CA2170031A1 - Antimicrobial quinolinyl-(1h-1,2,4-triazol-1-yl)alkanol derivatives - Google Patents

Abstract

A compound of formula (I) in which R1 and R2 are each hydrogen or lower alkyl, R3 is optionally substituted quinolyl or oxide thereof, and X
and Y are each hydrogen, halogen, cyano or lower alkyl, or pharmaceutically acceptable salts thereof, which has antimicrobial acivity.

Description

WO9S/060~7 ~ 1 7 0 ~ 3 ~ PCT/~94/01378 DESCRIPTION

ANTIMICROBIAL QUINOLINYL-(lH-1,2,4-TRIAZGL-l-YL)ALKANOL DERIVATIVES

TECHNICAL FIELD

The present invention relates to a new compound and a pharmaceutically acceptable salt thereof.

More particularly, it relates to a new auinoline derivative and a pharmaceutically acceptable salt thereof, which have antimicrobial activities (especially antifungal activities), to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for treating or prevenLing infectious diseases in a human being or an animal.

Accordingly, one object of the present invention is to provide the quinoline derivative and a pharmaceutically acceptable salr thereof, which are highly active against a number of pathogenic microorganisms in a human being or an animal.

Another object of the present invention is to provide a process for the preparation of the quinoline derivative and a salt thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinoline derivative or a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a method for treating or preventing infectious W095/06047 21 7 ~ ~ 3 ~ - 2 - PCT/JP94/01378 diseases caused by pathogenic microorganisms, which comprises administering said quinoline derivative to a human being or an animal.

DISCLOSURE OF INVENTION

The object qLinoline derivative of the present invention is novei and can be represented by the following general formula (~) :

Rl L~ 2 3 ( I ) N

~X
Y~

in which Rl and R2 are each hydrogen or lower alkyl, R3 i5 optionally substituted quinolyl or oxide thereof, and X and Y are each hydrogen, halogen, cyano or lower alkyl, or a pharmaceutically acceptable salts thereof.

The compound (I) of the present invention can be prepared by the processes as illustrated in the following schemes.

W095/06047 21 7~ ~ 3 I PCT/JPg4/01378 Process 1 J, Rl` R2 p~l ~ N ~ O (III) ~ ~23 ~ X - N

(II) (I) or a salt thereof or a salt thereof Process 2 1 oxidation of R 2 the optionally R
H 1R substituted OH ~R2 L-NN \~3 quinolyl LNN ~ ~b (I-a) (I-b) or a salt thereof or a salt thereof Process 3 hydrolysis of the R1 R1 lower alkoxy-substi- OH I R2 30OH ¦ R2 tuent of optionally N~
L-N ~ 3 substituted quinolyl L N~ ~Rd 35(I-c) or a salt thereof or a salt thereof ~=

W095/06047 PCT/JP94tO1378 Process 4 oxidation of the lower 21kylthio- or lower Rl Rl alkylsulfinyl-substituent OH I 2 OH I R2 ~f optionally substituted N ~ R
L - N ~ 3 quinolyl ' L-N

(I-e) or a salt thereof or a salt thereof Process 5 hydrolysis of the R1 cyano-substituent R
OH I 2 of optionally OH ~R2 NL~ N ~ substituted quinolyl L~N ~ Rh ~3 ~X
Y
or a salt thereof (I-h) in which R1, R2, R3, X and Y are each as defined above, R3 is optionally substituted quinolyl, Rb is N-oxide of optionally substituted quinolyl, Rc is quinolyl substituted by lower alkoxy and optionally by suitable substituent(s), Rd is quinolyl substituted by hydroxy and optionally by suitable substituent(s), Re is quinolyl substituted by lower alkylthio or lower alkylsulfinyl and optionally by suitable substituent(s), R3f is quinolyl substituted by lower alkylsulfinyl W095/06047 21 7 ~ 0 3 ~ PCTtJP9~/01378 or lower alkylsulfonyl and optionally by suitable substituent(s~, Rg is qulnolyl substituted by cyano and optionally by suitable substituent(s), and Rh is quinolyl substituted by carboxy and optionally by suitable substituent(s).

Some of the starting compound (II) or a salt thereof may be novel and can be prepared by a conventional manner.
And also the starting compound (III) or a salt thereof may be novel and can be prepared in a similar manner as that of Preparations mentioned below or by a conventional manner.
Suitable pharmaceutically acceptable salt of the object compound (I) is conventional non~toxic salts and may include a metal salt such as an alkali metal salt [e.g.
sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, etc ] an organic acid addition salt [e.g. formate, acetate, trifuloroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt ~e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], and the like.
In the above and subsequent description of this specification, suitable examples of the various definitions are explained in detail as follows :

The term "lower" is intended to mean 1 to 6, W095/06047 217 ~ 0 3 l 1 - 6 - PCT/~94101378 preferably 1 to 4 carbon atom(s), unless otherwise indicated.
Suitable "lower alkyl" may include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like, in which the most preferred example may be methyl.
Suitable 'loptionally substituted quinolyl" means quinolin-1-(or 2- or 3- or 4- or 5- or 6- or 7- or 8-)yl optionally substituted by one or more, preferably one or two suitable substituent(s) such as :
-hydroxy;
-protected hydroxy, in which the hydroxy group is protected by a conventional hydroxy-protective group such as acyl, tri(lower)alkylsily~l (e.g. t-butyldimethylsilyl, etc.), etc.;
-halogen (e.g. chlorine, bromine, iodine or fluorine);
-lower alkoxy, which may be straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc., more preferably C1-C4 alkoxy (e.g. methoxy, etc.);
-halo(lower)alkyl, which is aforementioned lower alkyl group substituted by one or more, preferably one to 'hree halogen as mentioned below (e.g. trifluoromethyl, etc.);
-halo(lower)alkoxy, which is hydroxy group substituted by aforementioned halo(lower)alkyl (e.g. trifluoromethoxy, etc.);
-lower alkyl as mentioned above, more preferably C1-C4 alkyl (e.g. methyl, t-butyl, etc.);
-lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc, more preferably C1-C4 alkylthio (e.g.
methylthio, etc.);
-lower alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulflnyl, butylsulfinyl, pentylsulfinyl, etc, more preferably C1-C4 W095/06047 -? ~ 7 ~ 3 ~ : PCT/~4/01378 .

alkylsulfinyl (e.s. methylsulfinyl, etc.)i -lower alkylsulfonyl, such as methylfulfonyl, ethylsulfonyl, prc~ylsulfonyl, isopropylsulfonyl, butylsulfonyl, per~ylsulfonyl, hexylsulfonyl, etc, more preferably C1-C4 alkylsulfonyl (e.g. methylsulfonyl, etc.);
aminoi nitro; cyaroi carboxy; and the like.
Preferable examples of optionally substituted quinolyl may be quinolyl optionally substituted by hydroxy, halogen, lower alk~xy, halo(lower)alkyl, halo(lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano or carboxy, in which the most preferable one may be quinolin-2-(or 4-)yl optionally substituted by hydroxy, fluorine, chlorine bromine, methoxy, trifluoro~ethyl, trifluoromethoxy, t-butyl, methylthio, methylsulfinyl, methylsulfonyl, cyano or carboxy.
Suitable oxide of "optionally substituted quinolyl"
means N-oxide of aforementioned optlonally substituted quinolyl, in which more preferable example may be N-oxide of quinolyl which is optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo(lower)alkyl, halo(lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and cyano, halo(lower)alkyl, halo(lower)alkoxy, and the most preferable one may be N-oxide of quinolin-2-(or 4-)yl or N-oxide of ~-fluoroquinolin-2-yl.
Suitable "quinoiyl substituted by lower alkoxy and optionally by sultable substituent(s)" means aforementioned optionally substituted quinolyl, wherein said quinolyl is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyl (e.g.
quinolin-2-(or 4-)yl, etc.) substituted at least by lower - alkoxy (e.g. methoxy, etc.).

Suitable "quinolyl substituted by hydroxy and WO95/06047 ~ 1 7 Q ~ 3 I PCTIJP94101378 optionally by suitable substituent(s)" means aforementioned optionally substituted quinolyl group, wherein said quinolyl is substituted at least by hydroxy, in which more preferable example may be quinolyl (e.g. quinolin-2-(or 4-)yl, etc.) substituted at least by hydroxy.

Suitable "quinolyl substituted by lower alkylthio or lower alkylsulfinyl and optionally by suitable substituent(s)" means aforementioned optionally substituted quinolyl, wherein said quinolyl is substituted at least by lower alkylthio or lower alkylsulfinyl as mentioned above, in which more preferable example may be quinolyl (e.g.
quinolin-2-(or 4-)yl, etc.) substituted at least by lower alkylthio (e.g. methylthio, etc.) or lower alkylsulfinyl (e.g. methylsulfinyl, etc.).

Suitable "quinolyl substituted by lower alkylsulfinyl or lower alkylsulfonyl and optionally by suitable substituent(s)" means aforementioned optionally substituted quinolyl, wherein said quinolyl is substituted at least by lower alkylsulfinyl or lower alkylsulfonyl as mentioned above, in which more preferable example may be quinolyl (e.g. quinolin-2-(or 4-)yl, etc.) substituted at least by lower alkylsulfinyl (e.g. methylsulfinyl, etc.) or lower alkylsulfonyl (e.g. methylfulfonyl, etc.~.

Suitable "quinolyl substituted by cyano and optionally by suitable substituent(s)" means aforementioned optionally substituted quinolyl, wherein said quinolyl is substituted at least by cyano, in which more preferable example may be quinolyl (e.g. quinolin-2-(or 4-)yl, etc.) substituted at least by cyano.

Suitable "quinolyl substituted by lower alkoxy and optionally by suitable substituent(s)" means aforementioned Wo9S/06047 2 1 7 ~ ~ 3 ~ PCT1~4/01378 _ g _ optionally substituted quinolyl, wherein said quinolyl is substituted at least by lower alkoxy as mentioned above, in which more prefer2ble example may be quinolyl (e.g.
quinolin-2-(or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).

One preferable embodiment of Rl, R2, R3, X and Y are as follows.

Rl and R2 are eac~ hydrogen or lower alkyl, R3 is quinolyl optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo(lower)alkyl and halo(lower)alkoxy, and X and Y are each hydrogen or halogen.
Another preferable embodiment of Rl, R2, R3, X and Y
are as follows.

Rl and R2 are each hydrogen or lower alkyl, R3 is quinolyl or its N-oxide which is optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo(lower)alkyl, halo(lower)alkoxy, alkylsulfinyl, lower alkylsulfonyl, cyano and carboxy, and X and Y are each hydrogen or halogen.

The processes for preparing the object compound (I) or a salt thereof of the present invention are explained in detail in the following.
Process l The object compound (I) or a salt thereof can be prepared by reacting a compound (II) or a salt thereof with a compound (III) or a salt thereof.
Suitable salts of the compounds (II) and (III) can be WO95/06047 - j PCT/~4/01378 2l70a~ -10- -referred to the ones as exemplified for the compound (I).
The present reaction may be carried out in a conventional solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g.
lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.
sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to under heating.

