JPH10279567A - Triazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound, which is an excellent antifungal agent especially effective against mycoses in humans and animals. SOLUTION: This compound is represented by formula I [Ar<1> is a (substituted) phenyl; Ar<2> is a (substituted) naphthyl, a (substituted) 8- to 10-membered condensed bicyclic aromatic heterocyclic ring, etc.; R<1> is H or a lower alkyl; (n) is 0, 1 or 2; (p) and (q) are each 0, 1 or 2; A is a 4-7C aliphatic carboxylic ring or a 4- to 7-membered aliphatic heterocyclic ring containing at least one of N, O and S], e.g. 3-[[2-[2-(6-chloro-2-naphthyl)vinyl]-1,3-dioxan-5- yl]thio]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol. The objective compound is preferably obtained by reacting a compound of formula II with an aldehyde compound of formula III in a solvent such as methylene chloride at a temperature within the range of 0 deg.C to the boiling point temperature of the solvent under acidic conditions using hydrogen chloride, etc., for about 1-20 hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 1,2,2 compound of the formula (I) which is particularly effective against fungal diseases of humans and animals.
4-triazole compounds, pharmacologically acceptable salts thereof, compositions containing them as active ingredients for the treatment or prevention of fungal diseases, and their use for producing a medicament for the treatment or prevention of fungal diseases Or a method for treating or preventing a fungal disease, wherein a pharmacologically effective amount thereof is administered to a warm-blooded animal.

[0002]

2. Description of the Related Art Japanese Patent Laid-Open Publication No. 8-333350 (1996)
2.17) states that, in the formula (I), an analogous compound of the compound of the present invention in which Ar ² is a phenyl group or a 5- to 6-membered aromatic heterocyclic group which may have a substituent has an antifungal activity It is described.

[0003]

However, the present inventors have conducted intensive studies to find a more excellent antifungal agent, and have found that the compound of the present invention is an excellent fungicide, thereby completing the present invention. Was.

[0004]

The present invention is a compound having the formula (I) or a pharmaceutically acceptable salt thereof.

[0005]

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In the formula, Ar ¹ represents a phenyl group or a phenyl group having 1 to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group); Ar ² represents naphthyl; A condensed bicyclic aromatic heterocyclic group (the condensed bicyclic aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or a naphthyl group having 1 to 3 substituents or 8 to 10 members Condensed bicyclic aromatic heterocyclic group (the substituent is a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group , -S (O) _m R ² group (R ² : a lower alkyl group optionally substituted with a halogen atom; m: 0, 1 or 2) or -NHCOR ³ group (R ³ represents a lower alkyl group) ), The fused bicyclic aromatic A heterocyclic group has at least one nitrogen, oxygen or sulfur atom), R ¹ represents a hydrogen atom or a lower alkyl group, n represents 0, 1 or 2, p and q represent 0, 1 or 2 (However, p + q
≦ 2), A represents an aliphatic carbocyclic group having 4 to 7 carbon atoms or a 4- to 7-membered aliphatic heterocyclic group having at least one nitrogen, oxygen or sulfur atom.

A phenyl group having a halogen atom of Ar ¹ ,
A halogen atom of Ar ² , a naphthyl group having a lower alkyl group substituted with a halogen atom and a lower alkoxy group substituted with a halogen atom as a substituent, an 8- to 10-membered fused bicyclic aromatic heterocyclic group, and R ² Examples of the halogen atom of the alkyl group substituted with a halogen atom include a fluorine, chlorine and bromine atom.

A lower alkyl group of Ar ² and a naphthyl group having a lower alkyl group substituted with a halogen atom as a substituent, and a fused 8- to 10-membered bicyclic aromatic heterocyclic group;
¹ lower alkyl group, lower alkyl group optionally substituted by a halogen atom of R ² and lower alkyl group of a lower alkyl group of R ³ may be a linear or branched alkyl group having 1 to 6 carbon atoms. And includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl groups, preferably a straight or branched alkyl having 1 to 4 carbon atoms. And represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

A naphthyl group having a lower alkoxy group of Ar ^{2 and} a lower alkoxy group substituted with a halogen atom as a substituent and a lower alkoxy group of an 8- to 10-membered condensed bicyclic aromatic heterocyclic group have 1 to 1 carbon atoms. Denotes 6 straight or branched chain alkoxy groups, for example methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy or isohexyloxy groups, preferably a straight-chain or branched alkoxy group having 1 to 4 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec −
Butoxy and tert-butoxy groups. Ar ² 8 ~
The 10-membered fused bicyclic aromatic heterocyclic group is, for example, quinolyl,
Isoquinolyl, benzofuranyl, benzothiophenyl,
Examples include indolyl, benzimidazolyl, benzoxazolyl or benzothiazolyl groups.

The aliphatic carbocyclic group consisting of 4 to 7 carbon atoms of A is, for example, a cyclobutane, cyclopentane, cyclohexane or cycloheptane ring.

At least one nitrogen, oxygen and sulfur atom of A
The 4- to 7-membered aliphatic heterocyclic group having, for example, an azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, thietane, tetrahydrothiophene, pentamethylene sulfide, dioxane, dithiane, tetrahydrooxazine or tetrahydrothiazine ring. .

As the compound having the formula (I), a compound in which Ar ¹ is a phenyl group having ¹ to 3 substituents (the substituent is a halogen atom or a trifluoromethyl group) is preferable. Compounds in which Ar ¹ is a phenyl group having ¹ to 2 substituents (the substituents represent a fluorine atom, a chlorine atom or a trifluoromethyl group) are particularly preferred.

Specifically, for example, Ar ¹ is a dichlorophenyl, difluorophenyl, chlorophenyl, fluorophenyl, (trifluoromethyl) phenyl or fluoro (trifluoromethyl) phenyl group, preferably 2,4-dichlorophenyl, , 4-difluorophenyl, 4-chlorophenyl, 2-fluorophenyl, 4-
A fluorophenyl, 4- (trifluoromethyl) phenyl or 2-fluoro-4- (trifluoromethyl) phenyl group, particularly preferably 2,4-dichlorophenyl, 2,4-difluorophenyl or 4- (trifluoromethyl); A compound which is a methyl) phenyl group.

The compound having the formula (I) includes naphthyl as Ar ² , an 8- to 10-membered condensed bicyclic aromatic heterocyclic group (the condensed bicyclic aromatic heterocyclic group has a nitrogen, oxygen or sulfur atom). A naphthyl group having 1 to 3 substituents or an 8 to 10-membered condensed bicyclic aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower group substituted with a halogen atom) An alkyl group, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group, or a —S (O) _m R ² group (R ² : a lower alkyl group which may be substituted with a halogen atom; Or 2), wherein the condensed bicyclic aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom), wherein Ar ² is naphthyl and an 8- to 10-membered condensed Cyclic aromatic heterocyclic group (the condensed bicyclic The aromatic heterocyclic group has 1 to 2 nitrogen, oxygen or sulfur atoms) or a naphthyl group having 1 to 3 substituents or an 8 to 10-membered fused bicyclic aromatic heterocyclic group (the substituent is A lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group, or a -S (O) _m R ² group (R ² : a halogen atom A lower alkyl group which may be substituted; m represents 0, 1 or 2), and the condensed bicyclic aromatic heterocyclic group has 1 to 2 nitrogen, oxygen or sulfur atoms. More preferably, Ar ² is naphthyl, an 8- to 10-membered fused bicyclic aromatic heterocyclic group (the fused bicyclic aromatic heterocyclic group is nitrogen,
Having 1-2 oxygen or sulfur atoms) or 1-2
Naphthyl group having 8 substituents or an 8- to 10-membered condensed bicyclic aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, A lower alkoxy group, a nitro group, a cyano group, or a -S (O) _m R ² group (R ² : a lower alkyl group optionally substituted with a halogen atom; m represents 0, 1 or 2); Compounds in which the condensed bicyclic aromatic heterocyclic group has 1 or 2 nitrogen or sulfur atoms) are more preferable, and in which Ar ² is naphthyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzoxa Zolyl or benzothiazolyl group or naphthyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl having 1-2 substituents, A benzimidazolyl, benzoxazolyl or benzothiazolyl group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group, or -S Compounds which are (O) _m R ² groups (R ^{2 represents a} lower alkyl group which may be substituted with a halogen atom; m represents 0, 1 or 2) are particularly preferred.

