JPH0859638A - New heterocyclic derivative or its salt - Google Patents

Abstract

PURPOSE: To obtain the subject derivative, represented by a specific formula, having enhancing actions on insulin sensitivity, excellent hypoglycemic actions and low toxicity, hardly causing side effects and useful as a preventing and therapeutic agent for diabetes, etc. CONSTITUTION: A derivative of formula I [ring A is imidazoline, tetrazolyl or formula II or III; the dotted line underlined is a single or a double bond; R<1> is H, a halogen, a (hydroxy)lower alkyl, a lower alkoxy, trifluoromethyl, nitro, carboxyl, a lower alkoxycarbonyl, etc.; R<2> and R<3> are each H or a halogen: R<4> is H or OH; R<5> is H or a lower alkyl: X is O, S or NH; Y is N or CH; (n) is O or 1], preferably 2-[4-[3-(4-trifluoromethylphenoxy) phenoxy]benzyl]-1,2,4-oxadiazolidin-3,5-dione. The compound is preferably obtained by reacting, e.g. an (N-carbamoyl-N-hydroxyaminomethyl) derivative of formula IV with a carbonyl compound of formula V (Y<1> and Y<2> are each a halogen, an alkoxy, an aralkylkoxy or an aryloxy).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel heterocyclic derivative useful as a medicine, particularly a hypoglycemic agent (insulin sensitivity enhancer), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them. Regarding

[0002]

2. Description of the Related Art Currently, synthetic hypoglycemic agents clinically used as therapeutic agents for diabetes are sulfonylurea agents and biguanides. However, the biguanide agent causes lactate acidosis, so that its application is limited and is rarely used. On the other hand, a sulfonylurea agent has a certain hypoglycemic effect and very few side effects, but sometimes it may cause hypoglycemia, so that it is necessary to pay sufficient attention to its use.

[0003] In recent years, attention has been paid to an insulin sensitivity enhancer which enhances insulin sensitivity in peripheral tissues and exhibits a blood glucose lowering action as a substitute for the above synthetic blood glucose lowering agent.

Under such circumstances, the present inventors have previously found that the bisoxa or thiazolidine derivative has an excellent insulin sensitivity-enhancing action, and filed a patent application [see International Publication No. 93/03021 (1993) ( Hereinafter, it is abbreviated as Reference 1.)].

[0005]

Although various studies have been made in the past as described above, the creation of excellent novel insulin sensitivity enhancers is still an important medical problem.

The present inventors have completed the present invention as a result of earnest research on a novel compound having an insulin sensitivity enhancing action.

[0007]

That is, the present invention relates to a novel heterocyclic derivative represented by the following general formula (I).

[0008]

[Chemical 5]

(Each symbol in the above formula has the following meaning.

A ring group: imidazolyl group, tetrazolyl group,

[0011]

[Chemical 6]

R ¹ : hydrogen atom, halogen atom, lower alkyl group, hydroxy lower alkyl group, lower alkoxy group, trifluoromethyl group, nitro group, carboxyl group, lower alkoxycarbonyl group, formula --CH ₂ --NHC
A group represented by ONH-COOR ⁵ or a formula —CH═N—O
Groups represented by H, R ^2, R ^3: same or different and each represents a hydrogen atom or a halogen atom, R ^4: a hydrogen atom or a hydroxyl group, R ^5: a hydrogen atom or a lower alkyl group, X: an oxygen atom, a sulfur atom or the formula - Group represented by NH-, Y: nitrogen atom or

[0013]

[Chemical 7]

A group represented by: n: 0 or 1) In the compound of the present invention, the compound described in the above-mentioned Reference 1 is a bis form in which a heterocyclic group is bonded to both of them through a linking group, Via one side, a heterocyclic group (A ring group in general formula (I)) is bonded to one side and an acyclic group (R ¹ in general formula (I)) is bonded to the other side. It is a novel compound having chemical structural characteristics.

The compound of the present invention will be described in detail below.

Unless otherwise specified, the term "lower" in the definition of the general formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, the "lower alkyl group" is specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group. Group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group Group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,
1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like,
The "hydroxy lower alkyl group" means a group in which any one or more hydrogen atoms of the above "lower alkyl group" are substituted with a hydroxyl group.

The "lower alkoxy group" is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy (amyloxy) group, an isooxy group. Examples thereof include a pentyloxy group, a tert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group and a hexyloxy group.

The "lower alkoxycarbonyl group" is methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
ec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group and the like straight chain having 1 to 6 carbon atoms Alternatively, a group formed by esterification with a branched alcohol and a carboxy group may be mentioned.

Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the compound (I) of the present invention, the compound having an oxadiazolidine ring has an acidic proton in the ring and thus can form a salt with a base. The present invention includes pharmaceutically acceptable salts of compound (I), and examples of such salts include alkali metals such as lithium, sodium and potassium, alkaline earth metals such as magnesium and calcium, and aluminum and the like. Salts with inorganic bases such as trivalent metals, methylamine, ethylamine, dimethylamine,
Examples thereof include salts with organic bases such as diethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine and ornithine.

Tautomers exist depending on the kind of the A ring group of the compound of the present invention. Also, depending on the type of substituent,
It may have a double bond or an asymmetric carbon atom, and geometric isomers and optical isomers exist based on their presence. The present invention includes all isolated forms and mixtures of these isomers.

Further, the compound (I) of the present invention or a salt thereof may be isolated as a hydrate, various solvates or polymorphic substances. In the present invention, these hydrates,
Also included are various pharmaceutically acceptable solvates such as ethanol solvates or polymorphic substances.

