JP3466273B2 - Tetrazole derivative, method for producing the same, and medicament comprising the same - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel tetrazole derivative having a hypoglycemic and hypolipidemic activity, a therapeutic agent for diabetes and a therapeutic agent for hyperlipidemia containing the same, which is used in the field of medicine. Is.

[0002]

2. Description of the Related Art Conventionally, various biguanide compounds and sulfonylurea compounds have been used as therapeutic agents for diabetes. However, biguanide compounds are rarely used at present because they cause lactic acid acidosis, and sulfonylurea compounds have a strong hypoglycemic effect, but often cause severe hypoglycemia, which requires caution in use. Is. Further, tetrazole derivatives having a substituent at the 5-position are also known, for example,
Journal of Medicinal Chemistry
al of Medicinal Chemistry), 35, 944 (19)
(1992), a series of 5-substituted tetrazole derivatives are described as having a hypoglycemic effect. However, these compounds are not sufficient in terms of activity.

[0003]

Means for Solving the Problems The present inventors have conducted various studies on 5-substituted tetrazole derivatives having stronger blood glucose and blood lipid lowering effects, and as a result, have a substituent in the 5-position substituent. It was found that the activity is remarkably enhanced by introducing a phenyl group or a pyridyl group substituted with an alkoxy group having an optionally heterocyclic residue, and completed the present invention. That is, the present invention provides (1) the general formula (I)

[Chemical 9] [In the formula, n represents an integer of 1 to 3 and A represents a heterocyclic residue which may have a substituent. Y represents a divalent hydrocarbon residue, and X represents CH or N. ] The tetrazole derivative represented by these, or its pharmacologically acceptable salt. (2) A therapeutic agent for diabetes or hyperlipidemia, comprising a tetrazole derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. (3) General formula (II)

[Chemical 10] [In the formula, each symbol has the same meaning as described above. ] It relates to a process for producing a tetrazole derivative represented by the general formula (I), which comprises reacting a compound represented by the formula with a metal azide compound.

In the compound represented by the general formula (I), -Y- which is substituted on the benzene ring or the pyridine ring is A
- (CH ₂₎ those that are substituted at substitutable positions and the para position of the _n -O- is preferable. In the above general formulas (I) and (II), the heterocyclic residue represented by A is 1) a 5-membered ring and 2) a heterocyclic ring having at least one nitrogen atom as a ring-constituting atom. It is a residue (a nitrogen-containing heterocyclic residue), and 3) the ring is preferably an aromatic ring having an unsaturated bond, 4)
It may have two or more nitrogen atoms as ring-constituting atoms, and may also have heteroatoms such as oxygen and sulfur atoms in addition to nitrogen. 5) Substitution at any position on the ring It may have a group. Specific examples of the heterocyclic residue represented by A include, for example, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl), triazolyl (1,2,
3-triazol-4-yl, 1,2,4-triazol-3-yl), tetrazolyl, oxazolyl (2-oxazolyl, 4-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl) and the like can be mentioned. These heterocyclic residues may have one or more substituents at any position on the ring, and examples of the substituents include a hydrocarbon residue, a heterocyclic group or an amino group. Further, it may have a substituent.

Examples of the hydrocarbon residue include an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, an alicyclic-aliphatic hydrocarbon residue, an araliphatic hydrocarbon residue, and an aromatic hydrocarbon residue. Groups. Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, heptyl, Saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms such as octyl, preferably those having 1 to 4 carbon atoms, and, for example, ethenyl, 1-propenyl, 2-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl , 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3 -Pentinyl, 4-
C2-C8 unsaturated aliphatic hydrocarbon residues such as pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, preferably C2-4 I can give you one. Examples of the alicyclic hydrocarbon residue include a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, preferably one having 5 or 6 carbon atoms, and 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl 5 carbons
~ 7 unsaturated alicyclic hydrocarbon residue, preferably 5 carbon atoms
Or 6 can be given. The alicyclic-aliphatic hydrocarbon residue has 4 to 9 carbon atoms among those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded, for example, cyclopropylmethyl, cyclopropylethyl ,
Examples include cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl. To be Examples of the aromatic-aliphatic hydrocarbon residue include benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-
C7-C9 phenylalkyl such as phenylpropyl, α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl and other C11-13
Naphthylalkyl can be mentioned. Examples of the aromatic hydrocarbon residue include phenyl and naphthyl (α-naphthyl, β-naphthyl).

The heterocyclic group is a 5- or 6-membered ring containing 1 to 3 selected from N, O and S in addition to carbon as atoms constituting the ring, and is a group bonded through carbon. Specific examples thereof include thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (2-thiazolyl, 4 -Thiazolyl, 5-thiazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl, 5-imidazolyl),
Pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl,
Pyridazinyl (3-pyridazinyl, 4-pyridazinyl,
Unsaturated compounds such as 5-pyridazinyl and 6-pyridazinyl, piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (2-morpholinyl, 3-morpholinyl) , Tetrahydrofuryl (2
-Tetrahydrofuryl, 3-tetrahydrofuryl) and the like saturated ones. The amino group may be substituted, and examples of the substituted amino group include an N-monosubstituted amino group and an N, N-disubstituted amino group.
The “N-monosubstituted amino group” means an amino group having one substituent, and examples of the substituent include, for example, a lower alkyl group (eg, methyl, ethyl, propyl, butyl, i
-Butyl, t-butyl, etc., having 1 to 4 carbon atoms, cycloalkyl group (eg, cyclopentyl, cyclohexyl, etc., having 3 to 7 carbon atoms), aryl group (eg, phenyl,
Naphthyl etc.), aromatic heterocyclic group (eg pyridyl, thienyl, furyl, oxazolyl, thiazolyl etc.), non-aromatic heterocyclic group (eg piperidinyl, pyrrolidinyl, morpholinyl etc.), aralkyl group (eg benzyl, phenethyl etc.) ), Acyl groups (eg, acetyl, propionyl, etc.), carbamoyl groups, N-monosubstituted carbamoyl groups (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, etc.), N, N-disubstituted carbamoyl groups. (Eg, N, N-dimethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, N, N-diethylcarbamoyl, etc.), lower alkoxycarbonyl group (eg, those having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), hydroxyl group, lower alkoxy group ( Eg methoxy, ethoxy,
And those having 1 to 4 carbon atoms such as propoxy and butoxy), aralkyloxy groups (eg, benzyloxy, phenethyloxy, naphthylmethyloxy, etc.) and the like.
The “N, N-disubstituted amino group” means an amino group having two substituents, and one example of the substituent is the same as the substituent in the above “N-monosubstituted amino group”. Other examples include lower alkyl groups, cycloalkyl groups, aryl groups, aralkyl groups, and the like. In addition, two substituents may combine with a nitrogen atom to form a cyclic amino group, and examples of such a cyclic amino group include, for example, 1-azetidinyl, pyrrolidino, piperidino, morpholino, piperazino and 4
Lower alkyl group (eg, those having 1 to 4 carbon atoms such as methyl, ethyl, propyl), aralkyl group (eg, benzyl, phenethyl, naphthylmethyl, etc.), aryl group (eg, phenyl, 4-methylphenyl, naphthyl) Such)
And the like.

The hydrocarbon residue or the heterocyclic group as the substituent on the heterocyclic residue represented by A may have a substituent at any position. When the hydrocarbon residue contains an alicyclic group or when the heterocyclic group is saturated,
The ring (including N atom) may have 1 to 3 lower alkyl groups having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, isopropyl). When the hydrocarbon residue contains an aromatic hydrocarbon residue or when the heterocyclic group is unsaturated, it has 1 to 4 substituents which are the same or different on the ring. The substituent may be, for example, halogen (fluorine, chlorine, iodine), hydroxy, cyano, nitro, trifluoromethyl, lower alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like having 1 to 1 carbon atoms). 4), lower alkyl groups (eg, those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl), lower alkoxycarbonyl (eg, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, etc. 2 to 2 carbon atoms) 4), lower alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, etc., having 1 to 3 carbon atoms)
And lower alkylamino groups (having 1 to 4 carbon atoms such as methylamino, ethylamino and dimethylamino).

When the heterocyclic residue represented by A has two or more hydrocarbon residues as its substituents, and these hydrocarbon residues are substituting each other at adjacent positions on the heterocycle. , And these may be bonded to each other to form a condensed ring. In this case, it means that the two hydrocarbon residues are linked to each other to form a saturated or unsaturated divalent chain hydrocarbon residue having 3 to 5 carbon atoms. Specific examples of the chain hydrocarbon residue include, for example, -CH ₂ CH ₂ CH _2- , -CH ₂ CH ₂ C.
H ₂ CH _2- , -CH ₂ CH ₂ CH ₂ CH ₂ CH _2- , -CH = CHCH _2- , -CH = CH-CH = C
H-, -CH = CH-CH = CH-CH _2- , -CH = CH-CH ₂ CH ₂ CH _2- and the like. General formula among the heterocyclic residues represented by A

[Chemical 11] (In the formula, B ¹ is a sulfur atom, an oxygen atom or NR [wherein R is a hydrogen atom, a lower alkyl group (for example, one having 1 to 3 carbon atoms such as methyl or ethyl) or an aralkyl group (benzyl group, phenethyl etc.)] Show. A group represented by], B ² is a nitrogen atom or C-R ² (R ² is. Showing a lower alkyl group which may be substituted with hydrogen or a hydroxyl group) shows a. R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic residue, and when R ¹ and R ² are respectively bonded to adjacent carbon atoms, R ¹ and R ² are They may be bonded to each other to form a condensed ring. } Is preferable. The hydrocarbon residue represented by R ¹ and the heterocyclic residue and the substituents of these groups are the above-mentioned hydrocarbon residue, the heterocyclic group and the substituents of those groups. It is the same as the group. Examples of the lower alkyl group represented by R ² include those having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t-butyl, pentyl, etc. The thing of -3 is preferable. The alkyl group may have a hydroxyl group at any position, but the α-position is particularly preferable. B ² is C-
When R ² and R ² are hydrogen atoms, R ¹ may be substituted on the carbon atom represented by B ² . The heterocyclic residue is attached via a possible atom on the ring, preferably a group attached via the carbon atom adjacent to the nitrogen atom. For example, when B ¹ is NR and B ² is C—R ² , a group bonded via B ² is also a preferable example.