Specifically, for example, when Ar ² is fluoronaphthyl, chloronaphthyl, bromonaphthyl, bromo-fluoronaphthyl, difluoronaphthyl, dichloronaphthyl,
Dibromonaphthyl, (trifluoromethyl) naphthyl,
(Ditrifluoromethyl) naphthyl, (trichloromethyl) naphthyl, fluoro- (trifluoromethyl) naphthyl, fluoro- (trifluoromethoxy) natyl, fluoromethoxy- (trifluoromethyl) naphthyl,
(Difluoromethoxy) naphthyl, (trifluoromethoxy) naphthyl, (2,2,2-trifluoroethoxy) naphthyl, (1,1,2,2-tetrafluoroethoxy) naphthyl, (2,2,3,3- Tetrafluoropropoxy) naphthyl, fluoro- (2,2,3,3-tetrafluoropropoxy) naphthyl, nitronaphthyl,
Fluoro-nitronaphthyl, cyanonaphthyl, chloro-
Cyanonaphthyl, (methylthio) naphthyl, (methylsulfinyl) naphthyl, (methylsulfonyl) naphthyl, fluoro- (methylsulfonyl) naphthyl, (trifluoromethylthio) naphthyl, (trifluoromethylsulfinyl) naphthyl, (trimethylsulfonyl) naphthyl, chloroquinolyl , Bromoquinolyl, (trifluoromethyl) quinolyl, (trifluoromethoxy) quinolyl, (2,2,3,3-tetrafluoropropoxy)
Quinolyl, (trifluoromethyl) isoquinolyl, bromobenzofuranyl, (trifluoromethyl) benzofuranyl, (2,2,3,3-tetrafluoropropoxy)
Benzofuranyl, bromobenzothienyl, (trifluoromethyl) benzothienyl, (2,2,3,3-tetrafluoropropoxy) benzothienyl, (methylsulfonyl) benzothienyl, (trifluoromethyl) benzooxazolyl, bromoindolyl , (Trifluoromethyl) indolyl, dichloro-methylindolyl, bromobenzimidazolyl, (trifluoromethyl) benzimidazolyl, (trifluoromethyl) benzothiazolyl or (2,2,3,3-tetrafluoropropoxy)
A benzothiazolyl group, preferably 6-fluoro-2
-Naphthyl, 6-chloro-2-naphthyl, 6-bromo-
2-naphthyl, 6,8-difluoro-2-naphthyl, 6
-(Trifluoromethyl) -2-naphthyl, 6- (trichloromethyl) -2-naphthyl, 6- (difluoromethoxy) -2-naphthyl, 6- (trifluoromethoxy)
-2-naphthyl, 6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl, 6-nitro-2-naphthyl, 8-fluoro-6-nitro-2-naphthyl, 6-
Cyano-2-naphthyl, 6- (methylsulfinyl)-
2-naphthyl, 7-fluoro-6- (methylsulfonyl) -2-naphthyl, 6- (trifluoromethylsulfonyl) -2-naphthyl, 6-chloro-2-quinolyl, 6
-Bromo-2-quinolyl, 6- (trifluoromethyl)
-2-quinolyl, 6- (2,2,3,3-tetrafluoropropoxy) -2-quinolyl, 5- (trifluoromethyl) -2-benzothienyl, 5- (trifluoromethyl) -2-benzooxa Zolyl, 3,5-dichloro-1
-Methyl-2-indolyl group, particularly preferably 6-
Bromo-2-naphthyl, 6- (trifluoromethyl)-
2-naphthyl, 6- (trifluoromethylsulfonyl)
-2-naphthyl or 6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl, a compound which is a 3,5-dichloro-1-methyl-2-indolyl group.

As the compound having the formula (I), a compound in which R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl or isopropyl group is preferable, and a compound in which R ¹ is a methyl group or an ethyl group is further preferable. Compounds in which R ¹ is a methyl group are particularly preferred.

In the compound having the formula (I), n is 0
Or a compound that is 2.

As a compound having the formula (I), p is 0
Or a compound of 1 is preferred.

As the compound having the formula (I), q is 0
Or, a compound in which 1 is preferable, and a compound in which q is 0 is particularly preferable.

As the compound having the formula (I), A is an aliphatic carbocyclic group having 4 to 7 carbon atoms or a 4- to 7-membered aliphatic heterocyclic ring having 1 to 2 nitrogen, oxygen or sulfur atoms. And A is an aliphatic carbocyclic group having 4 to 6 carbon atoms or a 4- to 6-membered aliphatic heterocyclic group having 1 to 2 nitrogen, oxygen or sulfur atoms. Is more preferred. Specifically, for example, A is cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, thietane, tetrahydrothiophene, pentamethylene sulfide, dioxane, dithiane, dihydrooxazine,
A tetrahydrooxazine, dihydrothiazine or tetrahydrothiazine ring, preferably cyclobutane, cyclohexane, azetidine, piperidine, tetrahydropyran, dioxane, dithiane, tetrahydrooxazine or tetrahydrothiazine ring, particularly preferably cyclohexane, tetrahydropyran Or a compound having a dioxane ring.

Representative compounds of the present invention are listed in Tables 1 to 13. The present invention is not limited to these compounds.

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

[0026]

[Table 5]

[0027]

[Table 6]

[0028]

[Table 7]

[0029]

[Table 8]

[0030]

[Table 9]

[0031]

[Table 10]

[0032]

[Table 11]

[0033]

[Table 12]

[0034]

[Table 13]

Preferred compounds in Tables 1 to 13 are 1,
6,16,26,34,35,42,52,57,6
2,67,82,90,93,98,115,120,
123 and 133, and particularly preferable compounds are 3-[[2- [2- (6-chloro-2-naphthyl)].
Vinyl] -1,3-dioxan-5-yl] thio] -2
-(2,4-difluorophenyl) -1- (1H-1,
2,4-triazol-1-yl) -2-butanol (Compound No. 1), 3-[[2- [2- (6-bromo-
2-naphthyl) vinyl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1
-(1H-1,2,4-triazol-1-yl) -2
-Butanol (compound No. 6, a compound corresponding to Example 2), 2- (2,4-difluorophenyl) -3-
[[2- [2- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1 , 2,4
-Triazol-1-yl) -2-butanol (Compound No. 26, compound corresponding to Example 3), 2- (2,4
-Difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -3-[[2- [2- [6-
(Trifluoromethoxy) -2-naphthyl] vinyl]-
1,3-Dioxan-5-yl] sulfonyl] -2-butanol (Compound No. 52) 3-[[6- (2-bromo-2-naphthyl) vinyl]-
Tetrahydro-2H-pyran-3-yl] thio] -2-
(2,4-difluorophenyl) -1- (1H-1,
2,4-triazol-1-yl) -2-butanol (Compound No. 57), 2- (2,4-difluorophenyl) -3-[[6- [2- [6- (2,2,3, 3-tetrafluoropropoxy) -2-naphthyl] vinyl]-
Tetrahydro-2H-pyran-3-yl] thio] -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol (Compound No. 67, compound corresponding to Example 5) 2- (2,4-difluorophenyl) -3-[[2-
[4- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] -1,3-butadienyl]-
1,3-dioxan-5-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol (Compound No. 93) 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[2- [6- (trifluoromethylsulfonyl) -2-
Naphthyl] vinyl] -1,3-dioxan-5-yl]
Thio] -2-butanol (Compound No. 115) 3-[[2- (6-Bromo-2-naphthyl) -1,3-
Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol (Compound No. 123;
(A compound corresponding to Example 1).

The triazole compound (I) of the present invention has at least two asymmetric carbons, and has optical isomers and diastereomers. The enantiomers can be obtained as enantiomers by a general optical resolution technique or an asymmetric synthesis technique. Further, diastereomers can be separated by using an ordinary separation method such as fractional recrystallization or chromatography. Compound (I) of the present invention includes one or a mixture of these isomers.

The triazole compound (I) of the present invention can be used as it is or in the form of a pharmacologically acceptable salt as an antifungal agent. Pharmaceutically acceptable salts of compound (I) include, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid A salt of a carboxylic acid such as malic acid, a salt of a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid, or a salt of an amino acid such as glutamic acid or aspartic acid. Salt.

The hydrate of the compound (I) and the hydrate of the salt of the compound (I) are also included in the compounds of the present invention.

The compound (I) of the present invention and a pharmaceutically acceptable salt thereof exhibit excellent antifungal activity. When the compound (I) and a pharmaceutically acceptable salt thereof are used as an antifungal agent, As such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., orally with tablets, capsules, granules, powders, syrups, etc., parenteral or with injections etc. It can be administered locally with an agent or the like.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxy Cellulose derivatives such as methylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; Salt derivatives; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (for example, the above-mentioned excipients). Gelatin; polyvinylpyrrolidone;
Disintegrants (eg, excipients described above; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinyl pyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, Talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; luxes such as veegum, gay wax; boric acid; glycol; fumaric acid; carboxylic acids such as adipic acid: sodium benzoate Sodium salts such as sodium carboxylate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; Starch derivatives etc.), stable (For example, paraoxybenzoic acid esters such as methyl parapent and propyl parapen; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol; phenols such as cresol; thimerosal; acetic anhydride; Sorbic acid, etc.), flavoring agents (e.g., commonly used sweeteners, sour agents, flavors, etc.), suspending agents (e.g., polysorbate 80, sodium carboxymethylcellulose, etc.), diluents, formulation solvents (e.g., , Water, ethanol, glycerin, etc.) by a known method. The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 5 mg) and the upper limit is 2000 mg per dose.
(Preferably 1000 mg), for intravenous administration,
The lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 6 per serving.
It is desirable to administer 00 mg (preferably 500 mg) to an adult 1 to 6 times a day depending on the symptoms.

[0041]

BEST MODE FOR CARRYING OUT THE INVENTION Among the compounds having the formula (I) of the present invention, the compound (1a) wherein n = 0 and A is a 1,3-dioxane ring is produced by the following method. Can be done.

[0042]

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(In the above formula, Ar ¹ , Ar ² , R ¹ , p and q have the same meanings as described above.)
This is a method for producing the target compound (1a) by reacting the aldehyde compound (3) with the compound (2) described in 3350 (Heisei 8.12.17).

The reaction between (2) and (3) is usually carried out under acidic conditions, and the acid used is, for example, hydrogen chloride, sulfuric acid, nitric acid, boron trifluoride, methanesulfonic acid, benzenesulfonic acid, p- It is toluenesulfonic acid, and the amount of the acid used is 1 to 2 molar equivalents relative to (2). Aldehyde (3) is used in 1 to 2 molar equivalents. As the solvent, methylene chloride, chloroform, 1,2-dichloroethane,
An aprotic solvent such as benzene, toluene, xylene, diethyl ether and tetrahydrofuran is used.
The reaction is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent, and the reaction time is 2 to 10 hours. Water generated by the reaction can be removed by azeotropic distillation, but molecular sieves may be used as a dehydrating agent. The reaction solution is neutralized with aqueous sodium bicarbonate or the like, and then treated in a conventional manner (extraction with an organic solvent and evaporation of the solvent to obtain an oily product, which is purified by chromatography or crystallization) to obtain the compound (1a).

