1H. doublet. J= 14 Hz):
5.19 (1H, doublet, J=l4 Hz):
5.56 (1H. singlet);
6.87-7,00 (2H. multiplet);
7.16-7.11 (1H. multiplet);
7.78 (1H. singlet);
7.88 (1H, singlet).
IR spectrum vmax (KBr) cm'1: 3302,1488,1047.
Mass spectrum m/z (FAB): 360 (M++l).
8(vii) (2R.3R)-3-f[trans-2-K 1 E.3E)-4-(4-Cvano-2-fluoroDhenvn-1.3-butadien-1 -vll-
1.3-dioxan-5-vnthio1-2-(2.5-difluorophenvl)-1 -d H-1,2.4-triazol-1 -vl)-2-butanol
In the same manner as that described in Example l(iii) above, a reaction was
carried out using 1.02 g (2.84 mmol) of (2R,3R)-2-(2,5-difluorophenyl)-3-[[l-
(hydroxymethyl)-2-hydroxyethyl]thioj-1 -(IH-1,2,4-triazol-1 -yl)-2-butanol [prepared
as described in Step 8(vi) above], 571.6 mg (2.84 mmol) of 3-fluoro-4-[(lE.3E)-5-
oxo-l,3-pentadienyl]benzonitrile and 594.5 mg (3.13 mmol) of p-toluenesulfonic acid
monohydrate and the reaction product was purified by chromatography on a silica gel
(75 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give
1.03 g (yield 66%) of the title compound as a colorless non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCb) 8 ppm:
1.20 (3H, doublet, J=7 Hz);
3.35 (IH, quartet, J=7 Hz);
3.41 (IH, triplet of triplets, J=l 1, 5 Hz);
3.62 (IH, triplet, J=ll Hz);
3.64 (IH, triplet, J=l 1 Hz);
-4.31 (IH, double doublet of doublets, J=l 1, 5,2 Hz);
4.43 (IH, double doublet of doublets, J=l 1, 5,2 Hz);
4.86 (IH, doublet, J=14 Hz);

5.03 (IH, doublet, J=14 Hz);
5.06-5.08 (2H, multiplet);
5.90 (IH. doublet of doublets. J= 15. 4 Hz);
6.62 (IH, doublet of doublets, J=15. 10 Hz);
6.75 (IH. doublet, J= 16 Hz);
6.95 (IH, doublet of doublets, J=16. 10 Hz);
6.85-6.98 (2H, multiplet);
7.07-7.12 (IH, multiplet);
7.34 (IH. doublet, J= 10 Hz);
7.40 (IH. doublet. J=8 Hz);
7.58 (IH, triplet, J=8 Hz);
7.79 (IH, singlet);
7.81 (IH, singlet).
IR spectrum vmax (KBr) cm"1: 3416.2231, 1487, 1141.

543 mg (1.00 mmol) of.(2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cy
"fluorophenyl)-l,3-butadien-l-yl]-l,3-dioxan-5-yl]thio]-2-(2,4-difluo
l,2,4-triazol-l-yl)-2-butanol (prepared as described in Examples 1 o

added to a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride
(which had been pre-washed with hexane) in 5 ml of N.N-dimethylformamide at
ambient temperature with stirring. After the evolution of hydrogen gas had ceased,
the mixture was cooled to 0°C and then 117.8 mg (1.50 mmol) of acetyl chloride were
added to the reaction mixture. This resulting mixture was stirred at 70°C for 28
hours. After cooling to ambient temperature, the reaction mixture was partitioned
between ethyl acetate and a saturated aqueous ammonium chloride solution. The
organic layer was washed with water and aqueous sodium chloride solution and then
concentrated under reduced pressure. The oily residue thus obtained was purified by
chromatography on a silica gel (50 g) column using a 1:2 to 2:1 mixture of ethyl
acetate and hexane as the eluant to afford 226.2 mg of an oil containing a mixture of
the title compound and the starting material in a ratio of 7:3. The oil was further
purified by chromatography recycled 18 times in recycle HPLC [JAIGEL-1H (20mm
i.d x 600 mm) and JAIGEL-2H (20mm i.d. x 600 mm), which are products of Japan
Analytical Industry, Co. Ltd., were combined in series] using chloroform as the eluant
to give 120 mg (yield 21%) of the title compound as a non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDC13) 6 ppm:
1.35 (3H, doublet of doublets, J=7,2 Hz);
2.11 (3H, singlet);
3.08 (1H, triplet of triplets, J=l 1, 5 Hz);
3.52 (2H, triplet, J=l 1 Hz);
3.92 (1H, quartet, J=7 Hz);
4.15-4.23 (2H, multiple!);
5.00 (1H, doublet, J=4 Hz);
5.32 (1H, doublet of doublets, J=15, 3 Hz);
5.38 (1H, doublet, J=l5 Hz);
5.85 (1H, doublet of doublets, J=15,4 Hz);
6.58 (1H, doublet of doublets, J=15, 12 Hz);
6.74 (1H, doublet, J=l 5 Hz);
6.85-6.98 (3H, multiplet);
"7.28-7.36 (3H, multiplet);
7.57 (1H, doublet of triplets, J=8,4 Hz);

7.94 (1H. singlet);
7.95 (1H. singlet).
IR spectrum vm„ (KBr) cm'1: 2231, 1746.1504. 1141.
Mass spectrum m/z (FAB): 585 (NT+1).
Example 10
U1 R.2R)-2-f rtrans-2-fr 1 E.3E)-4-(4-Cvano-2-fluorophenvl)-1,3-butadien-1 -vl 1-1.3-
dioxan-5-vl]thio]-1 -(2.4-difluorophenvP-1 -(1H-1.2.4-triazol-1 -vl)methvl1propvn
benzoate




543 mg (1.00 mmol) of (2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-
fluorophenyl)-l ,3-butadien-l -yl]-1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1 -(1H-
l,2,4-triazol-l-yl)-2-butanol (prepared as described in Examples 1 or 4 above) were
added to a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride
in oil (which had been pre-washed with hexane) in 3 ml of N,N-dimethylformamide at
ambient temperature with stirring. After the evolution of hydrogen gas had ceased,
210.9 mg (1.50 mmol) of benzoyl chloride were added to the mixture. The resulting
mixture was stirred at ambient temperature for 6 hours. At the end of this time, the
reaction mixture was partitioned between ethyl acetate and a saturated aqueous
sodium hydrogen carbonate solution. The organic layer was washed with water and
an aqueous sodium chloride solution and then concentrated under reduced pressure.
The oily residue thus obtained was purified by chromatography on a silica gel (40 g)



column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 234.2 mg
(yield 36%) of the title compound as a colorless non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCb) 6 ppm:
1.47 (3H. doublet of doublets, J=7. 2 Hz);
3.08 (1H. multiplet);
3.53 (1H. triplet, J=ll Hz);
3.54 (1H. triplet, J= 11 Hz);
4.03 (1H, quartet, J=7 Hz);
4.18-4.22 (2H, multiplet);
5.01 (1H, doublet, J=4 Hz);
5.50 (1H, doublet of doublets, J=15, 3 Hz);
5.55 (1H, doublet, J=15 Hz);
5.86 (1H, doublet of doublets, J=15, 4 Hz);
6.59 (1H, doublet, J=15, 10 Hz);
6.74 (1H, doublet, J= 16 Hz);
6.88-6.97 (3H, multiplet);
7.34 (1H, doublet, J= 10 Hz);
7.40-7.50 (4H, multiplet);
7.56-7.64 (2H, multiplet);
7.86 (1H, singlet);
7.89 (1H, singlet);
7.94 (2H, doublet, J=8 Hz).
IR spectrum vmax (KBr) cm"1: 2231, 1724, 1504, 1276.
Mass spectrum m/z (FAB): 647 (M^+l).