Process 2 The object compound (I-b) or a salt thereof can be prepared by oxidizing the optionally substituted quinolyl of a compound (I-a) or a salt thereof.
Suitable salts of the compounds (I-a) and (I-b) can be referred to the ones as exemplified for the compound (I).
Suitable oxidizing agent used in this reaction may be a conventional one which is capable of converting a nitrogen or sulfur atom to its oxide such as potassium permanganate, chrcmic compound (e.g. chromium trioxide, chromic acid, sod-um chromate, dichromic acid, sodium dichromate, pyrid nium dichromate, etc.), peroxy acid (e.g.
3-chloroperbenzoic acid, etc.), and the like.
The reaction is usually carried out in a conventional solvent such as waler, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,~-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at room temperature or under warming.

Process 3 The compound (I-d) or a salt thereof can be prepared by hydrolyzing the lower alkoxy-substituent of optionally substituted quinolyl of the compound (I-c) or a salt thereof.
Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I).
The hydrolysis is preferably carried out in the presence of a base or an acid. Preferable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g.
magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (e.g. magnesium 217 ~

carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and the like.
Preferable acid may include an organic acid (e.g.
formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g.
phenol, anisole, etc.).
In addition, hydrolysis using trlhaloborane (e.g.
tribromobrane, etc.) in halo(lower)alkane (e.g.
dichloromethane, etc.) can also be used in this reaction.
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquid base or acid can be also used as the solvent.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.

Process 4 The compound (I-f) or a salt thereof can be prepared by oxidizing the lower alkylthio- or lower alkylsulfinyl-substituent of optionally substituted quinolyl of the compound (I-e) or a salt thereof.
Suitable salts of the compounds (I-e) and (I-f) can be referred to the ones as exemplified for the compound (I).
This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. reactive derivatives, solvents reaction temperature, etc.] of this reaction are to be -2 1 7 ~ O ~ 1 PCT/~94/01378 . . .

referred to those as explained in Process 2.

Process 5 The compound (I-h) or a salt thereof can be prepared by hydrolyzing the cyano-substituent of optionally substituted quinolyl o~ the compound (I-g) or a salt thereof.
Suitable salts of the compounds (I-g) and (I-h) can be referred to the ones as exemplified for the compound (I).
This reaction can be carried out in substantially the same manner as Process 3, and therefore the reaction mode and reaction condition [e.g. reactive derivatives, solvents reaction temperature, etc.] of this reaction are to be referred to those as explai~ed in Process 3.
The object compounds obtained according to the above Processes can be isolated and purified in a conventional manner for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, high performance liquid chromatography, and the like, and also can be converted into its salt by a conventional manner.

Especially the compound having the following formula is more preferable.

N ~,R

~N (IA~
~ X

in which Rl, R2, R3, X and Y are each as defined above.

W095/06047 2 1 7 ~ O ~ 1 PCTl~4/01378 Further, the compound having the following formula is the most preferabie.

OH la N (IB) ~X

y in which R3, X and Y are each as defined above, and Ra is lower alkyl.

In order to show the usefulness of the compound (I) of the present invention, a biological datum of the representative compound is shown in the following.

~ Antimicrobial activity :
1. Test Method In vitro antimicrobial activity of the test compound was determined by the two-fold agar-plate dilution method as described below.
One loopful of an overnight culture of a microorganism in Sabouraud broth containing 2 % Glucose (105 viable cells per ml) was streaked on yeast nitrogen base dextrose agar (YNBDA) containing graded concentrations of the test compound, and the m; n i m~ l inhibitory concentration (MIC) was expressed in terms of ug/ml after incubation at 30C
for 45 hours.

2. Test Compound The enantiomeric pair A of Example 1-2) W O 9S/06047 2 1 ~ O D 3 ~ PCT/JP94/01378 3. Test Result orga~ism MIC (ug/ml) Cryptococcus neoformans FP1385 0.39 From the tes_ result, it is realized that the compound (I) of the present invention has an anti-microbial activity (especially, antirungal activity).

The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in a~mixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizlng, thickening and coloring agents and perfumes may be used. The compound (I) or a pharmaceutical acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial effect upon the process or condition of diseases.
For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary, or oral administration, or insufflation. While the dosage of therapeutically effective amount of the compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 20 mg of the compound (I) per :~g weight of a human being or an animal, in the case of in_ramuscular administration, a daily dose of 0.1 - 20 mg of the compound (I) per kg weight of a human being or an anima:, in case of oral administration, a daily dose of 0.5 - 50 mg of the compound (I) per kg weight of a human being or an animal is generally given for treating or preventing infect ous diseases.

The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

EXAMPLES

Preparation 1 To a refluxing mixture of p-fluoroaniline (3.0 ml) and 6N hydrochloric acid (15.9 ml) was added trans-2-pentenal (3.26 ml) over l hour. After the addition, the solution was stirred for 1.5 hours under reflux, and then cooled down to room temperature. The solution was neutralized with 4N aqueous sodium hydroxide and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solution was evaporated and the residue was chromatographed on silica gel (110 g, eluent : ethyl acetate - hexane, 1:15, V/V) to give 2-ethyl-6-fluoroquinoline (2.2 g).
IR (Neat): 1600, 860, 825 cm~l NMR (CDC13, o) : 1.39 (3H, t, J=7.6Hz), 2.99 (2H, q, J=7.6Hz), 7.27-7.50 (3H, m), 8.00-8.07 (2H, m) W095/06047 2 1 ~ O 0 3 I PCT/~94/01378 The following compound was obtained by the similar manner to that of Preparation 1.

Preparation 2 2-Ethyl-8-fluoroquinoline IR (Neat) : 1720, 1600 cm~1 NMR (CDCl3, o) : 1.41 (3H, t, J=7.6Hz), 3.06 (2H, q, J=7.6Hz), 7.31-7.46 (3H, m), 7.52-7.59 (lH, m), 8.07-8.12 (lH, m) Preparation 3 To a stirred solution of lithium diisopropylamide in a mixture of n-hexane and tetrahydrofuran (1.55M, 8.2 ml) in tetrahydrofuran (8.0 ml) was added dropwise over 20 minutes a solution of 2-ethylquinoline (2.0 g) in tetrahydrofuran (4.0 ml) at -70C under an atmosphere of nitrogen. After stirring at -75C for 20 minutes, to the solution was added methyl iodide (2.5 ml) and the resultant mixture was allowed to warm to ambient temperature over 30 minutes. To the mixture was added water (10 ml), and solvents were removed by evaporation to give a residue, which was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (10:0-8:2, V/V) to give 2-(1-methylethyl)-quinoline (1.58 g).
NMR (CDCl3, o) : 1.40 (6H, d, J=7.OHz), 3.27 (lH, sept, J=7.OHz), 7.34 (lH, d, J=8.5Hz), 7.41-7.55 (lH, m), 7.60-7.82 (2H, m), 8.05 (lH, d, J=7.5Hz), 8.09 (lH, d, J=8.5Hz) Preparation 4 2-(1-Methylethyl)-6-methylthioquinoline (1.96 g) was obtained in substantially the same manner as that of Preparation 3.
NMR (CDCl3, o) : 1.38 (6H, d, J=6.9Hz), 2.58 (3H, s), W095/06047 2 17 ~ ~ 3 I PCT/~4/01378 3.23 (lH, sept, J=6.9Hz), 7.32 (lH, d, J=8.6Hz), 7.46-7.66 (2H, m), 7.85-8.08 (2H, m) APCI-Mass : e/z = 218 (M+H)+

Fxample 1-1) 2-Ethylquinoline (704 mg) was added over 5 minutes to a stirred solution of lithium diisopropylamide (2.89 ml of 1.55 M solution in tetrahydrofuran) in tetrahydrofuran (4.5 ml) at -70C under an atmosphere of nitrogen. The solution was stirred at -70C for 1 hour. Then a solution of 1-(2,4-difluorophenyl)-2-(lH-1,2,4-triazol-1-yl)ethanone (1.0 g) in tetrahydrofuran (5.0 ml) was added with stirring at -70C over 5 minutes, after the addition, the solution was stirred for 3 hours. To the solution was added water (5 ml) at 0C and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (60 g, eluent : ethyl acetate - hexane, 1:2, V/V) to give an enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(quinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (288 mg) and an enantiomeric pair B of the same (232 mg).

enantiomeric pair A :
IR (Nujol) : 3050, 1590 cm~1 NMR (DMSO-d6, o) : 1.08 (3H, d, J=7.lHz), 3.91 (lH, q, J=7.1Hz), 4.12 and 4.80 (2H, ABq, J=14.3Hz), 6.95-7.01 (lH, m), 7.13 (lH, s), 7.17-7.86 (6H, m), 8.01-8.13 (2H, m), 8.19 (lH, s), 8.45 (lH, d, J=8.4Hz) enantiomeric pair B :
IR (Neat) : 3100, 1590 cm~l NMR (DMSO-d6, o) : 1.56 (3H, d, J=6.8Hz), 3.95 (lH, W095/06047 21 7 Q ~ 3 1 PCT/~94/01378 q, J=7.0Hz), 4.82 (2H, s), 6.53-6.58 (lH, m), 6.89-7.94 (8H, m), 8.17 (lH, d, J=8.3Hz), 8.30 (lH, s) The followirg compounds were obtained in substantially the same manner as that of Example 1-1).

Exa~ple 1-2) Dihydrochloride of enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-l-yl)butan-2-ol NMR (DMSO-d6, o) : 1.21 (3H, d, J=7.OHz), 4.35-4.42 (lH, m), 4.38 and 5.09 (2H, ABq, J=14.3Hz), 6.97-7.05 (lH, m),~ 7.25-7.42 (2H, m), 7.94-8.17 (4H, m), 8.59-8.66 (2H, m), 8.79 (lH, br s), 8.92 (lH, d, J=8.8Hz) Dihydrochloride of enantiomeric pair B of 2-(2,4-difluorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol NMR (DMSO-d6, o) : 1.64 (3H, d, J=6.8Hz), 4.20 (lH, q, J=6.9Hz), 4.95 and 5.05 (2H, ABq, J=14.3Hz), 6.58-6.65 (lH, m), 6.97-7.11 (lH, m), 7.74 (lH, d, J=8.7Hz), 7.76-7.93 (2H, m), 8.02 (lH, s), 8.29-8.36 (lH, m), 8.58 (lH, d, J=8.7Hz), 8.97 (lH, s) Example 1-3~
Enantiomeric pair A of-2-(2,4-difluorophenyl)-3-(quinolin-4-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (Nujol) : 3150, 1580 cm~l NMR (DMSO-d6, o) : 1.53 (3H, d, J=6.8Hz), 4.58 (lH, q, J=6.8Hz), 4.86 and 5.04 (2H, ABq, J=14.5Hz), 6.24 (lH, s), 6.49-6.59 (lH, m), 6.67-6.79 (lH, m), 6.99-7.11 (lH, m), 7.49-7.69 (4H, m), 7.86 W095/06047 PCT/~94/01378 2170~