Among the compounds of the present invention, as a particularly preferred compound, the A ring group is a tetrazolyl group or a compound of the formula

[0025]

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Compounds represented by the formula (X: oxygen atom, Y: nitrogen atom) are mentioned, and more preferred compounds are those in which R ¹ is hydrogen atom, lower alkyl group, hydroxy lower alkyl group, trifluoromethyl group, Nitro group, carboxyl group, lower alkyloxycarbonyl group, formula -CH
_{A group represented by 2-} NHCONH-COOR ⁵ or a formula-C
Compound is a group represented by H = N-OH, and among them compounds R ¹ is a trifluoromethyl group is preferable.

The following compounds are exemplified as more preferable compounds.

(1) 2- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] -1,
2,4-oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof.

(2) 5- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] tetrazole or a pharmaceutically acceptable salt thereof.

(3) 2- [4- (3-benzyloxyphenoxy) benzyl] -1,2,4-oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof.

(Production Method) The compound of the present invention can be synthesized by applying various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. The typical manufacturing method is illustrated below.

First production method

[0033]

[Chemical 9]

(In the formula, R ¹ , R ² , R ³ and n have the above-mentioned meanings, and Y ¹ and Y ² are the same or different, and are a halogen atom, an alkoxy group, an aralkyloxy group or an aryloxy group. In the compound (I) of the present invention, the compound (Ia) having an oxadiazolyl group is the (N-carbamoyl-N-hydroxyaminomethyl) derivative represented by the general formula (II) and the general formula (III). It can be produced by reacting with a carbonyl compound represented by

Examples of the halogen atom represented by the compounds Y ¹ and Y ² include those mentioned above, and the alkoxy group is not limited to a lower alkoxy group, but is usually a methoxy group, an ethoxy group, or the like. The lower alkoxy group of is used. The aryloxy group or aralkyloxy group is not particularly limited as long as it is an aromatic carbocyclic oxy group or an aromatic carbocyclic alkoxy group, but a phenoxy group or a benzyloxy group is common.

The reaction includes tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, dimethoxyethane (monoglyme), bis (2-methoxyethyl) ether (diglyme), methanol, ethanol,
Compound (II) and its compound in an organic solvent inert to the reaction such as cellosolve (trade name 2-ethoxyethanol), methyl cellosolve (trade name 2-methoxyethanol), dimethyl sulfoxide, sulfolane, etc. It is advantageous to carry out equimolar to excess molar amount of compound (III), preferably in the presence of a base such as sodium hydroxide or potassium hydroxide, under the temperature condition of 0 ° C to 150 ° C.

The starting compound (II) is, as shown in the following reaction formula, 1) reducing and halogenating the corresponding benzaldehyde compound (IV) to give a halogenomethyl compound (V), to which a protected hydroxyurea is added. N-protected hydroxy-N-carbamoylaminomethyl compound (VI) obtained by reaction
Or a hydroxyaminomethyl compound (VII) obtained by reductive amination of the corresponding benzaldehyde compound (IV) with hydroxylamine and a reducing agent in the presence of an acid catalyst with cyanic acid or isocyanic acid. Can be easily obtained by reacting.

[0038]

[Chemical 10]

(In the formula, R ¹ , R ² , R ³ and n have the above-mentioned meanings, Y ³ is a halogen atom, R ⁶ is a protecting group for a hydroxyl group which can be easily removed, and M is an alkali metal. Here, a halogen atom or an alkali metal means the above-mentioned one, and a benzyl group, an aralkyl group such as a p-methoxybenzyl group, a lower alkyl group such as a tert-butyl group, or an acetyl group as a hydroxyl-protecting group. Group, a trifluoroacetyl group, an acyl group such as a benzyloxycarbonyl group and the like, and a protective group for a hydroxyl group which can be easily removed.

The reaction in each step can be carried out by applying a conventional method. For example, the reaction for producing the halogenomethyl compound (V) from the benzaldehyde compound (IV) is preferably carried out by hydrogenation in an organic solvent inert to the reaction, such as alcohols such as methanol, ethers such as tetrahydrofuran, or a mixed solvent thereof. Sodium boron, etc.-CH
It is carried out by reducing -CH ₂ OH from O using a reducing agent commonly used and reacting it with a halogenating agent such as hydrogen halide. Further, the reaction for producing an N- (protected hydroxy) -N-carbamoylaminomethyl compound from the compound (V) is carried out in an organic solvent inert to a reaction commonly used in N-alkylation reaction such as dimethylformamide, preferably hydrogenation. It is carried out by reacting compound (V) with protected hydroxyurea in the presence of a commonly used base in N-alkylation reaction of sodium, potassium carbonate and the like. Further, the removal of the protecting group differs depending on the type of the protecting group, but treatment with an acid commonly used for removing the hydroxyl protecting group such as trifluoroacetic acid, or Pd-C in the case of a protecting group such as a benzyl group is used. The protecting group is eliminated by reduction such as catalytic reduction under a catalyst.

The reaction for producing the hydroxyaminomethyl compound (VII) from the compound (IV) is carried out by using alcohols such as methanol and ethanol, organic solvents such as benzene, toluene, xylene and other aromatic hydrocarbons, or water or If necessary, in the presence of a catalyst such as sodium acetate or p-toluenesulfonic acid in a solvent inert to the reaction such as a mixed solvent thereof, and optionally using an azeotropic dehydrator or a dehydrating agent, to give the compound (IV) It is carried out by reacting with hydroxylamine or a salt thereof and reducing the resulting hydroxyiminoalkyl group with a reducing agent commonly used for reductive amination such as borane-pyridine complex and sodium borohydride. The hydroxyiminoalkyl group can be subjected to a reduction step without isolation.

The reaction for producing the compound (II) from the compound (VII) is carried out in a reaction-inert organic solvent such as alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, or a mixed solvent thereof such as hydrochloric acid. It is carried out by reacting compound (VII) with an alkali metal cyanate in the presence of an acid catalyst.