rnR.2R)-2-rrtrans-2-f(lE.3EV4-(4-Cvano-2-fluorophenvn-1.3-bptadien-l-vn-1.3-
dioxan-5-vnthiol-l-(2.4-difluorophenvl)-1-(lH-1.2.4-triazol-l-vl)meth\i1propvl1
isobutvlcarbonate

543 mg (1.00 mmol) of (2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-
fluorophenyl)-L3-butadien-l-yl]-1.3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-l-(lH-
1.2,4-triazol-l-yl)-2-butanol (prepared as described in Examples 1 or 4 above) were
added to a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride
in oil (which had been pre-washed with hexane) in 3 ml of N.N-dimethylformamide at
0°C with stirring and then the resulting mixture was stirred at ambient temperature.
After the evolution of hydrogen gas had ceased, the reaction mixture was cooled to
0°C and then 204.9 mg (1.50 mmol) of isobutyl chloroformate were added to the
mixture. The resulting mixture was stirred at ambient temperature for 2 hours. At the
end of this time, the reaction mixture was partitioned between ethyl acetate and a
saturated aqueous ammonium chloride solution. The organic layer was washed with
water and an aqueous sodium chloride solution and then concentrated underreduced
pressure. The resulting oily residue was purified by chromatography on a silica gel
(25 g) column using a 1:2 mixture of ethyl acetate and hexane as the eluant to give
192.3 mg (yield 30%) of the title compound as a colorless non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDC13) 5 ppm:
0.95 (3H, doublet, J=7 Hz);
. 0.97 (3H, doublet, J=7 Hz);
1.34 (3H, doublet of doublets, J=7,2 Hz);
3.05 (1H, triplet of triplets, J=12, 5 Hz);

3.49 (1H. triplet. J=12 Hz);
3.50 (1H, triplet, J=12 Hz);
3.89-3.99 (3H. multiple!):
4.19 (1H, double doublet of doublets. J-12. 5. 2 Hz):
4.34 (1H. double doublet of doublets. J=12. 5. 2 Hz):
4.97 (1H. doublet. J=4 Hz):
5.34 (1H. doublet of doublets. J=15, 4 Hz):
5.43 (1H. doublet, J=15 Hz):
5.86 (1H, doublet of doublets. J=15. 4 Hz);
6.58 (ffl, doublet of doublets, J=15. 10 Hz);
6.73 (1H, doublet, J= 15 Hz);
6.92 (1H, doublet of doublets, J=15, 10 Hz);
6.85-6.96 (2H, multiplet);
7.33 (1H, doublet, J= 10 Hz);
7.40 (1H, doublet, J=7 Hz);
7.45 (1H, doublet of triplets. J=8, 2 Hz);
7.57 (1H, triplet, J=8 Hz);
7.95 (1H, singlet);
7.97 (1H, singlet).
IR spectrum vmax(KBr) cm"1: 2231, 1749, 1504, 1141.
Mass spectrum m/z (FAB): 643 (M++l).

Example 12
\( 1 R.2R)-2-rftrans-2-ff 1 E.3E)-4-(4-Cvano-2-fluorophenvl)-1.3-butadien-1 -vll-1.3-
dioxan-5-vllthiol-1 -(2.4-dffluorophenvP-1 -\( 1H-1.2.4-triazol-1 -vl )methvnpropvr]
aminoacetate

12fi) rflR.2R)-2-rrtrans-2-fflE.3E)-4-(4-Cvano-2-fluorophenvn-l.3-butadien- 1-vll-
1.3-dioxan-5-vnthio1-1 -(2.4-difluorophenvl)-1 -[(1H-1.2.4-triazol-1 -vl )methvHpropvn
(U-dioxo-U-dihvdro^-isoindolvDacetate
280 mg (2.2 mmol) of oxalyl chloride and 15 ul of N,N-dimethylformamide
were added to a suspension of 410 mg (2.0 mmol) of N-phthaloylglycine in 10 ml of
dichloromethane at 0°C with stirring. After stirring this mixture at ambient
temperature for 3 hours, solvent was removed from the reaction mixture by
evaporation under reduced pressure and then the mixture was evaporated to dryness in
vacuo to afford the crude acid chloride as a solid.
542 mg (1.00 mmol) of (2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-
fluorophenyl)-l,3-butadien-l-yl]-l,3-dioxan-5-yl]thio]-2-(2r4-difluorophenyl)-l-(lH-
l,2,4-triazol-l-yl)-2-butanol (prepared as described in Examples 1 or 4) were added to
a suspension of 87 mg (2.00 mmol) of a 55% dispersion of sodium hydride in oil
(which had been pre-washed with hexane) in 5 ml of N,N-dimethylformamide at 0°C
with stirring and then the mixture was stirred at ambient temperature for 40 minutes.
After the reaction mixture was cooled to 0°C, a solution of the crude acid chloride
obtained above in 4 ml of tetrahydrofuran was added to the mixture. The resulting
mixture was stirred at ambient temperature for 1 hour. At the end of this time, the
reaction mixture was partitioned between ethyl acetate and water. The organic layer

was washed consecutively with a saturated aqueous sodium hydrogen carbonate
solution, a 10% aqueous sodium chloride solution and a saturated aqueous sodium
chloride solution and then concentrated under reduced pressure. The oily residue thus
obtained was purified by chromatography on a silica gel (10 g) column using a 1:1
mixture of ethyl acetate and hexane as the eluant to give 187 mg (yield 26%) of the
title compound as an oil.
'H-Nuclear magnetic resonance spectrum (400 MHz. CDCI3) 5 ppm:
1.37 (3H, doublet of doublets, J=7, 2 Hz);
2.99 (1H, triplet of triplets, J=l 1, 5 Hz);
3.47 (1H, triplet, J=ll Hz);
3.48 (1H, triplet, J=ll Hz);
3.82 (1H, quartet, J= 7 Hz);
4.1-4.2 (2H, multiple!);
4.45 (1H, doublet, J= 17 Hz);
4.57 (1H, doublet, J=l7 Hz);
4.97 (1H, doublet, J=4 Hz);
5.33 (1H, doublet, J= 15 Hz);
5.37 (1H, doublet of doublets, J=15,2 Hz);
5.84 (1H, doublet, J=15,4 Hz);
6.58 (1H, doublet of doublets, J=15, 11 Hz);
6.74 (1H, doublet, J=l 6 Hz);
6.8-7.0 (2H, multiplet);
6.92 (1H, doublet of doublets, J=16,11 Hz);
7.33 (1H, doublet of doublets, J=10,2 Hz);
7.35-7.45 (2H, multiplet);
7.57 (1H, triplet, J=8 Hz);
7.77 (2H, doublet of doublets, J=6,3 Hz);
7.91 (2H, doublet of doublets, J=6,3 Hz);
7.99 (1H, singlet);
8.12 (1H, singlet).
IR spectrum vmax (KBr) cm*1:2233,1726,1504, 1417.