(lH, dd, J=1.2Hz and 8.4Hz), 8.17 (lH, d, J=8.5Hz), 8.35 (lH, s), 8.65 (lH, d, J=4.6Hz) Enantiomeric pair B of 2-(2,4-difluorophenyl)-3-(quinolin-4-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (Nujol) : 3070, 1570 cm 1 NMR (DMSO-d6, o) : 1.16 (3H, d, J=6.9Hz), 3.78 and 4.76 (2H, ABq, J=14.2Hz), 4.48 (lH, q, J=7.OHz), 5.91 (1~, s), 6.92-7.02 (lH, m), 7.22-7.41 (2H, m), 7.60 (lH, s), 7.65 (lH, d, J=4.6Hz), 8.07-8.15 (2H, m), 8.27-8.32 (lH, m), 8.96 (lH, d, J=4.6Hz) ~x~mple 1-4) 2-(2,4-Difluorophenyl)-3-(quinolin-2-yl)-1-(lH-1,2,4-triazol-l-yl)propan-2-ol IR (CHC13) : 3050, 1590 cm~l NMR (DMSO-d6, o) : 3.40 and 3.67 (2H, ABq, J=14.8Hz), 4.64 and 4.77 (2H, ABq, J=14.2Hz), 6.72-6.82 (2H, m), 7.10-7.29 (2H, m), 7.33 (lH, d, J=8.4Hz), 7.49-7.57 (lH, m), 7.66-7.74 (lH, m), 7.79 (lH, s), 7.86-7.90 (lH, m), 8.19 (lH, d, J=8.4Hz), 8.37 (lH, s) F~x~le 1-5) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(8-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (CHC13) : 3150, 1590 cm 1 NMR (CDC13, o) : 1.17 (3H, d, J=7.0Hz), 3.92 (lH, q, J=7.0Hz), 3.28 and 4.76 (2H, ABq, J=14.2Hz), 6.77-6.89 (2H, m), 7.36-7.71 (5H, m), 7.99 (lH, s), 8.08 (lH, s), 8.23-8.28 (lH, m) Enantiomeric pair B of 2-(2,4-difluorophenyl)-3-(8-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol W095/06047 21 ~ O 0 31 PCT/~4/01378 IR (CHC13) : 3250, 1590 cm~1 NMR (CDCl3, o) : 1.65 (3H, d, J=7.OHz), 4.01 (lH, q, J=6.9Hz), 4.77 and 4.88 (2H, ABq, J=13.7Hz), 6.32-6.42 (lH, m), 6.53-6.64 (lH, m), 7.09-7.64 (6H, m), 7.96-8.01 (lH, m), 8.12 (lH, s) Fxample 2-1) To a solution of the enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(quinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (192 mg) in dichloromethane (2 ml) was added 80% 3-chloroperbenzoic acid (131 mg). The solution was stirred at room temperature for 16 hours. Then the solvent was evaporated and the residue was stirred with diethyl ether and filtered. The solid was dried in vacuo to give an enantiomeric pair A of 2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]quinoline N-oxide (170 mg).
IR (KBr) : 1614, 1274, 962 cm~1 NMR (DMSO-d6, o) : 1.06-1.13 (3H, m), 3.34-3.40 (lH, m), 4.12 (lH, d, J=14.3Hz), 5.00-5.25 ~lH, m), 6.27 (lH, br s), 6.90-6.98 (lH, m), 7.20-7.31 (lH, m), 7.61-8.21 (7H, m), 8.68 (lH, d, J=8.6Hz) ~xample 2-2) To a solution of the enantiomeric pair A o~ 2-(2,4-difluorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride (30 mg) in water (2 ml) and ethyl acetate (2 ml) was added sodium hydrogen carbonate (5.8 mg). After stirring for 1 minute, the organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol.

W095/06047 2 1 7 ~ 0 3 1 PCT/JP94101378 The following enantiomeric pair A was obtained by the similar manner to that of Example 2-1) from the above-obtained enantiomeric pair A.

2-[2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(lH-1,2,4-triazol-1-yl)propyl]-6-fluoroquinoline N-oxide IR (KBr) : 1616, 1286, 966 cm~l NMR (DMSO-d6, o) : 1.05-1.15 (3H, m), 3.34-3.40 (lH, m), 4.08 (lH, d, J=14.6Hz), 5.05-5.20 (lH, m), 6.13 (lH, br s), 6.90-6.97 (lH, m), 7.19-7.31 (2H, m), 7.59-7.99 (5H, m), 8.18 (lH, s), 8.68-8.76 (lH, m) The following compounds were obtained in substantially the same manner as that of Example 1-1).

Fx~ple 3-1) Enantiomeric pair A of 2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)-3-(6-trifluoromethoxyquinolin-2-yl)-butan-2-ol IR (KBr) : 3159, 1601 cm 1 NMR (CDCl3) : 1.17 (3H, d, J=7.lHz), 3.90 (lH, q, J=7.1Hz), 4.17 and 4.77 (2H, ABq, J=14.1Hz), 6.78-6.89 (2H, m), 7.52-7.68 (5H, m), 7.97 (lH, s), 8.13 (lH, d, J=9.OHz), 8.23 (lH, d, J=8.5Hz) Mass : M+l = 465 Dihydrochloride of enantiomeric pair B of the same NMR (DMSO-d6, ~) : 1.57 (3H, d, J=6.9Hz), 4.03 (lH, q, J=7.1Hz), 4.91 (2H, s), 6.54-6.63 (lH, m), 6.94-7.11 (2H, m), 7.54 (lH, d, J=8.6Hz), 7.73-7.77 (lH, m), 7.87 (lH, s), 7.99 (lH, s), 8.13 (lH, d, J=9.2Hz), 8.40 (lH, d, J=8.6Hz), 8.66 (lH, s) W095/06047 2 1 7 0 0 3 1 , ~ ~ ~i PCT/~94,0l378 Fxa~ple 3-2) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-methoxyquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (KBr) : 3140, 1599 cm~l NMR (CDC13, o) : 1.16 (3H, d, J=7.OHz), 3.84 (lH, q, J=7.OHz), 3.96 (3H, s), 4.15 and 4.78 (2H, ABq, J=14.1Hz), 6.75-6.80 (2H, m), 7.11 (lH, d, J=2.7Hz), 7.38-7.66 (3H, m), 7.53 (lH, s), 7.99 (lH, d, J=9.OHz), 8.00 (lH, s), 8.12 (lH, d, J=9.OHz) Mass : M+l = 411 enantiomeric pair B of the same IR (KBr) : 3236, 1601~cm~l NMR (CDC13, o) : 1.63 (3H, d, J=6.9Hz), 3.88 (3H, s), 3.85-3.98 (lH, m), 4.76 and 4.89 (2H, ABq, J=13.8Hz), 6.26-6.37 (lH, m), 6.54-6.60 (lH, m), 6.93-7.05 (3H, m), 7.30-7.36 (lH, m), 7.64 (lH, s), 7.81 (lH, s), 7.85 (lH, d, J=1.7Hz), 8.09 (lH, s) Mass : M+l = 411 Example 3-3) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(7-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (KBr) : 3217, 1601 cm~l NMR (CDC13, o) : 1.16 (3H, d, J=7.lHz), 3.87 (lH, q, J=7.1Hz), 4.16 and 4.77 (2H, ABq, J=14.0Hz), 6.77-6.89 (2H, m), 7.33-7.98 (5H, m), 7.45 (lH, s), 8.09 (lH, s), 8.22 (lH, d, J=8.4Hz) Mass : M+l = 399 enantiomeric pair B of the same NMR (CDC13, o) : 1.63 (3H, d, J=6.9Hz), 3.97 (lH, q, J=6.9Hz), 4.75 and 4.88 (2H, ABq, J=13.9Hz), 21 7 ~ ~ 3 .~ PCTIJP94/01378 6.30-6.39 (lH, m), 6.54-6.66 (lH, m), 6.98-7.10 (2H, m), 7.40-7.73 (4H, m), 7.93 (lH, d, J=8.4Hz), 8.09 (lH, s) Mass : M+l = 399 Fxample 3-4) Enantiomeric pair A of 2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)-3-(6-trifluoromethylquinolin-2-yl)butan-2-ol NMR (CDC13, o) : 1.18 (3H, d, J=7.lHz), 3.93 (lH, q, J=7.1Hz), 4.20 and 4.77 (2H, ABq, J=14.2Hz), 6.79-6.88 (2H, m), 7.50 (lH, s), 7.59 (lH, d, J=8.5Hz), 7.65-7.69 (lH, m), 7.92-7.97 (2H.m), 8.18-8.30 (2H, m), 8.32 (lH, d, J=8.4Hz) Mass : M+l = 449 Example 4-1) To a stirred solution of enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-methoxyquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (800 mg) in dichloromethane (8 ml) was added dropwise a solution of boron tribromide in dichloromethane (lN, 11.7 ml) at -78C, and the resulting mixture was allowed to warm to ambient temperature. After stirring for one hour at ambient temperature, the reaction mixture was taken up into cold aqueous sodium hydroxide.
The organic layer was separated, washed in turn with water and brine, dried over magnesium sulfate. Evaporation of the solution gave a residue, which was chromatographed on silica gel (40 ml) eluting with a mixture of n-hexane, ethyl acetate and methanol (1:2:0 to 0:10:1, V/V) to give enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-hydroxyquinolin-2-yl)-l-(lH-l~2~4-triazol-l-yl)butan-2 (573 mg).
NMR (DMSO-d6, o) : 1.04 (3H, d, J=7.0Hz), 3.83 (lH, q, J=7.OHz), 4.08 and 4.76 (2H, ABq, J=14.4Hz), W095/06047 ~ ~ 7 ~ o 3 ~ PCT/JP94/01378 6.91-7.00 (lH, m), 7.15-7.25 (2~, m), 7.32-7.46 (2H, m), 7.54-7.58 (2H, m), 7.95 (lH, d, J=9.lHz), 8.18 (lH, s), 8.22 (lH, d, J=8.5Hz) Fxam~le 4-2) Enantiomeric pair B of 2-(2,4-difluorophenyl)-3-(6-hydroxyquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol was obtained in substantially the same manner as that of Example 4-1).
IR (KBr) : 3120, 1601 cm~1 NMR (CDC13, o) : 1.61 (3H, d, J=6.8Hz), 3.89 (lH, q, J=6.9Hz), 4.77 and 4.90 (2H, ABq, J=13.8Hz), 6.17-6.21 (lH, m), 6.52-6.63 (lH, m), 6.90-6.98 (3H, m), 7.23-7.2~ (lH, m), 7.68 (lH, s), 7.71-7.81 (2H, m), 8.18 (lH, s) Mass : M+1 = 397 Fxample 5-1) Lithium diisopropylamide (27.0 ml of 1.55M solution in tetrahydrofuran) was added over 40 minutes to a solution of 6-chloro-2-ethylquinoline (8.00 g) in tetrahydrofuran (42 ml) at -70C under an atmosphere of nitrogen. The solution was stirred at -70C for 30 minutes. Then a solution of 1-(2,4-difluorophenyl)-2-(lH-1,2,4-triazole-1-yl)ethanone (6.21 g) in tetrahydrofuran (60 ml) was added with stirring at -70C over 2 hours. After the addition, the solution was stirred for 4 hours. To the solution was added saturated aqueous ammonium chloride (50 ml) at -70C and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel (600 g) (eluent :
ethyl acetate : hexane = 2:3, V/V) to give an enantiomeric pair A of 3-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (1.64 g) and an W095/06047 21 7 ~ 0 3 1 PCT/~4/01378 enantiomeric pai- B (1.57 g) of the same.

enantiomeric pai~ A
mp : 144-151C
IR (KBr) : 3159, 1595, 1497 cm 1 NMR (CDC13, o) : 1.16 (3H, d, J=7.OHz), 3.87 (lH, q, J=7.0H~), 4.18 and 4.76 (2H, A~3q, J=14.7Hz), 6.77-6.89 (2H, m), 7.49 (lH, d, J=8.4Hz), 7.51 (lH, s), 7.55-7.67 (lH, m), 7.71 (lH, dd,-J=2.3Hz and J=9.OHz), 7.76 (lH, br s), 8.84 (lH, d, J=2.3Hz), 7.97 (lH, s), 8.01 (lH, d, J=9.OHz), 8.14 (lH, d, J=8.4Hz) Mass : M+l = 415 enantiomeric pair B
NMR (CDC13, o) : 1.63 and 1.64 (total 3H, two d, J=6.9Hz), 3.98 (lH, q, J=6.9Hz), 4.75 and 4.88 (2H, ABq, J=13.8Hz), 6.30-6.38 (lH, m), 6.54-6.66 (lH, m), 6.96-7.09 (lH, m), 7.08 (lH, d, J=8.4Hz), 7.44 (lH, br s), 7.58-7.68 (3H, m), 7.86 (lH, d, J=8.4Hz), 7.87 (lH, d, J=8.9Hz), 8.07 (lH, s) Mass : M+l = 415 The following compounds were obtained in substantially the same manner as that of Example 5-13.

