JP2002212180A - Triazole-based antifungal agent having carbamoyl group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To develop a compound having excellent antibacterial activity. SOLUTION: A compound having general formula (I) (wherein, Ar1 is phenyl or the like; Ar2 is phenylene or the like; R1 is a 1-3C alkyl or the like; R2 and R3 are each a 1-6C alkyl or the like; X is -S- or the like; and p, q and r are each an integer of 0-2) or a pharmaceutically acceptable salt thereof is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a triazole compound having excellent antifungal activity, a pharmacologically acceptable salt thereof, and a method for producing the same.

[0002]

2. Description of the Related Art Various triazole compounds have been reported as antifungal agents.

For example, European Patent Publication No. 1083175 and “40th Interscience Conference on Antimicrobi
al Agents and Chemotherapy, ABSTRACTS ", 1087-109
1, pp. 200-201 (2000) describes a triazole compound (IIIa ') having the following structure.

[0004]

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JP-A-10-279567 describes a triazole compound (IV) having the following structure.

[0006]

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JP-A-11-80135 describes a triazole compound (V) having the following structure.

[0008]

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However, these compounds and the compound according to the present invention are different in the substituent on the terminal aryl group. Heretofore, no compound having the structure of the present invention has been known.

[0010] Fungal infections are classified into superficial mycosis and deep mycosis. In recent years, with the progress of medical treatment, immunodeficiency due to AIDS, cancer chemotherapy, the use of immunosuppressive drugs such as transplantation treatment, etc., resulted in an increase in patients whose biological defense mechanism has been significantly reduced, resulting in deep mycosis, especially Candidiasis is a problem. Fluconazole, itraconazole and the like, which are triazole antifungal agents, are known as agents for this. However, recently, emergence of pathogenic fungi showing low sensitivity to these drugs has been reported. In addition, amphotericin B, a polyene antifungal agent, is known to exhibit strong antifungal activity, but is highly toxic. Therefore, it has an even broader antifungal spectrum than conventional drugs,
The discovery and development of highly safe antifungal agents with stronger antifungal activity is a pressing desire for medical practice.

[0011]

An object of the present invention is to provide a drug having a broad antifungal spectrum and high safety, exhibiting excellent antifungal activity, and particularly effective against candidiasis. To provide. We have:
Administering a triazole compound (IIIa ′) to various animals,
When the metabolite was searched for, the metabolic process of the compound in which the cyano group was converted to a carbamoyl group was clarified, and the metabolite having the carbamoyl group exhibited an antibacterial activity comparable to that of the triazole compound (IIIa '). It was clarified to have.

Further, the present inventors have searched for the peripheral compounds, and found that triazole compounds having the following general formulas (I) and (II) (especially those having the general formula (I)) are antifungal The present invention has been found to show activity and is useful as a medicine (especially an antifungal agent), and that a compound having the general formula (II) is useful as an intermediate in synthesizing the general formula (I). Was completed.

[0013]

The present invention provides a compound represented by the general formula (I):

[0014]

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Wherein Ar ¹ is a phenyl group (the phenyl group is a halogen atom or a trifluoromethyl group 1 to 3
And Ar ² represents a phenylene group or a naphthylene group (the phenylene group and the naphthylene group are a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a halogen atom A C ₁ -C ₆ alkyl group having ₁ to 5 and a C ₁ -C having ₁ to 5 halogen atoms
₆ alkoxy group, an may) have 1 to 4 carbon substituents selected from become more substituent group, R ¹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, R ² and R ³ independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or together represents a C ₂ -C ₆ alkylene group, and X represents —S
—, —S (O) —, —S (O) ₂ —, or —CH ₂ —, and p, q and r each independently represent an integer of 0 to 2. Or a pharmacologically acceptable salt thereof.

Further, the present invention provides a compound represented by the general formula (II):

[0017]

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[In the formula, Ar ¹ is a phenyl group (the phenyl group is a halogen atom or a trifluoromethyl group 1-3)
And Ar ² represents a phenylene group or a naphthylene group (the phenylene group and the naphthylene group are a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a halogen atom A C ₁ -C ₆ alkyl group having ₁ to 5 and a C ₁ -C having ₁ to 5 halogen atoms
₆ alkoxy group, a may also) have four to substituents 1 are selected from become more substituent group, R ¹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, R ⁴ is hydrogen X represents an atom or a C ₁ -C ₆ alkyl group, and X represents —S—, —S (O)
—, —S (O) ₂ — or —CH ₂ —, and p, q and r independently represent an integer of 0 to 2. Or a pharmacologically acceptable salt thereof.

Still another embodiment of the present invention relates to a compound of the general formula (III):

[0020]

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[Wherein, Ar ¹ is a phenyl group (the phenyl group is a halogen atom or a trifluoromethyl group 1-3)
And Ar ² represents a phenylene group or a naphthylene group (the phenylene group and the naphthylene group are a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a halogen atom A C ₁ -C ₆ alkyl group having ₁ to 5 and a C ₁ -C having ₁ to 5 halogen atoms
₆ alkoxy groups, which may have 1 to 4 substituents selected from the group consisting of substituents), R ¹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, and X represents- S-, -S
(O) -, - S ( O) 2 -, or -CH ₂ - shows a, p,
q and r each independently represent an integer of 0 to 2. From the pharmacologically acceptable salt thereof represented by the general formula (Ia)

[0022]

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Wherein Ar ¹ is a phenyl group (the phenyl group is a halogen atom or a trifluoromethyl group 1-3)
And Ar ² represents a phenylene group or a naphthylene group (the phenylene group and the naphthylene group are a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a halogen atom A C ₁ -C ₆ alkyl group having ₁ to 5 and a C ₁ -C having ₁ to 5 halogen atoms
₆ alkoxy groups, which may have 1 to 4 substituents selected from the group consisting of substituents), R ¹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, and X represents- S-, -S
(O) -, - S ( O) 2 -, or -CH ₂ - shows a, p,
q and r each independently represent an integer of 0 to 2. ] Or a pharmacologically acceptable salt thereof.

In the above, the "halogen atom" in the substitution of Ar ¹ and Ar ² refers to a fluorine, chlorine, bromine and iodine atom, of which a fluorine and chlorine atom is preferred, and a more preferred is a halogen atom. It is a fluorine atom.

In the above, the “phenylene group” of Ar ²
Is a divalent group formed by removing two hydrogen atoms from benzene, and includes, for example, o-phenylene, m-phenylene, and p-phenylene groups.
It is a phenylene group.

In the above, the “naphthylene group” of Ar ²
Is a divalent group formed by removing two hydrogen atoms from naphthalene, such as 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene,
1,6-naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,6-naphthylene,
And a 2,7-naphthylene group, of which a 2,6-naphthylene group is preferred.

The "alkyl group" in the substitution of R ¹ , R ² , R ³ , R ⁴ and Ar ² means a linear or branched saturated hydrocarbon group, and is a C ₁ -C ₃ Examples of the alkyl group include a methyl, ethyl, propyl, and isopropyl group, and among them, a methyl group is preferable. C ₁ -C ₆
Examples of the alkyl group include, in addition to these C ₁ -C ₃ alkyl groups, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl , 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s
-Hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl group, and these are preferably a C ₁ -C ₄ alkyl group, more preferably C ₁
—C ₂ alkyl, most preferably methyl.

In the above, the “alkoxy group” in the substitution of Ar ² means a linear or branched saturated alkoxy group, and examples of the C ₁ -C ₆ alkoxy group include methoxy, ethoxy and propoxy. , Isopropoxy,
Butoxy, isobutoxy, s-butoxy, t-butoxy,
Pentyloxy, s-pentyloxy, isopentyloxy, 2-methylbutyloxy, neopentyloxy,
1-ethylpropoxy, hexyloxy, 4-methylpentyloxy (isohexyloxy), 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy (s-hexyloxy), 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, and 2-
Ethyl butoxy group, of which C _1-
A C ₄ alkoxy group, more preferably a C ₁ -C ₂ alkoxy group, most preferably a methoxy group.

In the above, the “C ₁ -C ₆ alkyl group having ₁ to 5 halogen atoms” in the substitution of Ar ² includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2
-Difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 3 -Fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4-fluoro Butyl, 4,4,4-trifluorobutyl, 5-fluoropentyl, 5,5,5-trifluoropentyl, 6-fluorohexyl, and 6,6,6-
A trifluorohexyl group, preferably a C ₁ -C ₄ alkyl group having ₁ to 4 halogen atoms, and more preferably a C ₁ -C ₄ alkyl group having ₁ to 3 halogen atoms.
—C ₂ alkyl, most preferably trifluoromethyl.

In the above, the “C ₁ -C ₆ alkoxy group having ₁ to 5 halogen atoms” in the substitution of Ar ² includes, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2 2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, 2-chloroethoxy,
2,2-dichloroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy,
2,2,3,3-tetrafluoropropoxy, 2,2
3,3,3-pentafluoropropoxy, 4-fluorobutoxy, 4,4,4-trifluorobutoxy, 5-fluoropentyloxy, 5,5,5-trifluoropentyloxy, 6-fluorohexyloxy, and 6 ,
6,6-trifluorohexyloxy group, of which C ₁ -C having ₁ to 4 halogen atoms is preferred.
_{It is a 4-} alkoxy group, more preferably a C ₁ -C ₂ alkoxy group having ₁ to 3 halogen atoms, and most preferably a trifluoromethoxy group.

In the above, the term “alkylene group” in which R ² and R ³ are combined refers to a divalent group formed by removing two hydrogen atoms from a linear or branched saturated hydrocarbon. ,
The C ₂ -C ₆ alkylene group such as ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-methyltrimethylene and 2-methyltrimethylene group and the like, C ₃ -C Suitable Among ₆ alkylene groups, more preferably trimethylene and tetramethylene groups.

Ar ¹ is preferably a halogen atom of 1 to 2
Phenyl group having 1 or 2 fluorine atoms, more preferably 2,4-difluorophenyl group, 2-fluorophenyl group, or 2,5-difluoro group. A phenyl group, most preferably a 2,4-difluorophenyl group.

Ar ² is preferably a p-phenylene group which may have one halogen atom or a 2,6-naphthylene group which may have one halogen atom, and more preferably a fluorine atom A p-phenylene group which may have one or a 2,6-naphthylene group which may have one fluorine atom, more preferably p-phenylene, 2-fluoro-1,4-phenylene (However, substitution (CH = CH) _r
The carbon bonded to is referred to as 1-position; the same applies hereinafter), 3-fluoro-1,4-phenylene or 2,6-naphthylene group, most preferably 2-fluoro-1,4-phenylene group.

R ¹ is preferably a methyl group.

R ² and R ³ are preferably a hydrogen atom.

R ⁴ is preferably a hydrogen atom, a methyl group, an ethyl group or a propyl group, more preferably a hydrogen atom or a methyl group.

[0037] X is, preferably -S- or -CH ₂ -, and most preferably a -S-.

P is preferably ² when Ar ² is a (substituted) phenylene group, and is 1 when Ar ² is a (substituted) naphthylene group.

Q is preferably 0.

R is preferably 0.

The “pharmacologically acceptable salt” in the compound according to the present invention refers to the triazole group in the compound according to the present invention and the carboxyl group (when R ⁴ is a hydrogen atom) in the general formula (II). And salts commonly used in pharmaceutical compounds.

Such salts in the triazole group in the compounds according to the invention include, for example, hydrofluoric acid,
Hydrohalides such as hydrochloride, hydrobromide, hydroiodide; inorganic salts such as nitrate, perchlorate, sulfate, phosphate; methanesulfonate, trifluoromethanesulfone Acid salts, lower organic sulfonates such as ethanesulfonate; aryl sulfonates such as benzenesulfonate, p-toluenesulfonate, etc .; amino acid salts such as ornithate, glutamate; Examples include carboxylic acid salts such as acids, succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid.

Examples of such salts at the carboxyl group in the general formula (II) include alkali metal salts such as sodium salt, potassium salt and lithium salt; and alkaline earth metals such as calcium salt and magnesium salt. salt;
Metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts; inorganic salts such as ammonium salts;
t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt,
Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt,
Organic amine salts such as diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt can be exemplified.

The compound according to the present invention absorbs moisture when left in the air or recrystallized,
When adsorbed water is attached, it may become a hydrate. The triazole compound and the pharmacologically acceptable salt thereof according to the present invention each include such a hydrate.

Further, the compound according to the present invention may absorb some other solvent and form a solvate. The triazole compound and the pharmacologically acceptable salt thereof according to the present invention each include such a solvate.