Among the heterocyclic groups represented by the above formula, particularly the general formula

[Chemical 12] [In the formula, R ¹ and R ² are as defined above, and R ³ and R ⁴ are
Hydrogen or optionally substituted hydrocarbon residue
Alternatively, although it represents a heterocyclic residue, R ³ and R ⁴ may combine to form a condensed ring. B represents an oxygen atom or a sulfur atom. ] Thiazolyl or oxazolyl represented by The hydrocarbon residue, heterocyclic residue and their substituents represented by R ³ and R ⁴ are the above-mentioned hydrocarbon residue, heterocyclic residue and their substituents for the aromatic 5-membered heterocyclic residue. It is the same as the substituent. R ³ and R ⁴ may form a condensed ring, and in this case as well, when the aromatic 5-membered heterocyclic residue has two hydrocarbon residues at positions adjacent to each other as its substituents. It is the same as that described as the condensed ring to be formed. In a ring having X as its constituent atom, X is C
When it is H, it represents a benzene ring, and when X is N, it represents a pyridine ring. CH is preferably CH. n represents an integer of 1 to 3, preferably 1 or 2. The divalent hydrocarbon residue represented by Y may be linear or branched, and may be saturated or unsaturated. Usually, alkylene and alkenylene having 1 to 5 carbon atoms can be mentioned. For example, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,3-
Propylene, 1-methyl-1,2-ethylene, 1,4-
Examples include alkylene such as butylene, and alkenylene such as -CH = CH-CH = CH-. Of these, 1,3-propylene and 1,4-butylene are preferable.

Since the compound (I) of the present invention has an acidic nitrogen in the tetrazole ring and a basic nitrogen when it has a pyridine ring, a basic salt and an acidic salt are present. The salt is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid and the like. To be Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Suitable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
Examples thereof include salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
Examples thereof include salts with citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include:
Examples thereof include salts with aspartic acid and glutamic acid. The compound (I) of the present invention or a pharmacologically acceptable salt thereof has a hypoglycemic action and low toxicity. For example, when the compound of Example 1 is orally administered to mice at 15 mg / kg for 4 days, No changes in body weight and liver weight were observed relative to controls. Example 14
No death was observed when the compound produced in 1. was orally administered at a rate of 100 mg / kg or intraperitoneally administered at a rate of 50 mg / kg. The compound of the present invention can be used as a therapeutic agent for diabetes and a therapeutic agent for hyperlipidemia in mammals including humans. (I) is to be orally or parenterally administered as a solid preparation such as tablets, capsules, granules and powders; or as a liquid preparation such as syrups and injections by mixing with a pharmaceutically acceptable carrier. You can

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations, It is added as a solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol,
Examples thereof include dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; and polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,
Hydrophilic polymers such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like can be mentioned. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like. The administration method is usually, for example, tablets,
Orally used as capsules (including soft capsules and microcapsules), powders, granules, etc.
In some cases, it can be parenterally administered as an injection, a suppository, a pellet or the like. The dose is 1 for oral administration to adults
The daily dose is 0.05 to 10 mg / kg, and it is desirable to administer this amount once to three times a day.

The production method of the compound (I) of the present invention is described below. (Method A) A tetrazole derivative (I) is produced by reacting a nitrile derivative (II) with an azide compound. The reaction from (II) to (I) is described, for example, in the Journal of American Chemical Society.
hemical Society), 80, 3908 (1958)
It is carried out according to the method described by reaction with ammonium chloride and sodium azide in N, N-dimethylformamide. The amount of ammonium chloride and sodium azide used is 1 to 7 mol, preferably 1 to 5 mol, per 1 mol of compound (II), and it is carried out at 50 to 180 ° C. for 1 to 50 hours. In addition, the reaction from (II) to (I) depends on the journal of organic chemistry.
ganic Chemistry), 56, 2395 (1991)
It is also carried out according to the method described, by reacting compound (II) with trimethyltin azide or tributyltin azide and then treating with an acid. The tetrazole derivative and the salt thereof thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer, chromatography and the like.

(Method B)

[Chemical 13] [In the formula, Y ¹ represents a divalent hydrocarbon residue containing an unsaturated bond, Y ² represents a saturated divalent hydrocarbon residue, and other symbols have the same meanings as described above. ] As the hydrocarbon residue containing a divalent unsaturated bond represented by Y ¹ , a divalent hydrocarbon residue represented by Y containing an unsaturated bond is represented by Y
The hydrocarbon residue divalent saturated represented by ^2, include the saturated among divalent hydrocarbon residue represented by Y. In this method, among the compounds produced according to Method A,
(I-2) is produced by subjecting (I-1) to a reduction reaction. This reduction reaction can be carried out by a method known per se, but is advantageously carried out by catalytic reduction using a metal catalyst.
This catalytic reduction is carried out according to a conventional method in a solvent in the presence of a catalyst, 1 to
It is carried out in a hydrogen atmosphere of 150 atm. As the solvent, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol,
Aromatic hydrocarbons such as benzene, toluene, xylene,
Ethyl ether, isopropyl ether, dioxane,
Examples thereof include ethers such as tetrahydrofuran, chloroform, dichloromethane, halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane, ethyl acetate, acetic acid, or a mixed solvent thereof. As a catalyst, a metal such as a nickel compound, a transition metal catalyst such as palladium, platinum, or rhodium can be advantageously used. The reaction temperature is 0 to 100 ° C, preferably 10 to 80 ° C, and the reaction time is 0.5 to 50 hours. The tetrazole derivative and the salt thereof thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer, chromatography and the like.
The nitrile derivative (II) used as a starting material in the method of the present invention can be produced, for example, as follows.

(Method C)

[Chemical 14] [In the formula (IV), Z represents a halogen atom, and in the formula (VIII-1),
Q represents a leaving group, and other symbols have the same meanings as described above. ]
Examples of the halogen atom represented by Z include fluorine, chlorine, bromine and iodine. Examples of the leaving group represented by Q include halogen atoms such as chlorine, bromine and iodine, as well as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and the like.

The production process of condensing the compound (III) and the compound (IV) to obtain the compound (V) and then the aldehyde derivative (VI-1) can be carried out, for example, by chemical and pharmaceutical buretin [Chemical and Pharmaceu].
Bulletin], 39, 1440 (1991)
,), Journal of Medicinal Chemistry, 35, 261
It is performed according to the method described on page 7 (1992). Then, the compound (VI-1) is subjected to a reduction reaction to produce an alcohol compound (VII-1). This reduction reaction can be carried out by a method known per se. For example, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, catalytic hydrogenation and the like are used.
That is, this reaction is carried out by treating the compound (VI-1) with a reducing agent. Examples of the reducing agent include alkali metal borohydrides (eg, sodium borohydride, lithium borohydride, etc.), metal hydrogen complex compounds such as lithium aluminum hydride, metal hydrides such as sodium hydride, organic tin compounds (hydrogen (Triphenyltin etc.), nickel compounds, metals such as zinc compounds and metal salts, catalytic reducing agents using transition metal catalysts such as palladium, platinum, rhodium and hydrogen, and diborane. This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-
Halogenated hydrocarbons such as tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol,
Alcohols such as isopropanol and 2-methoxyethanol, amides such as N, N-dimethylformamide, and mixed solvents thereof are appropriately selected and used according to the type of reducing agent. The reaction temperature is -20 ° C to 150 ° C,
Particularly, 0 ° C to 100 ° C is preferable, and the reaction time is about 1
It is about 24 hours.

Then, the compound (VII-1) is reacted with a halogenating agent or a sulfonylating agent to produce (VIII-1). Hydrochloric acid, thionyl chloride, phosphorus tribromide and the like are preferably used as the halogenating agent, and in this case, (VIII-1) in which Q is chlorine or bromine is produced. This reaction is carried out at -10 to 80 ° C in a suitable inert solvent (eg, benzene, toluene, xylene, chloroform, dichloromethane, etc.) or using an excess halogenating agent as a solvent. The amount of halogenating agent used is 1-2 with respect to (VII-1).
It is 0 mol. As the sulfonylating agent, methanesulfonyl chloride, p-tosyl chloride, benzenesulfonyl chloride and the like are preferably used, and Q is represented by methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy (VIII-1) is produced. To do. This reaction is carried out in a suitable inert solvent (eg, benzene, toluene, xylene, ethyl ether, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, etc.) with a base (eg, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate). ,sodium carbonate,
(For example, potassium carbonate) at −10 to 30 ° C. The amount of sulfonylating agent and base used is (VII-1) 1
It is 1 to 2 mol per mol, respectively. When 1 mol of the compound (VIII-1) in which Q is chlorine, bromine or sulfonyloxy produced as described above is reacted with 1 to 1.5 mol of sodium iodide or potassium iodide, Q is iodine ( VIII-1) can also be produced. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol or ethanol at 20 to 80 ° C. Then, (II-1) is produced by reacting (VIII-1) with potassium cyanide or sodium cyanide. The reaction is usually a solvent (eg, ether, tetrahydrofuran, dioxane, chloroform, dichloromethane,
1,2-dichloroethane, methanol, ethanol, ethyl acetate, acetone, 2-butanone, N, N-dimethylformamide, dimethylsulfoxide, etc.) 0 ° C to 100
The amount of potassium cyanide or sodium cyanide used is 1 to 8 mol per 1 mol of (VIII-1).