Fxample 5-2) Enantiomeric pair A of 3-(6-bromoquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 138-149C
IR (KBr) : 3217, 1595, 1500 cm 1 NMR (CDCl3, o) : 1.16 (3H, d, J=7.lHz), 3.87 (lH, q, J=7.iHz), 4.20 and 4.76 (2H, ABq, J=14.7Hz), 6.78-6.89 ~2H, m), 7.49 (lH, d, J=8.4Hz), 7.51 W095/06047 2 1 7 0 ~ 3 1 PCT/~4/01378 .

(lH, s), 7.55-7.67 (lH, m), 7.75 (lH, br s), 7.84 (lH, dd, J=2.lHz and J=9.OHz), 7.95 (lH, d, J=9.OHz), 7.97 (lH, s), 8.02 (lH, d, J=2.lHz), 8.14 (iH, d, J=8.4Hz) MAss : M+ = 459, M+2 = 461 enantiomeric pair B of the same IR (KBr) : 3220, 1595, 1497 cm 1 NMR (CDC13, ~) : 1.63 (3H, d, J=6.9Hz), 3.98 (lH, q, J=6.9Hz), 4.75 and 4.88 (2H, ABq, J=13.9Hz), 6.29-6.38 (lH, m), 6.54-6.66 (lH, m), 6.96-7.08 (lH, m), 7.Q8 (lH, d, J=8.4Hz), 7.43 (lH, br s), 7.64 (lH, s), 7.71-7.88 (4H, m), 8.07 (lH, s) Mass : M+ = 459, M+2 - 461 Fxample 5-3) Enantiomeric pair A of 3-(6-tert-butylquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (KBr) : 3178, 1597, 1500 cm 1 NMR (CDC13, ~) : 1.15 (3H, d, J=7.1Hz), 1.45 (9H, s), 3.84 (lH, q, J=7.lHz), 4.14 and 4.78 (2H, ABq, J=14.3Hz), 6.75-6.88 (2H, m), 7.42 (lH, d, J=8.4Hz), 7.52-7.65 (lH, m), 7.54 (lH, s), 7.77 (lH, d, J=2.1Hz), 7.88 (lH, dd, J=2.1Hz and J=8.9Hz), 8.00 (lH, s), 8.03 (lH, d, J=8.9Hz), 8.18-8.22 (lH, br s), 8.20 (.lH, d, J=8.4Hz) Mass : M+l = 437 enantiomeric pair B of the same IR (KBr) : 3260, 1597, 1498 cml NMR (CDCl3, ~) : 1.38 (9H, s), 1.62 (3H, d, J=6.9Hz), 3.94 (lH, q, J=6.9Hz), 4.76 and 4.88 (2H, ABq, J=13.8Hz), 6.29-6.38 (lH, m), 6.55-6.66 (lH, m), 7.00-7.13 (lH, m), 7.02 (lH, d, J=8.3Hz), 7.59 (lH, d, J=2.1Hz), 7.64 (lH, s), 7.77 (lH, dd, W095/06047 PCT/~4101378 21~3~ - 28 -J=2.1H7 and J=9.OHz), 7.85-8.03 (3H, m), 8.09 (lH, s) Mass : M+l = 437 ~xample 5-4) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(5-methoxyquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl~butan-2-ol mp : 133-138C
IR (KBr) : 3197, 1593, 1500 cm~l NMR (CDCl3, ~) : 1.15 (3H, d, J=7.0Hz), 3.85 (lH, q, J=7.1Hz), 4.04 (3H, s), 4.16 and 4.77 (2H, ABq, J=14.3Hz), 6.75-6.83 (2H, m), 6.89 (lH, dd, J=2.9Hz and J=5.9Hz), 7.41 (lH, d, J=8.6Hz), 7.53 (lH, s), 7.56-7.7~ (3H, m), 8.01 (lH, s), 8.18 (lH, s), 8.63 (lH, d, J=8.6Hz) Mass : M+l = 411 enantiomeric pair B of the same mp : 115-117C
IR (KBr) : 3217, 1595, 1497 cm 1 NMR (CDC13, ~) : 1.63 (3H, d, J=6.3Hz), 3.94 (3H, s), 3.98 (lH, q, J=6.3Hz), 4.76 and 4.88 (2H, ABq, J=13.8Hz), 6.27-6.36 (lH, m), 6.54-6.66 (lH, m), 6.78 (lH, dd, J=1.3Hz and 7.3Hz), 6.98-7.10 (2H, m), 7.47-7.62 (2H, m), 7.64 (lH, s), 7.90 (lH, s), 8.09 (lH, s), 8.34 (lH, d, J=8.6Hz) Mass : M+l = 411 Fxample 5-5) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-methylthioquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 120-125C
IR (KBr) : 3120, 1591, 1504 cm~l NMR (DMSO-d6, o) : 1.07 (3H, d, J=7.0Hz), 3.34 (3H, ~ wo 9s/~6n~7 2 1 7 00 ~ 1 PCT/~94/Ul378 s), 3.87 (lH, q, J=7.OHz), 4.78 and 4.10 (2H, ABq, J=14.3Hz), 6.91-7.00 tlH, m), 7.03 (lH, s), 7.16-7.28 (lH, m), 7.33-7.46 (lH, m), 7.56 (lH, s), 7.66 (lH, d, J=8.5Hz), 7.68 (lH, dd, J=2.2Hz and J=8.9Hz), 7.80 (lH, d, J=2.2Hz), 8.00 (lH, d, J=8.9Hz), 8.19 (lH, s), 8.34 (lH, d, J=8.5Hz) Mass : M+l = 427 enantiomeric pair B of the same IR (KBr) : 3255, 1591, 1497 cm 1 NMR (CDC13, o) : 1.61-1.65 (3H, m), 2.54 (3H, s), 3.88-3.98 (lH, m), 4.75 and 4.88 (2H, ABq, J=14.3Hz), 6.28-6.37 (lH, m), 6.54-6.66 (lH, m), 6.96-7.09 (2H, m),~ 7.38 (lH, d, J=2.lHz), 7.54 (lH, dd, J=2.lHz and J=8.8Hz), 7.64 (lH, s), 7.68 (lH, br s), 7.811 (lH, d, J=8.8Hz), 7.812 (lH, d, J=8.5Hz), 8.08 (lH, s) Mass : M+l = 427 ~x~m~le 5-6) Enantiomeric pair A of 3-(6-cyanoquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 136-144C
IR (KBr) : 3260, 2229, 1620, 1597, 1500 cm 1 NMR (CDC13, ~) : 1.18 (3H, d, J=7.lHz), 3.94 (lH, q, J=7.1Hz), 4.21 and 4.76 (2H, ABq, J=14.4Hz), 6.78-6.89 (2H, m), 7.40 (lH, s), 7.49 (lH, s), 7.57-7.70 (2H, m), 7.89-7.94 (2H, m), 8.16 (lH, d, J=8.8Hz), 8.26-8.30 (2H, m) Mass : M+l = 406 Fxample 5-7) Enantiomeric pair A of 2-(2,4-dichlorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol W09S/06047 PCTtJP94/01378 ~17~31 mp : 140-150C
IR (KBr) : 3140, 1606, 1506 cm 1 NMR (CDCl3, o) : 1.12 (3H, d, J=7.lHz), 4.44 (lH, q, J=7.lHz), 4.20 and 5.22 (2H, ABq, J=14.2Hz), 7.20 (lH, dd, J=2.2Hz and J=8.6Hz), 7.41 (lH, d, J=2.2Hz), 7.45-7.54 (3H, m), 7.58 ~lH, dd, J=2.8Hz and J=8.3Hz), 7.80 (lH, d, J=8.6Hz), 7.98 (lH, s), 8.01 (lH, br s), 8.08 (lH, dd, J=5.2Hz and J=9.lHz), 8.18 (lH, d, J=8.5Hz) Mass : M+ = 431 enantiomeric pair B of the same mp : 136-142C
IR (KBr) : 3255, 1605,~ 1504 cm~l NMR (CDC13, ~) : 1.64 (3H, d, J=6.9Hz), 4.57 (lH, q, J=6.9Hz), 4.78 and 5.34 (2H, ABq, J=13.9Hz), 6.68 (lH, dd, J=2.2Hz and J-8.7Hz), 7.11 (lH, d, J=8.4Hz), 7.16-7.21 (2H, m), 7.31 (lH, dd, J=2.7Hz and J=8.8Hz), 7.40-7.50 (lH, m), 7.64 (lH, s), 7.70 (lH, br s), 7.89 (lH, d, J=8.4Hz), 7.92 (lH, dd, J=5.4Hz and J=9.2Hz), 8.09 (lH, s) Mass : M+ = 431 Fxample 5-8~
Enantiomeric pair A of 3-(6-chloroquinolin-2-yl)-2-(2,4-dichlorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 154-160C
IR (KBr) : 3236, 1595, 1493 cm~l NMR (CDC13, ~) : 1.11 (3H, d, J=7.1Hz), 4.20 and 5.21 (2H, ABq, J=14.2Hz), 4.44 (lH, q, J=7.lHz), 7.20 (lH, dd, J=2.2Hz and J=8.7Hz), 7.41 (lH, d, J=2.2Hz), 7.50 (lH, d, J=8.4Hz), 7.51 (lH, s), 7.71 (lH, dd, J=2.3Hz and J=9.OHz), 7.80 (lH, d, J=8.7Hz), 7.85 (lH, d, J=2.3Hz), 7.93 (lH, br s), 7.98 (lH, s), 8.02 (lH, d, J=9.OHz), 8.15 (lH, d, WO9S/06047 2 ~ 7 ~ 0 3 ~ PCTl~94/01378 J=8.4Hz) Mass : M+ = 447, M+2 = 449 enantiomeric pai- B of the same IR (KBr) : 3260, 1597, 1493 cm 1 NMR (CDCl3, o) : 1.64 (3H, d, J=6.9Hz), 4.58 (lH, q, J=6.9H~), 4.78 and 5.34 (2H, ABq, J=13.9Hz), 6.68 (lH, dd, J=2.2Hz and J=8.6Hz), 7.10-7.20 (3H, m), 7.58-7.68 (4H, m), 7.84 (lH, s), 7.88 (lH, s), 8.09(1~, s) Mass : M+ = 447, M+2 = 449 ~xample 5-9) Enantiomeric pair A of 3-(6-bromoquinolin-2-yl)-2-(2,4-dichlorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 156-161C
IR (KBr) : 3275, 1593, 1489 cm~l NMR (CDCl3, ~) : 1.11 (3H, d, J=7.lHz), 4.43 (lH, q, J=7.1Hz), 4.20 and 5.20 (2H, ABq, J=14.2Hz), 7.20 (lH, dd, J=1.8Hz and J=8.6Hz), 7.41 (lH, d, J=1.8Hz), 7.48-7.52 (2H, m), 7.80 (lH, d, J=8.6Hz), 7.82-7.86 (lH, m), 7.93-8.03 (4H, m), 8.14 (lH, d, J=8.4Hz) Mass : M+l = 493 enantiomeric pair B of the same IR (KBr) : 3255, 1593, 1491 cm 1 NMR (CDCl3, o) : 1.63 (3H, d, J=6.9Hz), 4.57 (lH, q, J=6.9HZ), 4.78 and 5.33 (2H, ABq, J=13.9Hz), 6.68 (lH, dd, J=2.1Hz and J=8.7Hz), 7.09-7.20 (3H, m), 7.64-7.87 (6H, m), 8.09 (lH, s) Mass : M+l = 493 ~xample 5-10) Enantiome~ic pair A of 2-(2,4-dichlorophenyl)-3-(5-PCT/~4/01378 w095/06047 ~ l 7 ~ ~ 3 t methylthioquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 159-164C
IR (KBr) : 3178, 1589, 1488 cm 1 NMR (CDC;3, o) : 1.11 ~3H, d, J=7.lHz), 2.61 (3H, s), 4.18 and 5.22 (2H, ABq, J=14.1Hz), 4.40 (lH, q, J=7.lHz), 7.19 (lH, dd, J=2.2Hz and J=8.6Hz), 7.40-7.45 (2H, m), 7.52 (lH, s), 7.55 (lH, d, J=2.lHz), 7.65 (lH, dd, J=2.lHz and J=8.9Hz), 7.80 (lH, d, J=8.6Hz), 7.96 (lH, d, J=8.9Hz), 7.99 (lH, s), 8.11 (lH, d, J=8.5Hz), 8.15 (lH, s) Mass : M+ = 459 enantiomeric pair B of the same IR (K3r) : 3255, 1589, 1488 cm 1 NMR (CDC13, o) : 1.53 (3H, d, J=6.9Hz), 2.54 (3H, s), 4.53 (lH, q, J=6.9Hz), 4.77 and 5.34 (2H, ABq, J=13.9Hz), 6.67 (lH, dd, J=2.lHz and J=8.7Hz), 7.05 (lH, d, J=8.4Hz), 7.16-7.21 (2H, m), 7.38 (lH, d, J=2.lHz), 7.54 (lH, dd, J=2.lHz and J=8.9Hz), 7.64 (lH, s), 7.78-7.83 (3H, m), 8.13 (lH, s) Mass : M+ = 459 Example 5-11) Enantiomeric pair A of 3-(6-cyanoquinolin-2-yl)-2-(2,4-dichlorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 152-156C
IR (KBr) : 3142, 2229, 1593, 1462 cm 1 NMR (DMSO-d6, o) : 1.05 (3H, d, J=7.1Hz), 4.14 and 5.28 (2H, A3q, J=14.3Hz), 4.52 (lH, q, J=7.lHz), 6.70 (lH, s), 7.32 (lH, dd, J=2.2Hz and J=8.6Hz), 7.53 (lH, s), 7.59 (lH, d, J=8.6Hz), 7.60 (lH, d, J=2.2Hz), 7.87 (lH, d, J=8.6Hz), 8.09 (lH, dd, J=1.8Hz and J=8.8Hz), 8.18 (lH, s), 8.26 (lH, d, 217~3~
. ~ ~ PCT1~94101378 J=8.8Hz), 8.57 (lH, d, J=8.6Hz), 8.70 (lH, d, J-1.8Hz) Mass : M+ = 438, M+2 = 440 Ex~le 5-12) Enantiomeric pair A of 3-(6-bromoquinolin-2-yl)-2-(4-fluorophenyl)-l-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 132-137C
IR (KBr) : 3255, 1593, 1510 cm 1 NMR (CDC13, o) : 1.15 (3H, d, J=7.OHz), 3.66 (lH, q, J=7.0Hz), 4.16 and 4.43 (2H, ABq, J=14.1Hz), 7.01 (2H, t, J=8.7Hz), 7.27-7.36 (2H, m), 7.52 (lH, d, ~=8.5Hz), 7.59 (lH, br s), 7.63 (lH, s), 7.74 (lH, s), 7.82 (lH, dd, J=2.0Hz and J=9.OHz), 7.93 (lH, d, J=9.OHz), 8.02 (lH, d, J=2.OHz), 8.14 (lH, d, J=8.5Hz) Mass : M+ = 441 enantiomeric pair B of the same IR (KBr) : 3255, 1593, 1510 cm~l NMR (CDCl3, o) : 1.69 (3H, d, J=6.9Hz), 3.80 (lH, q, J=6.9Hz), 4.48 and 4.68 (2H, ABq, J=13.9Hz), 6.69 (2H, t, J=8.6Hz), 7.04-7.11 (3H, m), 7.39 (lH, br s), 7.72-7.90 (6H, m) Mass : M+ = 441 ~x~le 5-13) Enantiomeric pair A of 2-(4-fluorophenyl)-3-(6-methylthioquinolin-2-yl)-1-(lH-1,2,4-triazol~l-yl)butan-2-ol mp : 121-127C
IR (KBr) : 3199, 1591, 1510 cm 1 NMR (DMSO-d6,~) : 1.05 (3H, d, J=7.OHz), 2.62 (3~, s), 3.77 (lH, q, J=7.0Hz), 4.12 and 4.72 (2H, ABq, J=14.2Hz), 6.78 (lH, s), 7.10 (2H, m), 7.45 W095/06047 21 7 ~ ~ 31 PCTl~94/0~378 (2H, dd, J=5.5Hz and J=8.8Hz), 7.57 (lH, d, J=8.4Hz), 7.61 (lH, s), 7.67 (lH, dd, J=2.2Hz and J=8.8Hz), 7.78 (lH, d, J=2.2Hz), 7.97 (lH, d, J=8.8Hz), 8.04 (lH, s), 8.31 (lH, d, J=8.4Hz) Mass : M+l = 409 enantiomeric pair B of the same IR (KBr) : 3260, 1591, 1508 cm 1 NMR (CDC13, o) : 1.68 (3H, d, J=6.9Hz), 2.53 -(3H, s), 3.76 (îH, q, J=6.9Hz), 4.49 and 4.68 (2H, ABq, J=13.9Hz), 6.64-6.73 (2H, m), 7.00 (lH, d, J=8.5Hz), 7.04-7.12 (2H, m), 7.38 (lH, d, J=2.1Hz), 7.52 (lH, dd, J=2.1Hz and J=8.9Hz), 7.61 (lH, br s), 7.75-7.83 (4H, m) Mass : M+l = 409 Example 5-14) Enantiomeric pair A of 2-(4-chlorophenyl)-3-(6-cyanoquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 139-144C
IR (KBr) : 3257, 2229, 1600, 1497 cm~l NMR (DMSO-d6, o) : 1.09 (3H, d, J=7.0Hz), 3.83 (lH, q, J=7.0Hz), 4.19 and 4~77 (2H, ABq, J=14.2Hz), 6.42 (lH, s), 7.33 (2H, d, J=8.7Hz), 7.44 (2H, d, J=8.7Hz), 7.61 (lH, s), 7.74 (lH, d, J=8.5Hz), 8.07 (lH, dd, J=1.8Hz and J=8.8Hz), 8.10 (lH, s), 8.20 (lH, d, J=8.8Hz), 8.51 (lH, d, J=8.5Hz), 8.67 (lH, d, J=1.8Hz) Mass : M+l = 404 Fxample 5-lS) 2-(2,4-Difluorophenyl)-3-(6-methylthioquinolin-2-yl)-l-(lH-1,2,4-triazol-1-yl)propan-2-ol IR (KBr) : 3217, 1591, 1497 cm~l NMR (CDC13, o) : 2.55 (3H, s), 3.22 (lH, ABq, 2~DO~
WO9Sl06047 ~ PCT/~4/01378 .