Mass speci rum m/z (FAB): 730 (M++l).
Specific ro;ation: [a]D25 ^-5.5° (c = 1.02, CHCl3).
12 (iil [(IE.■2R>2-rrtrans-2-[(lE.3E)-4-(4-Cvano-2-fluorophenvl)-1,3-biUaditin-l-yn-
1 Vriioxan 5-vlltliinl-l-(2.4-difluorophenvi)-1 -KltiM.2.4-triazol-l-vl^methvllpropyll
arainoacetiite
10^ mg (2.22 mmol) of methylhydrazioe were added to a solution of 1 BO mg
(0.25 mmrl)of[(1Rr2R)-2-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l,3-
butadien-1 yl>1,3 -dioxan-5-yl]thio]-1 -(2,4-difluorophenyl)-1 -[(1H-1,2,4-tri azol-1 -
yDmethy]]propyl] (l,3-dioxo-l,3-dihydro-2-isomdolyl)acetate [prepared as described
in Slep 12( i) »buw] iu 5 ;ul of dichloromcthcuic in an ioc bath. The resulting mixture
was stirred at ambient temperature for 5 hours. At the end of this time, ihe reaction
mixture was concentrated and evaporated lo dryness . Dichloromethane was
added to tr e resulting residue and the dichloromethane was then evaporated under
reduced pr assure. The resulting residue was dissolved in dichloromethane, the
solution was allowed to stand at ambient temperature for 12 hours, and was then
concentrat :d. The resulting residue was purified by chromatography on a silica gel (5
g) column asing a 9:1 mixture of ethyl acetate and ethanol as the eluant to give 126
rag (yield ': :5%) of the title compound as a pale yellow non-crystalline solid.
'H-Nuclea magnetic resonance spectrum (400 MHz, CDCI3) ppm:
1.35 (3H, (.oublet of doublets, J=7, 2 Hz);
3,04 (1H, 1 riplet of triplets, J—11, 5 Hz);
3.4-3.5 (4H, multiple!);
3.90(lH,cuartet,J=7Hz);
4.1-4,3 (2H, multiple!);
5.00 (1H,coublet J=4 Hz);
5.36 (IK, cooublet, J=15 Hz);
5.38 (IK, coublet of doublets, J=15, 2 Hz);
5.85 (IK, coublet of doublets, J—15, 4 Hz);
6.59 (IE, ( oublet of doublets, J=15, 10 Hz),

6.74 (1H, doublet, J=16 Hz);
6.80-6.95 (3H, multiplet);
7.3-7.4 (2H, multiplet); '•
7.40 (1H, doublet of doublets, J=8. 1 Hz);
7.57 (1H, triplet, J=8 Hz);
7.91 (1H. singlet);
7.92 (1H, singlet).
IR spectrum vmax (CHC13) cm-1: 2233, 1748, 1615, 1504. 1276. 1140.
Mass spectrum m/z (FAB): 600 (M++l).
Specific rotation: [a]D25 +14.6° (c = 0.52, CHCI3).
Example 13
[(R.2R)-2-rrtrans-2-rnE.3E)-4-(4-Cvano-2-fluoroDhenvl)-1.3-butadie
dioxan-5-vnthiol-1 -(2.4-difluorophenvl)-1-IY1H-1.2.4-triazol-1 -vl )metl
aminopropionate

13(i) TCIR.2R)-2-|Ttrans-2-r(lE.3E)-4-(4-Cvano-2-fluorophenvl)-1.3-butadien-l -vll-
1.3-dioxan-5-vnthio1-l-r2.4-difluorophenvl)-l -rCl H-l.2.4-triazol-1 -ynmethynpropyll
3-C1,3-dioxo-l .3-dihvdro-2-isoindolvl)propionate
280 mg (2.2 mmol) of oxalyl chloride and 15 ul of N,N-dimethylformamide
were added to a suspension of 438.4 mg (2.0 mmol) of N-phthaloyl-P-alanine
[prepared as described in J.Agric. Food Chem.,_47, 1276-1284 (1999)] in 3 ml of

dichloromethane with stirring. After stirring this mixture at ambient temperature for
40 minutes, the solvent was removed from the reaction mixture by evaporation undei
reduced pressure and then evaporated to dryness in vacuo to afford the crude acid
chloride as a solid.
543 mg (1.00 mmol) of (2R.3R)-3-[[trans-2-[(lE.3E)-4-(4-cyano-2-
fluorophenyl)-L3-butadien-l-yl]-1.3-dioxan-5-yl]thio]-2-(2.4-difluorophenyl)-l-(lH
l,2,4-triazol-l-yl)-2-butanol (prepared as described in Examples 1 or 4) were added i
a suspension of 48 mg (1.10 mmol) of a 55% dispersion of sodium hydride in oil
(which had been pre-washed with hexane) in 5 ml of N,N-dimethylformamide at 0°C
with stirring and then the resulting mixture was stirred at ambient temperature for 20
minutes. After the reaction mixture was cooled to 0°C, a solution of the crude acid
chloride obtained above in 4 ml of tetrahydrofuran was added to the reaction mixture
The resulting mixture was stirred at ambient temperature for 1 hour. At the end of
this time, the reaction mixture was partitioned between ethyl acetate and a saturated
aqueous ammonium chloride solution. The organic layer was washed with water,
then with a saturated aqueous sodium chloride solution and then concentrated under
reduced pressure. The resulting oily residue was purified by chromatography on a
silica gel (40 g) column using a 1:1 mixture of ethyl acetate ethyl acetate and hexane
as the eluant to give 100 mg (yield 13%) of the title compound as an oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCb) 5 ppm:
1.33 (3H, doublet of doublets, J=7,2 Hz);
2.82 (1H, triplet of doublets, J=7, 1 Hz);
2.92 (1H, triplet, J=7 Hz);
2.95-3.03 (lH,multiplet);
3.47 (1H, triplet, J=ll Hz);
3.49 (1H, triplet, J=ll Hz);
3.85 (1H, quartet, J=7 Hz);
3.94-4.00 (2H, multiplet);
4.05-4.11 (2H, multiplet);
'4.97 (1H, doublet, J=4 Hz);
5.31 (1H, doublet, J= 15 Hz);