The compounds of the present invention also include various isomers. For example, in the compound of the present invention, the carbon atom to which a hydroxyl group is bonded is an asymmetric carbon, and the carbon atom to which an R ¹ group is bonded is an asymmetric carbon atom unless R ¹ is a hydrogen atom. Therefore, the compounds of the present invention exist in stereoisomers based on the asymmetric carbon. Further, the compound of the present invention has 2,
Since it has a 5-disubstituted-1,3-dioxane ring, there are a stereoisomer in which the configuration at the 2-position and 5-position in the ring is trans and a stereoisomer which is cis. Further, the compound of the present invention has a carbon-carbon double bond unless both p and r are 0, so that various geometric isomers exist. further,
When X in the compound of the present invention is -S (O)-, a stereoisomer based on a sulfur atom exists. Each of them or a mixture in any ratio thereof is encompassed in the present invention. Such a stereoisomer may be obtained by using a stereospecific raw material compound, or by synthesizing the compound of the present invention using an asymmetric synthesis or asymmetric induction technique, or by synthesizing the synthesized compound of the present invention. If desired, it can be isolated using a conventional optical resolution method or separation method.

In the triazole compound having the general formula (I) or a pharmacologically acceptable salt thereof, preferably a compound represented by the general formula (Ib ′)

[0048]

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[Wherein, X has the same meaning as described above. Or a pharmacologically acceptable salt thereof.

In the triazole compound having the general formula (I) and the general formula (Ib ′) or a pharmaceutically acceptable salt thereof, preferably, a triazole compound in which X represents —S— or a pharmaceutically acceptable salt thereof. It is an acceptable salt.

In a triazole compound having the general formula (II) or a pharmacologically acceptable salt thereof, preferably a compound represented by the general formula (IIa ′)

[0052]

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[Wherein, R ⁴ and X have the same meanings as described above. ]
Or a pharmacologically acceptable salt thereof.

In the triazole compound having the general formula (II) and the general formula (IIa ′) or a pharmaceutically acceptable salt thereof, preferably, a triazole compound in which X represents —S— or a pharmaceutically acceptable salt thereof. An acceptable salt and a triazole compound in which R ⁴ represents a hydrogen atom or a methyl group or a pharmacologically acceptable salt thereof.

Specific examples of suitable compounds in the general formula (I) are shown in Table 1 below, and examples of suitable compounds in the general formula (II) are those shown in Table 2. However, the compound of the present invention is not limited to these.

In Tables 1 and 2, the meanings of the abbreviations are as follows. Me: methyl group, 2-FPh: 2-fluorophenyl group, 2,4-FPh: 2,4-difluorophenyl group, 2,5-FPh: 2,5-difluorophenyl group, -Ph-: 1 , 4-phenylene group, -2-FPh-: 2-fluoro-1,4-phenylene group

[0057]

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-3-FPh-: 3-fluoro-1,4-phenylene group

[0059]

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-Np-: a 2,6-naphthylene group.

[0061]

[Table 1]

[0062]

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Compound number Ar ¹ X p Ar ² -CONR ² R ³ 1-1 2,4-FPh -S- 2 -Ph- -CONH ₂ 1-2 2,5-FPh -S- 2 -Ph- -CONH ₂ 1-3 2-FPh -S- 2 -Ph-- _{CONH 2 1-4 2,4-FPh -CH 2} - 2 -Ph- -CONH 2 1-5 2,5-FPh -CH 2 - 2 -Ph- -CONH 2 1-6 2-FPh -CH 2 - 2 -Ph- -CONH ₂ 1-7 2,4-FPh -S- 2 -Ph- -CONHMe 1-8 2,5-FPh -S- 2 -Ph- -CONHMe 1-9 2-FPh -S- 2 -Ph- -CONHMe 1-10 2,4-FPh -CH 2 - 2 -Ph- -CONHMe 1-11 2,5-FPh -CH 2 - 2 -Ph- -CONHMe 1-12 2-FPh -CH _{2 - 2 -Ph- -CONHMe 1-13 2,4-} FPh -S- 2 -Ph- -CONMe 2 1-14 2,5-FPh -S- 2 -Ph- -CONMe 2 1-15 2-FPh _{-S- 2 -Ph- -CONMe 2 1-16 2,4-} FPh -CH 2 - 2 -Ph- -CONMe 2 1-17 2,5-FPh -CH 2 - 2 -Ph- -CONMe 2 1- _{18 2-FPh -CH 2 - 2} -Ph- -CONMe 2 1-19 2,4-FPh -S- 2 -2-FPh- -CONH 2 1-20 2,5-FPh -S- 2 -2- _{FPh- -CONH 2 1-21 2-FPh -S-} 2 -2-FPh- -CONH 2 1-22 2,4-FPh -CH 2 - 2 -2-FPh- -CONH 2 1-23 2,5 _{-FPh -CH 2 - 2 -2-FPh-} -CONH 2 1-24 2-FPh -CH 2 - 2 -2-FPh- -CONH 2 1-25 2,4-FPh -S- 2 -2-FPh --CONHMe 1-26 2,5-FPh -S- 2 -2-FPh- -CONHMe 1-27 2-FPh -S- 2 -2-FPh- -CONHMe 1-28 2,4-FPh -CH ₂ - 2 -2-FPh- -CONHMe 1-29 2,5 -FPh -CH 2 - 2 -2-FPh- -CONHMe 1-30 _{2-FPh -CH 2 - 2 -2} -FPh- -CONHMe 1-31 2,4-FPh -S- 2 -2-FPh- -CONMe 2 1-32 2,5-FPh -S- 2 -2- _{FPh- -CONMe 2 1-33 2-FPh -S-} 2 -2-FPh- -CONMe 2 1-34 2,4-FPh -CH 2 - 2 -2-FPh- -CONMe 2 1-35 2,5 _{-FPh -CH 2 - 2 -2-FPh-} -CONMe 2 1-36 2-FPh -CH 2 - 2 -2-FPh- -CONMe 2 1-37 2,4-FPh -S- 2 -3-FPh --CONH ₂ 1-38 2,5-FPh -S- 2 -3-FPh- -CONH ₂ 1-39 2-FPh -S- 2 -3-FPh- -CONH ₂ 1-40 2,4-FPh _{-CH 2 - 2 -3-FPh- -CONH} 2 1-41 2,5-FPh -CH 2 - 2 -3-FPh- -CONH 2 1-42 2-FPh -CH 2 - 2 -3-FPh- -CONH ₂ 1-43 2,4-FPh -S- 2 -3-FPh- -CONHMe 1-44 2,5-FPh -S- 2 -3-FPh- -CONHMe 1-45 2-FPh -S- 2 -3-FPh- -CONHMe 1-46 2,4- FPh -CH 2 - 2 -3-FPh- -CONHMe 1-47 2,5-FPh -CH 2 - 2 -3-FPh- -CONHMe 1- _{48 2-FPh -CH 2 - 2} -3-FPh- -CONHMe 1-49 2,4-FPh -S- 2 -3-FPh- -CONMe 2 1-50 2,5-FPh -S- 2 -3 _{-FPh- -CONMe 2 1-51 2-FPh -S-} 2 -3-FPh- -CONMe 2 1-52 2,4-FPh -CH 2 - 2 -3-FPh- -CONMe 2 1-53 2, _{5-FPh -CH 2 - 2 -3} -FPh- -CONMe 2 1-54 2-FPh -CH 2 - 2 -3-FPh- -CONMe 2 1-55 2,4-FPh -S- 1 -Np- -CONH ₂ 1-56 2,5-FPh -S- 1 -Np- -CONH ₂ 1-57 2-FPh -S- 1 -N _{p- -CONH 2 1-58 2,4-FPh -CH} 2 - 1 -Np- -CONH 2 1-59 2,5-FPh -CH 2 - 1 -Np- -CONH 2 1-60 2-FPh - _{CH 2 - 1 -Np- -CONH 2 1-61} 2,4-FPh -S- 1 -Np- -CONHMe 1-62 2,5-FPh -S- 1 -Np- -CONHMe 1-63 2-FPh -S- 1 -Np- -CONHMe 1-64 2,4-FPh -CH 2 - 1 -Np- -CONHMe 1-65 2,5-FPh -CH 2 - 1 -Np- -CONHMe 1-66 2- _{FPh -CH 2 - 1 -Np- -CONHMe 1-67} 2,4-FPh -S- 1 -Np- -CONMe 2 1-68 2,5-FPh -S- 1 -Np- -CONMe 2 1-69 _{2-FPh -S- 1 -Np- -CONMe 2} 1-70 2,4-FPh -CH 2 - 1 -Np- -CONMe 2 1-71 2,5-FPh -CH 2 - 1 -Np- -CONMe _{2 1-72 2-FPh -CH 2 -} 1 -Np- -CONMe 2

[0064]

[Table 2]

[0065]

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Compound number Ar ¹ X p Ar ² —COOR ⁴ 2-1 2,4-FPh -S- 2 -Ph- -COOMe 2-2 2,5-FPh -S- 2 -Ph- -COOMe 2-3 2-FPh -S- 2 -Ph- -COOMe 2 _{-4 2,4-FPh -CH 2 - 2} -Ph- -COOMe 2-5 2,5-FPh -CH 2 - 2 -Ph- -COOMe 2-6 2-FPh -CH 2 - 2 -Ph- - COOMe 2-7 2,4-FPh -S- 2 -2-FPh- -COOMe 2-8 2,5-FPh -S- 2 -2-FPh- -COOMe 2-9 2-FPh -S- 2- 2-FPh- -COOMe 2-10 2,4-FPh -CH 2 - 2 -2-FPh- -COOMe 2-11 2,5-FPh -CH 2 - 2 -2-FPh- -COOMe 2-12 2 _{-FPh -CH 2 - 2 -2-FPh-} -COOMe 2-13 2,4-FPh -S- 2 -3-FPh- -COOMe 2-14 2,5-FPh -S- 2 -3-FPh- -COOMe 2-15 2-FPh -S- 2 -3 -FPh- -COOMe 2-16 2,4-FPh -CH 2 - 2 -3-FPh- -COOMe 2-17 2,5-FPh -CH 2 - 2 -3-FPh- -COOMe 2-18 2 -FPh -CH 2 - 2 -3-FPh- -COOMe 2-19 2,4-FPh -S- 1 -Np- -COOMe 2-20 2,5 -FPh -S- 1 -Np- -COOMe 2-21 2- FPh -S- 1 -Np- -COOMe 2-22 2,4-FPh -CH 2 - 1 -Np- -COOMe 2-23 2,5 _{-FPh -CH 2 - 1 -Np- -COOMe 2-24} 2-FPh -CH 2 - 1 -Np- -COOMe 2-25 2,4-FPh -S- 2 -Ph- -COOH 2-26 2, 5-FPh -S- 2 -Ph- -COOH 2-27 2-FPh -S- 2 -Ph- -COOH 2-28 2,4-FPh -CH 2 - 2 -Ph- -COOH 2-29 2, 5-FPh -CH ₂ -2 -Ph- -COOH 2-30 2-FPh -CH ₂ -2 -Ph- -COOH 2-31 2,4- FPh -S- 2 -2-FPh- -COOH 2-32 2,5-FPh -S- 2 -2-FPh- -COOH 2-33 2-FPh -S- 2 -2-FPh- -COOH 2- _{34 2,4-FPh -CH 2 - 2} -2-FPh- -COOH 2-35 2,5-FPh -CH 2 - 2 -2-FPh- -COOH 2-36 2-FPh -CH 2 - 2 - 2-FPh- -COOH 2-37 2,4-FPh -S- 2 -3-FPh- -COOH 2-38 2,5-FPh -S- 2 -3-FPh- -COOH 2-39 2-FPh -S- 2 -3-FPh- -COOH 2-40 2,4 -FPh -CH 2 - 2 -3-FPh- -COOH 2-41 2,5-FPh -CH 2 - 2 -3-FPh- - _{COOH 2-42 2-FPh -CH 2 -} 2 -3-FPh- -COOH 2-43 2,4-FPh -S- 1 -Np- -COOH 2-44 2,5-FPh -S- 1 -Np - -COOH 2-45 2-FPh -S- 1 -Np- -COOH 2-46 2,4-FPh -CH 2 - 1 -Np- -COOH 2-47 2,5-FPh -CH 2 - 1 - _{Np- -COOH 2-48 2-FPh -CH 2} - 1 -Np- -COOH Among the compounds having the general formula (I) or (II) of the present invention, preferred compounds are exemplified compound numbers 1-1, 1-4, 1-19,
1-22, 1-55, 1-58, 2-1, 2-4, 2-7, 2-10, 2-19, 2-2
2, 2-25, 2-28, 2-31, 2-34, 2-43 and 2-46.

The compound represented by formula (I) or (II) of the present invention can be produced according to the following method.

[0068]

BEST MODE FOR CARRYING OUT THE INVENTION (Method A) Method A is a method for producing the compound of the present invention represented by the general formula (I), and is represented by the following reaction formula.

[0069]

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In the above reaction formula, Ar ¹ , Ar ² ,
R ¹ , R ² , R ³ , X, p, q and r are as defined above.

The present method is a method for producing a compound (I) by condensing an aldehyde compound (VII) or an acetal derivative thereof with an alcohol compound (VI).