The nitrile derivative thus obtained
(II-1) can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer, chromatography and the like. (D method)

[Chemical 15] [In the formula, J represents hydrogen or a lower alkyl group, R ⁵ represents a lower alkyl group, q represents 0 or 1, and other symbols have the same meanings as described above. Examples of the lower alkyl group represented by J or R ⁵ include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl.

In this method, an aldehyde derivative (VI-2) is reacted with a cyanomethylphosphonate derivative (IX) to produce an unsaturated nitrile derivative (II-2). (VI-2)
The reaction between (IX) and (IX) is carried out in the presence of a base in an appropriate solvent according to a conventional method. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane,
Examples thereof include alcohols such as methanol, ethanol and propanol, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and mixed solvents thereof. Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine, N, N-dimethylaniline, sodium hydride and potassium hydride. Examples of the metal hydride, sodium ethoxide, sodium methoxide, potassium t-butoxide, etc., and the amount of these bases to be used is preferably about 1 to 5 mol relative to the compound (VI-2). The amount of compound (IX) used is compound (VI-2)
In contrast, the amount is 1 to 5 mol, preferably 1 to 3 mol.
This reaction is generally -50 ° C to 150 ° C, preferably about-
It is carried out at 10 ° C to 100 ° C. Reaction time is 0.5
~ 30 hours. Compound produced in this way
(II-2) is converted to compound (II-3) by subjecting it to a reduction reaction.
To manufacture. This reduction reaction is carried out in the same manner as Method B. The nitrile derivative thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(E method)

[Chemical 16] [In the formula, R ⁶ and R ⁷ are the same or different and each represents a lower alkyl group, q represents 0 or 1, and the other symbols have the same meanings as described above. Examples of the lower alkyl group represented by R ⁶ and R ⁷ include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl.

In this method, first, an aldehyde or ketone derivative (VI-3) is reacted with a phosphonoacetic acid derivative or a γ-phosphonocrotonic acid derivative (X) to produce an unsaturated ester derivative (XI). The reaction of (VI-3) with (X) is carried out in the same manner as the reaction of the compound (VI-2) with (IX) in the method D. Then, the compound (XI) is subjected to a reduction reaction to produce an alcohol derivative (VII-2). This reduction reaction can be carried out by a method known per se. For example, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, etc. are used. That is, this reaction is carried out by treating the compound (XI) with a reducing agent. Examples of the reducing agent include alkali metal borohydrides (eg, sodium borohydride, lithium borohydride, etc.), metal-hydrogen complex compounds such as lithium aluminum hydride, and diborane. Use diisobutylaluminum hydride. Is more advantageously performed. This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, chloroform,
Carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,
Halogenated hydrocarbons such as 1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, N, N-dimethyl An amide such as formamide or a mixed solvent thereof is appropriately selected and used according to the type of the reducing agent. Reaction temperature is -20 ° C
150 [deg.] C., particularly 0 [deg.] C. to 100 [deg.] C. are suitable, and the reaction time is about 1 to 24 hours. Then the compound (VII-
Compound (VII-3) is produced by subjecting 2) to a reduction reaction. This reduction reaction is carried out in the same manner as Method B. The compound (VII-3) is the compound (VII-1) to (VIII-
The nitrile derivative (II-4) is produced by the treatment of 1) and the same treatment as in the method of leading to (II-1). The nitrile derivative thus obtained is a known separation and purification means such as concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Pyridine aldehyde derivatives used in methods D and E (VI-4)
Can be produced, for example, according to Method F.

(F method)

[Chemical 17] [In the formula (XV), Z ′ represents chlorine, bromine, or iodine,
Other symbols have the same meanings as described above. ]

In this method, first, 2-chloro-5-nitropyridine (XII) is reacted with an alcohol derivative (III) to give a compound.
(XIII) is produced. The reaction of (XII) and (III) is carried out in the presence of a base in an appropriate solvent according to a conventional method. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1, Examples include 1,2,2-tetrachloroethane and a mixed solvent thereof.
Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, pyridine, triethylamine, N,
Amines such as N-dimethylaniline, metal hydrides such as sodium hydride and potassium hydride, potassium t-
Butoxide and the like are used.
About 1 to 5 mol is preferable with respect to (III). This reaction is generally -50 ° C to 150 ° C, preferably about -10 ° C to 100 ° C.
It is performed at ℃. The reaction time is 0.5 to 30 hours.
Then, the compound (XIII) was subjected to a reduction reaction to give an amine derivative.
(XIV-1) is produced. This reduction reaction can be carried out by a method known per se, but is advantageously carried out by catalytic reduction using a metal catalyst. This catalytic reduction is carried out in a solvent according to a conventional method,
It is carried out in the presence of a catalyst in a hydrogen atmosphere at 1 to 150 atm. As the solvent, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran,
Examples thereof include halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, ethyl acetate, acetic acid, or a mixed solvent thereof. As a catalyst, a metal such as a nickel compound, a transition metal catalyst such as palladium, platinum, or rhodium can be advantageously used. The reaction temperature is 0 to 100 ° C, preferably 10 to 80 ° C, and the reaction time is 0.5 to 50 hours.
Then, the compound (XIV-1) is subjected to a Sandmeyer reaction known per se to produce a halogen derivative (XV). In this reaction, first, the compound (XIV-1) was treated with sodium nitrite (NaNO ₂ ) in a solvent in the presence of hydrochloric acid, hydrobromic acid or hydroiodic acid.
A diazotization is carried out by dropping an aqueous solution, and then the compound is reacted with an aqueous solution of sodium halide or potassium halide to produce a compound (XV). Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, ethers such as acetone, 2-butanone, dioxane and tetrahydrofuran, or a mixed solvent thereof. The reaction temperature is −80 ° C. to 100 ° C., preferably −50 to 6
The reaction time is 0 ° C. and 0.5 to 50 hours. Then compound (XV) was added to butyllithium, sec.-butyllithium, ter.
After treatment with t.-butyllithium, methyllithium, phenyllithium, etc. to give a lithio compound, or after treatment with phenylmagnesium bromide, it was reacted with N, N-dimethylformamide (DMF) to react with the compound (VI-4 ) Is manufactured.

(G method)

[Chemical 18] [G in the formulas (XVI-1) and (II-5) represents a cyano group (CN) or COOR ⁷ , and other symbols have the same meanings as described above. ].

The reaction from the compound (XIV-2) to the compound (XVI-1) is performed according to the method described in Journal of Medicinal Chemistry, Volume 35, page 2617 (1992). That is, the compound (XIV-2) is diazotized in the presence of a hydrohalic acid (HZ '), further acrylic acid ester (CH ₂ = CHCOOR ⁷ ) or acrylonitrile (CH ₂ = CHCN) with a copper catalyst (e.g., (Cuprous oxide, cupric oxide, cuprous chloride, cupric chloride, cuprous bromide, cupric bromide, etc.)
It is carried out by the Meerwein arylation reaction. Then, the compound (XVI-1) is subjected to a dehydrohalogenation reaction to produce a compound (II-5). This dehydrohalogenation reaction is carried out in the presence of a base in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol,
Ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform,
Examples thereof include dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and mixed solvents thereof. Examples of the base include alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide etc.), alkali metal carbonates (eg sodium carbonate). , Potassium carbonate, etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate etc.), alkali metal acetates (eg sodium acetate, potassium acetate etc.) ) And the like, trialkylamines (eg trimethylamine, triethylamine, etc.), picoline,
N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] non-5-ene, 1,8- Diazabicyclo [5,4,0]-
Examples include organic bases such as 7-undecene. The amount of these bases to be used is preferably about 1-5 mol with respect to the compound (XVI-1). This reaction is generally carried out at -20 ° C to 150 ° C, preferably about -10 ° C to 120 ° C.

(Method H)

[Chemical 19] [In the formula, each symbol has the same meaning as described above. ] In this method,
A propionitrile derivative (II-6) is produced by subjecting an α-halogenopropionitrile derivative (XVI-2) to a reduction reaction. This method is easily carried out, for example, by catalytic reduction in the same manner as Method B, or by a conventional method using zinc or iron and acetic acid.

(Method I)

[Chemical 20] [In the formula, each symbol has the same meaning as described above. ]

In this method, the compound (VI-2) is first condensed with the cyanoacetic acid ester derivative to produce the compound (XVII). This condensation reaction is carried out in a solvent in the presence of a base. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran, pyridine. , N, N-dimethylformamide, dimethylsulfoxide, and acetic acid. Examples of the base include sodium alkoxide (eg, sodium methoxide, sodium ethoxide, etc.), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate, piperidine, piperazine, pyrrolidine, morpholine, diethylamine, secondary amines such as diisopropylamine. Kinds are used. The amount of the base used is 0.01 to 5 molar equivalents, preferably 0.05 to 2 molar equivalents, relative to compound (VI-2). This reaction is carried out at 0 to 150 ° C., preferably 20 to 120 ° C. for 0.5 to 3
It will take 0 hours. Then, the compound (XVII) is subjected to a reduction reaction to produce the compound (XVIII). This reduction reaction can be carried out by a method known per se. For example,
Reduction with a metal hydride, reduction with a metal-hydrogen complex compound, catalytic hydrogenation and the like are used. That is, this reaction is carried out by treating the compound (XVII) with a reducing agent. As the reducing agent, an alkali metal borohydride (eg,
Sodium borohydride, lithium borohydride, etc.),
A metal-hydrogen complex compound such as lithium aluminum hydride,
Catalytic reducing agent using hydrogen with a metal hydride such as sodium hydride, an organic tin compound (hydrogen triphenyltin, etc.), a metal such as a nickel compound and a zinc compound, and a metal salt, a transition metal catalyst such as palladium, platinum, and rhodium. And diborane, etc., among which alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.) is preferably used. This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, chloroform,
Carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,
Halogenated hydrocarbons such as 1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N, N-dimethylformamide An amide such as the above, or a mixed solvent thereof is appropriately selected and used according to the type of the reducing agent. The reaction temperature is -20 ° C to 1
50 [deg.] C., especially 0 [deg.] C. to 100 [deg.] C. are suitable, and the reaction time is about 1 to 24 hours. Then compound (XVIII)
Is hydrolyzed and then decarboxylated to give the compound
(II-3) is manufactured. This hydrolysis reaction is carried out in the presence of an acid or a base in a water-containing solvent according to a method known per se, and the obtained carboxylic acid derivative (XIX) is subjected to a decarboxylation reaction with or without isolation. Compound (II-3) is produced. This decarboxylation reaction is carried out by heating in a solvent. Examples of the solvent include halogenated aromatic hydrocarbons such as benzene, toluene and xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like. Hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, dioxane, alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, amides such as N, N-dimethylformamide, chlorobenzene, o-dichlorobenzene, Pyridine or a mixed solvent thereof may be used. The reaction temperature is preferably 50 ° C. to 250 ° C., particularly 70 ° C. to 160 ° C., and the reaction time is about 1 to 24 hours.

