Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• the present invention relates to a new compound and a pharmaceutically acceptable salt thereof-
• a new quinoline 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 preventing infectious diseases in a human being or an animal.
• one object of the present invention is to provide the quinoline derivative and a pharmaceutically acceptable salt 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 diseases caused by pathogenic microorganisms, which comprises administering said quinoline derivative to a human being or an animal.
• the object quinoline derivative of the present invention is novel and can be represented by the following general formula (I) :
• R-'- and R 2 are each hydrogen or lower alkyl
• R is optionally substituted quinolyi 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.
• Process 1 The compound (I) of the present invention can be prepared by the processes as illustrated in the following schemes.
• R 1 , R 2 , R , X and Y are each as defined above, R- 3 is optionally substituted quinolyi,
• R is N-oxide of optionally substituted b .
• quinolyi R is quinolyi substituted by lower alkoxy and optionally by suitable substituent (s)
• R ⁇ is quinolyi substituted by hydroxy and optionally by suitable substituent (s)
• R g is quinolyi substituted by lower alkylthio or lower alkylsulfinyl and optionally by suitable substituent (s)
• R is quinolyi substituted by lower alkylsulfinyl or lower alkylsulfonyl and optionally by suitable substituent (s)
• R g is quinolyi substituted by cyano and optionally by suitable substituent (s) , and quinolyi 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.
• 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, triethyla ine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, etc.] an organic acid addition salt [e.g.
• 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, triethyla ine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenz
• 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.
• 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.
• lower is intended to mean 1 to 6, 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 "optionally substituted quinolyi” 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) alkylsilyl (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 C ⁇ -C4 alkoxy (e.g. methoxy, etc.);
• -halo(lower)alkyl which is aforementioned lower alkyl group substituted by one or more, preferably one to three 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.) ;
• C1-C4 alkyl e.g. methyl, t-butyl, etc.
• -lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc, more preferably ⁇ -C ⁇ alkylthio (e.g. methylthio, etc. ) ;
• -lower alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, etc, more preferably - ⁇ -C ⁇ alkylsulfinyl (e.g. methylsulfinyl, etc.);
• -lower alkylsulfonyl such as methylfulfonyl, ethylsulfonyl, prcpylsulfonyl, isopropylsulfonyl, butylsulfonyl, per.rylsulfonyl, hexylsulfonyl, etc, more preferably C ⁇ -C 4 alkylsulfonyl (e.g. methylsulfonyl, etc.); amino; nitro; cyano; carboxy; and the like.
• optionally substituted quinolyi may be quinolyi optionally substituted by hydroxy, halogen, lower alkoxy, 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 quinolyi” means N-oxide of aforementioned optionally substituted quinolyi, in which more preferable example may be N-oxide of quinolyi 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 6-fluoroquinolin-2-yl.
• Suitable "quinolyi substituted by lower alkoxy and optionally by suitable substituent(s)” means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).
• quinolyi substituted by lower alkoxy and optionally by suitable substituent(s) means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).
• Suitable "quinolyi substituted by hydroxy and optionally by suitable substituent (s)" means aforementioned optionally substituted quinolyi group, wherein said quinolyi is substituted at least by hydroxy, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4- )yl, etc.) substituted at least by hydroxy.
• Suitable "quinolyi substituted by lower alkylthio or lower alkylsulfinyl and optionally by suitable substituent(s)" means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkylthio or lower alkylsulfinyl as mentioned above, in which more preferable example may be quinolyi (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.).
• quinolyi e.g. quinolin-2- (or 4-)yl, etc.
• lower alkylthio e.g. methylthio, .etc.
• lower alkylsulfinyl e.g. methylsulfinyl, etc.
• Suitable "quinolyi substituted by lower alkylsulfinyl or lower alkylsulfonyl and optionally by suitable substituent(s) " means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkylsulfinyl or lower alkylsulfonyl as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkylsulfinyl (e.g. methylsulfinyl, etc.) or lower alkylsulfonyl (e.g. ethylfulfonyl, etc.).
• quinolyi substituted by lower alkylsulfinyl or lower alkylsulfonyl e.g. ethylfulfonyl, etc.
• Suitable "quinolyi substituted by cyano and optionally by suitable substituent(s)" means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by cyano, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by cyano.
• Suitable "quinolyi substituted by lower alkoxy and optionally by suitable substituent (s)" means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).