Here, the “acetal derivative” of the aldehyde compound (VII) refers to a derivative in which the aldehyde group of the aldehyde compound (VII) is protected as a group represented by the formula CH (OR ^x ) (OR ^y ). . In the formula, R ^x and R ^y independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group, or R ^x and R ^y together represent a C ₂ -C ₄ alkylene group.

In the above, the “C ₁ -C ₄ alkyl group” includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl group. is there.

Examples of the “C ₂ -C ₄ alkylene group” include ethylene, trimethylene, tetramethylene, 1-methyltrimethylene and 2-methyltrimethylene groups. The “acetal derivative” of the aldehyde compound (VII) is preferably a derivative in which both R ^x and R ^{y of the} group represented by the formula CH (OR ^x ) (OR ^y ) are methyl groups.

In this method, an aldehyde compound (VII) or an acetal derivative thereof is reacted with an alcohol compound (VI) in an inert solvent in the presence of an acetalization reagent while removing water or alcohol produced by the reaction. Is achieved by

The starting alcohol compound (VI) is disclosed in JP-A-8-333350 or JP-A-11-8013.
It can be manufactured according to the method disclosed in Japanese Patent Publication No. 5 or the F method described later.

The starting aldehyde compound (VII) and its acetal derivative can be produced by the following methods (1) to (5).

(1) Among the aldehyde compounds (VII), compounds wherein p, q and r are all 0 can be produced by a method obvious to those skilled in the art. For example, the formula HO ₂ C—Ar ² —CO
_It can be produced by amidating one of the carboxyl groups of the dicarboxylic acid compound represented by ₂ H and reducing the other to an aldehyde group.

(2) q of the aldehyde compound (VII)
Is a compound of the formula OHC-Ar ² -CONR ^{2 which} can be produced according to the method described in (1).
Using the compound represented by R ³ as a starting material,
It can be manufactured according to the method disclosed in JP-A-33350 or JP-A-10-279567.

(3) q of the aldehyde compound (VII)
Is 1 or 2 can be produced according to the method disclosed in JP-A-8-333350.

(4) Among the aldehyde compounds (VII),
The compound in which p is 2, q and r are 0, and the acetal derivative thereof can also be produced according to Method E described later.

(5) The acetal derivative of the compound (VII) can be produced by a method obvious to those skilled in the art, using the aldehyde compound (VII) which can be produced according to the methods described in (1) to (4) as a starting material. For example, in the presence of an acid such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid, an aldehyde compound (VI
It can be produced by reacting I) with an alcohol compound represented by the formulas R ^x OH and R ^y OH.

In the reaction of Method A, the aldehyde compound (VII) or its acetal derivative can be used in an amount of 0.5 to 2 molar equivalents, preferably 0.9 to 1.2 molar equivalents, relative to the alcohol compound (VII). Is equivalent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples of such a solvent include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether and tetrahydrofuran. And a mixture thereof, preferably a halogenated hydrocarbon or ether, particularly preferably dichloromethane or tetrahydrofuran.

Examples of the acetalizing reagent used include inorganic acids such as hydrogen chloride, sulfuric acid and nitric acid; Lewis acids such as boron trifluoride, zinc chloride, magnesium bromide, titanium tetrachloride and aluminum chloride; Sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and citric acid or chlorotrimethylsilane , Silylating reagents such as trimethylsilyl trifluoromethanesulfonate, preferably sulfonic acids, and particularly preferably p
-Toluenesulfonic acid or camphorsulfonic acid.

The amount of the acetalization reagent used is 0.5 to 3 molar equivalents, preferably 1.0 to 1.4 molar equivalents, relative to compound (VI).

The water or alcohol produced by the reaction can be removed by azeotropic distillation with the solvent used or by suction under reduced pressure. However, an adsorbent such as molecular sieves can also be used.

The reaction temperature varies depending on the type of the acetalization reagent and the solvent, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of 5 ° C. to 40 ° C.

The reaction time varies depending on the type of the acetalizing reagent and the solvent and the reaction temperature, but is usually 0.5 to 24 hours, preferably 1 to 5 hours.

After completion of the reaction, the target compound (I) can be collected from the reaction mixture by a conventional method after neutralizing the reaction solution with aqueous sodium bicarbonate or the like. For example, it can be obtained by adding an organic solvent which does not mix with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.

The obtained compound (I) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Method B) Method B is a method for producing a compound (IIb) in which R ⁴ is a C ₁ -C ₆ alkyl group among the compounds represented by the general formula (II) which are the compounds of the present invention. Is shown by the following reaction formula.

[0092]

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In the above reaction formula, Ar ¹ , Ar ² ,
R ¹ , X, p, q and r are as defined above, and R ^4a is C
Shows the ₁ -C ₆ alkyl group.

This method is a method for producing a compound (II) by condensing an aldehyde compound (VIIIa) or an acetal derivative thereof with an alcohol compound (VI).

Here, the “acetal derivative” of the aldehyde compound (VIIIa) refers to the aldehyde compound (VIII
a) The derivative in which the aldehyde group of a) is protected as a group represented by the formula CH (OR ^x ) (OR ^y ) (wherein R ^x and R ^y have the same meanings as described above). Aldehyde compound (VIIIa)
Preferably, as an "acetal derivative" of the formula CH (O
A derivative in which both R ^x and R ^{y of the} group represented by R ^x ) (OR ^y ) are methyl groups.

The present method comprises reacting an aldehyde compound (VIIIa) or an acetal derivative thereof with an alcohol compound (VI)
It is achieved by performing the reaction in an inert solvent in the presence of an acetalization reagent while removing water or alcohol generated in the reaction. The reaction can be carried out according to the above-mentioned Method A.

The starting alcohol compound (VI) is disclosed in JP-A-8-333350 or JP-A-11-80.
It can be produced according to the method disclosed in Japanese Patent Publication No. 135 or the method F described later. In addition, the raw material aldehyde compound (VIIIa) and its acetal derivative are represented by the following (1 ′)
To (5 ′). Among (1 ′) aldehyde compounds (VIIIa), compounds wherein p, q and r are all 0 can be produced by a method obvious to those skilled in the art. For example, it can be produced by esterifying one of the carboxyl groups of the dicarboxylic acid compound represented by the formula HO ₂ C—Ar ² —CO ₂ H and reducing the other to an aldehyde group. (2 ′) Among the aldehyde compounds (VIIIa), the compound wherein q is 0 and p or r is not 0 is a compound of the formula OHC-Ar ² —COOR ^{4a which} can be produced according to the method described in (1 ′).
Starting from a compound represented by the formula:
It can be manufactured according to the method disclosed in JP-A-350-350 or JP-A-10-279567. Among the (3 ′) aldehyde compounds (VIIIa), compounds wherein q is 1 or 2 can be produced according to the method disclosed in JP-A-8-333350. Among the (4 ′) aldehyde compounds (VIIIa), compounds wherein p is 2 and q and r are 0, and their acetal derivatives can also be produced according to Method E described below. (5 ′) The acetal derivative of the compound (VIIIa)
The aldehyde compound (VIIIa) which can be produced according to the methods described in (1 ′) to (4 ′) can be produced by a method obvious to those skilled in the art using the aldehyde compound (VIIIa) as a starting material. For example, it can be produced sulfuric acid, hydrochloric acid, in the presence of an acid such as p- toluenesulfonic acid, by the action of compound (VIIIa) to an alcohol compound represented by the formula R ^x OH and wherein R ^y OH. (Method C) The method C is a method for producing a compound (Ic) in which R ² and R ³ are hydrogen atoms among the compounds of the present invention represented by the general formula (I). Indicated by the reaction equation.

[0098]

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In the above reaction formula, Ar ¹ , Ar ² ,
R ¹ , X, p, q and r are as defined above.

In this method, an aldehyde compound (IX) or an acetal derivative thereof is condensed with an alcohol compound (VI) to produce a compound (III) (Step C-1), and then the nitrile group of the compound (III) Is converted to a carbamoyl group (Step C-2) to produce a compound (Ia).

Here, the “acetal derivative” of the aldehyde compound (IX) refers to a derivative of the aldehyde compound (IX) in which the aldehyde group is protected as a group represented by the formula CH (OR ^x ) (OR ^y ) (formula (I)). Wherein R ^x and R ^y have the same meanings as described above.) The “acetal derivative” of the aldehyde compound (IX) is preferably a derivative in which both R ^x and R ^{y of the} group represented by the formula CH (OR ^x ) (OR ^y ) are methyl groups.

Hereinafter, each step will be described in detail. (Step C-1) In this step, an aldehyde compound (IX) or an acetal derivative thereof is converted to an alcohol compound (VI)
And reacting in an inert solvent in the presence of an acetalization reagent while removing water or alcohol produced by the reaction to produce compound (III). The reaction can be carried out according to the above-mentioned Method A.

Incidentally, the starting alcohol compound (VI) is disclosed in JP-A-8-333350 or JP-A-11-80.
It can be manufactured according to the method disclosed in JP-A-135 or the method F described later. The raw material aldehyde compound (IX) and its acetal derivative are as follows (1 ″)
To (5 ″). Among (1 ″) aldehyde compounds (IX), compounds wherein p, q and r are all 0 can be produced by a method obvious to those skilled in the art. For example, it can be produced by converting one of the carboxyl groups of the dicarboxylic acid compound represented by the formula HO ₂ C—Ar ² —CO ₂ H into a nitrile group and reducing the other to an aldehyde group. (2 ″) Among the aldehyde compounds (IX), the compound wherein q is 0 and p or r is 1 or 2 is a compound of the formula OHC-Ar ^{2 which} can be produced according to the method described in (1 ″). JP-A-8-3333 using a compound represented by -CN as a starting material
It can be manufactured according to the method disclosed in JP-A No. 50 or JP-A-10-279567. Among the (3 ″) aldehyde compounds (IX), the compound wherein q is 1 or 2 can be produced according to the method disclosed in JP-A-8-333350. Among the (4 ″) aldehyde compounds (IX), the compound wherein p is 2 and q and r are 0, and the acetal derivative thereof can also be produced according to Method E described later. (5 ″) The acetal derivative of the compound (IX) is
The aldehyde compound (IX) which can be produced according to the methods described in (1 ″) to (4 ″) can be produced by a method obvious to those skilled in the art, using the aldehyde compound (IX) as a starting material. For example, in the presence of an acid such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid, compound (IX) is converted to a compound of formula R
can be prepared by the action of an alcohol compound represented by ^x OH or wherein R ^y OH. (Step C-2) This step is a step of converting the nitrile group of compound (III) into a carbamoyl group to produce compound (Ia). The reaction is achieved by reacting compound (III) with a base in a solvent.

Examples of the solvent used include water; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; amides such as N, N-dimethylformamide. Of these, sulfoxides (particularly, dimethyl sulfoxide) are preferred. Sulfoxide).

Examples of the base used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium carbonate, sodium carbonate, and the like.
Examples thereof include alkali metal carbonates such as potassium carbonate. Of these, alkali metal hydroxides (particularly sodium hydroxide) are preferred.

The amount of the base used is usually in the range of 1 to 10 molar equivalents, preferably 2 to 5 molar equivalents, relative to compound (III).

The reaction temperature depends mainly on the reagent, but is usually from 0 ° C. to room temperature.

The reaction time depends mainly on the reaction temperature and the amount of base, but is usually 0.5 to 24 hours.

After completion of the reaction, compound (Ia) can be collected from the reaction mixture by a conventional method. For example, after neutralizing the reaction mixture, an organic solvent immiscible with water is added, the mixture is washed with water, and the solvent is evaporated to obtain the compound (Ia). Compound (Ia) can be further purified by a usual method such as recrystallization, reprecipitation, or chromatography, if desired. (Method D) In the method D, the compound of the present invention represented by the general formula (II) wherein R ⁴ is a hydrogen atom (II
c) and a compound of the present invention represented by the general formula (I), which is represented by the following reaction formula.

[0110]

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In the above reaction formula, Ar ¹ , Ar ² ,
R ¹ , R ² , R ³ , R ^4a , X, p, q and r are as defined above.

In this method, first, the ester group of the ester compound (IIb) is saponified to obtain a carboxylic acid compound (IIc) or a salt thereof (Step D-1), and then the carboxylic acid compound (IIc) or a salt thereof Is amidated to produce the compound (I).

Hereinafter, each step will be described in detail. (Step D-1) In this step, the ester compound (IIb), which can be produced according to the method B, is saponified by allowing a base to act in a solvent, usually in the presence of water, to form a carboxylic acid compound (IIc) or a carboxylic acid compound (IIc). This is a step of producing a salt.

The solvent used for saponification is not particularly limited as long as it is a solvent usually used in organic synthetic chemistry for saponifying esters to carboxylic acids.
Alcohols such as methanol and ethanol; ketones such as acetone; nitriles such as acetonitrile; ethers such as tetrahydrofuran and 1,4-dioxane; and a mixed solvent thereof with water. Among them, a mixed solvent of ethers and water is preferable.