The nitrile derivative can also be produced by the J method or K method. (J method)

[Chemical 21] [Each symbol in the formula has the same meaning as described above. In this method, the nitrile derivative (II-5) is produced by reacting the compound (XX) with the compound (XXI). The reaction of (XX) and (XXI) is carried out in the presence of a base in an appropriate solvent according to a conventional method.
Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, methanol,
Alcohols such as ethanol and propanol, N, N
-Dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane,
Examples include 1,1,2,2-tetrachloroethane and a mixed solvent of two or more of these. Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine, N, N-dimethylaniline, sodium hydride and potassium hydride. Examples of the metal hydride, sodium ethoxide, sodium methoxide, potassium t-butoxide, etc., and the amount of these bases to be used is preferably about 1 to 5 mol relative to the compound (III). This reaction is generally carried out at -50 ° C to 150 ° C, preferably about -10 ° C to 100 ° C. The reaction time was 0.
5 to 30 hours.

(K method)

[Chemical formula 22] [Each symbol in the formula has the same meaning as described above. In this method, first, an ester derivative (XXIII) is produced by reacting a compound (XX) with a compound (XXII). This reaction is carried out in the same manner as the reaction between compound (XX) and compound (XXI) in Method J. Then, the compound (XXIII) is treated in the same manner as in the reaction of the compound (XI) to the compound (VII-2) in Method E to produce an alcohol derivative (VII-4). Compound (VII-4) can be obtained by reacting compound (VIII-4) in the same manner as in the reaction from compound (VII-3) to compound (VIII-2) in Method E.
-3). The compound (VIII-3) is treated in the same manner as in the reaction of the compound (VIII-2) to the compound (II-4) in Method E to produce a nitrile derivative (II-6).

[0030]

INDUSTRIAL APPLICABILITY The compound (I) according to the present invention has a blood glucose and blood lipid lowering action. Experimental data supporting this point will be described. Experimental Example Blood glucose and hypolipidemic action in mice A test compound was added to powder feed (CE-2, CLEA Japan, Inc.) in an amount of 0.
The mixture was mixed at a ratio of 01% or 0.005%, and was given to KKA ^y -mice (9 to 14 weeks old) freely for 4 days. During this time, water was given freely. Blood was collected from the orbital vein and the glucose and triglyceride levels in plasma were measured by the enzymatic method using iatrochem-GLU (A) and iatro-MA7, respectively.
Each measurement was carried out by quantifying with 01 TG kit (Yatron). Each value was expressed as a reduction rate (%) with respect to the drug non-administration group, and is shown in [Table 1].

[Table 1] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Compound Dose ¹⁾ Hypoglycemic action Lipid lowering action (Example No.) ( %) (%) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 1 0.01 45 45 28 2 0.01 21 19 3 0. 01 15 26 5 0.01 0.01 26 10 7 0.01 36 37 7 8 0.01 38 38 32 9 0.01 31 33 33 14 0.005 53 74 16 16 0.005 43 48 22 0.005 46 85 23 23 0.005 26 23 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ¹⁾ Feed compound concentration (% by weight) Thus, the tetrazole derivative according to the present invention (I) has an excellent blood glucose and blood lipid lowering action, and is used as a drug such as an antidiabetic agent, an antihyperlipidemic agent, an antihypertensive agent. Useful.

Reference Example 1 2-chloro-5-nitropyridine (25 g), 2- (5
To a solution of -methyl-2-phenyl-4-oxazolyl) ethanol (32.1 g) in THF (250 ml) was added oily sodium hydride (60%, 6.92 g) in small portions under ice cooling, and the mixture was stirred. The reaction mixture was stirred at room temperature for 15 hours, then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ) and then the solvent was distilled off under reduced pressure. The remaining crystals were collected by filtration and recrystallized from ethanol to give 2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-nitropyridine (25.4
g, 49%). Yellow-brown crystals. Melting point 110.5 ~
111.5 ° C. Reference Example 2 2- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -5-nitropyridine (13.4
g), palladium carbon (5%, 1.5 g) and a mixture of ethyl acetate (200 ml) -methanol (150 ml) were subjected to catalytic reduction at room temperature and 1 atm. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residual crystals were collected by filtration and 5-amino-2-
[2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (11.4 g, 93%) was obtained. Recrystallized from ethyl acetate-hexane. Brown crystals.
Melting point 107-108 [deg.] C.

Reference Example 3 5-amino-2- [2- (5-methyl-2-phenyl-
4-oxazolyl) ethoxy] pyridine (10.0
g), concentrated hydrochloric acid (8.47 ml) and acetone (100 m)
l) to the mixture of sodium nitrite (NaNO ₂ ) (2.46
A solution of g) in water (10 ml) was added dropwise at a temperature below 10 ° C. After stirring for 30 minutes at 10 ℃, potassium iodide (KI)
A solution of (2.46 g) in water (10 ml) was added dropwise. The reaction mixture was further stirred at 30 to 35 ° C. for 1 hr and 35 to 40 ° C. for 1 hr, and then concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
After (MgSO ₄ ) the solvent was evaporated under reduced pressure and the residual oil was subjected to silica gel chromatography. From the portion eluted with ethyl acetate-hexane (1: 3, v / v), 5-iodo-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (7.22 g) was obtained. , 52%). Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 105-106 [deg.] C. Reference Example 4 5-Iodo-2- [2- (5-methyl-2-phenyl-
To a solution of 4-oxazolyl) ethoxy] pyridine (2.5 g) in tetrahydrofuran (40 ml) was added a solution of n-butyllithium in hexane (1.6 M, 4.61 ml) dropwise at -65 ° C under a nitrogen stream. After stirring the mixture at the same temperature for 15 minutes, N, N-dimethylformamide (0.71
ml) was added dropwise. The cooling bath was removed and after stirring for an additional 30 minutes, saturated aqueous ammonium chloride solution (6 ml) was added. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to give 5-formyl-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (1.
5g, 79%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 99-100 [deg.] C.

Reference Example 5 A solution of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (7.0 g) in ethanol (100 ml) was cooled with sodium borohydride (0. 473 g) was added, and the mixture was stirred at room temperature for 2 hours. After adding acetic acid (2 ml) to the reaction mixture, it was poured into ice-water and the precipitated crystals were collected by filtration. Recrystallized from ethyl acetate-hexane to give 4- [2- (5-methyl-2-phenyl-
4-Oxazolyl) ethoxy] benzyl alcohol (6.9 g, 88%) was obtained. Colorless plate crystals. Melting point 11
2 to 113 ° C. Reference Example 6 A solution of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl alcohol (6.8 g) in chloroform (100 ml) was thionyl chloride (3.1 g).
g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, and dried (MgS
After O ₄ ), the solvent was distilled off and 4- [2- (5-methyl-
2-Phenyl-4-oxazolyl) ethoxy] benzyl chloride (6.5 g, 90%) was obtained. Colorless needles. Melting point 93-94 [deg.] C. Reference Example 7 A mixture of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl chloride (6.4 g), powdered potassium cyanide (4.0 g) and N, N-dimethylformamide (50 ml). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated, and 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzylcyanide (5.2 g, 8
1%) was obtained. Recrystallized from ethyl acetate-hexane.
Colorless needles. Melting point 109-110 [deg.] C.

Reference Example 8 Sodium hydride (oil, 60%, 2.0 g) was added little by little to a solution of diethyl cyanomethylphosphonate (8.2 g) in tetrahydrofuran (150 ml) at 0 ° C., and 15
Stir for the same temperature. Then, 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (13.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO _4), evaporated, 4- [2- (5-methyl-2-phenyl -
4-oxazolyl) ethoxy] cinnamonitrile (1
1.8 g, 85%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 112-113 [deg.] C. Reference Examples 9 to 15 The compounds of [Table 2] were obtained in the same manner as in Reference Example 8.

[Table 2] Note 1) (E) body: (Z) body = 3: 1 mixture. NMR (δ ppm in CDCl ₃ ): 1.2-2.1 (10H, m), 2.24 (3H,
s), 2.6-2.8 (1H, m), 2.89 (2H, t, J = 7Hz), 5.28 (d, J = 12Hz)
and 5.70 (d, J = 16.5Hz) (total 1H), 6.88 and 6.91 (tota
l 2H, each d, J = 9Hz), 7.02 (d, 12Hz) and 7.32 (d, J = 16.5
Hz) (total 1H), 7.37 and 7.76 (total 2H, each d, J = 9H
z) Note 2) Used in the next reaction without isolation Note 3) A mixture of (E) form: (Z) form = 5: 2. NMR (δ ppm in CDCl ₃ ): 2.24 (3H, s), 2.38 (3H, s), 2.
88 (2H, t, J = 7Hz), 4.21 and 4.23 (t, J = 7Hz) (total 2H),
5.28 (d, J = 12Hz) and 5.71 (d, J = 16.5Hz) (total 1H), 6.8
9 and 6.93 (total 2H, each d, J = 9Hz), 7.02 (d, J = 12Hz)
and 7.32 (d, J = 16.5Hz) (total 1H), 7.37 and 7.77 (tot
al 2H, each d, J = 9 Hz).