• quinolyi substituted by lower alkoxy and optionally by suitable substituent (s) means aforementioned optionally substituted quinolyi, wherein said quinolyi is substituted at least by lower alkoxy as mentioned above, in which more preferable example may be quinolyi (e.g. quinolin-2- (or 4-)yl, etc.) substituted at least by lower alkoxy (e.g. methoxy, etc.).
• R 1 , R 2 , R 3 , X and Y are as follows.
• R! and R 2 are each hydrogen or lower alkyl
• R 3 is quinolyi 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.
• R , R 2 , R , X and Y are as follows.
• R x and R ⁇ are each hydrogen or lower alkyl
• R J is quinolyi 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
• X and Y are each hydrogen or halogen.
• 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 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, ethanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction.
• a conventional solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N- dimethylformamide, ethanol, 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.
• 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
• reaction temperature is not critical, and the reaction is usually carried out under cooling to under heating.
• the object compound (I-b) or a salt thereof can be prepared by oxidizing the optionally substituted quinolyi 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, chrc ic compound (e.g. chromium trioxide, chromic acid, sodium chromate, dichromic acid, sodium dichro ate, pyridinium 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 water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
• a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,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.
• the compound (I-d) or a salt thereof can be prepared by hydrolyzing the lower alkoxy-substituent of optionally substituted quinolyi 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 carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and the like.
• an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
• an alkaline earth metal carbonate e.g. magnesium carbonate, calcium carbonate, etc.
• an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
• 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.).
• organic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
• 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.).
• hydrolysis using trihaloborane e.g. tribromobrane, etc.
• halo(lower) alkane e.g. dichloromethane, etc.
• 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.
• the compound (I-f) or a salt thereof can be prepared by oxidizing the lower alkylthio- or lower alkylsulfinyl- substituent of optionally substituted quinolyi 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 referred to those as explained in Process 2
• the compound (I-h) or a salt thereof can be prepared by hydrolyzing the cyano-substituent of optionally substituted quinolyi of 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 explained in Process 3.
• reaction mode and reaction condition e.g. reactive derivatives, solvents reaction temperature, etc.
• 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.
• R 1 , R 2 , R 3 , X and Y are each as defined above. Further, the compound having the following formula is the most preferable.
• R , X and Y are each as defined above, and R ⁇ is lower alkyl.
• test compound In vitro antimicrobial activity of the test compound was determined by the two-fold agar-plate dilution method as described below.
• the compound (I) of the present invention has an anti-microbial activity (especially, antifungal 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 admixture 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.
• 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 u ⁇ ual non-toxic, pharmaceutically acceptable carriers _; r 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, stabilizing, 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 ⁇ -ired antimicrobial effect upon the pro ⁇ SS or condition c iiseases.
• the composition 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 g of the compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 20 mg of the compound (I) per kg weight of a human being or an animal, 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 infectious diseases.
• 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 -70°C under an atmosphere of nitrogen. The solution was stirred at -70°C for 30 minutes. Then a solution of 1- (2, 4-difluorophenyl) -2- (1H-1, 2, 4-triazole-l-yl) ethanone (6.21 g) in tetrahydrofuran (60 ml) was added with stirring at -70°C over 2 hours. After the addition, the solution was stirred for 4 hours.
• Example 7-5 Enantiomeric pair A of 2- (2, 4-dichlorophenyl) -3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1,2, 4-triazol-l- yl)butan-2-ol from enantiomeric pair A of Example 7-3) mp : 147-148°C
• Example 7-13 2- (2, 4-Difluorophenyl) -3-methyl-3- (6- methylsulfonylquinolin-2-yl) -1- (1H-1, 2, 4-triazol-l- yl)butan-2-ol from the product of Example 5-17) mp : 74-79°C
• Example 8 A solution of enantiomeric pair A of 3- (6- cyanoquinolin-2-yl)-2- (2,4-dichlorophenyl)-1- (IH, 1,2, - triazol-l-yl)butan-2-ol (70.0 g) in cone, sulfuric 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.
• Example 10 Enantiomeric pair A of 2- (2, -difluorophenyl)-3- quinolin-2-yl)-1- (1H-1,2,4-triazol-l-yl)butan-2-ol was separated by high-performance liquid chromatography using a chiral column (Daicel, CHIRALCEL OD) and HITACHI L-6300 propel pump eluting with a solvent system comprised of hexane 2-propanol (80:20). The column was monitored by a UV detector set at 210 n . 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. enantiomeric pair Al
• the folllowing compounds were obtained in substantially the same manner as that of Example 9-1) .

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