The base to be used is not particularly limited as long as it is a base usually used in organic synthetic chemistry for saponifying an ester to a carboxylic acid, and examples thereof include lithium hydroxide, sodium hydroxide and potassium hydroxide. And alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Of these, alkali metal hydroxides (particularly sodium hydroxide) are preferred.

The amount of the base used is usually in the range of 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (IIb).

The reaction temperature varies depending on the amount of the base and the like.
It is usually in the range of 0 ° C. to the boiling point of the solvent, preferably room temperature to 80 ° C.

The reaction time depends mainly on the reaction temperature and the amount of the base, but is usually 0.5 to 24 hours.

After completion of the reaction, compound (IIc) or a salt thereof can be collected from the reaction mixture by a conventional method. For example, an organic solvent immiscible with water and water are added to the reaction mixture, the aqueous layer is separated, and water is distilled off to obtain a salt of compound (IIc). Further, after neutralizing the reaction mixture, an organic solvent immiscible with water and water are added, the organic layer is separated, and the solvent is distilled off to obtain the compound (IIc). Compound (IIc) or a salt thereof can be further purified by a usual method such as recrystallization, reprecipitation or chromatography, if necessary. (Step D-2) In this step, compound (II) was prepared in an inert solvent.
c) or a step of reacting a salt or a reactive derivative thereof with an amine compound represented by the formula HNR ² R ³ or ammonia or a salt thereof to produce an amide compound (I).

Here, the reactive derivative of the compound (IIc) means that the carboxyl group part of the compound (IIc) has the formula -C (=
O) a compound activated as a group represented by Z (wherein
Z is a halogen atom such as chlorine atom; azido group; a cyano group; a halogeno C ₁ -C ₆ alkanesulfonyloxy, such as trifluoromethanesulfonyloxy group; C ₁ -C ₆ alkanesulfonyloxy group such as methanesulfonyloxy group A C ₁ -C ₆ alkanoyloxy group such as an acetoxy group and a pivaloyloxy group; and a leaving group such as an aromatic heterocyclic group such as an imidazolyl group and a triazolyl group. ).

The term “salt” of an amine compound or ammonia represented by the formula HNR ² R ³ means a salt of a mineral acid such as a hydrochloride.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples of such a solvent include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether and tetrahydrofuran. Aprotic solvents such as nitriles such as acetonitrile; nitrogen-containing heterocyclic aromatic bases such as pyridine; and mixtures thereof. Of these, preferred are halogenated hydrocarbons, ethers, and nitrogen-containing heterocyclic aromatic bases. Particularly preferred are dichloromethane, tetrahydrofuran and pyridine.

When the reaction is carried out using the compound (IIc) or a salt thereof, a condensing agent is added to the compound (IIc) or a salt thereof with an amine compound represented by the formula HNR ² R ³ or ammonia or a salt thereof. It can be done by adding. The condensing agent is not particularly limited as long as it is generally used as a condensing agent in organic synthetic chemistry, and examples thereof include dicyclohexylcarbodiimide and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide. And carbodiimides.

When the reaction is carried out using a reactive derivative of a carboxylic acid compound, the carboxylic acid compound (IIc) or a salt thereof is usually prepared in the presence of a base by a method generally used in organic synthetic chemistry. , The formula HNR
It is achieved by adding an amine compound or ammonia or a salt thereof represented by ² R ^3. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4- (N, N-dimethylamino) pyridine. The amount of the base to be used is generally 0.5 to 5 molar equivalents (preferably 0.9 to 2.5 molar equivalents) relative to compound (IIc).

Examples of the reagent for converting the carboxylic acid compound (IIc) or a salt thereof into a reactive derivative thereof include thionyl halides such as thionyl chloride; and reactive phosphoric acid derivatives such as phosphorus oxychloride and diphenylphosphoric acid azide. Kind;
Acid chlorides such as acetyl chloride, pivaloyl chloride and oxalyl chloride; reactive sulfonic acid derivatives such as methanesulfonyl chloride and trifluoromethanesulfonic anhydride; phosgene, trichloromethyl chloroformate, triphosgene,
Reactive carbonic acid derivatives such as 1,1'-carbonyldiimidazole; reactive oxalic acid derivatives such as oxalyl chloride; and acid chlorides (particularly pivaloyl chloride) are preferred. it can. The amount of the reagent to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, relative to the carboxylic acid compound (IIc) or a salt thereof.

An amine compound represented by the formula HNR ² R ³ or ammonia or a salt thereof is a carboxylic acid compound (II
It is generally used in excess (preferably 1 to 5 molar equivalents) relative to c).

The reaction temperature depends mainly on the type of reagent, but is usually in the range of -30 ° C to room temperature, preferably 0 ° C.
It is in the range of ℃ to room temperature.

The reaction time depends mainly on the reaction reagent and the reaction temperature, but is usually from 10 minutes to 24 hours, preferably from 1 to 2 hours.

After completion of the reaction, the target compound (I)
Can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent which does not mix with water to a reaction mixture or a residue obtained by distilling a solvent of the reaction mixture, washing with water, and distilling the solvent.

If necessary, it can be further purified by a usual method such as recrystallization, reprecipitation or chromatography. (Step D-3) In this step, the compound (IIb) is reacted with an amine compound represented by the formula HNR ² R ³ or ammonia or a salt thereof in an inert solvent in the presence of an activating reagent. Is a process for directly obtaining the amide compound (I).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, dichloromethane, chloroform, 1,2-
Aprotic solvents such as halogenated hydrocarbons such as dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether and tetrahydrofuran; and mixtures thereof. Of these, aromatic hydrocarbons and halogenated hydrocarbons are preferred, and toluene is particularly preferred.

The activating reagent to be used is not particularly limited as long as it is an activating reagent usually used in organic synthetic chemistry for converting esters into amides. For example, trimethylaluminum and triethylaluminum can be used. Tri (lower alkyl) aluminums; alkali metal cyanides such as sodium cyanide; hydroxyaromatic nitrogen-containing heterocyclic compounds such as 2-hydroxypyridine; bases such as sodium methoxide and butyllithium Boron halides such as boron tribromide. Among these, more preferred are tri (lower alkyl) aluminums, and particularly preferred is trimethylaluminum.

The amount of the activating reagent to be used is 1 to 5 molar equivalents, preferably 1.5 to 3.0 molar equivalents, based on the ester compound (IIb).

The amine compound represented by the formula HNR ² R ³ or ammonia or a salt thereof is an ester compound (II
It can be used in an amount of 0.5 to 5 molar equivalents, preferably 0.9 to 2.5 molar equivalents to b).

The reaction temperature varies depending on the type of the activating reagent, the starting materials used and the solvent, but is usually in the range of room temperature to the boiling point of the solvent, preferably in the range of 50 to 90 ° C.

The reaction time depends on the activating reagent, the starting materials used,
Depending on the type of solvent and reaction temperature, usually 0.5
To 24 hours, preferably 1 to 5 hours.

After completion of the reaction, the desired compound (I) can be collected from the reaction mixture by decomposing the activating reagent by pouring a sodium bicarbonate solution or the like into the reaction solution, and then subjecting it to a conventional method. For example,
An organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, the mixture is washed with water, and the solvent is distilled off.

The obtained compound (I) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Method E) Method E is an aldehyde compound (VII), (VIIIa) or (IX) which is a starting compound of Method A to Method C.
An aldehyde compound wherein q and r are 0 and p is 2 (VII
This is a method for producing a), (VIIIb), and (IXa), and their acetal derivatives, and is represented by the following reaction formula. Here, the aldehyde compound (VIIa), (VI
The “acetal derivative” of IIb) and (IXa) is a group in which the aldehyde group of the aldehyde compounds (VIIa), (VIIIb) and (IXa) is represented by the formula CH (OR ^x ) (OR ^y ) It refers to a protected derivative (wherein, R ^x and R ^y have the same meanings as described above). Aldehyde compounds (VIIa), (VI
IIb) and (IXa), preferably, R ^x and R ^{y of} a group represented by the formula CH (OR ^x ) (OR ^y )
Are derivatives wherein both are methyl groups.

[0139]

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In the above reaction formula, Ar ² , R ² , R ³ ,
And R ^4a have the same meaning as described above, and R ⁵ represents a C ₁ -C ₆ alkyl group which may have a fluorine atom.

The “C ₁ -C ₆ alkyl group optionally having a fluorine atom” for R ⁵ includes, for example, methyl, fluoromethyl, difluoromethyl, trifluoromethyl,
Ethyl, 1-fluoroethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl, 3-fluoropropyl, butyl, isobutyl, s-butyl, t-butyl,
-Fluorobutyl, pentyl or hexyl groups. R ⁵ is preferably, for example, methyl, ethyl,
1-fluoroethyl, 2-fluoroethyl, propyl,
Butyl or a C ₁ -C ₄ alkyl group which may have 1 to 3 fluorine atoms such as a 2,2,2-trifluoroethyl group, and more preferably a primary C ₁ -C 4 _{It is a 4-} alkyl group, most preferably an ethyl group.

In this method, first, the bromine compounds (X), (XI),
Or (XII) is replaced with a phosphate compound (XIII), (XI
V) or (XV) (Step E-1), and then the phosphate compound (XIII), (XIV), or (XV) is condensed with the dialdehyde compound (XVI) or its monoacetal derivative. To produce the aldehyde compound (VIIa), (VIIIb) or (IXa) (Step E-2).

Here, the “monoacetal derivative” of the compound (XVI) means that one of the two aldehyde groups of the dialdehyde compound (XVI) has the formula CH (OR ^x ) (OR ^y )
(Wherein R ^x and R ^y are as defined above). The “monoacetal derivative” of the aldehyde compound (XVI) is preferably a derivative represented by the formula CH (OR ^x ) (OR ^y ) in which both R ^x and R ^y are methyl groups.

Hereinafter, each step will be described in detail. (Step E-1) In this step, the bromine compound (X), (X
I) or (XII) can be obtained by converting the compound of the formula (R)^FiveO)_ThreeAt P
A phosphite compound represented by the formula^FiveIs as defined above
The phosphoric acid ester compound is obtained by heating
(XIII), (XIV) or (XV)
You. The starting bromine compounds (X), (XI) and (XII)
It can be manufactured by a method obvious to those skilled in the art. For example, literature
[J. Med. Chem. , 26, 1282
(1983), 35, 877 (1992).
Year)] and the formula CH _ThreeAr^TwoCONR^TwoR^Three, CH_ThreeA
r^TwoCOOR^FourOr CH_ThreeAr^TwoCompound represented by CN
With AIBN [2,2'-azobis (isobutyroni
Tolyl) in the presence of a radical initiator such as
In an inert solvent such as hydrogen or 1,2-dichloroethane,
With bromination reagents such as N-bromosuccinimide
It can be produced by heating.

The phosphite compound represented by the formula (R ⁵ O) ₃ P is generally commercially available, but can also be produced by a method obvious to those skilled in the art. For example, it can be produced by allowing phosphorus trichloride to act on an alcohol compound represented by the formula R ⁵ OH, usually in the presence of an organic amine such as triethylamine.

The amount of the phosphite compound used in the reaction is 1 to 50 molar equivalents, preferably 3 to 10 molar equivalents. The reaction can be usually carried out without a solvent, but an inert solvent such as toluene, xylene, mesitylene or chlorobenzene may be added as a solvent. The reaction temperature is usually 80
It is in the range of from 150 ° C to 150 ° C, preferably in the range of from 100 ° C to 130 ° C. The reaction time is usually 1 hour to 1 hour
0 hours.

After the completion of the reaction, volatile components are distilled off under reduced pressure to obtain a phosphate compound (XIII), (XIV) or (XV). Phosphate ester compound (XIII),
(XIV) and (XV) can usually be used in the reaction of Step E-2 without further purification, but if desired, can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. can do. (Step E-2) In this step, after a phosphate ester compound (XIII), (XIV), or (XV) is subjected to a condensation reaction with a dialdehyde compound (XVI) or a monoacetal derivative thereof in a solvent, This is a step of obtaining an aldehyde compound (VIIa), (VIIIb), or (IXa) or an acetal derivative thereof, if necessary, by subjecting it to a deprotection reaction.