Reference Example 16 4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] cinnamonitrile (4.0 g), palladium-carbon (5%, 0.5 g) and ethyl acetate ( 5
0 ml) of the mixture was subjected to catalytic reduction at 1 atm and room temperature.
After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to give 3- [4- [2
-(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propionitrile (3.7 g, 93
%) Was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 109-110 [deg.] C. Reference Examples 17 to 21 The compounds of [Table 3] were obtained in the same manner as in Reference Example 16.

[Table 3]

Reference Example 22 Sodium hydride (oil, 60%, 2.2 g) was added little by little to a solution of triethylphosphonoacetate (11.2 g) in tetrahydrofuran (200 ml) at 0 ° C., and the mixture was stirred at the same temperature for 15 minutes. . Then, 4- [2- (5-methyl-2
-Phenyl-4-oxazolyl) ethoxy] benzaldehyde (14.0 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-water, neutralized with 2N hydrochloric acid, and the precipitated crystals were collected by filtration. Recrystallized from ethyl acetate-hexane to give ethyl 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] cinnamate (15.1 g, 8
8%). Colorless needles. Melting point 114-115 [deg.] C. Reference Example 23 A toluene solution of diisobutylaluminum hydride (1.
5M, 67 ml) of ethyl 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] cinnamate (1
5.0 g) was added dropwise to a suspension of toluene (200 ml) at 0 ° C. After stirring for 2 hours at room temperature, add 2N HCl under ice cooling.
(200 ml) was added. The organic layer is washed with water and dried (MgS
O ₄ ) and then concentrated to give (E) -3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] -2-propen-1-ol (12.0 g, 90
%) Was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 127-128 [deg.] C.

Reference Example 24 (E) -3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] -2-propen-1-ol (3.1 g), palladium -Carbon (5
%, 0.5 g) and ethyl acetate (50 ml) were subjected to catalytic reduction at 1 atm and room temperature. After filtering off the catalyst,
The filtrate was concentrated under reduced pressure to give 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propan-1-ol (2.8 g, 90%). . Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 99-100 [deg.] C. Reference Example 25 A mixture of 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propan-1-ol (2.6 g) and benzene (50 ml) was added with phosphorus tribromide. (PBr ₃ ) (2.1 g) was added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), then the solvent was distilled off, and 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propyl bromide (0 .98 g, 32%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 78-
79 ° C.

Reference Example 26 5-amino-2- [2- (5-methyl-2-phenyl-
4-oxazolyl) ethoxy] pyridine (9.1 g),
HBr water (47%, 14.2 ml) and acetone (15
0 ml) to a mixture of sodium nitrite (NaNO ₂ ) (2.3
A solution of 3 g) in water (10 ml) was added dropwise at a temperature below 10 ° C. After stirring at 10 ° C for 30 minutes, acrylonitrile (C
H ₂ = CHCN) (12.1 ml) was added. Cuprous oxide (Cu ₂ O) (0.1 g) was added with vigorous stirring of the mixture. The reaction mixture was further stirred at 30 to 35 ° C. for 1 hr and then concentrated under reduced pressure. The residue was poured into water, made alkaline with concentrated aqueous ammonia, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the residual oil was subjected to silica gel chromatography. From the portion eluted with ethyl acetate-hexane (1: 1, v / v), 2-bromo-3- [2- [2- (5-methyl-2-
Phenyl-4-oxazolyl) ethoxy] -5-pyridyl] propionitrile (6.11 g, 48%) was obtained.
Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 93-94 [deg.] C. Reference Example 27 2-Bromo-3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl]
Propionitrile (2.0 g), palladium-carbon (5
%, 0.2 g) and dioxane (30 ml) were subjected to catalytic reduction at 1 atm and room temperature. After filtering off the catalyst,
The filtrate was concentrated under reduced pressure and the residual oil was subjected to silica gel chromatography. Ethyl acetate-hexane (2:
3, v / v), the portion eluted at 3- [2- [2-
(5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] propionitrile (1.3 g,
78%). Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 105-106 [deg.] C.

Reference Example 28 2-Bromo-3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl]
Propionitrile (4.5g), lithium bromide (LiBr)
(1.14 g), lithium carbonate (Li ₂ CO ₃ ) (2.17 g)
And a mixture of N, N-dimethylformamide (50 ml) was stirred at 120 ° C. for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ) and then the solvent was distilled off under reduced pressure to give (E) -3.
-[2- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] acrylonitrile (3.2, 89%) was obtained. Recrystallized from ethyl acetate-hexane. Pale yellow crystals. Melting point 116-117 [deg.] C. Reference Example 29 4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] benzaldehyde (2.0 g), ethyl cyanoacetate (0.795 g), piperidine (0.15 g) ) And pyridine (30 ml) were stirred at 100-110 ° C. for 2 hours. The reaction mixture was poured into water and the precipitated crystals were collected by filtration, dichloromethane-
Recrystallized from ethanol and ethyl 4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] -α-cyanocinnamate (2.45 g, 96
%) Was obtained. Colorless needles. Melting point 120-121 ° C.

Reference Example 30 Ethyl 4- [2- [2- (2-chlorolphenyl) -5-methyl-4-oxazolyl] ethoxy] -α-cyanocinnamate (2.25 g) and dioxane (30 ml). −
Sodium borohydride (0.06 g) was added to a mixture of ethanol (30 ml) under ice cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into ice-water to acidify it and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was evaporated under reduced pressure, and the residual oil was subjected to silica gel chromatography. Chloroform-methanol (5
0: 1, v / v), 3- [4- [2
-[2- (2-chlorophenyl) -5-methyl-4-
An oily product of ethyl oxazolyl] ethoxy] phenyl] -2-cyanopropionate (2.25 g, quant.) Was obtained. NMR (δ ppm in CDCl ₃ ): 1.27 (3H, t, J = 7Hz), 2.
39 (3H, s), 3.00 (2H, t, J = 6.5Hz), 3.12 (1H, dd, J = 14 & 8H
z), 3.22 (1H, dd, J = 14 & 6Hz), 3.66 (1H, dd, J = 8 & 6Hz), 4.2
2 (2H, q, J = 7Hz), 4.24 (2H, t, J = 6.5Hz), 6.87 (2H, d, J = 9H
z), 7.17 (2H, d, J = 9Hz), 7.25-7.5 (3H, m), 7.85-8.0 (1H,
m). Reference Example 31 3- [4- [2- [2- (2-chlorophenyl) -5)
-Methyl-4-oxazolyl] ethoxy] phenyl]-
Ethyl 2-cyanopropionate (2.24 g), 1N
A mixture of NaOH (15 ml) and ethanol (50 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water, acidified and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and the solvent was distilled off (MgSO ₄₎ After vacuo collected by filtration residual crystals. The crystals were added to pyridine (5 ml) -o-dichlorobenzene (50 ml) and heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the residual oil was subjected to silica gel chromatography. From the portion eluted with chloroform, 3- [4- [2- [2- (2- (chlorochlorophenyl) -5-methyl-4-oxazolyl] ethoxy] phenyl] propionitrile (1.5 g, 80%) was added. Obtained.
Recrystallized from dichloromethane-isopropyl ether. Pale yellow crystals. Melting point 88-89 [deg.] C.

Reference Example 32 In the same manner as in Reference Example 22, ethyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamate was obtained. Recrystallized from ethyl acetate-hexane. Colorless columnar crystals. Melting point 145-146 [deg.] C. Reference Example 33 In the same manner as in Reference Example 23, (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-peropen-1-ol was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 1
34-135 ° C. Reference Example 34 Activated manganese dioxide (MnO ₂ ) (9.0 g) was added to (E) -3.
-[4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-ol (3.7 g) in dichloromethane (80 ml) was added,
Stir for 1 hour at room temperature. The reaction mixture was filtered through a Celite layer, and the filtrate was concentrated under reduced pressure to give 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamoaldehyde (2.6 g, 70%). . Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 11
4-115 ° C.

Reference Example 35 Sodium hydride (oil, 60%, 0.32 g) was added little by little to a solution of diethyl cyanomethylphosphonate (1.3 g) in tetrahydrofuran (50 ml) at 0 ° C.
Stir at the same temperature for a minute. Then 4- (5-methyl-
2-Phenyl-4-oxazolylmethoxy) cinnamoaldehyde (2.0 g) was added, and the mixture was stirred for 30 minutes under ice cooling. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and concentrated under reduced pressure to give (E, E) -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2, 4-
Pentadiene nitrile (1.5 g, 68%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 120-121 [deg.] C. Reference Example 36 In the same manner as in Reference Example 24, 3- [4- (5-methyl-2)
-Phenyl-4-oxazolylmethoxy) phenyl] propan-1-ol was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 72-73 [deg.] C. Reference Example 37 In the same manner as in Reference Example 25, 3- [4- (5-methyl-2)
-Phenyl-4-oxazolylmethoxy) phenyl] propyl bromide was obtained. Recrystallized from ethyl ether-hexane. Colorless prism crystals. Melting point 80-81 [deg.] C.

Reference Example 38 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl bromide (1.5
g), powdered potassium cyanide (1.52 g) and N,
Mix a mixture of N-dimethylformamide (30 ml) at 80 ° C.
Stir for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎
Then, the mixture was concentrated under reduced pressure to obtain 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] butyronitrile (1.2 g, 92%). Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 73-74 [deg.] C. Reference Example 39 In the same manner as in Reference Example 38, 4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] butyronitrile was obtained. Recrystallized from ethyl ether-hexane. Colorless needles. Melting point 69-70 [deg.] C. Reference Example 40 In the same manner as in Reference Example 22, (E, E) -5 was obtained by reacting 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamoaldehyde with triethylphosphonoacetate.
Obtained ethyl [-(4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienoate. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 137-138 [deg.] C.