The benzaldehyde compound (IV) is
By etherification of the corresponding phenols with, for example, 4-fluorobenzaldehyde in the presence of a base,
Alternatively, it is produced by applying various methods such as reducing the corresponding nitrile compound (VIII) with a reducing agent such as diisobutylaluminum hydride. The halogenomethyl compound (V) can also be produced by reacting a halogenating agent with, for example, the tolyl compound (IX) as a raw material.

Second manufacturing method

[0045]

[Chemical 11]

(Wherein R ¹ , R ² , R ³ and n have the above-mentioned meanings, Y ⁴ is a halogen atom or an alkoxy group, and Y ⁴ is
⁵ and Y ⁶ are the same or different and each represents a halogen atom, an alkoxy group, an aralkyloxy group or an aryloxy group. The compound (Ia) of the present invention is prepared by using the corresponding hydroxyaminomethyl compound (VII) as a starting material,
It can also be produced by reacting the isocyanates (X) or N-acyl imides (XI) represented by

Examples of the halogen atom, alkoxy group, aralkyloxy group and aryloxy group include those mentioned above.

The reaction varies depending on the kind of the raw material compound, but the compound (in the solvent inert to the reaction such as ethers such as tetrahydrofuran, dioxane, diethyl ether, etc., organic solvent such as dimethylformamide, dimethylsulfoxide, etc. or a mixed solvent thereof). VII) and an equimolar to excess molar amount of compound (X) or (XI),
If necessary, it is carried out in the presence of a base such as potassium carbonate, sodium carbonate, calcium carbonate, trimethylamine or triethylamine, under cooling to room temperature, and treated with an aqueous solution of sodium hydroxide, potassium hydroxide or the like to produce.

Third method

[0050]

[Chemical 12]

(Wherein R ¹ , R ² , R ³ , n and Y ⁴ have the above-mentioned meanings) The compound (Ia) of the present invention corresponds to the corresponding N-hydroxy-
N-acylaminocarbonylaminomethyl compound (XII)
It can also be produced by treating the compound with a base for cyclization.

The base used here is the base used in the second production method, and compound (XII) is produced by reacting compounds (VII) and (X) in the absence of a base in the second production method. It is, so to speak, an intermediate of the second production method.

Therefore, the reaction of the base treatment is the same as in the second production method.

Fourth manufacturing method

[0055]

[Chemical 13]

(Wherein R ¹ , R ² , R ³ and n have the above-mentioned meanings) The tetrazole derivative represented by the general formula (Ib) is a mononitrile derivative represented by the general formula (XIII). , A cyano group is converted to a tetrazolyl group by a well-known reaction.

A cyano group

[0058]

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The reaction for converting into nitrile is carried out, for example, by heating the nitrile derivative (XIII) with sodium azide and ammonium chloride using dimethylformamide as a solvent.

Fifth manufacturing method

[0061]

[Chemical 15]

(In the reaction formula, R ¹ , R ² , R ³ , X and n
Has the meaning given above. The heterocyclic derivative represented by the general formula (Ic) is a general condensation reaction (Knoevenagel condensation) in which a benzaldehyde compound represented by the general formula (IV) is reacted with a thiazolidine or oxazolidine derivative represented by the formula (XIV). ) Is manufactured by.

Further, the heterocyclic derivative represented by the general formula (Id) is produced by reducing the compound (Ic).

The condensation reaction is carried out by acetic acid-piperidine mixture, β-
Alkali metal alcoholates such as alanine, alumina, titanium tetrachloride, tin tetrachloride, boron trifluoride, potassium fluoride, sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium acetate, sodium ethoxide, potassium t-butoxide, diethylamine In the presence of a base such as triethylamine, pentylamine, pyridine, ethanol, alcohol such as methanol, tetrahydrofuran, diethyl ether, methylene chloride, chloroform, benzene, toluene, acetonitrile, acetic acid,
Compound (IV) and compound (XIV) are used in organic solvent such as propionic acid, butyric acid, etc. or water or a mixed solvent thereof in an approximately equimolar or double molar amount or one of them in a slightly excess amount over its chemical equivalent, It is suitable to carry out at room temperature or under heating, preferably under heating.

The reaction for producing the compound (Id) of the present invention is a reduction reaction of a carbon-carbon double bond, and palladium-
A hydrogenation reaction using carbon or the like as a catalyst, a reduction reaction with a metal hydride such as lithium borohydride or sodium borohydride, and the like are selected. For the reduction reaction with a metal hydride, dimethylimidazolidinone is suitable as a solvent, sodium borohydride as a reducing agent, and the like, and the reaction temperature is usually under heating.

Sixth production method

[0067]

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(In the formula, R ¹ , R ² , R ³ , R ⁴ , X and n have the above-mentioned meanings, and Z means a halogen atom.) The book represented by the general formula (Ie). The compound of the invention can be produced by reacting the halide represented by the general formula (XV) with the oxazolidine or thiazolidine compound represented by the general formula (XIV).

Examples of the halogen atom include iodine atom, bromine atom, chlorine atom and the like.

The reaction is carried out in an organic solvent inert to the reaction such as dimethyl ether, tetrahydrofuran, dioxane, dimethylformamide or a mixed solvent thereof, in which the compound (XIV) is approximately equimolar or 2 times the molar amount of the compound (XV). Either one is used in a slightly excess amount over its chemical equivalent, and the compound (X is added in the presence of a base such as n-butyllithium, magnesium methyl carbonate, lithium diisopropylamide, potassium hexamethyldisilazide, etc.
It is advantageous to carry out V) as an active methylene compound.

The reaction temperature varies depending on the reaction conditions such as the type of base, but is usually -78 ° C to 100 ° C.

The reaction time is appropriately set in consideration of the reaction conditions.