The dialdehyde compound (XVI) or its monoacetal derivative is commercially available or can be obtained by a method known in the literature [Chem. Ber. 45, p. 1746 (191
2 years); Chem. Soc. , Perkin Tr
ans. 1, 1907 (1991), Bull. S
oc. Chim. Fr. 133, p. 301 (199).
6 years)] or a method analogous thereto. That is, the monoacetal derivative of the compound (XVI) is obtained, for example, by reacting bromine with furan in a C ₁ -C ₄ alcohol or a C ₂ -C ₄ diol to obtain a diacetal derivative of the compound (XVI), and then adding water or water. Mixed with an organic solvent such as acetone and chloroform or in chloroform, Amberlyst-15
Or an organic acid such as formic acid, trifluoroacetic acid, and toluenesulfonic acid, etc., to induce one acetal group into an aldehyde group. Here, “C ₁ -C ₄ alcohol” or “C ₂ -C ₄ diol” is an alcohol compound represented by the formula R ^x OH or R ^y OH (where R ^x and R ^y are dialdehyde compounds (XV
R ^x and R ^y in the definition of the monoacetal derivative of I)
Is the same as). In addition, dialdehyde compounds (XV
I) is, for example, a monoacetal derivative or a diacetal derivative of a dialdehyde compound (XVI), in the presence of water,
It can be obtained by reacting an aqueous solution of a mineral acid such as sulfuric acid or hydrochloric acid.

The dialdehyde compound (XVI) or its monoacetal derivative is a phosphate ester compound (XIII),
It can be used usually in an amount of 0.5 to 1.5 molar equivalents, preferably 0.9 to 1.2 molar equivalents, relative to (XIV) or (XV).

The solvent used in the condensation reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Examples of such a solvent include ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; hydrocarbons such as hexane, cyclohexane, benzene, and toluene; sulfoxides such as dimethyl sulfoxide, and mixtures thereof. it can. Preferred are ethers, particularly preferred is tetrahydrofuran.

The base to be used is not particularly limited as long as it has basicity for extracting an active proton from the phosphate compound (XIII), (XIV) or (XV). Such bases include, for example, organolithiums such as methyllithium, butyllithium and phenyllithium; metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium methoxide, potassium t- Metal alkoxides such as butoxide; alkali metalated sulfoxides such as dimsyl sodium can be mentioned. Preference is given to metal alkoxides, particularly preferably potassium t-butoxide.

The base is a phosphate compound (XIII),
It can be used in an amount of usually 0.9 to 1.5 molar equivalents, and preferably 1 to 1.1 molar equivalents, relative to (XIV) or (XV).

The reaction temperature of the condensation varies depending mainly on the reagent used, but is usually from -78 ° C to room temperature, preferably from -78 ° C.
20 ° C. to 10 ° C.

The reaction time varies depending mainly on the reaction temperature and the solvent, but is usually 0.5 to 24 hours, preferably 1 to 3 hours.

After the completion of the condensation reaction, if necessary, an aqueous solution of an acid is added to the mixture, and the mixture is stirred to remove the acetal protecting group, and the aldehyde compounds (VIIa), (VIII
b) is generated by (IXa).

The acid used is not particularly limited as long as it is an acid usually used in organic synthetic chemistry. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and trifluoromethanesulfonic acid; formic acid; Carboxylic acids such as acetic acid, trifluoroacetic acid, oxalic acid, and citric acid can be mentioned, preferably inorganic acids, and particularly preferably hydrochloric acid.

The amount of the acid is not particularly limited, but is preferably
The pH of the reaction solution after the addition of the acid is an amount exhibiting -1 to 3, and particularly preferably an amount exhibiting 0 to 1.

The reaction temperature of the acid treatment depends mainly on the reagent used, but is usually from -10 to 40 ° C, preferably from 0 ° C to room temperature.

The reaction time depends mainly on the pH and the reaction temperature, but is usually from 0.2 to 3 hours, preferably from 0.5 to 1.5 hours.

The aldehyde compounds (VIIa) and (VI
IIb) or (IXa) or an acetal derivative thereof can be collected from the reaction mixture by a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture, washing with water, and distilling off the solvent.

The aldehyde compounds (VIIa), (VI
IIb) or (IXa) or an acetal derivative thereof can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Method F) Method F is a method for preparing sulfide compounds (I-0), (II-
By oxidizing the sulfide group of (0), (III-0) or (VI-0), the sulfinyl compound (I-1), (II-
1), (III-1) or (VI-1), and further the sulfinyl compound (I-1), (II-1), (III-1) or (VI-
By oxidizing the sulfinyl group of 1), the sulfonyl compound (I-2), (II-2), (III-2) or (VI-2) as the starting compound, intermediate compound or target compound of the present invention
Which is represented by the following reaction formula.

[0162]

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In the above reaction formula, Ar ¹ , Ar ² ,
R ¹ , R ² , R ³ , R ⁴ , p, q and r are as defined above.

In this method, first, a sulfide compound (I-0),
(II-0), (III-0) or (VI-0) is oxidized to give a sulfinyl compound (I-1), (II-1), (III-1) or (VI-1)
(Step F-1), and then oxidizing the sulfinyl compound (I-1), (II-1), (III-1) or (VI-1) to obtain a sulfonyl compound (I-2); This is a method for producing (II-2), (III-2) or (VI-2) (Step F-2).

Hereinafter, each step will be described in detail. (Step F-1) This step is achieved by reacting a sulfide compound (I-0), (II-0), (III-0) or (VI-0) with an oxidizing agent in a solvent. .

The starting sulfide compound (I-0) can be produced according to the above-mentioned Method A, Method C or Method D. The sulfide compound (II-0) can be produced according to the above-mentioned Method B. The sulfide compound (III-0) can be produced according to the above-mentioned Method C. The sulfide compound (VI-0) is disclosed in JP-A-8-33
It can be produced according to the method disclosed in JP-A-3350.

Examples of the solvent used include water; alcohols such as methanol and ethanol; ketones such as acetone; halogenated hydrocarbons such as dichloromethane and dichloroethane; or diethyl ether, tetrahydrofuran, 1,4- Examples thereof include ethers such as dioxane and 1,2-dimethoxyethane, and a mixed solvent thereof. Of these, halogenated hydrocarbons (particularly, dichloromethane) are preferable.

Examples of the oxidizing agent to be used include hydrogen peroxide or peracids such as peracetic acid, perbenzoic acid and m-chloroperbenzoic acid. Preferably, hydrogen peroxide or m-chloroperoxy acid is used. It is benzoic acid.

The amount of the oxidizing agent to be used is generally 0.5 to 1.5 molar equivalents, preferably 0.9 to 1.1 molar equivalents, relative to the starting compound.

The reaction may be carried out in the presence of a base in order to suppress the decomposition of the compound. As the base, for example,
Alkali metal bicarbonates such as sodium bicarbonate are exemplified. The amount of the base to be used is generally 0.1 to 2 molar equivalents relative to the oxidizing agent used in the reaction.

The reaction temperature depends mainly on the reagent, but is usually in the range of 0 ° C. to the boiling point of the solvent (preferably 0 ° C. to room temperature)
It is.

The reaction time varies depending mainly on the reagent used and the reaction temperature, but is usually 0.5 to 24 hours (preferably 0.5 to 2 hours).

After completion of the reaction, the desired compounds (I-1), (II-
1), (III-1) or (VI-1) can be collected from the reaction mixture by a usual method. For example, after neutralization, an organic solvent which does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.

The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step F-2) This step is achieved by reacting the sulfinyl compound (I-1), (II-1), (III-1) or (VI-1) with an oxidizing agent in a solvent. .

The starting compound can be produced by Step F-1. Compound (I-1) can also be produced according to the above-mentioned Method A, Method C or Method D. The compound (II
-1) can also be produced according to the above-mentioned Method B.
Compound (III-1) can also be produced according to the above-mentioned Method C.

The type and amount of the oxidizing agent to be used, the type and amount of the base that may be used, the reaction temperature and the reaction time are as follows.
Same as step-1.

This step can be carried out in a single step together with the (F-1) th step. That is, using a sulfide compound (I-0), (II-0), (III-0) or (VI-0) as a raw material, an excess amount of an oxidizing agent (preferably 1.9) under similar reaction conditions. To 2.2 molar equivalents) to produce the sulfonyl compound (I-2), (II-2), (III-2) or (VI-2).

The target compound (I-
2), (II-2), (III-2) or (VI-2) can be collected from the reaction mixture by a conventional method after the reaction. For example, after neutralization, an organic solvent which does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.

The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. Compounds (I) and (II) produced according to Method A to Method F may optionally be dissolved in a solvent,
It can be converted to a pharmacologically acceptable salt by adding a pharmacologically acceptable acid or base.

The solvent used is not particularly restricted but includes, for example, aromatic hydrocarbons such as benzene and toluene;
Halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ether, tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols such as methanol and ethanol; ketones such as acetone; Nitriles; hydrocarbons such as hexane and cyclohexane, or mixtures thereof.

The acid used may be any one which is pharmacologically acceptable, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; acetic acid, fumaric acid, maleic acid, oxalic acid, Carboxylic acids such as malonic acid, succinic acid, citric acid and malic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; and amino acids such as glutamic acid and aspartic acid. Can be. Preferably they are inorganic acids or carboxylic acids, particularly preferably hydrochloric acid, nitric acid, fumaric acid, maleic acid or oxalic acid.

The base used may be any one which is pharmacologically acceptable, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide or calcium hydroxide, or an alkaline earth metal. Metal hydroxides;
Alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate and magnesium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; ammonia Inorganic salts such as; t
-Octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, benzylphenethylamine And salts with organic bases such as piperazine, tetramethylammonium and tris (hydroxymethyl) aminomethane.

The desired salt is usually obtained as a crystal or powder from a solution of the compound (I) or (II) and an acid or a base.
Further, it can be obtained as a precipitate by adding a solvent that does not dissolve the salt to the solution containing the salt, or can be obtained by removing the solvent from the solution containing the salt. Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.

[0184]

(Example 1) 4-[(1E, 3E) -4-
[Trans-5-[[(1R, 2R) -2- (2,4-
Difluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl]-
1,3-Butadienyl] -3-fluorobenzamide (Exemplary Compound No. 1-19)

[0185]

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Crushed sodium hydroxide (200 mg, 5.0
mmol) in dimethyl sulfoxide (6 ml) was stirred at room temperature, and the 4-[(1E, 3) obtained in Reference Example 5 was added thereto.
E) -4- [trans-5-[[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] thio] -1,3-dioxane-2-
Yl] -1,3-butadienyl] -3-fluorobenzonitrile (compound (IIIa ')) (500 mg, 0.92 mmol) and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution, the organic layer was separated, and washed with saturated saline. The aqueous layers were combined, ethyl acetate was added to separate the layers, and the organic layer was washed with saturated saline. The two organic layers were combined, dried over anhydrous magnesium sulfate and concentrated to give a red-brown oily residue. It was subjected to silica gel column chromatography, the fraction eluted with acetone was collected and concentrated,
A reddish-brown oily residue was obtained. Put it on a rover column (E.
Merck, LiChroprep Si 60 (40-63 μm), size B (310
-25)), and eluted with a mixed solvent of acetone-chloroform (3: 2) to obtain the title compound (140 mg, yield 27%) as a pale yellow, amorphous solid.

The ¹ H-NMR spectrum (400 MHz, acetone-
d ₆ ) δppm: 1.201 (3H, d, J = 7 Hz), 3.340 (1H, tt, J =
11, 5 Hz), 3.590 (1H, q, J = 7 Hz), 3.634 (1H, t, J =
11 Hz), 3.646 (1H, t, J = 11 Hz), 4.30-4.40 (2H, m),
5.04 (1H, d, J = 14 Hz), 5.06 (1H, d, J = 14 Hz), 5.1
33 (1H, d, J = 4.6 Hz), 5.249 (1H, br s), 5.892 (1H,
dd, J = 15.4, 4.6 Hz), 6.638 (1H, dd, J = 15.4, 10.4
Hz), 6.70-6.80 (1H, br), 6.80-6.90 (1H, m), 6.852
(1H, d, J = 15.8 Hz), 6.984 (1H, ddd, J = 12.1,8.9, 2.
5 Hz), 7.124 (1H, dd, J = 15.8, 10.4 Hz), 7.421 (1H,
td, J = 9.0, 6.8 Hz), 7.43-7.57 (1H, br), 7.678 (1
H, d, J = 11 Hz), 7.71 (1H, s), 7.72 (1H, d, J = 11 H
z), 7.75 (1H, s), 8.164 (1H, s) IR spectrum νmax KBr cm ^-1 : 3355, 1670, 1616, 1
499, 1425, 1384, 1276, 1140, 1050, 992, 966 Mass spectrum m / z (FAB): 561 (M + +1) High resolution mass spectrum m / z (FAB): C 27 H 28 F 3 O 4 N ₄ S (M
⁺ +1) Calculated: 561.1784, Observed: 561.1768 Specific rotation [α] _D ²⁵ -52.6 ° (c = 1.05, acetone). Example 2 4-[(1E, 3E) -4- [trans-
5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzoate methyl (exemplary compound number 2-7)

[0188]