Incidentally, among the aldehyde compounds (3) used in the above reaction, the compound (3a) where q = 0 and p = 1 and 2 generally starts from the aldehyde (4) by the following method ( Alternatively, it can be obtained as an intermediate) starting material through the unsaturated ester (5) (refer to Reference Examples 2, 3, 4, and 5 for the reaction conditions and isolation method in each step).
And 9, 10, 11, 12, 13, 14, 15).

[0046]

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(In the above formula, Ar ² has the same meaning as described above, and DIBAL-H represents diisobutylaluminum hydride.) In the unsaturated aldehyde (3), p = 0.
The acetylene compound (3b) wherein q = 1 can be generally obtained from the compound (6) via the alcohol (7) by the following method. That is, compound (6) was added to Tetrahedron Letters,
50 , 4467 (1975), by reacting propargyl alcohol to give an alcohol compound (7). Org. Che
m. , 48 , 4155 (1993), the aldehyde form (3b) is obtained by oxidation with Dess-Martin reagent. Further, among the unsaturated aldehydes (3), the acetylene compound (3c) in which p = 1 and q = 1 is obtained by converting the above-mentioned (3b) to (8) by the following method in the same manner as described above. (For the reaction conditions and isolation method in each step, refer to Reference Example 44 of JP-A-8-333350,
45, 46, 47 and 48).

[0048]

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(In the above formula, Ar ² has the same meaning as described above.) Among the compounds having formula (I) of the present invention, the compound (1b) wherein n = 0 is produced by the following method. Can also be manufactured.

[0050]

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(In the above formula, Ar ¹ and R ¹ have the same meanings as described above, and R ² is —A- (CH = CH) _p- (C≡C) _q -Ar ²
Represents ) That is, Japanese Patent Application Laid-Open No. Hei 2-191262 (Heisei 2.
Epoxide compound (9) described in 7.27)
Is reacted with mercaptan (10) or its acetic acid ester derivative (11) under basic conditions.
This is a method for producing b). As the solvent used for the reaction, alcohols such as methanol, ethanol, and propanol, and aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran are preferable, and an acetyl derivative (11) is used. When the reaction is carried out in the above aprotic solvent, coexistence of alcohols or water is required. The base used in the reaction is sodium hydride,
Sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, and potassium hydroxide, and the amount used is 0.1 to 2 molar equivalents relative to compound (9). It is. The mercaptan (10) or its acetate derivative (11) is used in an amount of 1 to 3 molar equivalents. The reaction temperature ranges from room temperature to 100 ° C., and the reaction time ranges from 2 to 10 hours. The reaction solution is treated according to a conventional method (an organic solvent is extracted, and an oil obtained by distilling off the solvent is purified by column chromatography or recrystallization) to obtain a compound (1b).

The R ² SH (10) used in the above reaction
Alternatively, R ² SAc (11) can be obtained, for example, by the following method. That is, the compound (10a) or (11a) wherein A in R ² is a 1,3-dioxane ring
Can be prepared using the known compound (12) described in JP-A-8-333350 as a starting material, according to the following process chart, and according to the method described in the same. See Reference Examples 5, 6, and 7 in the publication for the reaction conditions and isolation method in each step.

[0053]

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(In the above formula, Ar ² , p, and q have the same meanings as described above, and mCPBA represents m-chloroperbenzoic acid.) A in R ⁴ is a cyclohexane ring or a tetrahydropyran ring. Compounds (10b), (10c), (1
1b) and (11c) are aldehydes (13) described in Reference Example 40 of JP-A-8-333350.
b) Alternatively, the aldehyde (13c) described in Reference Example 21 of the present specification was used as a starting material in JP-A-8-333350.
In accordance with the method described in Japanese Patent Application Laid-Open Publication No. H10-209, each can be prepared according to the following process chart. The reaction conditions and isolation method in each step are described in Reference Examples 41, 42, and 43 of JP-A-8-333350, and Reference Examples 24 and 2 of the present specification.
See 5, 26.

[0055]

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(Where Y is CH ₂ or O, Ar is
² , p and q have the same meanings as described above. In addition, the phosphorane (14) in the above formula can be prepared according to the following process chart using the alcohol (15) as a starting material. That is, the alcohol (15) is converted to a normal method (for example,
Organic Reactions, 29, 1 (19
83)) with halide (16) (X = C
l, Br or I). Then
Conventional methods (for example, Organic Reactions,
14, 270 (1965)), toluene,
Treatment with triphenylphosphine in a solvent such as xylene, tetrahydrofuran or acetone gives the phosphonium salt (17) (X = Cl, Br or I) as a precipitate. Next, the phosphonium salt (17) is subjected to a conventional method (for example, Organic Reactions, 1).
4,270 (1965)) and treatment with a strong base such as sodium hydride or butyllithium in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dimethylsulfoxide.
Occurs. Phosphorane (14) is used for reaction with an aldehyde (eg, (13b) or (13c)) without isolation. See Reference Examples 22, 23 and 24 for the reaction conditions and isolation method in each step.

[0057]

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(In the above formula, X represents a chlorine atom, bromine atom or iodine atom, and Ar ² , p and q have the same meanings as described above.) The alcohol (15) in the above formula is necessary. Depending on the corresponding aldehyde or carboxylic acid ester (for example,
(3a), (3b), (3c), (4), (5) or (8)) can be prepared by reducing with a reducing agent such as diisobutylaluminum hydride by a conventional method. See Reference Example 4 for the reaction conditions and isolation method in each step.

The production of the compound (I) of the present invention wherein n = 1 or n = 2 can be carried out by the method described below. That is, the compound (I) of the present invention, wherein n = 0, obtained by the above-mentioned method, was prepared according to JP-A-8-3.
According to the method described in JP-A-33350, by oxidizing with an equivalent amount of an oxidizing agent in a solvent, n = 1
Can be produced, and the compound (I) wherein n = 2 can be produced by oxidizing with an oxidizing agent of 2 equivalents or more. The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but preferred examples include halogenated hydrocarbons such as dichloromethane and chloroform. Examples of the oxidizing agent used include peracetic acid and m-chloroperbenzoic acid. The reaction temperature is usually 30 minutes to 2 hours. The reaction solution is treated according to a conventional method (the crude product obtained by washing with an aqueous sodium hydrogen carbonate solution and distilling off the solvent is purified by chromatography or recrystallization) and the compound (I) (n
= 1 or 2).

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

[0061]

【Example】

Example 1 (2R, 3R) -3-[[trans-2- (6-bromo-2-naphthyl) -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1
H-1,2,4-triazol-1-yl) -2-butanol

[0062]

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(2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H-1,2,4-triazole- 1-yl) -2-butanol (Japanese Unexamined Patent Publication (Kokai) No. 2-1912)
62)) and 78 mg of 6-bromo-2-naphthaldehyde (0.
33 mmol) was dissolved in 1 ml of methylene chloride, 64 mg (0.33 mmol) of p-toluenesulfonic acid monohydrate and 1 g of molecular sieves 4A were added, and the mixture was stirred for 3 hours. After adding a sodium bicarbonate solution to the reaction solution and stirring for 10 minutes, the molecular sieves were removed by filtration, the organic layer was collected and dried, and the solvent was distilled off under reduced pressure. The obtained oil was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (3: 1) to give 124 mg (yield 77%) of the trans isomer as the title compound as colorless crystals. Obtained. Further, the compound was eluted with a mixed solution of ethyl acetate-hexane (5: 1) to obtain 16 mg (10% yield) of the cis isomer as a colorless powder. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.22 (3H, d,
J = 7.0Hz), 3.37 (1H, q, J = 7.0Hz), 3.45-3.60 (1H, m), 3.80 (1
H, t, J = 11.3Hz), 3.82 (1H, t, J = 11.3Hz), 4.44 (1H, ddd, J = 1
1.3,4.8,2.2Hz), 4.56 (1H, ddd, J = 11.3,4.8,2.2Hz), 4.85
(1H, d, J = 14.0Hz), 5.06 (1H, d, J = 14.0Hz), 5.62 (1H, s), 6.7
-6.8 (2H, m), 7.3-7.4 (1H, m), 7.53-7.65 (2H, m), 7.7-7.83
(4H, m), 7.94 (1H, s), 8.00 (1H, s) IR spectrum KBr cm ^-1 : 3446,3397,1615,1595,149
8,1137 Mass spectrum m / e: 575,547,497,422,352,265,224
(100%), 196,117. Example 2 (2R, 3R) -3-[[trans-2- [2-
[(E)-(6-Bromo-2-naphthyl) vinyl]-
1,3-dioxan-5-yl] thio] -2- (2,4
-Difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0064]

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In the same manner as in Example 1, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol and 3- (6-bromonaphthalene- described in Reference Example 5)
By reacting with 2-yl) propenal and treating, the title compound as a main product was obtained as colorless crystals in a yield of 44% in the NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.20 (3H, d,
J = 7.0Hz), 3.35 (1H, q, J = 7.0Hz), 3.4-3.5 (1H, m), 3.67 (1H,
t, J = 11.3Hz), 3.69 (1H, t, J = 11.3Hz), 4.35 (1H, ddd, J = 11.
3,4.7,2.0Hz), 4.46 (1H, ddd, J = 11.3,4.7,2.0Hz), 4.85 (1
H, d, J = 14.1Hz), 5.02 (1H, s), 5.05 (1H, d, J = 14.1Hz), 5.17
(1H, d, J = 4.3Hz), 6.30 (1H, dd, J = 16.1,4.3Hz), 6.7-6.8 (2
H, m), 6.94 (1H, d, J = 16.1Hz), 7.3-7.4 (1H, m), 7.5-7.8 (7H,
m), 7.96 (1H, s) IR spectrum KBr cm ^-1 : 3414,1617,1596,1499,1135 Mass spectrum m / e: 601 (M ⁺ ), 523,448,378,318,262,22
4 (100%), 196, 152, 141. Example 3 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[2- [trans-2-[(E) -6- (2,
2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl] -1,3-dioxan-5-yl] thio]
-1- (1H-1,2,4-triazol-1-yl)
-2-butanol