J=14.9Hz), 3.72 and 3.73 (total lHj two ABq, J=14.9Hz), 4.55 and 4.73 (2H, ABq, J=14.1Hz), 6.57-6.77 (2H, m), 7.09 (lH, d, J=8.4Hz), 7.37-7.50 (2H, m), 7.55 (lH, dd, J=2.2Hz and 8.9Hz), 7.79 (lH, s), 7.81 (lH, d, J=8.9Hz), 7.82 (lH, s), 7.86 (lH, d, J=8.4Hz), 8.29 (lH, s) Mass : M+l = 413 Fxam~le 5-16) 2-(2,4-Difluorophenyl)-3-methyl-1-(lH-1,2,4-triazol-1-yl)-3-(quinolin-2-yl)butan-2-ol mp : 110-114C
IR (Nujol) : 3120.3, 1616.1, 1594.8 cm 1 NMR (CDC13, o) : 1.46`(3H, s), 1.63 (3H, d, J=3.4Hz), 4.15 (lH, dd, J=2.2, 14.0Hz), 5.26 (lH, dd, J=1.8, 14.0Hz), 6.55-6.85 (2H, m), 7.48-7.90 (6H, m), 7.95-8.30 (4H, m) APCI-Mass : e/z = 395 (M+H)+
Elemental Analysis Calculated for C20H2109N3 :
C 66.99%, H 5.11%, N 14.20%
Found : C 67.25%, H 5.15%, N 14.23%

~xample 5-17) 2-(2,4-Difluorophenyl)-3-methyl-3-(6-methylthioquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol mp : 129-130C
IR (Nujol) : 3116.4, 1589.1, 1492.4 cm 1 NMR (CDCl3, o) : 1.45 (3H, s), 1.~1 (3H, s), 2.61 (3H, s), 4.16 (lH, dd, J=2.lHz and J=14.OHz), 5.26 (lH, dd, J=2.1Hz, and 14.0Hz), 6.55-6.80 (2H, m), 7.40-7.70 (5H, m), 7.85-8.15 (4H, m) Elemental Analysis Calculated for C23H22F2N40S :
C 62.71%, H 5.03%, N 12.72%
Found : C 62.71%, H 5.11%, N 12.55~

2 'Y ~ ~ q PcTtmg4/0l378 WO9S/06047 l I U ~

APCI-Mass : e/z = 441 (M+H)+

The follow-ng compounds were obtained in substantially the same manner as that of Example 4-1).
~xample 6-1) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(5-hydroxyquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair A of Example 5-4) mp : 127-139C
IR (KBr) : 3120, 1595, 1500 cm 1 NMR (DMSO-d6, o) : 1.06 (3H, d, J=7.OHz), 3.87 (lH, q, J=7.OHz), 4.09 and 4.78 (2H, ABq, J=14.3Hz), 6.92-7.00 (2H, m),~ 7.23-7.29 (lH, m), 7.25 (lH, s), 7.51-7.64 (2H, m), 7.56 (lH, s), 7.60 (lH, d, J=8.6Hz), 8.18 (lH, s), 8.56 (lH, d, J=8.6Hz), 10.57 (lH, s) Mass : M+l = 397 Fxam~le 6-2) Enantiomeric pair B of 2-(2,4-difluorophenyl)-3-(5-hydroxyquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2~ol from enantiomeric pair B of Example 5-4) mp : 78-95C
IR (KBr) : 3120, 1595, 1497 cm 1 NMR (CDCl3, o) : 1.63 (3H, d, J=6.9Hz), 3.93 (lH, q, J=6.9Hz), 4.78 and 4.91 (2H, ABq, J=13.8Hz), 6.19-6.29 (lH, m), 6.53-6.64 (lH, m), 6.74 (lH, t, J=4.4Hz), 6.92-7.04 (lH, m), 6.97 (lH, d, J=8.5Hz), 7.46 (2H, d, J=4.4Hz), 7.68 (lH, s), 8.10-8.80 (lH, br s), 8.20 (lH, s), 8.36 (lH, d, J=8.5Hz) Mass : M+l = 397 The following compounds were obtained in substantially WOg5/06047 21 7 ~ O ~

the same manner as that of Example 7-6).