Reference Example 41 In the same manner as in Reference Example 16, ethyl (E, E) -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienoate. Was subjected to catalytic reduction reaction, and 5- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) phenyl] ethyl valerate was obtained. Recrystallized from hexane. Colorless columnar crystals. Melting point 57
-58 ° C. Reference Example 42 5- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl valerate (2.55 g)
A solution of the above in ether (20 ml) was cooled to below the freezing point, and lithium aluminum hydride (LiAlH ₄ ) (0.247 g) in ether (4
0 ml) suspension. The mixture was stirred below freezing for 15 minutes, water (2 ml) was added dropwise, the insoluble material was filtered off, and the filtrate was concentrated to 5- [4- (5-methyl-2-phenyl-4-).
Oxazolylmethoxy) phenyl] -1-pentanol (2.15 g, 94%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless columnar crystals. Melting point 78-79 [deg.] C. Reference Example 43 In the same manner as in Reference Example 25, 5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1-
In the reaction of pentanol and phosphorus tribromide, 5- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Phenyl] pentyl bromide was obtained. Recrystallized from ether-hexane. Colorless needles. Melting point 58-59 [deg.] C.

Reference Example 44 In the same manner as in Reference Example 38, 5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] pentyl bromide was reacted with potassium cyanide to give 5- [4-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] hexanenitrile was obtained. Recrystallized from ether-hexane. Colorless prism crystals. Melting point 76-
77 ° C. Reference Example 45 4-chloromethyl-5-methyl-2-phenyloxazole (9.2 g), p-hydroxyacetophenone (7.95 g), potassium carbonate (6.73 g) and N,
A mixture of N-dimethylformamide (DMF) (100 ml) was stirred at 70-80 ° C for 2.5 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎ After the solvent was distilled off 4 '- (5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone (11.6 g, 85%) . Recrystallized from ethyl acetate-ether. Colorless prism crystals. Melting point 126-12
7 ° C. Reference Example 46 In the same manner as in Reference Example 22, by reacting 4 ′-(5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone with trimethylphosphonoacetate, (E) -3- [4
Methyl-(5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-butenoate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 125-126 [deg.] C.

Reference Example 47 In the same manner as in Reference Example 23, methyl (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-butenoate was replaced with diisobutyl hydride. Subjected to reduction reaction with aluminum, (E) -3- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Phenyl] -2-buten-1-ol was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point
126-127 ° C. Reference Example 48 In the same manner as in Reference Example 34, (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-buten-1-ol was treated with active manganese dioxide. It was subjected to an oxidation reaction to obtain (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-buten-1-al. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 94-
95 ° C. Reference Example 49 (E) -3- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-buten-1-al and diethyl cyanomethylphosphonate in the same manner as in Reference Example 35. By reaction with (E, E) -5- [4- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
Phenyl] -2,4-hexadienenitrile was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 134-136 ° C

Reference Example 50 In the same manner as in Reference Example 45, 4-chloromethyl-5-methyl-
Reaction of 2-phenyloxazole with m-hydroxybenzaldehyde gave 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde. Recrystallized from ethanol. Colorless prism crystals. Melting point 67-68 [deg.] C. Reference Example 51 In the same manner as in Reference Example 22, 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde was reacted with triethylphosphonoacetate to give 3- (5-methyl-2-phenyl-4). -Oxazolylmethoxy) ethyl cinnamate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 94-95 [deg.] C. Reference Example 52 In the same manner as in Reference Example 23, ethyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamate was subjected to a reduction reaction with diisobutylaluminum hydride,
(E) -3- [3- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) phenyl] -2-propene-1
-I got all. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 120-121 [deg.] C.

Reference Example 53 In the same manner as in Reference Example 34, (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-ol was activated. It was subjected to an oxidation reaction with manganese dioxide to obtain (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-al. Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 10
3-104 ° C. Reference Example 54 As in Reference Example 35, (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-al and diethyl cyanomethylphosphonate. By reaction with (E, E) -5- [3-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienenitrile was obtained as an oil. Reference Example 55 In the same manner as in Reference Example 45, 2-chloromethyl-5-methyl-
Reaction of 4-phenylthiazole with p-hydroxybenzaldehyde gave 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) benzaldehyde.
Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 81-82 [deg.] C.

Reference Example 56 In the same manner as in Reference Example 22, 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) benzaldehyde was reacted with trimethylphosphonoacetate to prepare 4- (5-methyl-
Methyl 4-phenyl-2-thiazolylmethoxy) cinnamate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 142-143 [deg.] C. Reference Example 57 In the same manner as in Reference Example 23, methyl 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) cinnamate was subjected to a reduction reaction with diisobutylaluminum hydride, and (E)
-3- [4- (5-Methyl-4-phenyl-2-thiazolylmethoxy) phenyl] -2-propen-1-ol was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 125-126 [deg.] C. Reference Example 58 In the same manner as in Reference Example 34, (E) -3- [4- (5-methyl-4-phenyl-2-thiazolylmethoxy) phenyl]
2-propen-1-ol was subjected to an oxidation reaction with active manganese dioxide to give (E) -3- [4- (5-methyl-
4-Phenyl-2-thiazolylmethoxy) phenyl]-
2-Propen-1-al was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 116-1
17 ° C.

Reference Example 59 As in Reference Example 35, (E) -3- [4- (5-methyl-4-phenyl-2-thiazolylmethoxy) phenyl]
Reaction of 2-propen-1-al with diethyl cyanomethylphosphonate gives (E, E) -5- [4- (5-
Methyl-4-phenyl-2-thiazolylmethoxy) phenyl] -2,4-pentadienenitrile was obtained. Recrystallized from ethyl acetate-ether. Colorless prism crystals. Melting point 108-109 [deg.] C. Reference Example 60 In the same manner as in Reference Example 45, 2-chloromethyl-5-methyl-
Reaction of 4-phenyloxazole and p-hydroxybenzaldehyde gave 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) benzaldehyde. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 90-91 [deg.] C. Reference Example 61 In the same manner as in Reference Example 22, 4- (5-methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde was reacted with trimethylphosphonoacetate to give 4- (5-methyl-4-phenyl-2). -Methyl (oxazolylmethoxy) cinnamate was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 109-110
° C.

Reference Example 62 In the same manner as in Reference Example 23, methyl 4- (5-methyl-4-phenyl-2-oxazolylmethoxy) cinnamate was subjected to a reduction reaction with diisobutylaluminum hydride,
(E) -3- [4- (5-methyl-4-phenyl-2-
Oxazolylmethoxy) phenyl] -2-propene-1
-I got all. Recrystallized from chloroform-isopropyl ether. Colorless prism crystals. Melting point 154-15
5 ° C. Reference Example 63 In the same manner as in Reference Example 34, (E) -3- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-ol was treated with active manganese dioxide. It was subjected to an oxidation reaction to obtain (E) -3- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-al. Recrystallized from chloroform-ether. Colorless prism crystals. Melting point 1
44-146 ° C. Reference Example 64 In the same manner as in Reference Example 35, (E) -3- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-al and diethyl cyanomethylphosphonate. By reaction with (E, E) -5- [4-
(5-Methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2,4-pentadienenitrile was obtained. Then, in the same manner as in Reference Example 16, (E, E) -5- [4
-(5-Methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2,4-pentadienenitrile was subjected to catalytic reduction reaction to give 5- [4- (5-methyl-4-phenyl-2- Oxazolylmethoxy) phenyl] valeric acid nitrile was obtained. Recrystallized from ethyl acetate-ether-hexane. Colorless prism crystals. Melting point 65-66 [deg.] C.

Reference Example 65 In the same manner as in Reference Example 45, 4-chloromethyl-5-methyl-
By reacting 2- (2-naphthyl) oxazole with p-hydroxybenzaldehyde, 4- [5-methyl-2
-(2-Naphthyl) -4-oxazolylmethoxy] benzaldehyde was obtained. Recrystallized from chloroform-ether. Colorless prism crystals. Melting point 163-164 [deg.] C. Reference Example 66 In the same manner as in Reference Example 22, 4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] benzaldehyde was reacted with trimethylphosphonoacetate to give 4- [5
Methyl 2-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] cinnamate was obtained. Recrystallized from chloroform-ether. Colorless prism crystals. Melting point 185-1
86 ° C. Reference Example 67 In the same manner as in Reference Example 23, methyl 4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] cinnamate was subjected to a reduction reaction with diisobutylaluminum hydride, and (E ) -3- [4- [5-Methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2-
Propene-1-ol was obtained. Recrystallized from chloroform-ether. Colorless prism crystals. Melting point 159-16
0 ° C.

Reference Example 68 (E) -3- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] in the same manner as in Reference Example 34.
Phenyl] -2-propen-1-ol was subjected to an oxidation reaction with active manganese dioxide to give (E) -3- [4- [5
-Methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2-propen-1-al was obtained. Recrystallized from chloroform-ether. Colorless prism crystals. Melting point 179-180 [deg.] C. Reference Example 69 (E) -3- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] in the same manner as in Reference Example 35.
Phenyl] -2-propen-1-al was reacted with diethyl cyanomethylphosphonate to give (E, E) -5-
[4- [5-Methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2,4-pentadienenitrile was obtained. Recrystallized from ethyl acetate-ether. Colorless prism crystals. Melting point 159-160 [deg.] C. Reference Example 70 In the same manner as in Reference Example 45, 4-chloromethyl-5-methyl-
The reaction of 2- (2-naphthyl) oxazole with 4- (4-hydroxyphenyl) butyronitrile yields 4-
[4- [5-Methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] butyronitrile was obtained.
Recrystallized from chloroform-ether. Colorless prism crystals. Melting point 149-151 [deg.] C.