[0066]

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In the same manner as in Example 1, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol and 3- [6- (2,2,3,3) described in Reference Example 12
-Tetrafluoropropoxy) -naphthalen-2-yl] propenal,
The title compound, the main product, was obtained as colorless needle crystals in a yield of 4
NMR spectrum (270 MHz, CDCl ₃ ) δppm obtained at 5%: 1.20 (3H, d,
J = 7.0Hz), 3.35 (1H, q, J = 7.1Hz), 3.4-3.5 (1H, m), 3.67 (1H,
t, J = 11.3Hz), 3.69 (1H, t, J = 11.3Hz), 4.35 (1H, ddd, J = 11.
3,4.7,2.0Hz), 4.4-4.5 (1H, m), 4.47 (2H, brt, J = 11.4Hz),
4.84 (1H, d, J = 14.1Hz), 5.02 (1H, s), 5.05 (1H, d, J = 14.1H
z), 5.17 (1H, d, J = 4.5Hz), 6.11 (1H, tt, J = 53.0,4.8Hz), 6.2
7 (1H, dd, J = 16.2,4.8Hz), 6.7-6.8 (2H, m), 6.94 (1H, d, J = 1
6.2Hz), 7.1-7.2 (2H, m), 7.3-7.4 (1H, m), 7.6-7.9 (6H, m) IR spectrum KBr cm ^-1 : 3420,1617,1620,1500,127
4,1135 Mass spectrum m / e: 653,613,589,511,402,369,342,28
4 (100%), 252,224. Example 4 (2R, 3R) -3-[[trans-2- (3,5-dichloro-1-methyl-2-indolyl) -1,3-dioxan-5-yl] thio] -2- (2 , 4-Difluorophenyl) -1- (1H-1,2,4-triazole-
1-yl) -2-butanol

[0068]

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In the same manner as in Example 1, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-1-yl) -2-butanol was allowed to react with 3,5-dichloro-1-methyl-2-indolecarbaldehyde described in Reference Example 15, and the obtained crude product was purified. The residue was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 3) to give the title compound, the trans isomer (33% yield), as a colorless oil. Further, elution with a mixed solvent of ethyl acetate-hexane (9:11) yielded the cis isomer (yield 8%) as a colorless oily trans isomer: NMR spectrum (270 MHz, CDCl3) δ ppm: 1.25 (3
H, d, J = 7.3 Hz), 3.38 (1H, q, J = 7.3 Hz), 3.52 (1H,
tt, J = 11.4,4.7 Hz), 3.79 (1H, t, J = 11.4 Hz), 3.80
(1H, t, J = 11.4 Hz), 3.94 (3H, s), 4.42 (1H, ddd, J
= 11.4,4.7,2 Hz), 4.52 (1H, ddd, J = 11.4,4.7,2 Hz),
4.86 (1H, d, J = 14.1 Hz), 5.06 (1H, d, J = 14.1 Hz),
5.09 (1H, s), 5.94 (1H, s), 6.7-6.8 (2H, m), 7.24
(2H, s), 7.39 (1H, m), 7.58 (1H, s), 7.81 (2H, s) IR spectrum CHCl ₃ cm ^-1 : 3420, 2993, 1618, 149
9, 1676, 1408, 1277, 1138, 1074, 967, 855. NMR spectrum of cis isomer (270MHz, CDCl3) δpp
m: 1.25 (3H, d, J = 7.2 Hz), 3.23 (1H, br.s), 3.36
(1H, q, J = 7.2 Hz), 4.30 (1H, d, J = 12.1 Hz), 4.3-4.
6 (3H, m), 4.90 (1H, d, J = 14.2 Hz), 5.07 (1H, s),
5.16 (1H, d, J = 14.2 Hz), 6.03 (1H, s), 6.7-6.8 (2
H, m), 7.25 (2H, s), 7.39 (1H, m), 7.58 (1H, s),
7.80 (2H, s). Example 5 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[(3R ^* , 6S ^* )-6-[(E) -2-
[6- (2,2,3,3-tetrafluoropropoxy)
-2-naphthyl] vinyl] -3,4,5,6-tetrahydro-2H-pyran-3-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0070]

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Trans-5-acetylthio-2-[(E) -2- [6- (2,2,3,3-
Tetrafluoropropoxy) -2-naphthyl] vinyl]
-3,4,5,6-tetrahydro-2H-pyran (32
0 mg, 0.72 mmol) in N, N-dimethylformamide (7 ml) was stirred under ice-cooling, and a methanol solution of sodium methoxide (4.8 N, 0.02 mmol) was added.
76 ml, 0.36 mmol) was added. The mixture was stirred under ice cooling for 0.5 hour and then at room temperature for 0.5 hour. (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-[(1H-1,2,4-triazole) described in JP-A-2-191262 (2.7.27) -1-yl) methyl] oxirane (258 m
g, 1.03 mmol) at room temperature, and the mixture was stirred at 50 ° C. for 30 minutes. After cooling, the mixture was partitioned between ethyl acetate and water, the organic layer was dried, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 30 g of silica gel, and ethyl acetate-hexane (2: 1).
Elution with a mixed solvent gave 239 mg of the title compound (yield 51
%) Was obtained as a pale yellow amorphous solid.

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 1.13 and 1.18 (ca 1: 1, 3H intotal, each d, eac
h J = 7 Hz), 1.1-1.3 (1H, m), 1.5-1.8 (2H, m), 1.9-
2.0 (1H, m), 2.2-2.4 (1H, m), 2.9-3.1 (1H, m), 3.35
(1H, q, J = 7 Hz), 3.45 (1H, t, J = 11 Hz), 4.0-4.1
(1H, m), 4.29 (1H, ddd, J = 11, 4, 2 Hz), 4.45 (2H,
br t, J = 12 Hz), 4.80 (1H, br s), 4.81 and 4.86 (ca
1: 1, 1H in total, each d, each J = 14 Hz), 5.09 (1H,
d, J = 14 Hz), 6.12 (1H, t, J = 53, 5 Hz), 6.29 (1H,
dd, J = 16, 6 Hz), 6.65-6.80 (3H, m), 7.1-7.2 (2H,
m), 7.38 (1H, td, J = 9, 7 Hz), 7.59 (1H, d), 7.65-
7.85 (5H, m) IR spectrum KBr cm ^-1 : 3410, 1618, 1603, 1501,
1273, 1183, 1123, 966, 854.

Reference Example 1 6-bromonaphthalene-2-methanol

[0074]

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537 mg of lithium aluminum hydride (1
In a mixture of 4.1 mmol) and tetrahydrofuran, a solution of 2.50 g (9.4 mmol) of 6-bromonaphthalene-2-carboxylic acid methyl ester dissolved in tetrahydrofuran was added dropwise at 5-10 ° C in a nitrogen stream over 5 minutes. . Subsequently, after stirring at the same temperature for 1 hour, the mixture was treated with water and dilute alkali. The insoluble matter was removed by filtration through Celite. The filtrate was evaporated under reduced pressure,
2.0 g (yield 90%) of powder was obtained. This was subjected to the next reaction without purification.

Reference Example 2 6-bromo-2-naphthaldehyde

[0077]

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1.0 g (4.2 mmol) of 6-bromonaphthalene-2-methanol, 1.83 of active manganese dioxide
g (21 mmol) and 50 ml of chloroform at 30 ° C.
For 5 hours. After 4 hours, active manganese dioxide was added in half as above. After the completion of the reaction, insolubles were removed by filtration using celite and washed with methylene chloride. The filtrate and the washing were combined and concentrated under reduced pressure to obtain 900 mg (91%) of a pale yellow powder. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 7.67 (1H, d)
d, J = 9.0,2.0Hz), 7.83-7.89 (2H, m), 7.98 (1H, dd, J = 9.0,1.
5Hz), 8.08 (1H, d, J = 2Hz), 8.32 (1H, s), 10.15 (1H, s) Mass spectrum m / e: 236,234 (M ⁺ ), 207,205,189,155,12
6 (100%). Reference Example 3 3- (6-bromo-2-naphthyl) acrylic acid methyl ester

[0079]

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6-bromo-2-naphthaldehyde 600
mg (2.55 mmol) and 1.02 g (3.06 mmol) of triphenylphosphoranylideneacetic acid methyl ester were dissolved in 10 ml of tetrahydrofuran, stirred at room temperature for 3 hours, and the oily residue obtained by evaporating the solvent was removed. It was subjected to column chromatography using silica gel. Eluted with benzene, 720 mg (yield 97%) of the title compound was obtained as colorless crystals. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.84 (3H,
s), 6.55 (1H, d, J = 16Hz), 7.57 (1H, dd, J = 9.2Hz), 7.67-7.78
(3H, m), 7.83 (1H, d, J = 16Hz), 7.89 (1H, s), 8.00 (1H, d, J = 2H
z) Mass spectrum m / e: 292,290 (M ⁺ , 100%), 261,259,232,1
80,152,126,76.

Reference Example 4 3- (6-bromonaphthalen-2-yl) prop-2-
En-1-ol

[0082]

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720 mg (2.47 mmol) of 3- (6-bromo-2-naphthyl) acrylic acid methyl ester was dissolved in 7 ml of toluene, and stirred at 0 ° C. while stirring at 3.3 ° C. in 3.3 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene.
(4.95 mmol) was added. After 30 minutes, ice and water were added and the mixture was stirred for 10 minutes, and insoluble materials were removed by filtration using a small amount of Celite. Extraction with ethyl acetate, drying and evaporation of the solvent gave 630 mg (97% yield) of the title compound as a colorless crystalline NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 4.18 (2H,
m), 4.95 (1H, t, J = 5.5Hz), 6.57 (1H, dt, J = 15.8,5.0Hz), 6.7
2 (1H, d, J = 15.8Hz), 7.61 (1H, dd, J = 9.0,2.0Hz), 7.75 (1H,
d, J = 9.0Hz), 7.80-7.90 (3H, m), 8.16 (1H, bs) Mass spectrum m / e: 264,262 (100%) (M ⁺ ), 246,222,221,
220,219,208,206,181,165,154,152,141,126.