Seventh manufacturing method

[0074]

[Chemical 17]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , Z and n have the above-mentioned meanings.) The imidazole derivative of the general formula (If) is represented by the general formula (X
It can be produced by reacting a halogen compound represented by V) with imidazole (XVI).

The reaction is carried out in an organic solvent inert to the reaction such as dimethylformamide, ethanol, acetone, dioxane, isopropanol, 2-butanone and tetrahydrofuran, or a mixed solvent thereof, generally 3-10.
It can be obtained by heat-reacting with a double molar amount of imidazole and treating in the same manner as in the usual alkylation reaction of amine.

More preferably, it can also be produced by a method in which an equimolar amount of N-protected imidazole is used to carry out alkylation on the 3-position nitrogen, and then a protecting group such as a trityl group or an acetyl group is removed. .

[0078]

Embedded image

(In the formula, R ¹ , R ² , R ³ and n have the above-mentioned meanings, and Trityl means a trityl group.) The compound represented by the general formula (Ig) is represented by the general formula (Ig) It can be produced by reacting an aldehyde derivative represented by IV) with an imidazole derivative protected by a trityl group represented by the general formula (XVI).

The reaction is carried out in an organic solvent inert to the reaction such as dimethyl ether, tetrahydrofuran, dioxane, dimethylformamide, or a mixed solvent thereof, in which the compound (XV) is approximately equimolar or twice the molar amount of the compound (XVI). Either one is used in a slightly excess amount over its chemical equivalent, and the compound (XV is used in the presence of a base such as n-butyllithium, magnesium methyl carbonate, lithium diisopropylamide, potassium hexamethyldisilazide).
It is advantageous to carry out after generating the anion at the 2-position of the imidazole derivative of I).

The reaction temperature will differ depending on the reaction conditions such as the type of base, but is usually -78 ° C to 100 ° C.

The reaction time is appropriately set in consideration of the reaction conditions.

The compound of the present invention represented by the general formula (I-h) can be prepared by treating (I-g) with 90% acetic acid; heating, trifluoroacetic acid, etc. by a general method for deprotecting the trityl group. It can be manufactured by

The compound of the present invention represented by the general formula (Ii) is obtained by reducing the hydroxyl group of the compound (Ih) by a reduction reaction of a protonic acid with triethylsilane or the like, or by reacting the compound (Ig) with a triethyl group. It can also be produced by treating with fluoroacetic acid and triethylsilane to simultaneously reduce the hydroxyl group and deprotect the trityl group.

Other Production Methods The compound of the present invention has an ether structure, an amide structure, an imino structure, etc. in its structure.
It can be produced by applying a conventional method such as amidation, N-alkylation, reductive amination and deesterification.

The compound of the present invention thus produced is isolated and purified as a free compound, its salt, hydrate, various solvates and the like. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to an ordinary salt-forming reaction.

Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization and various fractional chromatography.

Tautomers and geometric isomers can be separated by selecting an appropriate raw material or by utilizing the difference in physicochemical properties between isomers.

The optical isomers can be optically resolved by selecting an appropriate starting compound or by a racemic resolution method of a racemic compound [for example, a method for leading to a diastereomeric salt with a generally optically active base and performing optical resolution]. Etc.] can lead to stereochemically pure isomers.

[0090]

The compound (I) of the present invention and salts thereof are
It has excellent hypoglycemic action based on insulin sensitivity enhancing action, low toxicity and few side effects, especially with non-insulin dependent diabetes mellitus (type II) and various complications of diabetes. It is useful as a concomitant drug.

The excellent blood glucose lowering action based on the insulin sensitivity enhancing action of the present invention has been confirmed by the following test methods.

Blood glucose lowering activity 4-5w male kk mouse was obtained from CLEA Japan, Inc. The animals were individually fed with a high-calorie diet (CMF, Oriental Yeast Co., Ltd.) and tested using a body weight of 40 g.

For the measurement of blood glucose level, 10 μl of blood was collected from the tail vein, deproteinized with 100 μl of 0.33 N perchloric acid, centrifuged, and glucose in the supernatant phase was measured by the glucose oxidase method. Blood sugar is 200 mg / d
A group of 6 animals of 1 or more was used for the test.

The drug was suspended in 0.5% methylcellulose and orally administered daily for 4 days. Blood was collected from the tail vein before drug administration and on the 5th day, and blood glucose was measured by the above method.

A pharmaceutical composition containing, as an active ingredient, one or more compounds of the compound represented by the general formula (I) and pharmaceutically acceptable salts thereof is used as a carrier for a commonly used preparation or Using excipients and other additives, tablets, powders,
It is prepared into fine granules, granules, capsules, pills, solutions, injections, suppositories, etc., and is orally or parenterally administered.

The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, body weight, age, sex and the like of the patient to whom it is applied, but it is usually 1 to 200 orally per day for an adult.
It is 0 mg, and it is administered once or in several divided doses. Since the dose varies depending on various conditions, a dose smaller than the above dose range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose,
It is mixed with mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate.
According to a conventional method, the composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing or solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. In addition to the inert diluent, this composition may contain solubilizing or solubilizing agents, humectants, auxiliary agents such as suspending agents, sweeteners, flavors, fragrances and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such a composition may further contain additives such as an isotonicity agent, a preservative, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizer (eg lactose), and a solubilizing or solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

[0100]

The present invention will be described in more detail with reference to the following examples.

The starting material also contains a novel substance, and its production example will be additionally described as a reference example.