5.35 (1H, doublet, J=l5 Hz);
5.84 (1H, doublet of doublets, J=15, 4 Hz);
6.57 (1H, doublet of doublets, J=15. 10 Hz);
6.73 (1H, doublet, J= 16 Hz);
6.77-6.85 (2H. multiplet);
6.92 (1H. doublet of doublets. J=16. 10 Hz):
7.29-7.35 (2H, multiplet);
7.40 (1H, doublet of doublets. J=8. 1 Hz);
7.57 (1H, triplet, J=8 Hz);
7.71-7.75 (2H, multiplet);
7.83-7.89 (2H, multiplet);
7.86 (1H, singlet);
7.97 (1H, singlet).
13(ii)r(lR.2R)-2-rrtrans-2-rnE.3E)-4-(4-Cvaiio-2-fluorophenvn-1.3-butadien-l-vl1-
1,3-dioxan-5-vnthio1-1 -(2.4-difluorophenvl)- l-fdH-l .2.4-triazol-1 -vDmethvllpropvn
3-aminopropionate
222.7 mg (4.38 mmol) of methylhydrazine were added to a solution of 100 mg
(0.13 mmol) of [(1 R,2R)-2-[[trans-2-[( 1 E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-
butadien-1 -yl]-1,3-dioxan-5-yl]thio]-1 -(2,4-difluorophenyl)-1 -[(1H-1.2,4-triazol-1 -
yl)methyl]propyl] 3-(l,3-dioxo-l,3-dihydro-2-isoindolyl)propionate [prepared as
described in Step 13(i) above] in 2 ml of dichloromethane in an ice bath. The
resulting mixture was stirred at ambient temperature for 20 hours. At the end of this
time, the reaction mixture was concentrated and then evaporated to dryness in vacuo.
Dichloromethane was added to the resulting residue and the dichloromethane was
then evaporated under reduced pressure. The resulting residue was then dissolved in
dichloromethane, the solution was allowed to stand at ambient temperature for 12
hours and then concentrated. The residue thus obtained was purified by
chromatography on a silica gel (15 g) column using a 9:1 mixture of ethyl acetate and
methanol to give 41.5 mg (yield 50%) of the title compound as a pale yellow non-
crystalline solid.



Example 14
Sodium hydrogen r(lR:2R)-2-rftrans-2-f(lE.3E)-4-(4-cvano-2-fluorophenvn-1.3-
butadien-1 -vH-1.3-dioxan-5-vl]thiol-l -(2.4-difluorophenvl)-1 -[(1H-1.2.4-triazol-1 -
vDmethvllpropvll phosphate

14 (i) Diallvl r(lR.2RV2-fftrans-2-f(lE.3E)-4-r4-cvano-2-fluorophenvn-1.3-butadiei
1 -vl1-l 3-dioxan-5-vnthioV 1 -(2.4-difluorophenvn-1 -UIH-1.2.4-triazol-1 -
yDmethyllpropyl] phosphite
490 mg (2.00 mmol) of bis(allyloxy)(diisopropylamino)phosphine [prepared
s described in Tetrahedron Lett., 30,4219 (1989)] were added to a suspension of 570
ig (1.00 mmol) of (2R,3R)-3-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l,3-
utadien-1 -yl]-1,3-dioxan-5-yl]thio]-2-(2,4-difluorophenyl)-1 -(1H-1.2.4-triazol-1 -yl)-
-butanol (prepared as described in Examples 1 or 4 above) and 350 mg (5.00 mmol)
of tetrazole in 4 ml of a 1:1 mixture of acetonitrile and dichloromethane. The
resulting mixture was stirred at ambient temperature for 15 hours. At the end of this
time, the reaction mixture was concentrated and the resulting residue was dissolved in
sthyl acetate. The solution thus obtained was washed with a saturated aqueous
sodium hydrogen carbonate solution and with a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting oily residue was purified by chromatography on a
silica gel (15 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant
to give 609 mg (yield 89%) of the title compound as a colorless oil.
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCh) 8 ppm:
1.29 (3H, doublet, J=7 Hz);
3.25 (1H, triplet of triplets, J==ll, 5 Hz); .

3.60-3.70 (3H. multiplet):
4.30-4.60 (6H. multiplet);
4.95 (1H, doublet, J= 15 Hz);
5.08 (1H, doublet, J=4 Hz);
5.20-5.30 (2H. multiplet);
5.30-5.40 (3H. multiplet);
5.89 (1H. doublet of doublets. J=15. 4 Hz);
5.90-6.10 (2H. multiplet);
6.62 (1H, doublet of doublets. J=15, 10 Hz);
6.70-6.85 (2H. multiplet);
6.75 (1H, doublet, J= 16 Hz);
6.95 (1H, doublet of doublets, J=16, 10 Hz);
7.30-7.45 (3H, multiplet);
7.58 (1H, triplet. J=8 Hz);
7.64 (1H, singlet);
8.19 (1H. singlet).
IR spectrum vmax (CHC13) cm"1: 2233, 1732, 1616, 1501.
Mass spectrum m/z (FAB): 687 (M++l).
14 (ii) Diallvl raR.2RV2-rftrans-2-faE.3E)-4-(4-cvano-2-fluorophenvl)-l,3-
butadien-1 -vll-1.3-dioxan-5-vllthio1-1 -f2,4-difluorophenvl)-1 -\{ 1H-1,2.4-triazol-1 -
vDmethvllpropvU phosphate
0.42 ml of an approximately 5 M nonane solution of tert-butyl hydroperoxide
were added to a solution of 530 mg (0.772 mmol) of diallyl [(lR,2R)-2-[[trans-2-
[(lE,3E)-4-(4-cyano-2-fluorophenyl)-l,3-butadien-l-yl)-l,3-dioxan-5-yl]thio]-l-(2,4-
difluorophenyl)-l-[(lH-l,2,4-triazol-l-yl)methyl]propyl] phosphite [prepared as
described in Step 1-4(1) above] in 3 ml of dichloromethane at 0°C. The resulting
mixture was stirred at 0°C for 1 hour. At the end of this time, 5 ml of a saturated
aqueous sodium thiosulfate solution were added to the reaction mixture and this
mixture was stirred at ambient temperature for 1 hour. The reaction product was then

extracted with ethyl acetate. The organic layer was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was purified by
chromatography on a silica gel (15 g) column using a 2:1 to 4:1 mixture of ethyl
acetate and hexane as the eluant to afford 447 mg (yield 82%) of the title compound
as a viscous colorless solid.
'H-Nuclear magnetic resonance spectrum (400 MHz. CDCI3) 5 ppm:
1.29 (3H, doublet, J=7 Hz);
3.18 (1H, triplet of triplets, J=l 1, 5 Hz);
3.63 (2H, triplet of doublets, J=l 1, 2Hz);
3.79 (1H, quartet, J=7 Hz);
4.28 (1H, double doublet of doublets. J=l 1, 5, 2 Hz);
4.38 (1H, double doublet of doublets, J=l 1, 5. 2 Hz);
4.45-4.60 (2H, multiple!);
4.66 (2H, multiplet);
5.05 (1H, doublet, J=4 Hz);
5.08 (1H, doublet, J= 15 Hz);
5.27 (1H, broad doublet, J=10 Hz);
5.31 (1H, broad doublet, J=10 Hz);
5.34 (1H, broad doublet, J=l 7 Hz);
5.43 (1H, broad doublet, J=17 Hz);
5.72 (1H, doublet, J=l5 Hz);
5.88 (1H, doublet of doublets, J=15,4 Hz);
5.85-6.05 (2H, multiplet);
6.61 (1H, doublet of doublets, J=15,11 Hz);
6.75 (1H, doublet, J=16 Hz);
6.80-6.90 (2H, multiplet);
6.94 (1H, doublet of doublets, J=16,11 Hz);
7.30-7.40 (3H, multiplet);
7.57 (1H, triplet, J=8 Hz);
7.69 (1H, singlet);
8.40 (1H, singlet).