Reference Example 5 3- (6-bromonaphthalen-2-yl) propenal

[0085]

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In the same manner as in Reference Example 2, 630 mg (2.40 mmol) of 3- (6-bromonaphthalen-2-yl) prop-2-en-1-ol was added to 1.0 g of activated manganese dioxide.
Oxidized with 4 g (12.0 mmol), 529 mg of the title compound
(Yield 85%) as a colorless crude crystal NMR spectrum (270 MHz, CMSO _d6 ) δ ppm: 7.02 (1H,
dd, J = 15.8,7.9Hz), 7.72 (1H, dd, J = 9.3,2Hz), 7.89 (1H, d, J
= 15.8Hz), 7.98 (3H, bs), 8.26-8.33 (2H, m), 9.75 (1H, d, J =
7.9Hz) Mass spectrum m / e: 262,260 (M ⁺ ), 234,232,181,152 (10
0%), 126, 76.

Reference Example 6 Toluene-4-sulfonic acid (2,2,3,3-tetrafluoropropyl) ester

[0088]

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To a mixture of 16.12 g (122 mmol) of 2,2,3,3-tetrafluoropropanol and 23 ml of pyridine were added 27.93 g (146.5 mmol) of toluene-4-sulfonyl chloride at room temperature under a nitrogen stream at room temperature. Stirred for minutes. The reaction solution was poured into ice water and extracted with chloroform. The solvent was distilled off, and the obtained oil was subjected to column chromatography using silica gel. Elution with a mixed solvent of ethyl acetate-hexane (1:10) gave the title compound 3
NMR spectrum (270 MHz, CDCl ₃ ) δ ppm of 4.4 g (yield 98.5%) as an oily substance: 2.48 (3H,
s), 4.34 (2H, brt, J = 11.6Hz), 5.86 (1H, tt, J = 53.0,4.2H
z), 7.40 (2H, d, J = 8.2 Hz), 7.81 (2H, d, J = 8.2 Hz) IR spectrum KBr cm ^-1 : 1308,1284,1129 Mass spectrum m / e: 286,267,237,185,155 (100%), 91.

Reference Example 7 6- (2,2,3,3-tetrafluoropropoxy) naphthalene-2-carboxylic acid methyl ester

[0091]

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39.6 mg of 60% sodium hydride (0.
99 mmol) with hexane and dimethylacetamide 2
and 6-hydroxynaphthalene-2-carboxylic acid methyl ester 200 mg (0.9 mg) at 0 ° C. under a nitrogen stream.
9 mmol) was added slowly. When the generation of hydrogen gas ceased, a solution of 311 mg (1.09 mmol) of toluene-4-sulfonic acid (2,2,3,3-tetrafluoropropyl) ester dissolved in 1 ml of dimethylacetamide was added dropwise at the same temperature. After the dropwise addition, the mixture was stirred at 100 ° C. for 2.5 hours, poured into ice water, and extracted with ethyl acetate. After drying, the solvent is distilled off,
The resulting oil was subjected to column chromatography using silica gel. The mixture was eluted with a mixed solvent of ethyl acetate-hexane (1: 9) to give the title compound (302 mg, yield 96.4).
%) As colorless crystals (270 MHz, CDCl ₃ ) δ ppm: 3.95 (3H,
s), 4.46 (2H, brt, J = 11.9Hz), 6.14 (1H, tt, J = 53.0,4.8H
z), 7.10 (1H, d, J = 2.4 Hz), 7.17 (1H, br d, J = 8.8 Hz), 7.69 (1
H, d, J = 8.8Hz), 7.80 (1H, d, J = 8.8Hz), 8.02 (1H, br d, J = 8.8
HZ), 8.49 (1H, s). Reference Example 8 6- (2,2,3,3-tetrafluoropropoxy)-
Naphthalene-2-methanol

[0093]

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In the same manner as in Reference Example 1, 6- (2,2,2
3,3-tetrafluoropropoxy) naphthalene-2-
The carboxylic acid methyl ester was reduced with lithium aluminum hydride to give the title compound as colorless needle crystals in 100% yield.
I got it.

Reference Example 9 6- (2,2,3,3-tetrafluoropropoxy)-
2-naphthaldehyde

[0096]

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In the same manner as in Reference Example 2, 6- (2,2,
3,3-tetrafluoropropoxy) naphthalene-2-
Methanol was oxidized with activated manganese dioxide to give the title compound as colorless crystals in 100% yield. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 4.52 (2H, br
t, J = 11.8Hz), 6.12 (1H, tt, J = 53,4.7Hz), 7.22 (1H, d, J = 2.
5Hz), 7.28 (1H, br d, J = 8.8Hz), 7.84 (1H, d, J = 8.4Hz), 7.96
(2H, d, J = 8.6Hz), 8.29 (1H, s). Reference Example 10 3- [6-2,2,3,3-tetrafluoropropoxy) -naphthalen-2-yl] acrylic acid methyl ester

[0098]

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In the same manner as in Reference Example 3, 6- (2,2,2
Colorless crystals of the title compound were obtained from (3,3-tetrafluoropropoxy) -2-naphthaldehyde and triphenylphosphoranylideneacetic acid methyl ester in 100% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm
： 3.83 (3H, s), 4.49 (2H, brt, J = 11.9Hz), 6.11 (1H, tt, J =
53,4.7Hz), 6.52 (1H, d, J = 15.9Hz), 7.16 (1H, s), 7.21 (1H, b
rd, J = 8.5Hz), 7.67 (1H, d, J = 8.6Hz), 7.75 (1H, d, J = 8.6H
z), 7.81 (1H, d, J = 8.5Hz), 7.83 (1H, d, J = 15.9Hz), 7.88 (1H,
s) IR spectrum KBr cm ^-1 : 3024,1711,1762,1181,1130 Mass spectrum m / e: 342 (100%), 311,283,199,168,139,
105,90.

Reference Example 11 3- [6- (2,2,3,3-tetrafluoropropoxy) naphthalen-2-yl] prop-2-en-1-ol

[0102]

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In the same manner as in Reference Example 4, 3- [6- (2,
2,3,3-tetrafluoropropoxy) naphthalene-
2-yl] acrylic acid methyl ester was reduced with diisobutylaluminum hydride to give the title compound as colorless crystals in a yield of 91.8%.

Reference Example 12 3- [6- (2,2,3,3-tetrafluoropropoxy) naphthalen-2-yl] propenal

[0105]

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In the same manner as in Reference Example 5, 3- [6- (2,
2,3,3-tetrafluoropropoxy) naphthalene-
2-yl] prop-2-en-1-ol was oxidized with activated manganese dioxide to give the title compound as colorless crystals, yield 8%.
NMR spectrum obtained at 2.3% (270 MHz, CDCl ₃ ) δ ppm: 4.50 (2H, br
t, J = 11.8Hz), 6.12 (1H, tt, J = 53,4.7Hz), 6.81 (1H, dd, J = 1
5.9,7.6Hz), 7.18 (1H, d, J = 2.3Hz), 7.24 (1H, br d, J = 8.9H
z), 7.62 (1H, d, J = 15.9Hz), 7.69 (1H, br d, J = 8.6Hz), 7.79
(1H, d, J = 8.6Hz), 7.85 (1H, d, J = 8.9Hz), 7.95 (1H, s), 9.75
(1H, d, J = 7.6Hz) IR spectrum KBr cm ^-1 : 1673,1617,1505,1249 Mass spectrum m / e: 312 (100%), 284,258,197,181,169,
153,141,115,105. Reference Example 13 5-chloro-1-methylindole-2-carboxylic acid methyl ester

[0107]

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To a suspension of sodium hydride (55%, mineral oil dispersion, 113 mg, 2.6 mmol; washed with hexane) in N, N-dimethylformamide (7.5 ml), commercially available 5-chloroform was added under ice-cooling. Indole-2-carboxylic acid (508 mg, 2.60 mmol) was added and stirred. After the generation of hydrogen gas was stopped, methyl iodide (400 mg, 2.8 mmol) was added, and the mixture was stirred under ice cooling for 30 minutes. Add sodium hydride (55%, mineral oil dispersion, 113 mg, 2.6 mmol) and methyl iodide (450 mg, 3.2 mmol) and add
Stirred for hours. Benzene and water were added to the reaction solution, and the organic layer was washed with brine. The solvent was removed under reduced pressure, and the residue was recrystallized from a mixed solvent of benzene and hexane.
240 mg of the title compound having the formula was obtained as colorless crystals.
Further, the mother liquor was subjected to column chromatography using 7 g of silica gel and eluted with benzene to give the title compound 8
NMR spectrum (60 MHz, CDCl ₃ ) δ ppm obtained 0 mg (total yield 55%): 3.89 (3H, s),
4.04 (3H, s), 7.2-7.5 (3H, m), 7.63 (1H, d, J = 2Hz). Reference Example 14 (5-chloro-1-methyl-2-indolyl) methanol

[0109]

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5-chloro-1-methylindole-2-
Carboxylic acid methyl ester (320 mg, 1.44 mm
ol) in toluene (5 ml) under ice-cooling at 1.0 M
-Diisobutylaluminum hydride toluene solution (3
ml, 3 mmol). After 30 minutes, water and dilute hydrochloric acid were added, the mixture was filtered, and the precipitate was washed with benzene. The organic layer was separated from the filtrate and the washing solution, and washed with brine. The solvent was removed under reduced pressure, and the residue was recrystallized from a mixed solvent of benzene and hexane to obtain 128 mg of the title compound having a melting point of 100 to 101 ° C as colorless crystals. Further, the mother liquor was subjected to column chromatography using 7 g of silica gel,
Elution with a mixed solvent of ethyl acetate-benzene (1: 9)
106 mg (84% total yield) of the title compound were obtained.