Reference Example 1

[0103]

[Chemical 19]

6 g of 3- (4-trifluoromethylphenoxy) phenol was added to 3.3 g of anhydrous potassium carbonate, 4-
Fluorobenzaldehyde (3.0 g) and dimethyl sulfoxide (20 ml) were heated and stirred at 100 ° C. for 10 hours.
After the reaction was completed, 40 ml of water and 80 ml of benzene were added for liquid separation, the organic layer was washed with water, and subjected to silica gel column chromatography using chloroform as an eluent to give 4- [3-
6 g of (4-trifluoromethylphenoxy) phenoxy] benzaldehyde was obtained.

Mass spectrum (m / z): 358 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 6.79 (1H, t), 6.88-6.90 (2
H, m), 7.09-7.11 (4H, m), 7.40
(1H, t), 7.60 (2H, d), 7.87 (2
H, d), 9.94 (1H, s) The compounds of Reference Examples 2 to 8 were synthesized in the same manner as in Reference Example 1 above (see Tables 1 and 2 below for chemical structural formulas, chemical names and physicochemical properties). Posted.).

Example 1 a) 4- [3- (4-trifluoromethylphenoxy) phenoxy] benzaldehyde 6 obtained in Reference Example 1
g, 2.0 g of ammonium acetate, 1.8 g of hydroxylamine hydrochloride and 10 ml of water were stirred with 50 ml of methanol at room temperature for 2 hours, and then heated under reflux for 30 minutes. After completion of the reaction, methanol was distilled off under reduced pressure, and ethyl acetate was 50 m.
1, and 20 ml of water were added to separate the layers. The organic layers were collected and evaporated under reduced pressure, and then subjected to silica gel column chromatography using chloroform as an eluent to obtain 4.0 g of 4- [3- (4-trifluoromethylphenoxy) phenoxy] benzaldoxime.

The resulting 4- [3- (4-trifluoromethylphenoxy) phenoxy] benzaldoxime 3.
0 g was dissolved in 30 ml of ethanol, 1.2 g of pyridine-borane was added, and then 12 ml of 4N-hydrochloric acid was added dropwise under ice cooling. After leaving it at room temperature for 4 hours, add sodium hydroxide water to make it alkaline, and then methylene chloride 50m.
l and 100 ml of water were added for liquid separation. The organic layers were collected and subjected to silica gel column chromatography using chloroform as an eluent to obtain 2.5 g of N- [4 '-[3- (4-trifluoromethylphenoxy) phenoxy] benzyl] hydroxylamine.

Mass spectrum (m / z): 374 [(M-
H) ^- ] (FAB / Neg) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.02 (2H, s), 6.70 (1H, d),
6.74-6.81 (2H, m), 7.01 (2H,
d), 7.06 (2H, d), 7.28-7.34 (3
H, m), 7.57 (2H, d) b) 1.5 g of N- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] hydroxylamine obtained in the above a) was added to 30 ml of tetrahydrofuran. After dissolution, 0.7 g of ethoxycarbonyl isocyanate was added under ice cooling. After leaving it for 30 minutes, an aqueous solution of sodium hydroxide was added to make it alkaline. After standing at room temperature for 2 hours, 6N-hydrochloric acid was added to acidify the mixture, and 30 ml of ethyl acetate was added to separate the layers. The organic layers were collected and dried under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform as an eluent to give 2- [4- [3-
(4-Trifluoromethylphenoxy) phenoxy] benzyl] -1,2,4-oxadiazolidine-3,5-
1.0 g of dione was obtained.

Melting point: 34-36 ° C. Mass spectrometry value (m / z): 443 [(M−H) ⁻ ] (FA
B / Neg) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.78 (2H, s), 6.73-6.82 (3
H, m), 7.01 (2H, d), 7.07 (2H,
d), 7.31-7.34 (3H, m), 7.58 (2
H, d) c) 2- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] -1, obtained in b) above,
2,4-oxadiazolidine-3,5-dione 0.8 g
Was heated with 0.2 g of sodium carbonate and 20 ml of water to dissolve it, and then allowed to cool, and the crystallized crystals were collected by filtration, 2- [4-
[3- (4-Trifluoromethylphenoxy) phenoxy] benzyl] -1,2,4-oxadiazolidine-
0.63 g of 3,5-dione sodium salt was obtained.

Decomposition point: 160 ° C. water Elemental analysis value (as C ₂₂ H ₁₄ N ₂ O ₅ F ₃ Na) C (%) H (%) N (%) F (%) theoretical value 56.66 3.03 6.01 12.22 Experimental value 56.49 3.03 6.07 12.26 Mass spectrum value (m / z): 489 [(M + Na) ⁺ ].
FAB / Pos. Nuclear magnetic resonance spectrum (DMSO-d
₆ , TMS internal standard) δ: 4.40 (2H, s), 6.7-7.45 (10
H, m), 7.74 (2H, d) In the same manner as in Example 1, the following compounds of Examples 2 to 8 were obtained.