IR spectrum vmax (KBr) cm"1: 2231, 1616. 1504. 1420.
Mass spectrum m/z (FAB)r 703 (M""+l).
14 (Hi) Diallvl fdR.2R)-2-rrtrans-2-rnE.3E)-4-(4-cvano-2-nuorophenvl)-1.3-
butadien-1 -vll-1.3-dioxan-5-vnthiol-1 -(2.4-difluorophenvl)-1 -\(1H-1.2.4-triazol-1 -
yl)methvl]propvn phosphate [Alternative to steps 14(i) and 14(H)!
A suspension of 860 mg (1.52 mmol) of (2R.3R)-3-[[trans-2-[(lE.3E)-4-(4-
cyano-2-fluorophenyl)-1,3-butadien-1 -yl]-1,3-dioxan-5-yl]thio]-2-(2.4-
difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2-butanol (prepared as described in
Examples 1 or 4 above) and 40 mg (1.67 mmol) of sodium hydride in 5 ml of
dimethylformamide was stirred at ambient temperature for 10 minutes. 300 mg (1.53
mmol) of diallylphosphoryl chloride [prepared as described in Tetrahedron Lett.. 28,
2259 (1987)] were added to the brown reaction mixture and the resulting mixture was
then stirred at ambient temperature for 2 hours. At the end of this time, the reaction
mixture was diluted with ethyl acetate and the ethyl acetate solution was washed with
a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate and the
concentrated under reduced pressure. The resulting residue was purified in the same
manner as that described in Step 14(ii) above to afford 204 mg (yield 19%) of the title
compound as a viscous colorless solid. The NMR, IR and mass spectral data were
identical to those of the compound prepared in Step 14(H) above.
14(iv) Sodium hydrogen r(lR.2R)-2-[rtrans-2-f(lE.3E)-4-(4-cvano-2-fluoroDhenvl)-
1,3-butadien-1 -vll-1.3-dioxan-5-vnthiol-1 -(2.4-difluorophen vl)-1 -f (1H-1.2.4-triazol-
l-yl)methvl] prop vll phosphate
1 mg of dichlorobis(triphenylphosphine)palladium (II) and 192 mg (0.66
mmol) of tributyltin hydride were added to a solution of 185 mg (0.263 mmol) of
diallyl[(lR,2R)-2-[[trans-2-[(lE,3E)-4-(4-cyano-2-fluorophenyI)-l,3-butadien-l-yl]-
-1,3-dioxan-5-yl]thio]-1 -(2,4-difluorophenyl)-1 -[(1H-1,2,4-triazol-1 -yl)methyl]propyl]
phosphate [prepared as described in Steps 14(H) or 14(iii) above] in 1.5 ml of
dichloromethane. The resulting mixture was stirred at ambient temperature for 15

minutes. At the end of this time, hexane was added to the reaction mixture causing
insoluble material to precipitate and the supernatant solution of this mixture was
carefully removed by decantation. 3 ml of a saturated aqueous sodium hydrogen
carbonate solution were added to a solution of the residue in 5 ml of methanol and the
resulting mixture was stirred at ambient temperature for 15 hours. At the end of this
time, the reaction mixture was concentrated under reduced pressure, methanol was
added to the residue and the insoluble material was then removed by filtration. The
filtrate was concentrated under reduced pressure. The resulting residue was purified
by reverse phase chromatography on Cosmosil 75Ci8-PREP (20 ml. product of
Nacalai Tesque. Inc.) using a 3:2 mixture of methanol and water as the eluant. The
collected fraction containing the desired product was concentrated and lyophilized to
give 76 ml (yield 45%) of the title compound as a colorless solid.
'H-Nuclear magnetic resonance spectrum (400 MHz, D20) 8 ppm:
1.18 (3H. doublet, J=7 Hz);
2.89(lH,multiplet);
3.40-3.60 (2H, m);
3.74 (1H, quartet, J=7 Hz);
3.97(lH,multiplet);
4.14(lH,multiplet);
5.05 (1H, doublet, J=6 Hz);
5.09 (1H, doublet, J=15 Hz);
5.39 (1H, doublet, J=15Hz);
5.73 (1H, doublet of doublets, J=15, 5 Hz);
6.52 (1H, doublet of doublets, J=15, 10 Hz);
6.70-6.80 (2H, multiplet);
6.73 (1H, doublet of doublets, J=16 Hz);
6.95 (1H, doublet of doublets, J=16,11 Hz);
7.35-7.45 (2H, multiplet);
7.55-7.70 (2H, multiplet);
7.65 (1H, singlet);
'-8.69 (1H, singlet).
Mass spectrum vmax(KBr) cm"1: 3417, 2232, 1616, 1498, 1418.

Mass spectrum m/z (FAB): 645 (lvf+1).
Reference Example 1
(2R.3RV3-rftrans-2-fnE.3E)-4-(4-CvanophenvD-1.3-butadien-l-vH-1.3-dioxan-:
vnthio1-2-(2.4-difluorophenvl)-1 -(1H-1.2.4-triazol-1 -\i )-2-butanol
(Comparative Compound A)
l(i) 4-r(lE.3E)-5-Oxo-1.3-pentadienvnbenzonitrile
A solution of 13.1 g (99 mmol) of 4-formylbenzonitrile (commercially
available) and 40 g (120 mmol) of (triphenylphosphoranylidene)crotonaldehyde
[prepared as described in Tetrahedron Lett., 493 (1971)] in 200 ml of
dichloromethane was stirred at ambient temperature overnight. At the end of this
time, the reaction mixture was concentrated to dryness in vacuo. The resulting
residue was purified by chromatography on a silica gel (250 g) column using ethyl
acetate as the eluant to give a mixture of the desired compound and a geometrical
isomer thereof. A solution of the mixture of the two isomers in 150 ml of toluene v
heated at reflux under irradiation with a tungsten lamp (300 W) for 12 hours. The
reaction mixture was then concentrated in vacuo. The resulting residue was purifiec
by chromatography on a silica gel (1.2 kg) column using a 1:9 mixture of ethyl acet
and toluene as the eluant to afford 3.46 g (yield 19%) of the title compound as pale
brown needle-like crystals which were collected by filtration.
Melting point: 147 - 150°C
'H-Nuclear magnetic resonance spectrum (400 MHz, CDC13) 6 ppm:
6.36 (1H, doublet of doublets, J=15, 8 Hz);
7.00 (1H, doublet, J=l 6 Hz);
7.09 (1H, doublet of doublets, J=16, 10 Hz);
7.27 (1H, doublet of doublets, J=15, 10 Hz);
7.59 (2H, doublet, J=8 Hz);
7.67 (2H, doublet, J=8 Hz);