NMR spectrum (60 MHz, CDCl ₃ ) δ ppm:
3.80 (3H, s), 4.80 (2H, br d, J = 5Hz), 6.40 (1H, s), 7.1-7.4
(3H, m), 7.55 (1H, t, J = 2Hz). Reference Example 15 3,5-dichloro-1-methyl-2-indolecarbaldehyde

[0112]

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Dimethyl sulfoxide (184 mg, 2.
4 mmol) in dichloromethane (5 ml) was added with -7.
Oxalyl chloride (300 mg, 2.4 mmol
l) was added. Further, at -78 ° C, (5-chloro-1-
Methyl-2-indolyl) methanol (230 mg,
1.2 mmol) in dichloromethane (1.5 ml) was added. After 5 minutes, triethylamine (480 mg,
4.7 mmol) was added. Water, chloroform and ethyl acetate were added, and the mixture was stirred at room temperature. Insolubles were removed by filtration, and the organic layer was separated and washed with saline. The solvent was removed under reduced pressure, and the obtained crude product was subjected to column chromatography using silica gel, and eluted with benzene. The obtained crystalline crude product was recrystallized from a benzene-hexane mixed solvent to give the title compound (40 mg, yield 15%) having a melting point of 150-151 ° C as colorless crystals, and an NMR spectrum (270 MHz, CDCl ₃ ) δppm: 4.06 (3
H, s), 7.31 (1H, d, J = 8.6Hz), 7.40 (1H, dd, J = 8.6,
2.0Hz), 7.72 (1H, d, J = 2.0Hz), 10.17 (1H, s) Mass spectrum m / e: 231, 230, 229, 228, 227 (M +, 1
00%), 226, 200, 198,157. Reference Example 16 1- (tert-butyldimethylsilyloxy) -5-
Hexen-2-ol

[0114]

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5-hexene-1,2-diol (Bei
lstein registration number 173
8994, CAS number 36842-44-
1,10 g, 86 mmol) and triethylamine (8.
7 g, 86 mmol) was dissolved in N, N-dimethylformamide (100 ml), and while stirring under ice cooling, t was added.
tert-butylchlorodimethylsilane (13.0 g, 8
6 mmol) was added. After stirring the mixture for 10 minutes,
Partitioned between ethyl acetate and water. After drying the organic layer, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 200 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (1:10) to give the title compound (17.7).
g (89% yield) as a colorless oil.

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 0.07 (6H, s), 0.91 (9H, s), 1.4-1.6 (2H, m), 2.
0-2.3 (2H, m), 2.43 (1H, J = 4 Hz), 3.40 (1H, dd, J =
8,6Hz), 3.6-3.8 (2H, m), 4.97 (1H, dd, J = 10, 2 H
z), 5.06 (1H, dd, J = 16, 2Hz), 5.84 (1H, ddt, J = 16,
10, 7 Hz).

Reference Example 17 1- (tert-Butyldimethylsilyloxy) -5
Hexen-2-yl p-toluenesulfonate

[0118]

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1- (tert-butyldimethylsilyloxy) -5-hexen-2-ol (5.00 g, 22
mmol) in pyridine (7.2 ml) while stirring at room temperature while stirring p-toluenesulfonyl chloride (5.4).
g, 28 mmol) and the mixture was stirred at room temperature for 3.5 hours. p-Toluenesulfonyl chloride (1.0
g, 5.2 mmol) and 4- (N, N-dimethylamino) pyridine (530 mg, 4.34 mmol).
Was added and the mixture was further stirred at room temperature for 0.5 hour.
The mixture was partitioned between water and chloroform, and after drying the organic layer,
The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 150 g of silica gel to give ethyl acetate-
Elution with a mixed solvent of hexane (1:20) gave 7.62 g (yield 91%) of the title compound as a colorless oil.

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 0.07 (6H, s), 0.85 (9H, s), 1.6-1.9 (2H, m), 1.
9-2.1 (2H, m), 2.44 (3H, s), 3.5-3.7 (2H, m), 4.50
(1H, quint, J = 7 Hz), 4.95 (1H, d, J = 16 Hz), 4.95
(1H, d, J = 10 Hz), 5.70 (1H, ddt, J = 16, 10, 7 Hz),
7.33 (2H, d, J = 8 Hz), 7.81 (2H, d, J = 8 Hz).

Reference Example 18 2- (p-toluenesulfonyloxy) -5-hexen-1-ol

[0122]

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While stirring 1- (tert-butyldimethylsilyloxy) -5-hexen-2-yl p-toluenesulfonate (7.6 g, 20.0 mmol) at room temperature, tetrafluoroammonium was added. Fluoride solution in tetrahydrofuran (1.0 N, 98.3 ml, 9
8.3 mmol) and acetic acid (10.8 g, 197 mmol)
The mixture of l) was added dropwise. After the mixture was stirred at room temperature for 30 minutes, tetrahydrofuran was mostly distilled off under reduced pressure. The mixture was partitioned between ethyl acetate and an aqueous sodium hydrogen carbonate solution, and the organic layer was dried, and then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 85 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 3) to give the title compound (4.83 g, yield 91%) as a colorless oil. .

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 1.6-1.8 (2H, m), 1.9-2.1 (2H, m), 2.1 (1H, b
r), 2.45 (3H, s), 3.69 (1H, dd, J = 13, 6 Hz), 3,73
(1H, dd, J = 13, 3 Hz), 4.63 (1H, qd, J = 7, 3 Hz), 4.
94 (1H, d, J = 16 Hz), 4.95 (1H, J = 11 Hz), 5.66 (1H,
ddt, J = 16, 11, 7 Hz), 7.36 (2H, d, J = 8 Hz), 7,82
(2H, d, J = 8 Hz).

Reference Example 19 [cis and trans-5- (p-toluenesulfonyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl] methanol

[0126]

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2- (p-toluenesulfonyloxy)-
5-hexen-1-ol (4.82 g, 17.8 mm
ol) in dichloromethane (193 ml) was stirred under ice-cooling, and m-chloroperbenzoic acid (purity 67%, 4.
(6 g, 17.9 mmol). The mixture was left at 0 ° C. for 112 hours. Trifluoroacetic acid (0.94m
l) was added and the mixture was left for 24 hours. Further trifluoroacetic acid (0.94 ml) was added and the mixture was
Left for 4 hours. The crude product extracted by a conventional method was subjected to column chromatography using 500 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to give the trans isomer of the less polar title compound. 1
7 g (43% yield) were obtained as a colorless oil. The mixture was further eluted with a mixed solvent having the same ratio to obtain 2.13 g (yield: 42%) of the more polar cis isomer as a colorless oil.

The NMR spectrum of the trans isomer (270
MHz, CDCl ₃ ) δppm: 1.3-1.5 (1H, m), 1.5-1.8 (2H,
m), 2.0-2.2 (1H, m), 2.2 (1H, br), 2.45 (3H, s),
3.27 (1H, t, J = 11 Hz), 3.3-3.4 (1H, m), 3.46 (1H, d
dd, J = 11, 6, 4 Hz), 3.56 (1H, ddd, J = 11, 7, 3 Hz),
3.94 (1H, ddd, J = 11, 5, 2 Hz), 4.39 (1H, tt, J = 1
2, 6 Hz), 7.35 (2H, d, J = 8 Hz), 7.80 (2H, d, J = 8 H
z).

The NMR spectrum of the cis isomer (270 MHz,
CDCl ₃ ) δppm: 1.3-1.5 (1H, m), 1.6-1.8 (2H, m),
2.0-2.1 (1H, m), 2.45 (3H, s), 2.7 (1H, br), 3.3-3.
7 (3H, m), 3.99 (1H, d-like, J = ca 11 Hz), 4.57 (1
H, br s), 7.34 (2H, d, J = 8Hz), 7.80 (2H, d, J = 8H
z).

Reference Example 20 [trans-5- (p-chlorobenzylthio) -3,
4,5,6-tetrahydro-2H-pyran-2-yl]
Methanol and its cis isomer

[0131]

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To a suspension of sodium hydride (60%, mineral oil dispersion, 182 mg, 4.55 mmol; washed with hexane) in N, N-dimethylformamide (8 ml) was added 4-chloro-α-toluene under ice-cooling. Thiol (8
11 mg, 5.11 mmol) and stirred. After the evolution of hydrogen gas subsided, [cis-5- (p-toluenesulfonyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-yl] methanol (1.70 g,
4.26 mmol) was added. The mixture was stirred at room temperature for 24 hours and at 50 ° C. for 1 hour. Further, an N, N-dimethylformamide (8 ml) solution of sodium 4-chloro-α-toluenethiolate (4.55 mmol) prepared in the same manner as described above was added, and the mixture was added at room temperature for 1 hour.
Stir for 5 hours. The crude product extracted by a conventional method was subjected to column chromatography using 50 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to give 299 mg of the trans isomer of the title compound (yield 26).
%) As a colorless oil.

The NMR spectrum of the trans isomer (270
MHz, CDCl ₃ ) δppm: 1.3-2.7 (6H, m), 3.25 (1H, t, J
= 11 Hz), 3.3-3.8 (3H, m), 3.70 (2H, s), 3.99 (1H,
ddd, J = 11, 5, 2 Hz), 7.25 (2H, d, J = 8 Hz), 7.28 (2
H, d, J = 8 Hz).

Similarly, [trans-5- (p-toluenesulfonyloxy) -3,4,5,6-tetrahydro-
2H-pyran-2-yl] methanol (4.07 g, 1
(4.2 mmol) as a starting material to give 2.17 g (56% yield) of the cis isomer of the title compound as a colorless oil.