Example 2 2- [4- (3-phenoxyphenoxy) benzyl]-
1,2,4 oxadiazolidine-3,5-dione starting compounds: 4 - [(3-phenoxy) phenoxy] benzaldehyde Mass spectrometry value (m / z): 375 ( M-1) - nuclear magnetic resonance spectrum ( CDCl ₃ , TMS internal standard) δ: 4.78 (2H, s), 6.68-6.77 (3
H, m), 6.99-7.04 (4H, m), 7.12
(1H, t), 7.25-7.36 (5H, m) Example 3 2- [4- [3- (4-hydroxymethylphenoxy))
Phenoxy] benzyl] -1,2,4-oxadiazolidine-3,5-dione Raw material compound: 4- [3- (4-hydroxymethylphenoxy) phenoxy] benzaldehyde Melting point: 119-125 ° C MeOH-ether mass spectrometry value (M / z): 405 [MH] ⁺ nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.77 (2H, s), 5.10 (2H, s),
6.65 (1H, m), 6.72-6.77 (2H,
m), 7.03-7.12 (4H, m), 7.36-
7.43 (5H, m), 10.56 (1H, s), 1
2.45 (1H, brs) Example 4 2- [4- [3- (4-Nitrophenyl) phenoxy]
Benzyl] -1,2,4-oxadiazolidine-3,5
-Dione raw material compound: 4- [3- (4-hydroxymethylphenoxy) phenoxy] benzaldehyde mass spectrometric value (m / z): 420 (M-1) ⁺ nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.80 (2H, s), 6.75 (1H, m),
6.84-6.90 (2H, m), 7.02-7.05
(4H, m), 7.33-7.40 (3H, m), 8.
18-8.21 (2H, m), 9.60 (1H, br
s) Example 5 4- [3- [4-[(3,5-dioxo-1,2,4-
Oxadiazolidin-2-yl) methyl] phenoxy]
Phenoxy] benzoic acid butyl starting compound: 4- [3- (4-formylphenyl) phenoxy] benzoate mp: 93-95 ° C. Elemental analysis (as _{C 23 H 18 N 2 O 7} · 0.1H 2 O) C (%) H (%) N (%) Theoretical value 63.33 4.21 6.42 Experimental value 63.03 4.18 6.53 Mass spectrometry value (m / z): 433 (M-1) ⁻ Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.91 (3H, s), 4.77 (2H, s),
6.60 (1H, t), 6.82-6.86 (2H,
m), 6.99-7.02 (4H, m), 7.32-
7.36 (3H, m), 7.97 (2H, d) Example 6 2- (4- (3-benzyloxyphenoxy) benzyl] -1,2,4-oxadiazolidine-3,5-dione starting compound: 4- [3-benzyloxy-phenoxy] benzaldehyde mp: 117-118 ° C. elemental analysis (as _{C 22 H 18 N 2 O 5} · 390.43) C (%) H (%) N (%) theoretical Value 67.69 4.65 7.18 Experimental value 67.79 4.60 7.09 Mass spectrum (m / z): 390 (MH ⁺ ) FAB / Po
s. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.77 (2H, s), 5.09 (2H, s),
6.57 (1H, dd, J = 2.44 and 8.5
4Hz), 6.67 (1H, t, J = 2.44Hz),
6.81 (1H, dd, J = 2.44 and 7.9
3Hz), 7.01 (2H, d, J = 8.55Hz),
7.27-7.43 (8H, m), 12.43 (1H,
brs) Example 7 2- [4- [3- (4-trifluoromethylbenzyloxy) phenoxy] benzyl] -1,2,4-oxadiazolidine-3,5-dione Raw material compound: 4- [3- (4-Trifluoromethylbenzyloxy) phenoxy] benzaldehyde Mass spectrum (m / z): 459 (M + H) ⁺ FAB
(Pos.) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.78 (2H, s), 5.22 (2H, s),
6.58-6.61 (1H, m), 6.68-6.70
(1H, m), 6.80-6.84 (1H, m), 7.
01 (2H, d, J = 8.55 Hz), 7.28-7.
33 (1H, m), 7.35 (2H, d, J = 8.55)
Hz), 7.64 (2H, d, J = 7.93Hz),
7.75 (2H, d, J = 7.93Hz), 12.44
(1H, brs) Example 8 2- [4- [3- (4-Methylphenoxy) phenoxy] benzyl] -1,2,4-oxadiazolidine-
3,5-dione Raw material compound: 4- [3- (4-methylphenoxy) phenoxy] benzaldehyde Melting point: 87-89 ° C Mass spectrum (m / z): 391 (M ⁺ +1) ⁺ FA
B (Pos.) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.29 (3H, s), 4.76 (2H, s),
6.56-6.58 (1H, m), 6.69-6.72
(2H, m), 6.96 (2H, d, J = 7.93H
z), 7.04 (2H, d, J = 8.54Hz), 7.
20 (2H, d, J = 8.54Hz), 7.33-7.
37 (3H, m), 7.37 (1H, brs) Example 9 4- [3- [4-[(3,5-dioxo-1,2,4-
Oxadiazolidin-2-yl) methyl] phenoxy]
Phenoxy] methyl benzoate 1.34 g of methanol 3
To a solution of 0 ml and 10 ml of water was added 1.34 g of lithium hydroxide monohydrate. The reaction mixture was stirred overnight at room temperature, diluted with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous ethyl sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1), washed with hexane-ethyl acetate, and then 4- [3- [4 0.24 g of-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] phenoxy] benzoic acid was obtained.

Melting point: 160-164 ° C. Mass spectrum (m / z): 419 [(M−H) ⁻ ] (FA
B / Neg) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.74 (2H, s), 6.72 (1H, t),
6.79-6.82 (2H, m), 6.99-7.02
(4H, m), 7.31-7.36 (3H, m), 8.
02 (2H, d) Example 10 a) To a solution of 4- [3- (4-trifluoromethylphenoxy) phenoxy] benzaldehyde (5.0 g) in ethanol (50 ml) was gradually added sodium borohydride (0.79 g) under ice cooling. In addition, the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography, and 1- [4- [3- (4-trifluoromethylphenoxy) phenoxy was obtained from the elution part of hexane-ethyl acetate (17: 3). ] Phenyl] methanol (4.2 g, yield 84%) was obtained.