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(1) 3-fluoro-4-[(1E, 3
E) -4,4-Dimethoxy-1,3-pentadienyl]
Methyl benzoate Diethyl 2-fluoro-4- (methoxycarbonyl) benzylphosphonate obtained in Reference Example 4 (2.00 g, 6.57 m
mol) in tetrahydrofuran (10 ml) was added potassium t-butoxide (810 mg, 7.22 mmol) at -78 ° C, and the mixture was stirred at 0 ° C for 10 minutes. Commercially available fumaric aldehyde monodimethyl acetal (1.0 g, 7.68 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. An aqueous ammonium chloride solution was poured into the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane-ethyl acetate-dichloromethane (9: 1: 1) to give the title compound (1.00 g, yield 54%) as a pale-yellow oil As obtained.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δpp
m: 3.35 (6H, s), 3.92 (3H, s), 4.92 (1H, d, J = 5H
z), 5.84 (1H, dd, J = 15, 5 Hz), 6.56 (1H, dd, J = 15,
10Hz), 6.77 (1H, d, J = 15 Hz), 6.96 (1H, dd, J = 15,
10 Hz), 7.54 (1H, t, J = 8Hz), 7.69 (1H, dd, J = 8, 1
Hz), 7.78 (1H, dd, J = 8, 1 Hz) (2) 4-[(1E, 3E) -4- [trans-5-
[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] thio]-
1,3-Dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzoate Methyl 3-fluoro-4-[(1E, 3E)-obtained from (1)
4,4-Dimethoxy-1,3-pentadienyl] methyl benzoate (300 mg, 1.07 mmol), (2R, 3R) -2
-(2,4-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1
-(1H-1,2,4-triazol-1-yl) -2
-Butanol (described in JP-A-8-333350;
360 mg, 1.00 mmol) and (+)-10-camphorsulfonic acid (279 mg, 1.20 mmol) were dissolved in tetrahydrofuran (5 ml) and the mixture was left at room temperature for 30 minutes. After the mixture was concentrated and dried, the resulting residue was dissolved again in tetrahydrofuran (3 ml). The mixture was left at room temperature for 10 minutes and concentrated to dryness. The residue obtained by repeating the same operation two more times was added to tetrahydrofuran (3 ml).
And cooled to 0 ° C. This tetrahydrofuran solution was slowly poured into a cooled saturated aqueous sodium hydrogen carbonate solution, and the product was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and hexane-ethyl acetate-methanol (1: 1: 0 to 0: 1: 0 to 0: 1) was used.
0: 1) Elution with a mixed solvent gave a crude product (300 mg) as a pale yellow oil. The oil was crystallized from hexane-ethyl acetate (5: 1) to give the title compound (198 m
g, yield 34%) as a colorless solid.

Melting point: 75-77 ° C. ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 1.19 (3
H, d, J = 7 Hz), 3.32 (1H, q, J = 7 Hz), 3.40 (1H, tt,
J = 11, 5 Hz), 3.62 (1H, t, J = 11 Hz), 3.64 (1H, t,
J = 11 Hz), 3.92 (3H, s), 4.30 (1H, ddd, J = 11, 5, 2
Hz), 4.42 (1H, ddd, J = 11, 5, 2 Hz), 4.83 (1H, d, J =
14 Hz), 5.01 (1H.brs), 5.03 (1H, d, J = 14 Hz), 5.
06 (1H, d, J = 4 Hz), 5.86 (1H, dd, J = 15, 4 Hz), 6.7
2 (1H, dd, J = 15, 11 Hz), 6.70-6.85 (2H, m), 6.78
(1H, d, J = 16 Hz), 6.95 (1H, dd, J = 16, 11 Hz), 7.36
(1H, q, J = 8 Hz), 7.54 (1H, t, J = 8 Hz), 7.70 (1H, d
d, J = 11, 1 Hz), 7.78 (1H, dd, J = 11, 1 Hz), 7.79 (2
H, s) IR spectrum νmax KBr cm ^-1 : 3423, 1721, 1616, 1
499, 1438, 1420, 1388, 1297, 1275, 1214, 1141, 105
0, 992, 967 Mass spectrum m / z (FAB): 576 (M ⁺ +1) Specific rotation [α] _D ²⁵ -73.6 ° (c = 0.50, CHCl ₃ ). Example 3 4-[(1E, 3E) -4- [trans-
5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzoate sodium (Exemplary Compound No. 2-31)

[0192]

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4-[(1E, 3E) -4 obtained in Example 2
-[Trans-5-[[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] thio] -1,3-dioxan-2-yl]-
1,3-Butadienyl] -3-fluorobenzoate (150 mg, 0.261 mmol) was dissolved in a mixed solvent of tetrahydrofuran-water (3: 1) (2 ml), and a 1N aqueous solution of sodium hydroxide (0.26 ml) was added. At room temperature, add the mixture to 16
Stirred for hours. The solvent was removed under reduced pressure and the resulting residue was Co
The mixture was subjected to reverse phase column chromatography using smosil 75C ₁₈ -prep (Nakalai Tesque, 10 ml), and eluted with a mixed solvent of water and methanol (2: 3). The collected fractions were concentrated and lyophilized to give the title compound (110
mg, yield 72%) as a colorless solid.

¹ H-NMR spectrum (400 MHz, D ₂ O) δpp
m: 1.04 (3H, d, J = 7 Hz), 3.15-3.25 (1H, m), 3.55-
3.70 (3H, m), 4.20-4.30 (2H, m), 4.75 (1H, d, J = 15
Hz), 4.92 (1H, d, J = 15 Hz), 5.12 (1H, d, J = 6 Hz),
5.73 (1H, dd, J = 15, 6 Hz), 6.55 (1H, dd, J = 15, 10 H
z), 6.70 (1H, td, J = 8, 2 Hz), 6.77 (1H, d, J = 16H
z), 6.84 (1H, ddd, J = 13, 9, 3 Hz), 6.91 (1H, dd, J
= 16, 10 Hz), 7.01 (1H, td, J = 9, 6 Hz), 7.39 (1H,
d, J = 12 Hz), 7.45-7.55 (2H, m), 7.60 (1H, s), 8.06
(1H, s) IR spectrum νmax KBr cm ^-1 : 3416, 1614, 1596, 1
552, 1499, 1417, 1388, 1275, 1214, 1141, 1051, 99
1,966 Mass spectrum m / z (FAB): 584 (M ⁺ +1) Specific rotation [α] _D ²⁵ -45.5 ° (c = 0.70, CH ₃ OH). (Example 4) 6- [trans-5-[(2S, 3R)-]
3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) butyl] -1,3-dioxan-2-yl]- Methyl 2-naphthalenecarboxylate

[0195]

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(4S, 5R) -5- (2,4-difluorophenyl) -2- (hydroxymethyl) -4-methyl-6- (1H-1,2,4-triazol-1-yl)
-1,5-hexanediol (JP-A-11-80135)
681 mg, 2.0 mmol) and methyl 6-formyl-
2-naphthalene carboxylate (PCT Int. Appl. WO01
No. 72743; 470 mg, 2.2 mmol) and a mixed solution of p-toluenesulfonic acid monohydrate (683 mg, 3.6 mmol) in dry tetrahydrofuran (100 ml) were concentrated using a rotary evaporator. At room temperature and dried. The obtained residue was dissolved by adding dry tetrahydrofuran (80 ml), concentrated and dried in the same manner as described above. Dry tetrahydrofuran (80 ml) was added to the residue to dissolve it, and a saturated aqueous sodium hydrogen carbonate solution was poured into the mixture while stirring at 0 ° C. The product is extracted with ethyl acetate,
The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained oily residue was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to give 769 mg of the trans isomer as the title compound. (72% yield) as a white solid. This was recrystallized from ethyl acetate,
Colorless powdery crystals were obtained.

Melting point: 184 ° C.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm
: 0.87 (3H, d, J = 7 Hz), 1.17 (1H, ddd, J = 14, 10,
4 Hz), 1.51 (1H, ddd, J = 14, 10, 4 Hz), 2.0-2.2 (1
H, m), 2.2-2.4 (1H, m), 3.64 (1H, t, J = 11 Hz), 3.66
(1H, t, J = 11 Hz), 3.98 (3H, s), 4.26 (1H, ddd, J =
11, 4, 2 Hz), 4.38 (1H, ddd, J = 11, 4, 2 Hz), 4.51
(1H, d, J = 14 Hz), 4.89 (1H, s), 4.97 (1H, d, J = 14
Hz), 5.62 (1H, s), 6.6-6.8 (2H, m), 7.3-7.5 (1H,
m), 7.66 (1H, dd, J = 9, 2 Hz), 7.79 (1H, s), 7.88 (1
H, s), 7.89 (1H, d, J = 9 Hz), 7.96 (1H, d, J = 9 Hz),
8.01 (1H, s), 8.06 (1H, dd, J = 9, 2 Hz), 8.60 (1H,
s) IR spectrum νmax KBr cm ^-1 : 3428, 1708, 1499, 11
37 Mass spectrum m / z (ESI): 538 (M ⁺⁺ 1), 537 (M ⁺ , 100
%) High-resolution mass spectrum m / z (ESI): C ₂₉ H ₃₀ O ₅ N ₃ F ₂ (M ⁺
+1), Calculated: 538.2154, Observed: 538.2137. (Example 5) 6- [trans-5-[(2S, 3R)
-3- (2,4-Difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) butyl] -1,3-dioxan-2-yl] Sodium 2-naphthalenecarboxylate

[0199]

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The 6- [trans-5] obtained in Example 4
[(2S, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,
2,4-Triazol-1-yl) butyl] -1,3-
A solution of methyl dioxane-2-yl] -2-naphthalenecarboxylate (128 mg, 0.24 mmol) in dioxane (4 ml) was cooled to 0 ° C. and stirred, and a 1N aqueous sodium hydroxide solution (0.26 ml, 0.26 mmol) was added. Was added dropwise. 70 ° C the mixture
For 8 hours. The mixed solution was concentrated with a rotary evaporator, and the obtained oily residue was washed with Cosmosil 75C ₁₈ -p
Reversed phase column chromatography using rep (Nakalai Tesque, 10 ml) gave acetonitrile-water (3: 7).
Elution with a mixed solvent followed by lyophilization gave 69 mg (yield 53%) of the title compound as a colorless solid.

¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ
ppm: 0.73 (3H, d, J = 7 Hz), 0.96 (1H, brt, J = 11 H
z), 1.51 (1H, brt, J = 11 Hz), 2.0-2.2 (2H, m), 3.6
2 (1H, t, J = 12 Hz), 3.64 (1H, t, J = 12 Hz), 4.14 (1
H, br d, J = 11 Hz), 4.25 (1H, br d, J = 11 Hz), 4.67
(1H, d, J = 15 Hz), 4.72 (1H, d, J = 15 Hz), 5.60 (1H,
s), 5.64 (1H, br s), 6.8-7.0 (1H, m), 7.1-7.2 (1
H, m), 7.2-7.4 (1H, m), 7.48 (1H, d, J = 9 Hz), 7.68
(1H, s), 7.77 (1H, d, J = 9 Hz), 7.89 (1H, s), 7.89
(1H, d, J = 9 Hz), 8.00 (1H, d, J = 9 Hz), 8.28 (1H,
s), 8.32 (1H, s) IR spectrum ν max KBr cm ^-1 : 3417, 1566, 1499, 13
94, 1136 Mass spectrum m / z (FAB): 546 (M ⁺ +1), 144 (100%) High resolution mass spectrum m / z (FAB): C ₂₈ H ₂₆ O ₅ N ₃ F ₂ Na
₂ (M ⁺⁺ Na) calcd: 568.1636, found: 568.11641. (Example 6) 6- [trans-5-[(2S, 3R)
-3- (2,4-Difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) butyl] -1,3-dioxan-2-yl] -2-Naphthalenecarboxamide

[0202]

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Under a nitrogen atmosphere, ammonium chloride (99 mg,
While stirring a mixture of 1.86 mmol) and dry toluene (2 ml) at 0 ° C., trimethylaluminum (about 15% solution in toluene; 1.10 ml, 1.86 mmol) was added dropwise. After the mixture was stirred at room temperature for 1 hour, 6- [trans-5-[(2S, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4) obtained in Example 5 was obtained. -(1H
-1,2,4-triazol-1-yl) butyl]-
1,3-Dioxan-2-yl] -2-naphthalenecarboxylate (100 mg, 0.19 mmol) in dry toluene (4 mg
ml) solution was added dropwise. After stirring the mixture at 50 ° C. for 8.5 hours, water and a 0.5 N (+)-sodium potassium tartrate aqueous solution were added in this order at room temperature, and the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-methanol (10: 1) to give 30 mg (yield 31%) of the title compound. Obtained as a colorless oil.