Reference Example 71 In the same manner as in Reference Example 45, 4-chloromethyl-5-methyl-
By the reaction of 2- (2-naphthyl) oxazole with methyl 5- (4-hydroxyphenyl) valerate, 5- [4
Methyl-[5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] valerate was obtained. Then, in the same manner as in Reference Example 42, 5- [4- [5-methyl-2-
Methyl (2-naphthyl) -4-oxazolylmethoxy] phenyl] valerate was subjected to a reduction reaction with lithium aluminum hydride to give 5- [4- [5-methyl-2- (2-
Naphthyl) -4-oxazolylmethoxy] phenyl] pentan-1-ol was obtained. Recrystallized from ethyl acetate-ether. Colorless needles. Melting point 128-129 [deg.] C. Reference Example 72 5- [4- [5-methyl-2- (2-naphthyl) -4-
Methanesulfonyl chloride (0.345 g) was added dropwise to a mixture of oxazolylmethoxy] phenyl] pentan-1-ol (1.1 g), triethylamine (0.333 g) and dichloromethane (40 ml) under ice cooling. The mixture was stirred at room temperature for 2 hours, washed with water and dried (MgSO ₄ ).
Then, the solvent was distilled off and 5- [4- [5-methyl-2- (2
-Naphthyl) -4-oxazolylmethoxy] phenyl]
Pentyl methanesulfonate (1.21g, 92%)
Got Recrystallized from dichloromethane-ether. Colorless prism crystals. Melting point 132-133 [deg.] C.

Reference Example 73 In the same manner as in Reference Example 38, 5- [4- [5-methyl-2-
(2-naphthyl) -4-oxazolylmethoxy] phenyl] pentyl 6- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] by reaction of methanesulfonate with potassium cyanide. Phenyl] hexanenitrile was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 116-11
7 ° C. Reference Example 74 In the same manner as in Reference Example 35, 4- [3- (5-methyl-2-phenyl-4-oxazolyl) propoxy] benzaldehyde was reacted with diethyl cyanomethylphosphonate to give 4- [3- (5-methyl- 2-Phenyl-4-oxazolyl) propoxy] cinnamonitrile was obtained. Recrystallized from ethyl acetate-isopropyl ether-hexane.
Colorless prism crystals. Melting point 97-98 [deg.] C. Reference Example 75 In the same manner as in Reference Example 45, 2-chloromethyl-5-methyl-
2- (5-Methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde was obtained by the reaction of 4-phenyloxazole and o-hydroxybenzaldehyde. Recrystallized from ethyl acetate-ether. Colorless prism crystals. Melting point 95-96 [deg.] C. Reference Example 76 In the same manner as in Reference Example 22, 2- (5-methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde was reacted with trimethylphosphonoacetate to give 2- (5-methyl-4-phenyl-2). -Methyl (oxazolylmethoxy) cinnamate was obtained. Recrystallized from ethyl acetate-chloroform-ether. Colorless prism crystals. Melting point 128-129
° C.

Reference Example 77 In the same manner as in Reference Example 23, methyl 2- (5-methyl-4-phenyl-2-oxazolylmethoxy) cinnamate was subjected to a reduction reaction with diisobutylaluminum hydride,
(E) -3- [2- (5-methyl-4-phenyl-2-
Oxazolylmethoxy) phenyl] -2-propene-1
-I got all. Recrystallized from ethyl acetate-chloroform-ether. Colorless prism crystals. Melting point 128-12
9 ° C. Reference Example 78 As in Reference Example 34, (E) -3- [2- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-ol was treated with active manganese dioxide. It was subjected to an oxidation reaction to obtain (E) -3- [2- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-al. Recrystallized from chloroform-isopropyl ether. Colorless prism crystals. Melting point 112-113 [deg.] C. Reference Example 79 (E) -3- [2- (5-Methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-al and diethyl cyanomethylphosphonate in the same manner as in Reference Example 35. By reaction with (E, E) -5- [2-
(5-Methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2,4-pentadienenitrile was obtained. Recrystallized from ethanol-chloroform. Colorless prism crystals. Melting point 128-129 [deg.] C.

Reference Example 80 In the same manner as in Reference Example 45, 2- (benzo [b] furan-2-
4- [4- [2- [benzo [b] furan-2] by the reaction of (yl) -4-chloromethyl-5-methyloxazole with 4- (4-hydroxyphenyl) butyronitrile.
-Yl) -5-methyl-4-oxazolylmethoxy] phenyl] butyronitrile was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 118-119 [deg.] C. Reference Example 81 In the same manner as in Reference Example 45, 4-chloromethyl-2- (furan-2-yl) -5-methyloxazole was reacted with 4- (4-hydroxyphenyl) butyronitrile to give 4
-[4- [2- (furan-2-yl) -5-methyl-4
-Oxazolylmethoxy] phenyl] butyronitrile was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.85-2.05 (2H, m), 2.31 (2H,
t, J = 7Hz), 2.42 (3H, s), 2.72 (2H, t, J = 7.5Hz), 4.97 (2H,
s), 6.52 (1H, dd, J = 3.5 & 2Hz), 6.9-7.0 (3H, m), 7.10 (2
H, d, J = 9Hz), 7.53 (1H, dd, J = 2 & 1Hz). Reference Example 82 In the same manner as in Reference Example 45, 3-chloromethyl-1-methyl-
5-phenyl-1,2,4-triazole and 4- (4-
By reaction with (hydroxyphenyl) butyronitrile,
4- [4- (1-methyl-5-phenyl-1,2,4-
Triazol-3-ylmethoxy) phenyl] butyronitrile was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 106-10
7 ° C.

Reference Example 83 In the same manner as in Reference Example 1, 2- (5-methyl-2-nitropyridine was reacted with 5-methyl-2-phenyl-4-oxazolylmethanol to give 2- (5-methyl-2- Phenyl-
4-Oxazolylmethoxy) -5-nitropyridine was obtained. Yield 84%. Recrystallized from dichloromethane-isopropyl ether. Pale yellow prism crystal. Melting point 142
-143 ° C. Reference Example 84 In the same manner as in Reference Example 2, 2- (5-methyl-2-phenyl-)
4-oxazolylmethoxy) -5-nitropyridine was subjected to catalytic reduction reaction to give 5-amino-2- (5-methyl-2).
-Phenyl-4-oxazolylmethoxy) pyridine was obtained. Yield 81%. Recrystallized from methanol-isopropyl ether. Colorless prism crystals. Melting point 106-10
7 ° C. Reference Example 85 5-amino-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (4.00 g), 47%
To a mixture of HBr (12.2 g) and acetone (80 ml), sodium nitrite (1.08 g) in water (2 m
l) The solution was added dropwise at a temperature of 5 ° C or lower. After stirring for 30 minutes, add methyl acrylate (6.12 g) and add 10
Cuprous oxide (Cu) with stirring at a temperature of ~ 20 ° C
₂ O) (0.20 g) was added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. Concentrated aqueous ammonia was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography. 2 from the portion eluted with ethyl acetate-hexane (1: 5, v / v)
-Bromo-3- [2- (5-methyl-2-phenyl-4)
Methyl -oxazolylmethoxy) -5-pyridyl] propionate was obtained as an oil (2.27 g, 37%). NMR (δ ppm in CDCl ₃ ): 2.48 (3H, s), 3.18 (1H, dd,
J = 14.5 & 7Hz), 3.39 (1H, dd, J = 14.5 & 8Hz), 3.76 (3H, s),
4.34 (1H, dd, J = 8 & 7Hz), 5.28 (2H, s), 6.78 (1H, d, J = 8.5H
z), 7.35-7.5 (4H, m), 7.95-8.1 (3H, m).

Reference Example 86 2-Bromo-3- [2- (5-methyl-2-phenyl-
Methyl 4-oxazolylmethoxy) -5-pyridyl] propionate (4.00 g), 1,8-diazabicyclo [5,4,0] -7-undecene (DBU) (1.41)
90-10 with a mixture of g) and toluene (80 ml).
Stir at 0 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (Mg
After SO ₄ ) the solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography. From the portion eluted with ethyl acetate-hexane (1: 3, v / v), (E) -3-
Crystals of methyl [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] acrylate (2.71 g, 83%) were obtained. Recrystallized from diethyl ether-isopropyl ether. Colorless prism crystals.
Melting point 116-117 [deg.] C. Reference Example 87 Similar to Reference Example 23, reduction of methyl (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] acrylate with diisobutylaluminum hydride. Subjected to reaction, (E) -3- [2- (5
-Methyl-2-phenyl-4-oxazolylmethoxy)
-5-Pyridyl] -2-propen-1-ol was obtained.
Yield 76%. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 116-11
7 ° C. Reference Example 88 In the same manner as in Reference Example 34, (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] -2-propen-1-ol was activated. Subjected to an oxidation reaction with manganese dioxide, (E) -3- [2- (5-
Methyl-2-phenyl-4-oxazolylmethoxy)-
5-Pyridyl] -2-propen-1-al was obtained. Yield 92%. Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. Melting point 147-148
° C. Reference Example 89 In the same manner as in Reference Example 24, (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] -2-propen-1-ol was contacted. After reduction, 3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propanol was obtained. Yield 82%. Recrystallized from diethyl ether-hexane. Colorless needles. Melting point 89-90 [deg.] C.

Reference Example 90 In the same manner as in Reference Example 72, 3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl]
Methanesulfonylation of propanol to give 3- [2-
(5-Methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propyl methanesulfonate was obtained as an oil. Yield 89%. NMR (δ ppm in CDCl ₃ ): 1.95-2.15 (2H, m), 2.48 (3
H, s), 2.70 (2H, t, J = 7.5Hz), 3.01 (3H, s), 4.24 (2H, t, J =
6.5Hz), 5.28 (2H, s), 6.78 (1H, d, J = 8.5Hz), 7.35-7.5
(4H, m), 7.95-8.1 (3H, m). Reference Example 91 In the same manner as in Reference Example 38, 3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl was used. ]
By the reaction of propyl methanesulfonate with potassium cyanide, 4- [2- (5-methyl-2-phenyl-
4-Oxazolylmethoxy) -5-pyridyl] butyronitrile was obtained as an oil. Yield 95%. NMR (δ ppm in CDCl ₃ ): 1.85-2.05 (2H, m), 2.35 (2
H, t, J = 7Hz), 2.48 (3H, s), 2.73 (2H, t, J = 7.5Hz), 5.28 (2
H, s), 6.80 (1H, d, J = 8.5Hz), 7.35-7.5 (4H, m), 7.95-8.1
(3H, m). Reference Example 92 Similarly to Reference Example 64, (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] -2-propene 5- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] valeric acid nitrile was obtained by reacting -1-al with diethyl cyanomethylphosphonate and then catalytically reducing it. Obtained as an oil. Yield 96%. NMR (δ ppm in CDCl ₃ ): 1.55-1.85 (4H, m), 2.37 (2
H, t, J = 6.5Hz), 2.48 (3H, s), 2.59 (2H, t, J = 7Hz), 5.27 (2
H, s), 6.77 (1H, d, J = 8.5Hz), 7.35-7.5 (4H, m), 7.95-8.1
(3H, m).