Elemental analysis value (as C ₂₀ H ₁₅ O ₃ F ₃ ) C (%) H (%) N (%) F (%) Theoretical value 66.67 4.20 0 15.82 Experimental value 66.70 4.18 0 15.80 Mass spectrum (m / z): 360 (M ⁺ ) GC / MS Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.48 (2H, d, J =) 5.86 Hz), 5.1
7 (1H, t, J = 5.86Hz), 6.71-6.7
3 (1H, m), 6.81-6.87 (2H, m),
7.04 (2H, d, J = 8.30Hz), 7.18
(2H, d, J = 8.79Hz), 7.35 (2H,
d, J = 8.30 Hz), 7.40-7.45 (1H,
m), 7.74 (2H, d, J = 8.79 Hz) b) 1- [4- [3- (4-trifluoromethylphenoxy) phenoxy] phenyl] methanol (4.5 g) in 90 ml of methylene chloride, Ice-cooled thionyl chloride 2.9
7 g and dimethylformamide 0.1 ml were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. After completion of the reaction, the solvent was distilled off,
The residue was dissolved in diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, and dried over magnesium sulfate. After distilling off the solvent, 4.56 g of a crude benzyl chloride compound was obtained.

Mass spectrum (m / z): 377 (M ⁺ ) GC / MS 379 (M ⁺ +2) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.77 (2H, s) , 6.77-6.80 (1
H, m), 6.83-6.91 (2H, m), 7.07.
(2H, d, J = 8.55Hz), 7.20 (2H,
d, J = 8.54 Hz), 7.42-7.49 (3H,
m), 7.74 (2H, d, J = 8.54 Hz) c) 2.45 g of crude 4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl chloride obtained in b) above was added to acetonitrile (20 ml). ) ・ Water (3m
1), 0.41 g of potassium cyanide and 100 mg of triethylbenzylammonium chloride were added, and 3
Heated to reflux for hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography, and eluted with hexane-ethyl acetate (9: 1).
2.15 g of 4 '-[3- (4-trifluoromethylphenoxy) phenoxy] benzyl cyanide (90% yield)
I got

Elemental analysis value (as C ₂₁ H ₁₄ NO ₂ F ₃ ) C (%) H (%) N (%) F (%) Theoretical value 68.29 3.82 3.79 15.43 Experimental value 68 .38 3.82 3.81 15.42 Mass spectrum (m / z): 369 (M ⁺ ) (GC / M)
S) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.02 (2H, s), 6.77-6.78 (1
H, m), 6.83-7.10 (2H, m), 7.10
(2H, d, J = 8.55Hz), 7.19 (2H,
d, J = 9.15 Hz), 7.39 (2H, d, J =
8.55 Hz), 7.42-7.47 (1 H, m),
7.74 (2H, d, J = 8.54Hz) d) 4 '-[3- (4-trifluoromethylphenoxy) phenoxy] benzylcyanide 0.
A solution of 54 in dimethylformamide (10 ml) was added with sodium azide 0.15 g and ammonium chloride 0.12 g.
Was added, and the mixture was stirred at 130 ° C. for 24 hours. After completion of reaction, 1
An aqueous solution of N hydrochloric acid and chloroform were added to separate the layers. The organic layer was washed with water and dried over magnesium sulfate, then the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography, and 5- [4- [3] was extracted from the chloroform-methanol (95: 5) eluate. -(4-Trifluoromethylphenoxy) phenoxy] benzyl] tetrazole 0.1
5 g was obtained.

Melting point: 95-99 ° C. Elemental analysis value (as C ₂₁ H ₁₅ N ₄ O ₂ F ₃ ) C (%) H (%) N (%) F (%) Theoretical value 61.17 3.67 13 .59 13.82 Experimental value 60.86 3.79 13.29 13.60 Mass spectrum value (m / z): 412 (M ⁺ ) (EI) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.28 (2H, s), 6.73-6.76 (1
H, m), 6.81-6.88 (2H, m), 7.05.
(2H, d, J = 8.30Hz), 7.18 (2H,
d, J = 8.30 Hz, 7.31 (2H, d, J =
8.30 Hz), 7.38-7.46 (1 H, m),
7.74 (2H, d, J = 8.79Hz) e) 4.5 g of 5- [4 '-[3- (4-trifluoromethylphenoxy) phenoxy] benzyl] tetrazole obtained in d) above was added to sodium carbonate. After heating and dissolving in an aqueous solution and cooling, the crystals that crystallized were collected by filtration and dried to give 5- [4'-
4.2 g of the sodium salt of [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] tetrazole were obtained.

Melting point: 172 ° C. Elemental analysis value (as C ₂₁ H ₁₄ N ₄ O ₂ F ₃ Na + 0.5H ₂ O) C (%) H (%) N (%) F (%) theoretical value 56.89 3 .41 12.64 12.86 experimental value 56.97 3.97 12.56 13.12 mass spectrometry value (m / z): 457 [(M + Na) ⁺ ] F
AB / Pos. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 3.98 (2H, s), 6.70-7.41 (10
H, m), 7.73 (2H, d) In the same manner as in Example 10, the following Example 11 was synthesized using Reference Example 6 as a raw material.

Example 11 5- [4- (3-benzyloxyphenoxy) benzyl] tetrazole Raw material compound: 4- (3-benzyloxyphenoxy) benzaldehyde Mass spec (m / z): 359 (M ⁺ +1) ⁺ FA
B (Pos.) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.28 (2H, s), 5.08 (2H, s),
6.51-6.55 (1H, m), 6.61-6.64.
(1H, m), 6.76-6.81 (1H, m), 6.
97 (2H, d, J = 8.30 Hz), 7.20-7.
44 (8H, m) Example 12 0.9 g of 4- [3- (4-trifluoromethylphenoxy) phenoxy] benzaldehyde obtained in Reference Example 1,
0.4 g of 2,4-dioxothiazolidine and 0.2 g of sodium acetate were heated under reflux with 20 ml of acetic acid for 40 hours, and then allowed to cool to room temperature. The crystallized crystals were collected by filtration and recrystallized from methanol to obtain 0.9 g of 5- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzylidene] thiazolidine-2,4-dione.