~xample 7-1~
Enantiomeric pair A of 2-~2,4-difluorophenyl)-3-(6-methylsulfonylquinolln-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair A of Example 5-5) mp : 178-182C
IR (KBr) : 3140, 1599, 1498, 1309, 1146 cm~l NMR (DMS06-o) : 1.12 (3H, d, J=7.1Hz), 3.34 (3H, s), 3.97 (lH, q, J=7.1Hz), 4.14 and 4.83 (2H, ABq, J=14.3Hz), 6.69 (lH, s), 6.93-6.97 (lH, m), 7.18-7.30 (lH, m), 7.32-7.44 (lH, m), 7.56 (lH, s), 7.86 (lH, d, J=8.6Hz), 8.20 (lH, s), 8.20-8.35 (2H, m), 8.69-8.73 (2H, m) Mass : M+l = 459 Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair A of Example 5-5) mp : 160-165C
IR (KBr) : 3140, 1599, 1500, 1140 cm~l NMR (DMSO-d6, ~ : 1.11 (3H, d, J=7.0Hz), 2.86 (3H, s), 3.95 (lH, q, J=7.OHz), 4.14 and 4.82 (2H, ABq, J-14.3Hz), 6.84 (lH, s), 6.91-7.01 (lH, m), 7.17-7.29 (lH, m), 7.33-7.46 (lH, m), 7.56 (lH, s), 7.80 (lH, d, J=8.5Hz), 8:03 (lH, dd, J=2.OHz and J=8.8Hz), 8.20 (lH, s), 8.27 (lH, d, J=8.8Hz), 8.39 (lH, d, J=2.OHz), 8.61 (lH, d, J=8.5Hz) Mass : M+l = 443 Fx~le 7-2) Enantiomeric pair B of 2-(2,4-difluorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomerlc pair B of Example 5-5) 2 17 PCT/~94/01378 mp : 78-90C
IR (KBr) : 3275, 1616, 1497, 1309, 1144 cm 1 NMR (CDCl3, o) : 1.66 (3H, d, J=6.2Hz), 3.11 (3H, s), 4.07 (lH, q, J=6.2Hz), 4.77 and 4.89 (2H, ABq, J=14.2Hz), 6.30-6.40 (lH, m), 6.39-6.67 (lH, m), 6.99-7.11 (lH, m), 7.02-7.20 (lH, br s), 7.26 (lH, d, J=8.4Hz), 7.66 (lH, s), 8.08-8.14 (4H, m), 8.40 (lH, s) Mass : M+l = 459 F~xample 7-3) Enantiomeric pair A of 2-(2,4-dichlorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair A of Example 5-10) mp : 155-167C
IR (KBr) : 3132, 1595, 1506 cm~l NMR (DMSO-d6, o) : 1.05 (3H, d, J=7.lHz), 2.86 (3H, s), 4.12 and 5.28 (2H, ABq, J=14.2Hz), 4.51 (lH, q, J=7.lHz), 6.95 (lH, s), 7.32 (lH, dd, J=2.2Hz and J=8.7Hz), 7.53 (lH, s), 7.56 (lH, d, J=8.7Hz), 7.60 (lH, d, J=2.2Hz), 7.82 (lH, d, J=8.5Hz), 8.04 (lH, dd, J-2.OHz and J-8.8Hz), 8.18 (lH, s), 8.28 (lH, d, J=8.8Hz), 8.39 (1, d, J=2.0Hz), 8.62 (lH, d, J=8.5Hz) Mass : M+=475 Fxample 7-4) Enantiomeric pair B of 2-(2,4-dichlorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair B of Example 5-10) mp : 80-90C
IR (KBr) : 3366, 1593, 1495, 1138 cm~l NMR (D~SO-d6, o) : 1.58 (3H, d, J=6.9Hz), 2.80 (3H, s), 4.56 (lH, q, J=6.9Hz), 4.84 and 5.27 (2H, W095/06047 2 1 7 ~ 0 3 1~ ~ PCT/~94/01378 .

ABq, J=14.2Hz), 6.87 (lH, dd, J=2.2Hz and J-8.7Hz), 7.04 (lH, br s), 7.22 (lH, d, J=8.7Hz), 7.34 (lH, d, J=2.2Hz), 7.41 (lH, d, J=8.5Hz), 7.63 (lH, s), 7.89-7.95 (lH, m), 8.11 (lH, d, J=8.8Hz), 8.20 (lH, br s), 8.33 (lH, d, J=8.5Hz), 8.33 (lH, s) Masss : M+ = 475 E~ample 7-5) Enantiomeric pair A of 2-(2,4-dichlorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair A of Example 7-3) mp : 147-148C
IR (KBr) : 3216, 1618,~ 1464 cm~l NMR (DMSO-d6, ~) : 1.06 (3H, d, J=7.1Hz), 3.34 (3H, s), 4.13 and 5.29 (2H, ABq, J=14.4Hz), 4.54 (lH, q, J=7.1Hz), 6.80 (lH, br s), 7.32 (lH, dd, J=2.2Hz and J=8.6Hz), 7.53 (lH, s), 7.58 (lH, d, J=8.5Hz), 7.61 (lH, d, J=2.2Hz), 7.89 (lH, d, J=8.6Hz), 8.18 (lH, s), 8.24 (lH, dd, J=2.OHz and J=8.9Hz), 8.35 (lH, d, J=8.9Hz), 8.70-8.74 (2H, m) Mass : M+ = 491, M+2 = 493 Example 7-6) To a solution of enantiomeric pair B of 2-(2,4-dichlorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (1.56 g) in dichloromethane (16 ml) was added 80% 3-chloroperbenzoic acid (849 mg).
The additional stirring was continued for 2 hours, and then saturated aqueous sodium thiosulfate (20 ml) was added to the reaction mixture. After the stirring for 5 minutes, the mixture was extracted with ethyl acetate. The organic layer was separated, washed in turn with water and brine, dried over anhydrous magnesium sulfate. The solvent was W095/06047 ~2 1 7 ~ ~ 3 1 PCTl~4/01378 evaporated and the residue was chromatographed on silica gel (250 g, n-hexane - ethyl acetate = 1:1 to 0:1, V/V) to give enantiomeric pair A of 2-(2,4-dichlorophenyl)-3-(6-methylsulfonylqu nolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (803 mg).
mp : 87-95~C
IR (KBr) : 3255, 1616, 1311, 1144 cm~l NMR (DMSO-d6, o) : 1.59 (3H, d, J=6.9Hz), 3.28 (3H, s), 4.58 (lH, q, J=6.9Hz), 4.85 and 5.29 (2H, ABq, J=14.4Hz), 6.86 (lH, s), 6.87 (lH, dd, J=2.2Hz and J=8.7Hz), 7.21 (lH, d, J=8.7Hz), 7.34 (lH, d, J=2.2Hz), 7.49 (lH, d, J=8.5Hz), 7.64 (lH, s), 8.08-8.18 (2H, m), 8.33 (lH, s), 8.44 (lH, d, J=8.5Hz), ~8.52 (lH, br s) Mass : M+ = 491, M+2 = 493 ~x~m~le 7-7) Enantiomeric pair A of 2-(4-fluorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair A of Example 5-12) mp : 130-135C
IR (KBr) : 3277, 1599, 1510 cm~l NMR (DMSO-d3, o) : 1.08 (3H, d, J=7.0Hz), 2.86 (lH, s), 3.84 (lH, q, J=7.0Hz), 4.16 and 4.76 (2H, ABq, J=14.OHz), 6.61 (lH, s), 7.10 (2H, t, J=8.9Hz), 7.46 (2H, dd, J=5.5Hz and J=8.8Hz), 7.61 (lH, s), 7.70 (lH, d, J=8.5Hz), 8.02 (lH, dd, J=2.OHz and J=8.8Hz), 8.07 (lH, s), 8.24 (lH, d, J=8.8Hz), 8.36 (lH, d, J=2.0Hz), 8.57 (lH, d, J=8.5Hz) Mass : M+l = 425 Fx~ple 7-8) Enantiomeric pair A of 2-(4-fluorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-W095/06047 2 ~ 7 0 Q ~ 1 PcTl~94lol378 yl)butan-2-ol from enantiomeric pair B of Example 5-13) mp : 133-146C
IR (KBr) : 1603, 1508, 1313, 1144 cm~l NMR (DMSO-do, o~ : 1.10 (3H, d, J=7.OHz), 3.33 (3H, s), 3.84 (lH, q, J=7.0Hz), 4.19 and 4.76 (2H, ABq, J=14.lHz), 6.46 (lH, s), 7.10 (2H, t, J=8.9Hz), 7.45 (2H, dd, J=5.6Hz and J=8.8Hz), 7.61 (lH, s), 7.74 (lH, d, J=8.5Hz), 8.08 (lH, s), 8.21 (lH, dd, J=1.9Hz and J=8.9Hz), 8.28 (lH, d, J=8.9Hz), 8.66 (lH, d, J=8.5Hz), 8.68 (lH, d, J=1.9Hz) Mass : M+l = 441 Example 7-9) Enantiomeric pair B of 2-(4-fluorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair B of Example 5-13) mp : 78-84C
IR (KBr) : 3277, 1597, 1510 cm~l NMR (DMSO-d6, o) : 1.54 (3H, d, J=6.9Hz), 2.80 (3H, s), 3.96-4.05 (lH, m), 4.66 and 4.80 (2H, ABq, J=14.lHz), 6.66 (lH, s), 6.82 (2H, t, J=8.9Hz), 7.22 (2H, dd, J=5.5Hz and J=8.8Hz), 7.41 (lH, d, J=8.5Hz), 7.77 (lH, s), 7.91 and 7.92 (total lH, two dd, J=2.3Hz and J=8.7Hz), 8.08 (lH, d, J=8.7Hz), 8.08 (lH, s), 8.20 (lH, d, J=2.3Hz), 8.31 (lH, d, J=8.5Hz) Mass : M+l = 425 Fxample 7-10) Enantiomeric pair B of 2-(4-fluorophenyl)-3-(6-methylsulfonylquinol~n-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from enantiomeric pair B of Example 7-9) mp : 85-91C
IR (KBr) : 3277, 1601, 1508 cm 1 WO9S/06047 2 1 7 Q ~ 3 ~ PCT/~4/01378 NMR (DMSO-d6, ~) : 1.55 (3H, d, J=6.9Hz), 3.27 (3H, s), 4.03 (lH, q, J=6.9Hz), 4.67 and 4.82 (2H, ABq, J=14.2Hz), 6.51 (lH, s), 6.81 (2H, t, J=8.9Hz), 7.21 (2H, dd, J=5.5Hz and J=8.8Hz), 7.48 (lH, d, J=8.5Hz), 7.77 (lH, s), 8.09 (lH, s), 8.12 (2H, s), 8.41 (lH, d, J=8.6Hz), 8.53 (lH, s) Mass : M+l = 441 Fxample 7-11) 2-(2,4-Difluorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-l-(lH-1,2,4-triazol-1-yl)propan-2-ol mp : 65-70C
IR (KBr) : 3275, 1616, 1498, 1309, 1144 cm~l NMR (DMS0-d6, o) : 3.29 (3H, s), 3.47 and 3.72 (2H, ABq, J=13.9Hz), 4.65 and 4.79 (2H, ABq, J=14.3Hz), 6.52 (lH, s), 6.72-6.81 (lH, m), 7.10-7.22 (2H, m), 7.50 (lH, d, J=8.5Hz), 7.79 (lH, s), 8.03-8.10 (2H, m), 8.35 (lH, s), 8.45 (lH, d, J=8.5Hz), 8.56 (lH, br s) Mass : M+l = 445 2-(2,4-Difluorophenyl)-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)propan-2-ol mp : 75-82C
IR (KBr) : 3275, 1597, 1498, 1137 cm~l NMR (DMSO-d6, ~) : 2.81 (3H, s), 3.45 and 3.70 (2H, ABq, J=14.0Hz), 4.66 and 4.79 (2H, ABq, J=14.2Hz), 6.60-6.75 (lH, br s), 6.72-6.81 (lH, m), 7.10-7.26 (2H, m), 7.46 (lH, d, J=8.5Hz), 7.78 (lH, s), 7.88-7.94 (lH, m), 8.02 (lH, d, J=8.8Hz), 8.24 (lH, d, J=1.9Hz), 8.34 (lH, d, J=8.5Hz), 8.38 (lH, s) Mass : M+l = 429 W095/06047 2 1 7 0 ~ 3 1 - - PCT/~94/01378 .