9.67 (1H, doublet. J=8 Hz).
IR spectrum vmax(KBr) cm1: 2226, 1683. 1670. 1626.
Mass spectrum m/z (EI): 183 (M\ 100%). 154. 140. 127. 115.
Anal, calculated for C12H9NO: C, 78.67; H. 4.95; N.7.65.
Found: C, 78.56; H. 5.05; N. 7.62.
irii)(2R.3R)-3-rrtrans-2-l(lE.3E)-4-(4-Cvanophenvn-1.3-butadien-l-vn-1.3-dioxan-
5-vnthiol-2-r2.4-difluorophenvl)-1 -(1H-1.2.4-triazol-1 -vl)-2-butanol
A mixture of 240 mg (1.31 mmol) of 4-[(lE,3E)-5-oxo-l,3-
pentadienyljbenzonitrile [prepared as described in Step l(i) above], 392 mg (1.09
mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[[ 1 -(hydroxymethyl)-2-hydroxyethyl]-
thio]-l-(lH-l,2,4-triazol-l-yl)-2-butanol [prepared as described in Japanese Patent
Application (Kokai) Hei 8-333350)], 249 mg (1.31 mmol) of p-toluenesulfonic acid
monohydrate, 16 ml of dichloromethane and 3.9 g of molecular sieves 4A was stirred
at ambient temperature over night. Aqueous sodium hydrogen carbonate was then
added to the reaction mixture and insoluble material was removed by filtration. The
resulting filtrate was extracted with ethyl acetate and the organic layer was dried and
then concentrated. The resulting residue was purified by chromatography on silica gel
(15 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give
465 mg (yield 81%) of the title compound as a solid. This solid was recrystallized
from a mixture of ethyl acetate and hexane to afford crystals.
Melting point: 147 - 149°C
'H-Nuclear magnetic resonance spectrum (400 MHz, CDCI3) 5 ppm:
1.19 (3H, doublet, J=7 Hz);
3.33 (1H, quartet, J=7 Hz);
"3.40 (1H, triplet of triplets, J=l 1,5 Hz);
3.62 (1H, triplet, J=ll Hz);



3,64 (1H, triplet, J=ll Hz);
4.31 (1H. double doublet of doublets. J- 11. 5. 2 Hz);
4.43 (1H. double doublet of doublets. J= 11.5.2 Hz);
4.83 (1H, doublet. J= 14 Hz);
5.00 (1H. singlet);
5.03 (1H. doublet, J= 14 Hz):
5.06 (1H, doublet. J=4 Hz);
5.87 (1H, doublet of doublets. J=15. 4 Hz):
6.59 (1H, doublet of doublets. J=15, 10 Hz):
6.61 (1H, doublet, J= 15 Hz);
6.7-6.8 (2H, multiple!);
6.87 (1H, doublet of doublets, J=15, 10 Hz);
7.35 (1H, triplet of doublets, J=8, 7 Hz);
7.48 (2H, doublet, J=8 Hz);
7.60 (2H, doublet, J=8 Hz);
7.79 (2H, singlet).
IR spectrum vmax (KBr) cm"1: 2225, 1617, 1603, 1500, 1140 (KBr).
Mass spectrum m/z (FAB): 525 (M++]).
Specific rotation: [cc]D25 -73.4° (c = 1.30, CHC13).
Anal, calculated for C27H26F2N4O3S: C, 61.82; H, 5.00; N, 10.68
Found: C, 62.00; H, 5.01; N, 10.56.
Reference Example 2
(2R.3R)-4-frtrans-2-r(lE.3E)-4-(4-Cvano-2-fluorophenvl)-1.3-butadien-l-vn-K3-
dioxan-5-vn-2-(2,4-difluorophenvP-3-meth vl-1 -(1H-1.2,4-triazol-1 -vl )-2-butanol
(Comparative Compound C)
Using the procedure described in Example 1 (iii) above, a reaction was carried
out using 708 mg (3.51 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-l,3-pentadienyl]-






benzonitrile [prepared as described in Example l(ii) above] and 1000 mg (2.93 mmol)
of (4S.5R)-5-(2.4-difluorophenyl)-2-(hydroxymethyl )-4-methyl-6-( 1H-1.2.4-triazol-1 -
yl)-1.5-hexanediol [prepared as described in Japanese Patent Application (Kokai) Hei
11-80135]. The crude extract was purified by chromatography on a silica gel (20 g)
column using a 1:1 mixture of ethyl acetate and hexane as the eLuant to give 1.18 g
(yield 77%) of the title compound as a pale non-crystalline solid.
'H-Nuclear magnetic resonance spectrum (270 MHz. CDCl3) 6 ppm:
0.83 (3H, doublet, J=7 Hz);
1.09 (1H, multiplet);
1.43(lH,multiplet);
1.95-2.20 (2R multiple!):
3.45 (1H. triplet, J= 11 Hz);
3.47 (1H, triplet, J=ll Hz):
4.11 (1H, double doublet of doublets, J= 11, 5, 2 Hz);
4.23 (1H, double doublet of doublets. J= 11, 5. 2 Hz);
4.48 (1H, doublet, J= 14 Hz);
4.86 (1H, singlet);
4.94 (1H, doublet, J=l4 Hz);
5.03 (1H, doublet, J=4 Hz);
5.91 (1H, doublet of doublets, J=15, 4 Hz);
6.61 (1H, doublet of doublets, J=15, 10 Hz);
6.65-6.80 (3H, multiplet);
6.95 (1H, doublet of doublets, J=15, 10 Hz);
7.33 (1H, doublet of doublets, J=10, 1 Hz);
7.35-7.45 (1H, multiplet);
7.39 (1H, doublet of doublets, J=8, 1 Hz);
7.57 (1H, triplet, J=8 Hz);
7.77 (1H, singlet);
7.87 (1H, singlet).
-IR spectrum vmax(KBr) cm"1: 2231, 1615, 1499, 1141.
Mass spectrum m/z (EI): 524 (M+, 100%), 368, 224.





Specific rotation: [α]D25 -66° (c = 0.5. CHC13).
Formulation Examples
Formulation Example 1
Hard Capsules
The components shown below were mixed in the quantities shown below to
give the composition shown below which was then used to fill a standard two-
component hard gelatin capsule, after which the capsule was washed and dried to give
the desired hard capsule.
Powdered compound (lb) 100 mg
Lactose 150 mg
Cellulose 50 mg
Magnesium stearate 6 mg
___
Formulation Example 2
Soft Capsules
A mixture of compound (lb) in a digestible oil such as soy bean oil, cottonseed
oil or olive oil is prepared and is injected into gelatin to obtain a soft capsule
containing 100 mg of the active ingredient which is then washed and dried to give the
desired soft capsule.
Formulation Example 3
Tablets
Tablets having the composition indicated below are produced in accordance
with a conventional method.