NMR spectrum (400 MHz, CDCl ₃ ) δ ppm
： 0.86 (3H, d, J = 7 Hz), 1.16 (1H, ddd, J = 13, 10, 3
Hz), 1.51 (1H, ddd, J = 13, 10, 3 Hz), 2.0-2.2 (1H,
m), 2.2-2.4 (1H, m), 3.64 (1H, t, J = 11 Hz), 3.66
(1H, t, J = 11 Hz), 4.26 (1H, ddd, J = 11, 4, 2 Hz), 4.
37 (1H, ddd, J = 11, 4, 2 Hz), 4.51 (1H, d, J = 14 H
z), 4.90 (1H, s), 4.97 (1H, d, J = 14 Hz), 5.62 (1H,
s), 5.82 (1H, br s), 6.22 (1H, br s), 6.6-6.8 (2H,
m), 7.3-7.5 (1H, m), 7.67 (1H, dd, J = 8, 2Hz), 7.7
9 (1H, s), 7.86 (1H, dd, J = 8, 2 Hz), 7.88 (1H, s),
7.92 (1H, d, J = 8 Hz), 7.94 (1H, d, J = 8 Hz), 8.01
(1H, s), 8.33 (1H, s) Mass spectrum m / z (FAB): 523 (M ⁺ +1), 144 (100%) High resolution mass spectrum m / z (FAB): C ₂₈ H ₂₈ O ₄ N ₄ F ₂ Na
Calculated for (M ⁺⁺ Na): 545.1976, found: 545.1969. (Reference Example 1) 4-[(1E, 3E) -4- [trans-
5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] sulfinyl] -1,3-dioxan-2-yl] -1,3
-Butadienyl] -3-fluorobenzonitrile

[0205]

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4-[(1E, 3E) -4 obtained in Reference Example 5
-[Trans-5-[[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] thio] -1,3-dioxan-2-yl]-
1,3-Butadienyl] -3-fluorobenzonitrile (compound (VIIa-0)) (2.40 g, 4.42 mmol) was dissolved in dichloromethane (40 ml), and a saturated aqueous solution of sodium hydrogen carbonate (20 ml) and carbonic acid were added at room temperature. Sodium hydrogen (0.6 g) was added. Furthermore, metachloroperbenzoic acid (75% purity, 0.90
g, 3.91 mmol) and the mixture was stirred at room temperature for 6 hours. After stopping the reaction by adding water, the product was extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was concentrated to dryness to obtain 3.6 g of a crude product. This is silica gel (40
The mixture was subjected to column chromatography using g), and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to remove highly polar impurities. The concentrated and dried mixture was applied to a rover column (manufactured by E. Merck, LiChroprep Si 60 (40-63 μm), size C (440-37)), and eluted with ethyl acetate. 458.7 mg of a less polar isomer of the title compound, 323.8 mg of a more polar isomer of the title compound having an absolute configuration of R on the sulfur atom of R, and a mixture of these two isomers were obtained. The mixture was further subjected to a rover column (LiChroprep Si 60 (40-63 μm), size C (440-37), manufactured by E. Merck) twice more to give a total of 678.3 mg (27% yield) of (S ) -Isomer and 826.7 mg (33% yield)
The (R) -isomer of each was obtained as a crystalline solid. (S) -isomer (low-polar isomer)

[0207]

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175-178 ° C. (ethyl acetate-hexane) NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 1.08 (3H, d,
J = 7 Hz), 3.29 (1H, tt, J = 11, 5 Hz), 3.49 (1H, q, J
= 7 Hz), 4.21 (1H, t, J = 11 Hz), 4.33 (1H, t, J = 11 H)
z), 4.35-4.45 (2H, m), 4.78 (1H, d, J = 14 Hz), 5.12
(1H, d, J = 4Hz), 5.28 (1H, d, J = 14 Hz), 5.80 (1H,
s), 5.88 (1H, dd, J = 15, 4 Hz), 6.63 (1H, dd, J = 15,
11 Hz), 6.76 (1H, d, J = 16 Hz), 6.79-6.84 (2H, m),
6.95 (1H, dd, J = 16, 11 Hz), 7.34 (1H, dd, J = 10, 1
Hz), 7.35-7.45 (1H, m), 7.40 (1H, d, J = 10 Hz), 7.5
8 (1H, t, J = 8 Hz), 7.83 (1H, s), 7.85 (1H, s) IR spectrum νmax KBr cm ^-1 : 2231, 1616, 1500, 1
419, 1275, 1141 Specific rotation [α] _D ²⁵ -99.3 ° (c = 1.06, chloroform) (R) -isomer (highly polar isomer)

[0209]

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Melting point: 156-158 ° C. (ethyl acetate-hexane) NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 1.22 (3H, d)
d, J = 7, 1 Hz), 3.37 (1H, q, J = 7 Hz), 3.44 (1H, tt,
J = 11, 5 Hz), 4.01 (1H, t, J = 11 Hz), 4.14 (1H, t, J =
11 Hz), 4.26 (1H, ddd, J = 11, 5, 2 Hz), 4.50 (1H, d
dd, J = 11, 5,2 Hz), 4.72 (1H, d, J = 14 Hz), 4.97 (1
H, d, J = 14 Hz), 5.12 (1H, d, J = 4 Hz), 5.34 (1H, s),
5.89 (1H, dd, J = 16, 4 Hz), 6.63 (1H, dd, J = 16, 11
Hz), 6.7-6.8 (1H, m), 6.77 (1H, d, J = 16 Hz), 6.84
(1H, td, J = 8, 2 Hz), 6.96 (1H, dd, J = 16, 11 Hz),
7.35 (1H, dd, J = 10, 1 Hz), 7.41 (1H, dd, J = 8, 1 H
z), 7.49 (1H, td, J = 9, 7 Hz), 7.58 (1H, t, J = 8 H
z), 7.80 (1H, s), 7.94 (1H, s) IR spectrum νmax KBr cm ^-1 : 2231, 1616, 1500, 1
419, 1274, 1140 Specific rotation [α] _D ²⁵ -20.5 ° (c = 1.02, chloroform). (Reference Example 2) (2R, 3R) -2- (2,4-difluorophenyl) -3-[[1- (hydroxymethyl) -2
-Hydroxyethyl] sulfinyl] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0211]

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(1) (S) -isomer

[0213]

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The (S) -isomer (low-polar isomer) (60 mg, 0.11 mmol) obtained in Reference Example 1 was dissolved in methanol (2 ml), and stirred at room temperature, and 1N HCl solution was added. (1 ml)
Was added. The mixture was stirred at the same temperature for 2 hours, and then neutralized with a saturated aqueous sodium hydrogen carbonate solution. After the product was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution. After drying the extract over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel (35 g). Elution with a mixed solvent of ethyl acetate-methanol (10: 1) yielded the title compound (33.8 m
g, yield 84%) as an amorphous solid.

NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.07 (3H, d, J = 7 Hz), 2.69 (1H, br), 3.16-3.23 (1H,
m), 3.24 (1H, br), 3.79 (1H, q, J = 7 Hz), 4.14-4.2
5 (3H, m), 4.33-4.36 (1H, m), 4.84 (1H, d, J = 14 H
z), 5.36 (1H, d, J = 14 Hz), 5.86 (1H, s), 6.78-6.84
(2H, m), 7.39-7.44 (1H, m), 7.81 (1H, s), 7.88 (1H,
s). (2) (R) -isomer

[0216]

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The (R) -isomer (highly polar isomer) obtained in Reference Example 1 (60 mg, 0.11 mmol) was reacted and worked up in the same manner as described in (1). The residue was subjected to silica gel column chromatography using silica gel (35 g) and eluted with a mixed solvent of ethyl acetate-methanol (9: 1) to give the title compound (27.9 mg, yield 67%) as an amorphous solid As obtained.

NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.20 (3H, d, J = 7 Hz), 2.63 (1H, br), 3.30-3.36 (1H,
m), 3.44 (1H, br), 3.82 (1H, q, J = 7 Hz), 4.02-4.1
7 (4H, m), 4.86 (1H, d, J = 14 Hz), 4.96 (1H, d, J = 1
4 Hz), 5.18 (1H, s), 6.73-6.84 (2H, m), 7.45-7.51
(1H, m), 7.88 (1H, s), 7.92 (1H, s) IR spectrum νmax KBr cm ^-1 : 3369, 1729, 1617, 1
501, 1140, 1049. Reference Example 3 4-[(1E, 3E) -4- [trans-
5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] sulfonyl] -1,3-dioxan-2-yl] -1,3-
Butadienyl] -3-fluorobenzonitrile

[0219]

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4-[(1E, 3E) -4 obtained in Reference Example 5
-[Trans-5-[[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] thio] -1,3-dioxan-2-yl]-
1,3-Butadienyl] -3-fluorobenzonitrile (compound (IIIa ')) (400 mg, 0.74 mmol) was dissolved in dichloromethane (6 ml), and a saturated aqueous solution of sodium hydrogencarbonate (3 ml) was added at room temperature. Sodium hydrogen (0.1 g) was added. Furthermore, metachloroperbenzoic acid (75% purity; 27
9.4 mg, 1.22 mmol) and the mixture was stirred at room temperature for 6 hours. After stopping the reaction by adding water, the product was extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was concentrated to dryness to obtain 488.2 mg of a crude product. The crude product was subjected to column chromatography using silica gel (5 g), and eluted with ethyl acetate. The residue obtained by concentration to dryness was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (329.6 mg, yield 78%) as a crystalline solid.

Melting point 196-197 ° C. (ethyl acetate-hexane) NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 1.28 (3H, d,
J = 7 Hz), 3.62 (1H, q, J = 7 Hz), 4.15 (1H, t, J = 11 H
z), 4.16 (1H, t, J = 11 Hz), 4.2-4.3 (1H, m), 4.45-
4.5 (1H, m), 4.68-4.75 (1H, m), 4.99 (1H, d, J = 15
Hz), 5.08 (1H, d, J = 4 Hz), 5.31 (1H, d, J = 15 Hz),
5.76 (1H, s), 5.89 (1H, dd, J = 15, 4Hz), 6.65 (1H,
dd, J = 15, 11 Hz), 6.7-6.8 (2H, m), 6.77 (1H, J = 16
Hz), 6.96 (1H, dd, J = 16, 11 Hz), 7.25-7.35 (1H,
m), 7.35 (1H, d, J = 10 Hz), 7.42 (1H, d, J = 8 Hz), 7.
59 (1H, t, J = 8 Hz), 7.77 (1H, s), 7.79 (1H, s) IR spectrum νmax KBr cm ^-1 : 2232, 1617, 1500, 1
420, 1305, 1277, 1141 Specific rotation [α] _D ²⁵ -11.9 ° (c = 1.07, chloroform). (Reference Example 4) diethyl 2-fluoro-4- (methoxycarbonyl) benzylphosphonate

[0222]

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(1) Methyl 3-fluoro-4-methylbenzoate Commercially available 3-fluoro-4-methylbenzoic acid (3.10 g, 2
0.1 mmol) and N, N'-carbonyldiimidazole (3.58
g, 22.1 mmol) in dichloromethane (16 ml)
Stirred at room temperature for 1 hour. Methanol (1 ml) was added thereto, and the mixture was further stirred at room temperature for 15 hours. After the mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, and washed sequentially with water, an aqueous ammonium chloride solution, and saturated saline. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain a crude product of the title compound (3.8 g) as a colorless oil.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δpp
m: 2.33 (3H, d, J = 1 Hz), 3.91 (3H, s), 7.25 (1H,
t, J = 8 Hz), 7.66 (1H, br d, J = 8 Hz), 7.72 (1H, br
d, J = 8 Hz). (2) Methyl 4- (bromomethyl) -3-fluorobenzoate The crude methyl 3-fluoro-4-methylbenzoate (3.8 g, 17 mmol) obtained in (1) in dichloroethane (15 ml).
N-bromosuccinimide (3.26 g, 18.3 mmol) was added to the solution.
Was added and the mixture was heated at reflux for 1.5 hours. During the heating, 2,2′-azobis (isobutyronitrile) (20 mg) was added in several portions. After cooling to room temperature, hexane was added to remove precipitated insolubles. The obtained solution was concentrated, and the residue was subjected to column chromatography using silica gel (50 g). Elution was carried out with a mixed solvent of hexane-ethyl acetate (5: 1). The collected fractions were concentrated to give a crude product of the title compound (3.3 g) as a pale yellow oil.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δpp
m: 3.91 (3H, s), 4.52 (2H, s), 7.47 (1H, t, J = 8 H
z), 7.73 (1H, br d, J = 8 Hz), 7.81 (1H, dd, J = 8, 1
Hz). (3) Diethyl 2-fluoro-4- (methoxycarbonyl) benzylphosphonate (the title compound) The crude methyl 4- (bromomethyl) -3-fluorobenzoate (3.3 g) obtained in (2) and phosphorous acid Triethyl (8 m
The mixture of l) was heated at 110 ° C. for 1 hour. Excess triethyl phosphite was removed under reduced pressure. The obtained residue was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-methanol (10: 0 to 10: 1). The collected fractions were concentrated and the title compound (3.
78 g (total yield from (1) 62%) was obtained as a colorless oil.

¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δpp
m: 1.26 (6H, t, J = 7 Hz), 3.25 (2H, d, J = 22 Hz), 3.
92 (3H, s), 4.0-4.2 (4H, m), 7.46 (1H, td, J = 8, 3
Hz), 7.73 (1H, d, J = 8 Hz), 7.80 (1H, d, J = 8 Hz) IR spectrum νmax (neat) cm ^-1 : 3470, 2985, 172
6, 1579, 1439, 1423,1291, 1217, 1052, 1027, 971 Mass spectrum m / z (EI): 304 (M ⁺ ). (Reference Example 5) 4-[(1E, 3E) -4- [trans-
5-[[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] thio] -1,3-dioxan-2-yl] -1,3-butadienyl] -3-fluorobenzonitrile (compound (III
a '))

[0227]

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(1) 4- (bromomethyl) -3-fluorobenzonitrile (1.5 g, 7.0 mmol) [J. Med. Che
m., 40, 2064 (1997)] and triethyl phosphite (1.4 g, 8.4 mmol) was heated at 150 ° C. for 2 hours. The mixture was concentrated under reduced pressure, and heated at 100 ° C. for 1 hour while suctioning with a vacuum pump to remove volatile components, and 1.97 g (quantitative yield) of diethyl 4-cyano-2-fluorobenzylphosphonate was obtained as an oil. (Solidified in a freezer). The obtained oil was used in the next step without further purification.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm
: 1.27 (6H, t, J = 7.1 Hz), 3.24 (2H, d, J = 22.3 H
z), 4.00-4.05 (4H, m), 7.37 (1H, d, J = 9.2 Hz), 7.4
3 (1H, d, J = 7.9 Hz), 7.51 (1H, td, J _t = 9.2 Hz, J _d =
2.6 Hz).

IR spectrum νmax CHCl ₃ cm ^-1 : 2237,
1262, 1054, 1029.

Mass spectrum m / z (EI): 271 (M ⁺ ), 139,
109 (100%), 93. (2) A solution of diethyl 4-cyano-2-fluorobenzylphosphonate (209 mg, 0.77 mmol) obtained in (1) in dry tetrahydrofuran (4 ml) was cooled to -78 ° C and stirred, and butyllithium ( Hexane solution, 1.53N, 0.5 m
L, 0.77 mmol) was added dropwise. Add the solution at -78 ° C for another 3
After stirring for 0 minutes, a commercially available solution of fumaraldehyde monodimethylacetal (100 mg, 0.77 mmol) in dry tetrahydrofuran (2 mL) was added dropwise. Mixture at -78 ° C
After stirring for 2 hours, the dry ice bath was replaced with an ice bath, and the mixture was further stirred for 15 minutes. 0.1N hydrochloric acid (3.9m
L, 0.39 mmol) was added and the mixture was stirred in an ice bath for 30 minutes and at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added in an ice bath, and the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine in that order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crystalline residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give 3-fluoro-4
127 mg (87% yield) of-[(1E, 3E) -5-oxo-1,3-pentadienyl] benzonitrile were obtained as pale yellow crystals.

174-177 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.36 (1H,
dd, J = 15, 8 Hz), 7.14 (1H, d-like, J = 3 Hz), 7.16
(1H, d, J = 8 Hz), 7.28 (1H, ddd, J = 15, 8, 3Hz), 7.4
0 (1H, dd, J = 10, 1 Hz), 7.47 (1H, dd, J = 8, 1 Hz),
7.67 (1H, t, J = 8 Hz), 9.68 (1H, d, J = 8 Hz) IR spectrum νmax (KBr) cm ^-1 : 2230, 1681, 1672,
1621, 1421, 1159, 1124 Mass spectrum m / z (EI): 201 (M ⁺ ), 172 (100%), 158,
145 Elemental analysis: C ₁₂ H ₈ FNO Calculated: C, 71.64; H, 4.01 ; N, 6.96 Analytical values: C, 71.84; H, 4.27 ; N, 6.83 (3) (2) obtained in 3-fluoro -4-[(1E, 3
E) -5-Oxo-1,3-pentadienyl] benzonitrile (4.63 g, 23.0 mmol), (2R, 3R) -2-
(2,4-difluorophenyl) -3-[[1- (hydroxymethyl) -2-hydroxyethyl] thio] -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol (described in JP-A-8-333350; 8.73 g,
24.3 mmol), p-toluenesulfonic acid monohydrate (5.
07 g, 26.7 mmol) and dry tetrahydrofuran (2
00 ml) mixture was left at room temperature for 30 minutes. The mixture was concentrated on a rotary evaporator, sucked at room temperature with a vacuum pump and dried. Dry tetrahydrofuran (150 ml) was added to the obtained residue to dissolve it, and concentrated and dried in the same manner as described above. After repeating the same operation twice more, dry tetrahydrofuran (150 ml) was added to the residue to dissolve it, and a saturated aqueous sodium hydrogen carbonate solution was poured into the stirred solution. The product was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily residue was subjected to column chromatography using silica gel (500 g), and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to give the title compound 9.
35 g (74% yield) were obtained as a pale yellow amorphous solid.

NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.19 (3H, d, J = 7 Hz), 3.33 (1H, q, J = 7 Hz), 3.40 (1
H, tt, J = 11, 5 Hz), 3.62 (1H, t, J = 11 Hz), 3.64 (1
H, t, J = 11 Hz), 4.30 (1H, ddd, J = 11, 5, 2 Hz), 4.43
(1H, ddd, J = 11, 5, 2 Hz), 4.83 (1H, d, J = 14 Hz),
5.01 (1H, s), 5.03 (1H, d, J = 14 Hz), 5.07 (1H, d, J
= 4 Hz), 5.90 (1H, dd, J = 15, 4 Hz), 6.62 (1H, dd, J
= 15, 11 Hz), 6.7-6.8 (2H, m), 6.73 (1H, d, J = 16 H
z), 6.95 (1H, dd, J = 16, 11 Hz), 7.3-7.4 (1H, m), 7.
34 (1H, d, J = 9 Hz), 7.40 (1H, d, J = 8 Hz), 7.58 (1
H, t, J = 8 Hz), 7.79 (2H, s) IR spectrum νmax (KBr) cm ^-1 : 2232, 1616, 1499,
1418, 1140 Mass spectrum m / z (FAB): 543 (M ⁺ +1) Specific rotation [α] _D ²⁵ -76.6 ° (c = 1.00, CHCl ₃ ). (Test Example) In Vitro Antifungal Activity Measurement The antifungal activity of the test compound was evaluated by the minimum inhibitory concentration (MICs) measured by the following method.

The MICs were measured by a microfluidic dilution method.
The test compound was dissolved in dimethyl sulfoxide (DMSO). Two-fold serial dilutions of each compound were made in DMSO, with a final dilution of 0.165 M 3- (morpholino) propanesulfonic acid.
(MOPS) in RPMI1640 medium buffered to pH 7.0. The final concentration of DMSO did not exceed 1%. The inoculated fungus is finally 5.0 × 10 ^{2 to} 2.5 × 10 ³ cells / ml
Was prepared. The bacterial solution and the diluted compound were mixed in each well of the microplate, and cultured at 35 ° C. for 24 to 72 hours. The MICs of the compounds were measured when clear growth was observed in control wells containing no compound. MICs were defined as the lowest compound concentration that produced at least 80% growth inhibition compared to controls.

The smaller the MICs of a compound, the stronger the antifungal activity.

Next, regarding the antifungal activity against Candida albicans, the compound of Example 1 and “40th Interscienc
e Conference on Antimicrobial Agents and Chemother
apy, ABSTRACTS ", 1087-1091, pp. 200-201 (2000).
Shown in

[0237]

Table 3 In vitro antifungal activity------------------------------------------------------------------------------------------------------------------- −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Candida albicans Candida albicans Candida albicans ATCC 24433 SANK 51486 TIMM3164 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−− The compound of Example 1 ≦ 0.008 ≦ 0.008 0.031 Compound (IIIa ′) 0.016 ≦ 0.008 0.063 −−−−−−−−− Table 3 shows that the compound of Example 1 is particularly in the genus Candida as compared with the compound (IIIa '). Excellent or better in vitro
It was found to show antifungal activity. (Formulation Example 1) Hard Capsule A unit capsule is prepared by filling a compound having the following composition into each of the standard two-part hard gelatin capsules, and then washed and dried.

Compound of Example 1 100 mg Lactose 150 mg Cellulose 50 mg Magnesium stearate 6 mg 306 mg (Formulation Example 2) Soft capsule A mixture of the compound of Example 1 in a digestible oil, such as soybean oil, cottonseed oil or olive oil, is prepared and injected into gelatin with a positive displacement pump to give 100 mg. Is obtained, washed, and dried. (Formulation Example 3) Tablet A powder having the following formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 490 mg per tablet.

[0239] In addition, if desired, a coating can be applied.

[0240]

Industrial Applicability The triazole compound of the present invention and its pharmacologically acceptable salt exhibit excellent antifungal activity (particularly against Candida), and thus are useful as therapeutic and preventive agents for fungal infections. It is.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Makoto Mori 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Inside Sankyo Co., Ltd. (72) Inventor Toshiyuki 1-2-58 Hiromachi, Shinagawa-ku, Tokyo In Sankyo Co., Ltd. (72) Inventor Takuya Uchida 1-2-58 Hiromachi, Shinagawa-ku, Tokyo F-term in Sankyo Co., Ltd. 4C063 AA01 BB03 BB08 CC82 DD41 EE01 4C086 AA01 AA02 AA03 AA04 BC60 GA02 GA07 MA01 MA04 NA14 ZB35

Claims (3)

[Claims] 1. A compound of the general formula (I) [Ar ¹ is a phenyl group (the phenyl group may have 1 to 3 halogen atoms or trifluoromethyl groups)
And Ar ² represents a phenylene group or a naphthylene group (the phenylene group and the naphthylene group are each a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a C ₁ -C 5 having ₁ to 5 halogen atoms). -C ₆ alkyl group, and C ₁ -C ₆ alkoxy groups having from 1 to 5 carbon halogen atom, also may) have 1 to 4 carbon substituents selected from become more substituent group, R ¹ represents a hydrogen atom or a C ₁ -C ₃ alkyl group, R ² and R ³ are independently hydrogen or C ₁
-C _{6 represents} an alkyl group or, together with C ₂ -C
₆ represents an alkylene group, and X represents -S-, -S (O)-,-
Represents S (O) ₂ — or —CH ₂ —, and p, q and r each independently represent an integer of 0 to 2. Or a pharmacologically acceptable salt thereof. 2. A compound of the general formula (II) [Wherein, Ar ¹ represents a phenyl group (the phenyl group may have 1 to 3 halogen atoms or trifluoromethyl groups), and Ar ² represents a phenylene group or a naphthylene group (the phenylene group And a naphthylene group are C ₁ -C ₆
A substitution comprising an alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a C ₁ -C ₆ alkyl group having ₁ to 5 halogen atoms, and a C ₁ -C ₆ alkoxy group having ₁ to 5 halogen atoms. R ¹ is a hydrogen atom or C ₁ -C
_{3 represents} an alkyl group, R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and X represents —S—, —S (O) —, —S (O) ₂
— Or —CH ₂ —, and p, q and r independently represent an integer of 0 to 2. Or a pharmacologically acceptable salt thereof. 3. A compound of the general formula (III) [Wherein, Ar ¹ represents a phenyl group (the phenyl group may have 1 to 3 halogen atoms or trifluoromethyl groups), and Ar ² represents a phenylene group or a naphthylene group (the phenylene group And a naphthylene group are C ₁ -C ₆
A substitution comprising an alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a C ₁ -C ₆ alkyl group having ₁ to 5 halogen atoms, and a C ₁ -C ₆ alkoxy group having ₁ to 5 halogen atoms. R ¹ is a hydrogen atom or C ₁ -C
_{3 represents} an alkyl group, and X represents -S-, -S (O)-, -S
(O) ₂ — or —CH ₂ —, and p, q and r independently represent an integer of 0 to 2. Or a pharmacologically acceptable salt thereof represented by the general formula (Ia): [Wherein, Ar ¹ represents a phenyl group (the phenyl group may have 1 to 3 halogen atoms or trifluoromethyl groups), and Ar ² represents a phenylene group or a naphthylene group (the phenylene group And a naphthylene group are C ₁ -C ₆
A substitution comprising an alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, a C ₁ -C ₆ alkyl group having ₁ to 5 halogen atoms, and a C ₁ -C ₆ alkoxy group having ₁ to 5 halogen atoms. R ¹ is a hydrogen atom or C ₁ -C
_{3 represents} an alkyl group, and X represents -S-, -S (O)-, -S
(O) ₂ — or —CH ₂ —, and p, q and r independently represent an integer of 0 to 2. ] Or a pharmacologically acceptable salt thereof.