Example 1 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propionitrile (0.7 g), sodium azide (0.411 g), chloride A mixture of ammonium (0.337g) and N, N-dimethylformamide (15ml) was stirred at 120 ° C for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and 5- [2- [4- [2- (5-methyl-2
-Phenyl-4-oxazolyl) ethoxy] phenyl]
Ethyl] tetrazole (0.38 g, 48%) was obtained.
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 143-144 [deg.] C. Examples 2 to 14 In the same manner as in Example 1, compounds shown in [Table 4] and [Table 5] were obtained.

[Table 4]

[Table 5] 1) Na salt elemental analysis value C ₁₆ H ₁₈ N ₅ O ₂ Na ・ 1 / 2H ₂
Calculated as O: C, 55.81; H, 5.56; N, 20.34 Analytical value: C, 56.01; H, 5.82; N, 20.68

Example 15 (E) -5- [4- (5-methyl-2-phenyl-4-
Oxazolylmethoxy) styryl] tetrazole (1.
0 g), palladium-carbon (5%, 0.5 g) and dioxane (100 ml) were subjected to catalytic reduction at 1 atm and room temperature. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, 5-
[2- [4- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl] tetrazole (0.81 g, 81%) was obtained. Recrystallized from methanol-chloroform. Colorless plate crystals. Melting point 203-20
4 ° C. Example 16 In the same manner as in Example 15, 5- [4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1,3-butadiene-1-yl] tetrazole was added. Subjected to catalytic reduction, 5- [4- [4- (5-methyl-2-
Phenyl-4-oxazolylmethoxy) phenyl] butyl] tetrazole was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 116-117 [deg.] C.

Examples 17 to 27 In the same manner as in Example 1, compounds shown in [Table 6] and [Table 7] were obtained.

[Table 6]

[0064]

[Table 7]

Example 28 In the same manner as in Example 1, (E, E) -5- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienenitrile was used. By reaction with sodium azide-ammonium chloride, 5- [4- [3
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1,3-butadiene-1-yl] tetrazole was obtained. Recrystallized from methanol. Colorless prism crystals. Melting point 201-202 [deg.] C. Example 29 (E, E) -5- [2- (5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienenitrile and sodium azide as in Example 1. By reaction with ammonium chloride, 5- [4- [2
-(5-Methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1,3-butadiene-1-yl] tetrazole was obtained. Recrystallized from dichloromethane-methanol. Colorless prism crystals. Melting point 192-193 [deg.] C.

Example 30 to Example 35 The compounds of [Table 8] were obtained in the same manner as in Example 15.

[Table 8] 1) Oily substance. NMR (δ ppm in CDCl ₃ ): 1.15 (3H, d, J
= 7Hz), 1.35-1.85 (4H, m), 2.47 (3H, s), 2.47-2.68 (1H,
m), 2.68-2.95 (2H, m), 4.91 (2H, s), 6.73 (2H, d, J = 8.8H
z), 6.92 (2H, d, J = 8.8Hz), 7.35-7.52 (3H, m), 7.90-8.05
(2H, m).

Example 36 Reaction of 4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] butyronitrile with sodium azide-ammonium chloride as in Example 1. According to 5- [3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl]
Propyl] -1H-tetrazole was obtained. Yield 45
%. Recrystallized from methanol-ethyl acetate. Colorless prism crystals. Melting point 137-138 [deg.] C. Example 37 Similar to Example 1, by reaction of 5- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] valeric acid nitrile with sodium azide-ammonium chloride. , 5- [4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl]
Butyl] -1H-tetrazole was obtained. Yield 46%.
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 104-105 [deg.] C.

Formulation Example 1 (Production Example of Tablet) (1) 5- [2- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] ethyl] -tetrazole (Example Compound produced in 1) 10 g (2) Lactose 50 g (3) Corn starch 15 g (4) Carboxymethyl cellulose calcium 44 g (5) Magnesium stearate 1 g 1000 tablets 120 g (1), (2), the total amount of (3) and 30 g (4) is kneaded with water, vacuum dried and granulated. 14 at the end of this granulation
By mixing g (4) and 1 g (5) and tableting with a tableting machine, 1000 tablets each containing 10 mg of (1) are produced.

Formulation Example 2 (Production Example of Tablet) (1) 5- [3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propyl] -tetrazole (Example Compound produced in 7) 30 g (2) Lactose 50 g (3) Corn starch 15 g (4) Carboxymethyl cellulose calcium 44 g (5) Magnesium stearate 1 g 1000 tablets 140 g (1), (2), (3) total amount and 30 g (4) is kneaded with water, vacuum dried and granulated. 14 at the end of this granulation
By mixing g (4) and 1 g (5) and tableting with a tableting machine, 1000 tablets each containing 30 mg of (1) are produced.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI A61P 3/06 A61P 3/06 3/10 3/10 C07D 403/12 C07D 403/12 403/14 403/14 413/14 413 / 14 417/12 417/12 417/14 417/14 (56) Reference JP-A-1-143856 (JP, A) JP-A-3-500890 (JP, A) JP-A-3-500885 (JP, A) Special Table Sho 63-503139 (JP, A) European Patent Application Publication 528337 (EP, A 1) US Patent 4845231 (US, A) J. Med. Chem. , (1990), 33 (10), p. 2828-41 J.I. Med. Chem. , (1990), 33 (4), p. 1194-200 J. Med. Chem. , (1990), 33 (4), p. 1186-94 J. Med. Chem. , (1990), 33 (1), p. 240-5 J. Med. Chem. , (1990), 35 (5), p. 944-53 Chem. Pharm. Bull. , (1991), 39 (6), p. 1440-5 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 413/12 C07D 403/12 C07D 403/14 C07D 413/14 C07D 417/12 C07D 417/14 CA (STN) REGISTRY (STN) )

Claims (10)

(57) [Claims] 1. A general formula: [In the formula, n is an integer of 1 to 3 and A is a formula which may have a substituent. [Wherein B ¹ is S, O or NR (wherein R is a hydrogen atom,
An alkyl group having 1 to 3 carbon atoms or an aralkyl group is shown. A group represented by), B ² is a nitrogen atom or C-R
² (R ² is hydrogen or a carbon which may be substituted with a hydroxyl group
The alkyl groups of the numbers 1 to 5 are shown. ) Is shown. R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic residue, and when R ¹ and R ² are respectively substituted on adjacent carbon atoms, R ¹ and R ² are They may be bonded to each other to form a condensed ring. ] Aromatic 5
Indicates a member ring residue. Y is an alkylene having 1 to 5 carbon atoms or
Alkenylene and X represents CH or N. ] The tetrazole derivative represented by these, or its pharmacologically acceptable salt. 2. A is of the formula: [In the formula, R ¹ represents hydrogen or a hydrocarbon residue or a heterocyclic residue which may be respectively substituted, and R ² represents hydrogen or an alkyl group having 1 to 5 carbon atoms which may be substituted by a hydroxyl group, B represents an oxygen atom or a sulfur atom. ] The tetrazole derivative of Claim 1 which is a group shown by these, or its pharmacologically acceptable salt. 3. B ¹ is NR (wherein R is a hydrogen atom or carbon)
The alkyl groups or aralkyl groups of the formulas 1 to 3 are shown. And B ² is a nitrogen atom, the tetrazole derivative or a pharmaceutically acceptable salt thereof according to claim 1. 4. The tetrazole derivative according to claim 1, wherein n is 1 or 2, or a pharmacologically acceptable salt thereof. 5. The tetrazole derivative according to claim 1, wherein X is CH, or a pharmacologically acceptable salt thereof. 6. The tetrazole derivative according to claim 1, wherein Y is alkylene having 1 to 5 carbon atoms, or a pharmacologically acceptable salt thereof. 7. Y is —CH ₂ CH ₂ CH ₂ — or —CH ₂
The tetrazole derivative according to claim 1, which is CH ₂ CH ₂ CH ₂ —, or a pharmaceutically acceptable salt thereof. 8. A therapeutic agent for diabetes comprising the tetrazole derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 9. A therapeutic agent for hyperlipidemia, which comprises the tetrazole derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 10. A general formula: [In the formula, n represents an integer of 1 to 3, and A is a formula which may have a substituent. [Wherein B ¹ is S, O or NR (wherein R is a hydrogen atom,
An alkyl group having 1 to 3 carbon atoms or an aralkyl group is shown. A group represented by), B ² is a nitrogen atom or C-R
² (R ² is hydrogen or a carbon which may be substituted with a hydroxyl group
The alkyl groups of the numbers 1 to 5 are shown. ) Is shown. R ¹ represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic residue, and when R ¹ and R ² are respectively substituted on adjacent carbon atoms, R ¹ and R ² are They may be bonded to each other to form a condensed ring. ] Aromatic 5
Indicates a member ring residue. Y is an alkylene having 1 to 5 carbon atoms or
Alkenylene and X represents CH or N. ] The compound represented by the general formula [Chemical Formula 6] characterized by reacting a metal azide compound [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the tetrazole derivative represented by these.