If desired, the tablets can be coated with a suitable preparation coating.
Test Examples
Test Example 1
In Vitro Antifungal Activity
The antifungal activities of test compounds were assessed according to their
minimum inhibitory concentrations (MICs) which were measured by the methods
described below.
1(0 Measurement method for Candida species
A modified version of the procedure described in Japanese Journal of Medical
Mycology, 36, 62 (1995) was used, MICs being determined by the broth
microdilution method. Each test compound was dissolved in dimethyl sulfoxide
(DMSO). Serial two-fold dilutions of each compound were prepared with DMSO and
then final dilutions were prepared with RPMI1640 medium (product of Dainippon
Pharmaceutical Co., Ltd.) which was buffered to pH 7.0 with 0.165 M 3-
(morpholino)propanesulfonic acid (MOPS). The final concentration of DMSO did
not exceed 1%. Colonies of the test fungi were suspended in physiological saline
followed by adjustment to 5.0 x 102 to 2.5 x 103 cells/ml with RPMI1640 medium
which was buffered to pH 7.0 with 0.165 M MOPS. 100 uJ of the fungal suspension
were added to each of the wells of microtitre plates and then 100 ul of each diluted
test compound were added to one of said wells and mixed with the fungal suspension

therein, before incubating at 35°C for 24-72 hours. When obvious growth was
observed in the compound-free control wells, the MICs were determined for each test
compound. The MICs were defined as the lowest compound concentrations causing
at least 80% growth inhibition when compared with the control.
l(ii) Measurement method for Cnptococcus neoformans
A modified version of the Broth Dilution Antifungal Susceptibility Testing of
Yeast; Approved Standard M27-A (Vol. 17, No. 9. June 1997. NCCLS) was used.
MICs being determined by the broth microdilution method. Each test compound was
dissolved in DMSO. Serial two-fold dilutions of each compound were prepared with
DMSO and final dilutions were prepared with yeast nitrogen base medium (product of
Difco Laboratories) buffered to pH 7.0 with 0.165 M MOPS. The final concentration
of DMSO did not exceed 1%. Colonies of the test fungi were suspended in
physiological saline followed by adjustment to 5.0 x 103 to 2.5 x 104 cells/ml with
yeast nitrogen base medium buffered to pH 7.0 with 0.165 M MOPS. 100 ul of the
fungal suspension were added to each of the wells of microtitre plates and then 100 ul
of each diluted test compound were added to one of said wells and mixed with the
fungal suspension therein, before incubating at 35°C for 48-72 hours. When obvious
growth was observed in the compound-free control wells, the MICs were determined
for each test compound. The MICs were defined as the lowest compound
concentrations causing at least 50% growth inhibition when compared with the
control as measured by light absorbance at 485 nm.
l(iii-) Measurement method for Aspergillus species
A modified version of the protocol in Antimicrob. Agents Chemother., 39, 314
(1995) was used, MICs being determined by the broth microdilution method. Test
compounds were dissolved in dimethyl sulfoxide (DMSO). Serial two-fold dilutions
of each compound were prepared with DMSO and then final dilutions were prepared
with RPMI1640 medium (product of Dainippon Pharmaceutical Co., Ltd.) buffered to
pH 7.0 with 0.165 M MOPS. The final concentration of DMSO did not exceed 1%.
Colonies of the test fungi were suspended in physiological saline followed by
adjustment to about 1.0 x 104 cells/ml with RPMI1640 medium buffered to pH 7.0

with 0.165 M MOPS. 100 µl of the fungal suspension were added to each of the wel
of microtitre plates and then 100 ul of each diluted test compound were added to or
of the wells and mixed with the fungal suspension therein, before incubating at 30°
for 24-72 hours. When obvious growth was observed in the compound-free contn
wells, the MICs were determined for each test compound. The MICs were defined *
the lowest compound concentrations causing at least 80% growth inhibition whe
compared with the control.
The compound of formula (lb) of the present invention was tested for in vitro
activity using the above tests and its activity compared with that of Comparative
Compound A (prepared as described in Reference Example 1 above) and Comparativ
Compound B (prepared according to Example 27 of Japanese Patent Application
(Kokai) Hei 8-333350). the structures of which are shown below. Comparative
Compounds A and B are compounds disclosed in Japanese Patent Application
(Kokai) No. Hei 8-333350 and EP-A-0841327. The results were as shown in Table 1
Comparative Compounds A and B are represented by the following formulae:






The test microorganisms of b) through f) are as indicated below.
b) C.a. (1): Canadida albicans ATCC 64550.
c) C.a. (2): Canadida albicans TIMM 3164.
d) C.a. (3): Canadida albicans TIMM 3165.
e) C.n. : Cryptococcus neoformans TIMM 0362.
f) A.f. : Aspergillus fumigatus SANK 10569.
As can be seen from Table 1, the compound of formula (lb) of the
invention demonstrated in vitro antifungal activity that was equal
of Comparative Compounds A and B described in Japanese Patent Application
(Kokai) No, Hei 8-333350 and EP-A-0841327.
Test Example 2
Acid Stability Test
The stability of the compounds of the present invention in the presence
was assessed according to their half-life (t1/2) in an acidic solution as measure
method described below.
700 ul of 0.01 N (pH 2.0) hydrochloric acid were added to a solution
compound (the concentration of the test compound was 167 ng/ml) in 300 µl

acetonitrile to give a mixture in which the initial concentration of the test compound
was 50 jig/ml and the acetonitrile content was 30%. followed by incubation of the
mixture at 37°C. A small amount of the solution was taken from the reaction solution
at predetermined time intervals and the reaction was stopped in these samples by
neutralizing with an aqueous sodium hydroxide solution. Quantitative determination
of the residual rate of the test compound in the solution was determined by HPLC.
The half-life (t1/2) of the test compound in 0.01 N HC1 was determined
according to the following equation using the degradation rate constant kdeg which
was determined by semi-logarithmic regression analysis of the residual rate in the
solution.
t1/2 = (ln2)/kdeg