Example 7-12) 2-(2,4-Difluorophenyl)-3-methyl-3-(6-methylsulfinylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol frcm the product of Example 5-17) mp : 78-82C
IR (Nujol) : 3403.7, 1733.7, 1614.1, 1594.8, 1496.5 cm~l NMR (CDC13, o) : 1.51 (3H, s), 1.62 (3H, s), 2.83 (3H, s), 4.17 (lH, d, J=14.OHz), 5.30 (lH, d, J=14.0Hz), 6.55-6.83 (2H, m), 7.55-7.70 (3H, m), 7.72-7.95 (lH, m), 8.05 (lH, s), 8.10-8.30 (3H, m) APCI-Mass : e/z = 457 (M+H)+
Elemental Analysis Calculated for C23H22F2N402S 1/4 ethyl acetate :
C 60.24%, H 5.06%, N 11.71%
Found : C 59.96%, H 4.92%, N 11.72%

~xample 7-13) 2-(2,4-Difluorophenyl)-3-methyl-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol from the product of Example 5-17) mp : 74-79C
IR (Nujol) : 3390.2, 1733.7, 1616.1, 1457.9 cm 1 NMR (CDC13, o) : 1.53 (3H, s), 1.64 (3H, s), 3.16 (3H, s), 4.18 (lH, dd, J=2.2Hz and J=14.2Hz), 5.33 (lH, dd, J=2.2Hz and J-14.2Hz), 6.50-6.83 (3H, m), 7.50-7.80 (3H, m), 8.02 (lH, s), 8.10-8.35 (3H, m), 8.52 (lH, d, J=1.9Hz) APCI-Mass : e/z = 473 (M+H)+
Elemental Analysis Calculated for C23H22F2N403S l/10 ethyl acetate :
C 58.39%, H 4.77%, N 11.64%
Found : C 58.10%, H 4.78%, N 11.50 Ex~le 8 W095/06047 PCT/~4/01378 217~31 44 _ A solution of enantiomeric pair A of 3-(6-cyanoquinolin-2-~-l)-2-(2,4-dichlorophenyl)-1-(lH, 1,2,4-triazol-1-yl)butan-2-ol (70.0 g) in conc. sulfurlc acid (0.7 ml) and water (0.7 ml) was refluxed over 1.5 hours.
The resulting mixture was allowed to warm to room temperature and neutralized with sodium hydrogen carbonate.
The solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with ethyl acetate. The precipitate was collected by filtration to give enantiomeric pair A of 3-(6-carboxyquinolin-2-yl)-2-(2,4-dichlorophenyl)1-(lH-1,2,4-triazol-1-yl)butan-2-ol (27.1 mg).
IR (KBr) : 3097, 1699, 1286 cm 1 NMR (DMSO-d6, o) : 1.05 (3H, d, J=7.1Hz), 4.14 and 5.28 (2H, ABq, J=14.3Hz), 4.51 (lH, q, J=7.1Hz), 7.00 (lH, br s), 7.32 (lH, dd, J=2.2Hz and J=8.6Hz), 7.53-7.61 (3H, m), 7.81 (lH, d, J=8.5Hz), 8.15-8.29 (3H, m), 8.63-8.71 (2H, m), 13.28 (lH, br s) Mass : M=457, M+2 = 459 F.xample 9-1 ) A solution of a mixture of enantiomeric pair B of 2-(4-fluorophenyl)-3-(6-methylthioquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol (1.60 g) in ethyl acetate (75 ml) was triturated with 4N hydrogen chloride in ethyl acetate (1.96 ml) at 0C. The solid was filtered, washed with ethyl acetate and dried in vacuo to give enantiomeric pair B of 2-(4-fluorophenyl)-3-(6-methylthioquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride (1.89 g).
mp : 143-145C
IR (KBr) : 3238, 1603, 1510 cm 1 NMR (DMSO-d6, o) : 1.65 (3H, d, J=6.8Hz), 2.60 (3H, s), 4.38 (lH, q, J=6.8Hz), 4.85 and 4.96 (2H, 2 ~ 7 ~ ~ 31 PCTt~4/01378 A~3q, J=14.5Hz), 5.70-6.20 (lH, br s), 6.84 (2H, t, J=8.8Hz), 7.29 (2H, dd, J=5.5Hz and J=8.6Hz), 7.76-7.90 (3H, m), 8.00 (lH, s), 8.26 (lH, d, J=9.6Hz), 8.54 (lH, s), 8.67 (lH, d, J=8.7Hz) Mass : M+l = 409 (free) The following compound was obtained by the similar manner to that of Example 9-1).

Fxample 9-2) 3-(6-Bromoquinolin-2-yl)-2-(2,4-dichlorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride mp : 131-135C
IR (KBr : 3256, 1593, 1470 cm~l ~MR (DMSO-d6, o) : 1.60 (3H, d, J=6.9Hz), 4.58 (lH, q, J=6.9Hz), 4.92 and 5.32 (2H, ABq, J=14.3Hz), 6.10 (lH, br s), 6.90 (lH, dd, J=2.2Hz and J=8.6Hz~, 7.20 (lH, d, J=8.6Hz), 7.34 (lH, d, J=2.2Hz), 7.49 (lH, d, J=8.4Hz), 7.86 (lH, s), 7.88 (lH, dd, J=2.OHz and J=9.lHz), 8.01 (lH, d, J=9.lHz), 8.21 (lH, d, J=2.0Hz), 8.28 (lH, d, J=8.4Hz), 8.71 (lH, s) Fxample 10 Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-quinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol was separated by high-performance liquid chromatography using a chiral column (Daicel, CHIRALCEL OD) and HITACHI L-6300 inteligent pump eluting with a solvent system comprised of hexane 2-propanol (80:20). The column was monitored by a W detector set at 210 nm. The former fraction and the latter one were respectively evaporated under reduced pressure to give enantiomeric pair Al (4.5 mg) and A2 (11.0 mg) of the same.

WO9S/06047 217 ~ ~ ~ 1 PCT/~4/01378 enantiomeric pair Al [a] DO = +31.1 (C=0.6%, CHCl3) enantiomeric pai- A2 [a] DO = -33.2 (C=0.3%, CHC13) The following compounds were obtained in substantially the same manner zs that of Example 5-1).

Fxample 11-1) Enantiomeric pair A of 3-(6-cyanoquinolin-2-yl)-2-(4-fluorophenyl)-l-(lH-1,2,4-triazol-1-yl)butan-2-ol IR (KBr) : 3284, 2229, 1601, 1508 cm 1 NMR (CDC13, o) : 1.17 (3H, d, J=7.lHz), 3.74 (lH, q, J=7.lHz), 4.17 and 4.43 (2H, ABq, J=14.lHz), 7.03 (2H, t, J=8.7Hz), 7.28-7.35 (2H, m), 7.62 (lH, s), 7.65-7.69 (2H, m), 7.91 (lH, dd, J=1.8Hz and J=8.7Hz), 8.15 (lH, d, J=8.7Hz), 8.26 (lH, s), 8.26 (lH, d, J=8.7Hz) Mass : M+l = 388 Fxample 11-2) 3-(6-Cyanoquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)propan-2-ol IR (KBr) : 3149, 2229, 1618, 1595, 1502 cm 1 NMR (CDC13, o) : 3.28 (lH, ABq, Jz15.0Hz), 3.84 and 3.85 (total lH, two ABq, J=15.OHz), 4.54 (lH, ABq, J=14.lHz), 4.75 (lH, ABq, J=14.lHz), 6.59-6.79 (2H, m), 7.29 (lH, d, J=8.1Hz), 7.40-7.52 (lH, m), 7.83 (lH, dd, J=1.8Hz and J=8.8Hz), 7.84 (lH, s), 8.02 (lH, d, J=8.8Hz), 8.05 (lH, d, J=8.1Hz), 8.14 (lH, d, J=1.8Hz), 8.28 (lH, s) Mass : M+l = 392 Example 11-3) ~ ~ ~ n ~ PCT/JP94/01378 WO9S/06047 ~ l ~ U ~

Enantiomeri~ pair A of 3-(6-fluoroquinolin-2-yl)-2-(4-fluorophenyl)-l-(lH-1,2,4-triazol-1-yl)butan-2-ol NMR (CDCl3, o) : 1.15 (3H, d, J=7.lHz), 3.66 (lH, q, J=7.1H7), 4.16 and 4.44 (2H, ABq, J=14.1Hz), 7.02 (2H, t, J=8.9Hz), 7.29-7.40 (3H, m), 7.41-7.59 (3H, m), 7.64 (lH, s), 7.75 (lH, s), 8.06 (lH, dd, J=~.4Hz and J=9.lHz), 8.18 (lH, d, J=8.4Hz) Mass : M+l = 381 enantiomeric pai- B of the same NMR (CDCl3, o) : 1.69 (3H, d, J=7.1Hz), 4.12 (lH, q, J=7.lHz), 4.49 and 4.69 (2H, ABq, J=13.9Hz), 6.70 (2H, t, J=8.8Hz), 6.75-7.12 (3H, m), 7.29 (lH, dd, J=2.8Hz and J=9.2Hz), 7.43 (lH, dt, J=2.8Hz lS and J=9.2Hz), 7.48 (lH, s), 7.74 (lH, s), 7.81 (lH, s), 7.87-7.93 (2H, m) Mass : M+l = 381 The following compounds were obtained in substantially the same manner as that of Example 9-1).