The NMR spectrum of the cis isomer (270 MHz,
CDCl ₃ ) δppm: 1.3-1.5 (1H, m), 1.7-2.0 (3H, m),
2.23 (1H, dd, J = 7, 5 Hz), 2.75 (1H, br s), 3.4-3.6
(1H, m), 3.5-3.7 (2H, m), 3.70 (2H, s), 3.73 (1H,
dd, J = 12, 2 Hz), 3.92 (1H, d, J = 12 Hz), 7.27 (4H,
s).

Reference Example 21 [trans-5- (p-chlorobenzylthio) -3,
4,5,6-tetrahydro-2H-pyran-2-yl]
Acetaldehyde and its cis isomer

[0137]

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Oxalyl chloride (277 mg, 2.17 m
mol) in dichloromethane (8.9 ml).
Dimethylsulfoxide (227 m
g, 2.89 mmol) in dichloromethane (7.3 m
l) The solution was added. After the mixture was stirred at -70 ° C for 10 minutes, [trans-5- (p-chlorobenzylthio)
-3,4,5,6-tetrahydro-2H-pyran-2-
[Il] methanol (297 mg, 1.09 mmol) in dichloromethane (2.1 ml) was added. After the mixture was stirred at -45 ° C for 1 hour, triethylamine (7
34 mg, 7.26 mmol) was added. Mixture at 0 ° C
After stirring for 20 minutes at, the mixture was partitioned between ethyl acetate and water. After drying the organic layer, the solvent was distilled off, and the residue was subjected to column chromatography using 8 g of silica gel,
Elution with a mixed solvent of ethyl acetate-hexane (1: 2)
254 mg of the trans isomer of the title compound (86% yield)
Was obtained as a pale yellow oil.

The NMR spectrum of the trans isomer (270
MHz, CDCl ₃ ) δppm: 1.3-2.2 (5H, m), 2.5-2.8 (1H,
m), 3.2-3.4 (1H, m), 3.6-3.8 (2H, m), 3.9-4.1 (1H,
m), 7.26 (4H, m), 9.57 (1H, s). Similarly, [cis-5- (p-chlorobenzylthio)-
[3,4,5,6-tetrahydro-2H-pyran-2-yl] methanol (9.82 g, 36.0 mmol) as a starting material to give the cis isomer 5.75 of the title compound.
g (59% yield) as a colorless oil.

The NMR spectrum of the cis isomer (270 MHz,
CDCl ₃ ) δ ppm: 1.4-2.2 (5H, m),
2.71 (1H, m), 3.70 (2H,
s), 3.7-4.0 (2H, m), 7.27
(4H, s), 9.71 (1H, s).

Reference Example 22 2- (chloromethyl) -6- (2,2,3,3-tetrafluoropropoxy) naphthalene

[0142]

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The 6- (2,2,3,3-
Tetrafluoropropoxy) -naphthalene-2-methanol (5.20 g, 12.85 mmol), carbon tetrachloride (7.91 g, 51.4 mmol) and triphenylphosphine (5.06 g, 19.3 mmol) in dichloromethane (50 ml) And the mixture is heated at 65 ° C. for 2.7
Stirred for hours. The mixture is concentrated and the residue is separated on silica gel 3
The residue was subjected to column chromatography using 00 g, and eluted with a mixed solvent of ethyl acetate-hexane (1: 9) to obtain 3.27 g (yield: 83%) of the title compound.

NMR spectrum (270 MHz, CDCl ₃ )
δppm: 4.47 (2H, tt, J = 12, 2 Hz), 4.75 (2H, s),
6.12 (1H, tt, J = 53, 5 Hz), 7.16 (1H, d, J = 2 Hz),
7.20 (1H, dd, J = 9, 3 Hz), 7.7-7.8 (3H, m). Reference Example 23 Triphenyl chloride [[6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] ] Methyl] phosphonium

[0145]

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2- (chloromethyl) -6- (2,2,
3,3-tetrafluoropropoxy) naphthalene (3.
27 g, 10.7 mmol) and triphenylphosphine (2.8 g, 10.7 mmol) in xylene (33 m
1) and the mixture was stirred at 160 ° C. for 6.3 hours. After cooling the mixture, the title compound was collected by filtration as a precipitate, washed with ethyl acetate and dried in vacuo. Yield 3.97 g (65% yield).

Reference Example 24 trans-5- (p-chlorobenzylthio) -2-
[(E) -2- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl] -3,4
5,6-tetrahydro-2H-pyran

[0148]

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Triphenyl chloride [[6- (2,2,3,
A mixture of 3-tetrafluoropropoxy) -2-naphthyl] methyl] phosphonium (2.9 g, 5.10 mmol) and tetrahydrofuran (29 ml) was stirred at -70 ° C while a hexane solution of butyllithium (1. 6
N, 3.19 ml, 5.10 mmol) was added dropwise. After the mixture was stirred at -70 ° C for 1 hour, [trans-5- (p-chlorobenzylthio)-] described in Reference Example 21 was used.
3,4,5,6-tetrahydro-2H-pyran-2-yl] acetaldehyde (1.66 g, 6.12 mmol
l) Tetrahydrofuran solution was added. Mixture at -7
After stirring at 0 ° C. for 1 hour, the mixture was stirred at room temperature for 1 hour.
An aqueous ammonium chloride solution and ethyl acetate were added to the mixture,
The organic layer was separated. After concentration, the residue was purified on silica gel 30.
g, and eluted with a mixed solvent of ethyl acetate-hexane (1: 9) to give trans-5- (p-chlorobenzylthio) -2- [ (Z) -2- [6- (2,2,3
0.9 g (34% crude yield) of a crude product mainly comprising 3-tetrafluoropropoxy) -2-naphthyl] vinyl] -3,4,5,6-tetrahydro-2H-pyran as a pale yellow oil Obtained.

The oily crude product (0.9 g) thus obtained was combined with diphenyl disulfide (17.3 mg, 0.079 m
mol) was dissolved in benzene (20 ml) and irradiated with light from a tungsten lamp for 7.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 50 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (1: 9) to give the title compound 0 as the (E) -isomer. 0.7 g (26% overall yield) was obtained as a pale yellow solid.

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 1.5-1.7 (2H, m), 1.8-2.0 (1H, m), 2.1-2.2 (1H,
m), 2.75 (1H, m), 3.40 (1H, t, J = 11 Hz), 3.77 (2
H, s), 3.9-4.1 (1H, m), 4.11 (1H, ddd, J = 11, 4, 2
Hz), 4.50 (2H, br t, J = 12 Hz), 6.15 (1H, tt, J = 53,
5 Hz), 6.28 (1H, dd, J = 16, 6 Hz), 6.76 (1H, d, J =
16 Hz), 7.1-7.2 (2H, m), 7.3-7.4 (4H, m), 7,71 (1
H, d, J = 9 Hz), 7.7-7.8 (3H, m) IR spectrum KBr cm ^-1 : 2943, 2848, 1799, 1628,
1602, 1491, 1273, 1244, 1134, 1095, 1066, 967, 83
6.

Reference Example 25 trans-5- (p-chlorobenzylsulfinyl)-
2-[(E) -2- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl] -3,
4,5,6-tetrahydro-2H-pyran

[0153]

Embedded image

Trans-5- (p-chlorobenzylthio) -2-[(E) -2- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl]-
3,4,5,6-tetrahydro-2H-pyran (0.9
5 g, 1.81 mmol) of dichloromethane (10 m
l) While stirring the solution under ice cooling, m-chloroperbenzoic acid (purity 67%, 443 mg, 1.72 mmol) was added. After stirring the mixture at 0 ° C. for 1 hour, the mixture was extracted by a conventional method. The crude product was subjected to column chromatography using 70 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to give the title compound 0.6
2 g (63% yield) were obtained as a pale yellow solid.

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 1.5-1.8 (1H, m), 1.9-2.2 (2H, m), 2.2-2.3 (1H,
m), 2.7-2.9 (1H, m), 3.76 and 3.88 (ca 1: 1, 1H in
total, each t, each J = 11 Hz), 3.9-4.1 (3H, m), 4.
16 (1H, ddd, J = 11, 4, 2 Hz), 4.49 (2H, brt, J = 12
Hz), 6.14 (1H, tt, J = 53, 5 Hz), 6.28 (1H, dd, J = 1
6, 6 Hz), 6.73 (1H, d, J = 16 Hz), 7.1-7.2 (2H, m),
7.25-7.35 (1H, m), 7.35-7.40 (2H, m), 7.60 (1H, d,
J = 8 Hz), 7.65-7.80 (2H, m), 8.00 (1H, d, J = 7 Hz),
8.11 (1H, br s).

IR spectrum KBr cm ^-1 : 2941, 1699,
1629, 1601, 1493, 1483, 1265, 1102, 837.

Reference Example 26 trans-5-acetylthio-2-[(E) -2- [6
-(2,2,3,3-tetrafluoropropoxy) -2
-Naphthyl] vinyl] -3,4,5,6-tetrahydro-2H-pyran

[0158]

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Trans-5- (p-chlorobenzylsulfinyl) -2-[(E) -2- [6- (2,2,3
3-tetrafluoropropoxy) -2-naphthyl] vinyl] -3,4,5,6-tetrahydro-2H-pyran (0.62 g, 1.15 mmol) and 2,6-lutidine (0.614 g, 5.73 mmol) ) Was dissolved in tetrahydrofuran (60 ml) and trifluoroacetic anhydride (0.722 g, 3.44 mmol) was added thereto while stirring. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the mixture, the organic layer was separated and concentrated, and 6-[(E) -2-
[6- (2,2,3,3-tetrafluoropropoxy)
-2-Naphthyl] vinyl] -3,4,5,6-tetrahydro-2H-pyran-3-thiol as a yellow solid. This is taken in dichloromethane (15 ml)
Triethylamine (0.116 g, 1.15 mmol)
And acetyl chloride (90 mg, 1.15 mmol). The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, the organic layer was concentrated and the residue
The residue was subjected to column chromatography using 0 g, and eluted with a mixed solvent of ethyl acetate-hexane (1: 8) to obtain 0.322 g (yield 63%) of the title compound as a pale yellow solid.