Table 2 Stability in Acidic Solution
Compound t]2(min)
Compound (lb) 6.40
Comparative Compound (A) 3.12
Comparative Compound (B) 1.54
Comparative Compound (C) 2.42
The compound of formula (lb) of the present invention demonstrated stability
in the presence of acid that was superior to that of Comparative Compounds A. B and
C.
Test Example 3
Oral Absorption Rate
The oral absorption rate of the compounds of the present invention was
assessed according to the bioavailability (BA) of said compounds as measured by the
method described below.
A test compound in polyethylene glycol 400 (PEG 400) was administered
either orally (4 animals) or intravenously into the caudal vein (3 animals) of SD rats
(age 7 weeks) which had fasted overnight. The oral dose of the test compound was 20
mg per kg of rat body weight. The intravenous dose of the test compound injected
into the caudal vein was 2 mg per kg of rat body weight. The amount of PEG 400
used was 1 ml per kg of rat body weight for both oral and intravenous administration.
The bioavailability (BA) values were calculated according to the following equation
using the integrated values of the blood concentration of the test compound up to 48
hours after oral administration [AUCpo(0-48h)], and the integrated values of the blood
concentration extrapolated from 0 to infinite time after intravenous administration into
the caudal vein [AUCiV(0-oo)l.
BA(%)= {[(AUCPo(0-48))/(dosepO)]/[(AUCiV(0-Oo))/(doseiv)]} x 100







The larger the value of BA. the higher the oral absorption rate. The results for
the compound of formula (lb) of the present invention and those for Comparative
Compounds A. B and C are shown in Table 3.
Table 3 Bioavailability
Compound BA (%)
Compound (lb) 123
Comparative Compound (A) 50.7
Comparative Compound (B) 6.24
Comparative Compound (C) 57.8
The compound of formula (lb) of the present invention demonstrated an oral
absorption rate that was superior to Comparative Compounds A. B and C.
The results above show that the compounds of formula (I) and the
pharmaceutically acceptable salts and ester derivatives thereof of the present
invention demonstrate a superior in vitro and in vivo antifungal activity, acid stability
and oral absorption rate as compared with the compounds described in Japanese
Patent Application (Kokai) Hei 8-333350 and Japanese Patent Application (Kokai)
Hei 11-80135. The compounds of the present invention also show lower toxicity.
Consequently, the compounds of formula (I) and the pharmaceutically acceptable salts
and ester derivatives thereof of the present invention are particularly useful as
antifungal agents against a wide range of eumycetes.
, .

1. A compound of the following formula (1) or a pharmaceutical!?
acceptable salt or ester derivative thereof:

wherein Ar is a phenyl group which may optionally be substituted by from 1 to 3
substituents selected from the group consisting of halogen atoms and
trifluoromethyl group, in which ester derivative the hydroxyl group is protected
to give an ester derivative which is capable of being cleaved in the body of a live
animal to give the parent compound of formula (1) or a salt thereof.
2. A compound of formula (I) as claimed in claim 1 or a pharmaceutically
acceptable salt or ester derivative thereof wherein Ar is 2,4-difluorophenyl group
or 2-fluorophenyl group.
3. A compound of formula (I) as claimed in claim 1 or a pharmaceutically
acceptable salt or ester derivative thereof wherein Ar is a 2,4-difluorophenyl
group.

4. A compound of formula (1) as claimed in claim 1 or a pharmaceutical^
acceptable salt or ester derivative thereof, wherein said compound of formula
(X) is a compound of the following formula (la):

wherein Ar is a phenyl which may optionally be substituted by from 1 to 3
substitutents selected from the group consisting of halogen atoms and
trifluoromethyl groups.
5. (2R)-3R[trans-2[(1E, 3E)-4-(4-Cyano-2-fluorophenyl)-1,3
1.3 pharmaceutical^ acceptable salt or ester derivative thereof.
6. (2R,3R)-3-[[bans-2^(lE^E)^K4^yario-2-fluwophenyl)-1.3^tadlen-l-
butanol in crystalline form.

7. (2Rr3R)-3-[[tr»n«-2^(lE^EHK4-CyafX)-2-fkioroph«nyl)-l,3-buUdi«n-l-yl]-
l/3^loxan-5-yl]th»]-2^2/4^ifkjorophenyl)-HlH-l,2,4^lazol-yl)-24xjtanol in
crystalline form as claimed in claim 6 having main peaks at lattice distances of
3.14, 3.39, 3.71, 3.75,4.21,4.88, 5.28, 5.42, 5.89, 5.95, $.79, 6.86, 8.03 and
8.41. A determined by X-ray diffraction by the powder method using the copper
Karay.
8. in crystalline form as claimed in claim 6 having main peaks at lattice distances of
3.62, 3.96, 4.54, 4.59,4.79,4.91,5.32,5.48,6.18,7.99 and 15.93. A determined
by X-ray diffraction by the powder method using the copper Ka ray.
9. A pharmaceutical composition comprising an effective amount of a
pharmacologically active compound together with a pharmaceutlcally acceptable
carrier or diluent therefor, wherein said pharmacologically active compound is a
compound of formula (1) or a pharmaceutical acceptable salt or ester
tierivative thereof as claimed in any one of claims 1 to 8.
10. A compound of formula (I) or a pharmaceutlcally acceptable salt or ester
derivative thereof as claimed in any one of claims 1 to 8 for use as a
medicament.
*
11. A compound of formula (I) or a pharmaceutlcally acceptable salt or ester
derivative thereof as claimed in any one of claims 1 to 8 for usees an antifungal
agent.

12. A compound of the following formula (n) or an aeetal derivative thereof:

13. A compound of formula (II) as claimed in claim 12 having the following
formula (Ha):

A compound of the following formula (I) or a pharmaceuticalty acceptable
salt or ester derivative thereof.

wherein Ar is a phenyl group which may optionally be substituted from 1 to 3
substituents selected from the group consisting of halogen atoms and
trifluoromethyl groups, in which ester derivative the hydroxyl group is protected
to give an estar derivative which is capable of being cleaved in the body of a live
animal to give the parent compound of formula (I) or a salt thereof.

Documents:

512-cal-2000-granted-abstract.pdf

512-cal-2000-granted-claims.pdf

512-cal-2000-granted-correspondence.pdf

512-cal-2000-granted-description (complete).pdf

512-cal-2000-granted-drawings.pdf

512-cal-2000-granted-examination report.pdf

512-cal-2000-granted-form 1.pdf

512-cal-2000-granted-form 18.pdf

512-cal-2000-granted-form 2.pdf

512-cal-2000-granted-form 26.pdf

512-cal-2000-granted-form 3.pdf

512-cal-2000-granted-form 5.pdf

512-cal-2000-granted-reply to examination report.pdf

512-cal-2000-granted-specification.pdf

512-cal-2000-granted-translated copy of priority document.pdf


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Patent Number 229467
Indian Patent Application Number 512/CAL/2000
PG Journal Number 08/2009
Publication Date 20-Feb-2009
Grant Date 18-Feb-2009
Date of Filing 04-Sep-2000
Name of Patentee SANKYO COMPANY, LIMITED
Applicant Address 5-1 NIHONBASHI HONCHO 3-CHOME, CHUO-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 KONOSU TOSHIYUKI 2-58 HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
2 OIDA SADAO 2-58 HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
3 MORI MAKOTO 2-58 HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
4 UCHIDA TAKUYA 2-58 HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
5 OHYA SATOSHI 2-58 HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
6 NAKAGAWA AKIHIKO 2-58 HIROMACHI 1-CHOME, SHINAGAWA-KU, TOKYO 140-8710
PCT International Classification Number C07 405/12
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 11-255702 1999-09-09 Japan