~x~le 12-1) Enantiomeric pair A of 3-(6-cyanoquinolin-2-yl)-2-(4-fluorophenyl)-l-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride IR (KBr) : 3400, 2235, 1645, 1603, 1510 cm~l NMR (DMSO-d6, o) : 1.16 (3H, d, J=7.1Hz), 4.15 (lH, q, J=7.lHz), 4.39 and 4.96 (2H, ABq, J=14.2Hz), 7.16 (2H, t, J=8.8Hz), 7.51 (2H, dd, J=5.5Hz and J=8.8Hz), 7.87 (lH, d, J=8.7Hz), 8.06 (lH, s), 8.25 (lH, dd, J=1.7Hz and J=8.8Hz), 8.43 (lH, d, J=8.8Hz), 8.78 (lH, d, J=8.7Hz), 8.84 (lH, s), 8.84 (lH, d, J=1.7Hz) Fxample 12-2) PCT/~4/01378 wo gs/06047 2 1 7 ~

3-(6-Cyanoquinolin-2-yl)-2-(4-fluorophenyl)-1-(lH-1,2,4-triazol-1-yl)propan-2-ol dihydrochloride IR (KBr) : 3381, 2235, 1647, 1616, 1500cm~l MMR (DMSO-d6, ~) : 3.69 and 3.79 (2H, ABq, J=13.6Hz), 4.79 and 4.92 (2H, ABq, J=14.2Hz), 6.77-6.85 (lH, m), 7.10-7.29 (2H, m), 7.67 (lH, d, J=8.6Hz), 8.10 (lH, dd, J=1.5Hz and J=8.8Hz), 8.16 (lH, d, J=8.8Hz), 8.18 (lH, s), 8.53 (lH, d, J=8.6Hz), 8.68 (lH, d, J=1.5Hz), 8.96 (lH, s) Fxam~le 12-3) Enantiomeric pair A of 2-(4-fluorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride IR (KBr) : 3342, 1620, 1506 cm 1 NMR (DMSO-d6, ~) : 1.23 (3H, d, J=7.OHz), 4.38 (lH, q, J=7.0Hz), 4.91 and 5.02 (2H, ABq, J=14.2Hz), 7.19 (2H, t, J=8.9Hz), 7.54 (2H, dd, J=8.9Hz and J=5.4Hz), 7.88 (lH, d, J=8.8Hz), 7.99(lH, s), 8.07 (lH, dt, J=2.8Hz and J=8.8Hz), 8.18 (lH, dd, J=2.8Hz and J=9.OHz), 8.60 (lH, dd, J=5.OHz and J=8.8Hz), 8.74 (lH, s), 8.95 (lH, d, J=8.8Hz) ~x~le 12-4) Enantiomeric pair B of 2-(4-fluorophenyl)-3-(6-fluoroquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride IR (KBr) : 3342, 1620, 1506 cm~l NMR (DMSO-d6, o) : 1.65 (3H, d, J=6.9Hz), 4.40 (lH, q, J=6.9Hz), 4.91 and 4.99 (2H, ABq, J=14.6Hz), 6.85 (2H, t, J=8.9Hz), 7.32 (2H, dd, J=5.5Hz and J=8.9Hz), 7.84 (lH, d, J=8.9Hz), 7.93 (lH, dt, J=2.7Hz and J=9.OHz), 8.00 (lH, dd, J=2.7Hz and J=9.OHz), 8.13 (lH, s), 8.45 (lH, dd, J=5.0Hz and J=g.OHz), 8.73 (lH, d, J=8.9Hz), 8.78 (lH, s) Wo95/06047 ~17 ~ PCT/JP94/01378 ....

Fxample 13 Enantiomeric pair A of 3-(6-cyanoquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol was separated by using DAICEL chiralcel-OD
(hexane:isopropanol = 71:29, flow rate 3.0 ml/min, W
wavelength 240 nm) in substantially the same manner as that of Example 10 to give enantiomeric pair A1 and A2 of the same.

enantiomeric pair A1 retention time : 13.6 minutes [~]26 = -8.5 (C=0.25%, MeOH) enantiomeric pair A2 retention time : 22.0 minutes [a]D6 = +5 0~ (C=0.25%, MeOH) The folllowing compounds were obtained in substantially the same manner as that of Example 9-1).
Fxample 14-1) Enantiomeric pair A1 of 3-(6-cyanoquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride IR (KBr! : 3246, 2235, 1647, 1618, 1502 cm~

Fxample 14-2) Enantiomeric pair A2 of 3-(6-cyanoquinolin-2-yl)-2-(2,4-difluorophenyl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride IR (KBr) : 3284, 2235, 1649, 1618, 1504 cm~

Fx~pLe 15-1) Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-2~7~3~ 50 _ yl)butan-2-ol dihydrochloride IR (KBr) : 3381, 1645, 1616, 1500, 1309, 1149 cm 1 NMR (DMSO-do, o) : 1.16 (3H, d, J=7.2Hz), 3.36 (3H, s), 4.03 (lH, q, J=7.2Hz), 4.25 and 4.91 (2H, ABq, J=14.2Hz~, 6.95-7.03 (lH, m), 7.21-7.43 (2H, m), 7.85 (lH, s), 7.94 (lH, d, J=8.6Hz), 8.30 (lH, dd, J=2.OHz and J=8.6Hz), 8.42 (lH, d, J=8.9Hz), 8.62 (lH, s), 8.78 (lH, d, J=2.OHz), 8.82 (lH, d, J=8.6Hz) ~x~m~le 15-2) Enantiomeric pair A of 2-(2,4-dichlorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol dihydrochloride IR (KBr) : 3360, 1645, 1558, 1309, 1147cm 1 NMR (DMSO-d6, ~) : 1.08 (3H, d, J=7.1Hz), 3.35 (3H, s), 4.20 (lH, ABq, J=14.3Hz), 4.61 (lH, q, J=7.1Hz), 5.35 (lH, ABq, J=14.3Hz), 7.34 (lH, dd, J=2.2Hz and J=8.7Hz), 7.56 (lH, d, J=8.7Hz), 8.63 (lH, d, J=2.2Hz), 7.61 (lH, s), 7.95 (lH, d, J=8.6Hz), 8.28 (lH, dd, J=2.0Hz and J=8.9Hz), 8.42 (lH, d, J=8.9Hz), 8.50 (lH, s), 8.76 (lH, d, J=2.OHz), 8.81 (lH, d, J=8.6Hz) F~xample 16 Enantiomeric pair A of 2-(2,4-difluorophenyl)-3-(6-methylsulfonylquinolin-2-yl)-1-(lH-1,2,4-triazol-1-yl)butan-2-ol was separated by using DAICEL chiralcel-OD
(hexane:ethanol = 50:50, flow rate 3.0 ml/min, W
wavelength 240 nm) in substantially the same manner as that of Example 10 to give enantiomeric pair Al and A2 of the same.

enantiomeric pair Al retention time : 13.3 minutes WO9S/06047 2 1 7 0 0 3 ~ . PCTt~4101378 [a]30 = +3.~o (C=0.25, EtOH) enantiomeric pair A2 retention time : 27.0 minutes [a]30 = -4,0o (C=0.25, EtOH)

Claims (11)

1. A compound of the formula:

in which R1 and R2 are each hydrogen or lower alkyl, R3 is optionally substituted quinolyl or oxide thereof, and X and Y are each hydrogen, halogen, cyano or lower alkyl, or a pharmaceutically acceptable salts thereof.

2. The compound of Claim 1 having the following formula:

in which R1, R2, R3, X and Y are each as defined in Claim 1.

3. The compound of Claim 2, wherein R3 is quinolyl or its N-oxide, which is optionally substituted by the group consisting of hydroxy, protected hydroxy, halogen, lower alkoxy, halo(lower)alkyl, halo(lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, amino, nitro, cyano and carboxy.

4. The compound of Claim 3, wherein R3 is quinolyl or its N-oxide, which is optionally substituted by the group consisting of hydroxy, halogen, lower alkoxy, halo(lower)alkyl, halo(lower)alkoxy, lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano and carboxy.

5. The comopund of Claim 4, wherein R3 is quinolyl, hydroxyquinolyl, haloquinolyl, lower alkoxyquinolyl, halo(lower)alkylquinolyl, halo(lower)alkoxyquinolyl, lower alkylquinolyl, lower alkylthioquinolyl, lower alkylsulfinylquinolyl, lower alkylsulfonylquinolyl, cyanoquinolyl, carboxyquinolyl, N-oxide of quinolyl or N-oxide of haloquinolyl.

6. The compound of Claim 5 having the following formula:

in which R3, X and Y are each as defined in Claim 5, and R? is lower alkyl.

7. A process for the preparation of a compound of the formula:

or a salt there, which comprises (a) reacting a compound of the formula:

or a salt thereof, with a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; or (b) oxidizing the optionally substituted quinolyl of a compound of the formula :

or a salt thereof, to give a compound of the formula:

or a salt thereof; or (c) hydrolyzing the lower alkoxy-substituent of optionally substituted quinolyl of a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; or (d) oxidizing the lower alkylthio- or lower alkylsulfinyl-substituent of optionally substituted quinolyl of a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof; or (e) hydrolyzing the cyano-substituent of optionally substituted quinolyl of a compound of the formula:

or a salt thereof, to give a compound of the formula:

or a salt thereof;
wherein R1, R2, R3, X and Y are each as defined above, R? is optionally substituted quinolyl, R? is N-oxide of optionally substituted quinolyl, R? is quinolyl substituted by lower alkoxy and optionally by suitable substituent(s), R? is quinolyl substituted by hydroxy and optionally by suitable substituent(s), R? is quinolyl substituted by lower alkylthio or lower alkyl sulfinyl, and optionally by suitable substituent(s), R? is quinolyl substituted by lower alkylsulfinyl or lower alkyl sulfonyl, and optionally by suitable substituent(s), R? is quinolyl substituted by cyano and optionally by suitable substituent(s), and R? is quinolyl substituted by carboxy and optionally by suitable substituent(s).

8. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or excipient.

9. A method for treating or preventing infectious diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.

10. A compound of claim 1 and a pharmaceutically acceptable salt thereof for use as a medicament.

11. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.