NMR spectrum (270 MHz, CDCl ₃ ) δpp
m: 1.6-1.8 (2H, m), 1.8-2.0 (1H, m), 2.1-2.2 (1H,
m), 2.34 (3H, s), 3.39 (1H, t, J = 11 Hz), 3.55-3.70
(1H, m), 3.95-4.05 (1H, m), 4.11 (1H, ddd, J = 11,
4, 2 Hz), 4.46 (2H, br t, J = 12 Hz), 6.11 (1H, tt, J
= 53, 5 Hz), 6.28 (1H, dd, J = 16, 6 Hz), 6.74 (1H,
d, J = 16 Hz), 7.1-7.2 (2H, m), 7.59 (1H, J = 9, 2 H
z), 7.65-7.70 (2H, m), 7.74 (1H, d, J = 9 Hz) IR spectrum KBr cm ^-1 : 2940, 1689, 1628, 1601,
1187, 1125, 966, 864, 638.

Test Example 1 Candida albicans 4-9 × 1
0 to ^six mice inoculated (10 animals per group), 1,4,2
Four hours later, 20 mg / kg of the drug was orally administered and 21 days after infection.
The survival rate by day was determined. Table 2 shows the results of comparison between the compound of the present invention and commercially available fluconazole. From this result, it is clear that the compounds of the present invention show excellent antifungal activity.

Table 2 Compound Viability% 14 days 21 days Example 1 100 100 2 100 100 3 100 100 5 100 100 Fluconazole 70 60 Formulation Example 1 Capsule Compound of Example 2 or 3 50 mg Lactose 128 mg Corn starch 70 mg Magnesium stearate 2 mg 250 mg The powder of the above formulation was mixed and passed through a 60-mesh sieve, and the powder was placed in a 250 mg No. 3 gelatin capsule to prepare a capsule.

Formulation Example 2 Tablets Compound of Example 2 or 3 50 mg Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet-granulated using corn starch paste, dried, and then pressed into a tableting machine. Tableting with 1
Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

[0164]

The compounds of the present invention and pharmacologically acceptable salts thereof exhibit excellent antifungal activity, are stable to acids, have excellent absorbability, have low toxicity, and have fungi in humans and animals. Useful for illness.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 405/14 209 C07D 405/14 209 215 215 217 217 235 235 235 249 249 409/12 249 409/12 249 409/14 249 409 / 14 249 411/12 411/12 411/14 411/14 413/14 249 413/14 249 417/14 249 417/14 249

Claims (21)

[Claims] (1) Formula (1) Or a pharmacologically acceptable salt thereof. In the formula, Ar ¹ represents a phenyl group or a phenyl group having 1 to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group); Ar ² represents naphthyl; Aromatic heterocyclic group (the condensed bicyclic aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or a naphthyl group having 1 to 3 substituents or an 8 to 10 membered condensed bicyclic group Aromatic heterocyclic group (the substituent is a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group, -S (O) _m R ² group (R ² : lower alkyl group which may be substituted with a halogen atom; m: represents 0, 1 or 2) or —NHCOR ³ group (R ³ represents a lower alkyl group) The fused bicyclic aromatic heterocyclic group is Element, an oxygen or at least one organic sulfur atom),
R ¹ represents a hydrogen atom or a lower alkyl group; n represents 0, 1 or 2; p and q each represent 0, 1 or 2 (provided that p + q ≦ 2); Having at least one nitrogen, oxygen or sulfur atom
And a 7-membered aliphatic heterocyclic group. 2. The triazole compound according to claim 1, wherein Ar ¹ is a phenyl group having ¹ to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group) or a pharmaceutically acceptable salt thereof. Salt. 3. The triazole compound according to claim 1, wherein Ar ¹ is a phenyl group having ¹ to 2 substituents, wherein the substituent represents a fluorine atom, a chlorine atom or a trifluoromethyl group. Above acceptable salts. Wherein Ar ² is naphthyl, 8-10 membered fused bicyclic aromatic Hajime Tamaki (condensed bicyclic aromatic heterocyclic groups are nitrogen, at least one organic oxygen or sulfur atom) or 1
A naphthyl group having from 3 to 3 substituents or an 8- to 10-membered condensed bicyclic aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, Lower alkoxy group,
A nitro group, a cyano group, or a —S (O) _m R ² group (R ² : a lower alkyl group optionally substituted with a halogen atom; m represents 0, 1 or 2); Aromatic heterocyclic groups have at least one nitrogen, oxygen or sulfur atom)
4. The triazole compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. Wherein Ar ² is naphthyl, 8-10 membered fused bicyclic aromatic Hajime Tamaki (condensed bicyclic aromatic heterocyclic groups are nitrogen, one or two organic oxygen or sulfur atom) or 1 A naphthyl group having from 3 to 3 substituents or an 8- to 10-membered condensed bicyclic aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom,
A lower alkoxy group, a nitro group, a cyano group or a —S (O) _m R ² group (R ² : a lower alkyl group optionally substituted with a halogen atom; m: 0, 1 or 2)
The fused bicyclic aromatic heterocyclic group is nitrogen,
4. The triazole compound according to claim 1, which has one or two oxygen or sulfur atoms, or a pharmaceutically acceptable salt thereof. Wherein Ar ² is naphthyl, 8-10 membered fused bicyclic aromatic Hajime Tamaki (condensed bicyclic aromatic heterocyclic groups are nitrogen, one or two organic oxygen or sulfur atom) or 1 A naphthyl group having 2 to 2 substituents or an 8 to 10-membered condensed bicyclic aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom,
A lower alkoxy group, a nitro group, a cyano group or a —S (O) _m R ² group (R ² : a lower alkyl group optionally substituted with a halogen atom; m: 0, 1 or 2)
The fused bicyclic aromatic heterocyclic group is nitrogen,
4. The triazole compound according to claim 1, which has one or two oxygen or sulfur atoms, or a pharmaceutically acceptable salt thereof. 7. Ar ² is naphthyl, quinolyl, naphthyl having isoquinolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl or benzothiazolyl radical, or one to two substituents, quinolyl, isoquinolyl, benzofuranyl, benzothienyl , Indolyl, benzimidazolyl, benzoxazolyl or benzothiazolyl group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted by a halogen atom, a lower alkoxy group substituted by a halogen atom, a nitro group, a cyano group or -S (O) _m R ² groups (R ² :
A lower alkyl group optionally substituted with a halogen atom; m:
0, 1 or 2).
Or a pharmacologically acceptable salt thereof. 8. The triazole compound according to claim 1, wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group or a propyl group, or a pharmaceutically acceptable salt thereof. 9. The triazole compound according to claim 1, wherein R ¹ is a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof. 10. The triazole compound according to claim 1, wherein R ¹ is a methyl group, or a pharmaceutically acceptable salt thereof. 11. The triazole compound according to claim 1, wherein n is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. 12. The method according to claim 1, wherein n is 0 or 2.
Or a pharmacologically acceptable salt thereof. 13. The triazole compound according to claim 1, wherein p is 0, 1 or 2, or a pharmacologically acceptable salt thereof. 14. The method according to claim 1, wherein p is 0 or 1.
Or a pharmacologically acceptable salt thereof. 15. The method according to claim 1, wherein q is 0 or 1.
Or a pharmacologically acceptable salt thereof. 16. The triazole compound according to claim 1, wherein q is 0, or a pharmacologically acceptable salt thereof. 17. A is an aliphatic carbocyclic group having 4 to 7 carbon atoms or a 4- to 7-membered aliphatic heterocyclic group having 1 to 2 nitrogen, oxygen or sulfur atoms. Or a pharmacologically acceptable salt thereof. 18. A is an aliphatic carbocyclic group having 4 to 6 carbon atoms or a 4- to 6-membered aliphatic heterocyclic group having 1 to 2 nitrogen, oxygen or sulfur atoms. Or a pharmacologically acceptable salt thereof. 19. A is cyclobutane, cyclopentane, cyclohexane, cycloheptane, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, thietane, tetrahydrothiophene, pentamethylene sulfide, dioxane, dithian, dihydrooxazine, tetrahydrooxazine, dihydroxane 17. The triazole compound according to claim 1, which is a thiazine or tetrahydrothiazine ring, or a pharmaceutically acceptable salt thereof. 20. 3-[[2- [2- (6-chloro-2-
Naphthyl) vinyl] -1,3-dioxan-5-yl]
Thio] -2- (2,4-difluorophenyl) -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol, 3-[[2- [2- (6-bromo-2-naphthyl) vinyl] -1,3-dioxan-5-yl] thio] -2-
(2,4-difluorophenyl) -1- (1H-1,
2,4-triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -3-[[2-
[2- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4 -Triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[2- [6- (trifluoromethoxy) -2-naphthyl] vinyl] -1,3-dioxan-5-yl] sulfonyl] -2-butanol, 3-[[6- [2- (6-bromo- 2-naphthyl) vinyl] -tetrahydro-2H-pyran-3-yl] thio]
-2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -3-[[6-
[2- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] vinyl] -tetrahydro-2H
-Pyran-3-yl] thio] -1- (1H-1,2,4
-Triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -3-[[2-
[4- [6- (2,2,3,3-tetrafluoropropoxy) -2-naphthyl] -1,3-butadienyl]-
1,3-dioxan-5-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[2- [6- (trifluoromethylsulfonyl) -2-
Naphthyl] vinyl] -1,3-dioxan-5-yl]
Thio] -2-butanol or 3-[[2- (6-bromo-2-naphthyl) -1,3-
Dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol are also pharmacologically acceptable. Salt. 21. A medicament comprising the triazole compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.