Melting point: 153-154 ° C. Acetic acid Elemental analysis value (as C ₂₃ H ₁₄ NO ₄ SF ₃ ) C (%) H (%) N (%) S (%) F (%) Theoretical value 60.39 3 0.08 3.06 7.01 12.46 Experimental value 60.41 3.05 3.07 7.23 12.38 Mass spectrum value (m / z): 456 [(M−H) ⁺ ] F
AB / Neg nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 6.77-7.61 (12 H, m), 7.83 (1
H, s), 8.90 (1H, bs) Example 13 5- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzylidene] thiazolidine-2,4-dione 0 obtained in Example 12 0.2 g was stirred under hydrogen pressure with 10% -palladium on carbon 0.1 g and methanol 100 ml. After the reaction was completed, palladium carbon was filtered off and methanol was distilled off. The residue was subjected to column chromatography using chloroform as an eluent to give 5- [4- [3-
0.1 g of (4-trifluoromethylphenoxy) phenoxy] benzyl] thiazolidine-2,4-dione was obtained.

Melting point: resin Elemental analysis value (as C ₂₃ H ₁₆ NO ₄ SF ₃ ) C (%) H (%) N (%) S (%) Theoretical value 60.13 3.51 3.05 6.98 Experimental value 59.89 3.43 2.93 6.75 Mass spectrum value (m / z): 458 [(M−H) ⁻ ] F
AB / Neg nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.15 (1H, dd), 3.49 (1H, d)
d), 4.52 (1H, q), 6.69-7.34 (1
0H, m), 7.58 (2H, d), 8.11 (1H,
bs) Example 14 0.8 g of the crude benzyl chloride compound obtained in Example 10-C) was dissolved in 15 ml of dimethylformamide, 1.44 g of imidazole was added, and the mixture was stirred at 90 ° C. for 1 hour. After completion of the reaction, the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, and dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography, and chloroform-methanol (97:
3) From the elution part, 0.81 g of 1- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] imidazole (yield 93%) was obtained.

Elemental analysis value (as C ₂₃ H ₁₇ N ₂ O ₂ F ₃ ) C (%) H (%) N (%) F (%) theoretical value 67.31 4.18 6.83 13.89 experiment Value 67.12 4.19 6.72 13.94 Mass spectrum (m / z): 410 (M ⁺ ) GC / MS Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.18 ( 2H, s), 6.74-6.76 (1
H, m), 6.80-6.88 (2H, m), 6.91.
(1H, s), 7.06 (2H, d, J = 8.55H
z), 7.18 (1H, s), 7.19 (2H, d, J
= 8.54 Hz), 7.30 (2H, d, J = 8.54)
Hz), 7.41-7.45 (1H, m), 7.72-
7.74 (2H, m), 7.74 (1H, s) In the same manner as in Example 12, the compound of the following Example 15 was synthesized.

Example 15 5- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzylidene] -1,3-diazolidine-2,4-dione Starting compound: 4- [3- (4-tri Fluoromethylphenoxy) phenoxy] benzaldehyde Melting point: 215-218 ° C. Elemental analysis value (as C ₂₃ H ₁₅ N ₂ O ₄ F ₃ ) C (%) H (%) N (%) F (%) theoretical value 62.73 3.43 6.36 12.94 Experimental value 62.59 3.44 6.65 12.76 Mass spectrum value (m / z): 440 (M ⁺ ) (EI) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.42 (1H, s), 6.82 (1H, t, J =
2.44 Hz), 6.89-6.93 (2H, m),
7.07 (2H, d, J = 8.55Hz), 7.20
(2H, d, J = 8.55Hz), 7.45-7.49
(1H, m), 7.66 (2H, d, J = 8.55H
z), 7.75 (2H, d, J = 9.15Hz), 1
0.50 (1H, brs), 11.22 (1H, br
s) In the same manner as in Example 14, the compound of Example 16 below was synthesized.

Example 16 1- [4- (3-Benzyloxyphenoxy) benzyl] imidazole Raw material compound: 4- (3-benzyloxyphenoxy) benzaldehyde Mass spectrum (m / z): 357 [(M + H) ⁺ ] FAB
(Pos.) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.07 (2H, s), 5.17 (2H, s),
6.52-6.55 (1H, m), 6.62-6.64.
(1H, m), 6.76-6.81 (7H, m), 6.
90 (1H, s), 6.98 (2H, d, J = 8.79)
Hz), 6.99 (1H, s), 7.24-7.42
(8H, m), 7.75 (1H, s) Example 17 a) N-butyllithium (1.6M hexane solution) 4 was added to a solution of 2.1 g of N-tritylimidazole in 60 ml of tetrahydrofuran, under ice cooling. 0.06 ml was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled again, and 4-
A solution of 1.79 g of [3- (4-trifluoromethylphenoxy) phenoxy] benzaldehyde in 15 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 1N hydrochloric acid aqueous solution was added, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated saline and dried over magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography, and 1- (N-trityl) was extracted from the elution with hexane-ethyl acetate (4: 1).
1.15 g (34% yield) of imidazolyl-1- [4- [3- (4-trifluoromethylphenoxy) phenoxy] phenyl] methanol was obtained.

B) 1- (N-trityl) imidazolyl-1- [4- [3- (4-trifluoromethylphenoxy) phenoxy] phenyl] methanol 9 parts in 1.05 g.
10 ml of 0% acetic acid aqueous solution was added, and the mixture was stirred at 60 ° C. for 2 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with an aqueous sodium carbonate solution, water and saturated saline, and dried over magnesium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography, and 1-imidazolyl-1- [4- [3- (4-trifluoro) was obtained from a chloroform-methanol (19: 1) eluate. 0.54 g (yield 81%) of methylphenoxy) phenoxy] phenyl] methanol was obtained.

Melting point: 133-136 ° C. Elemental analysis value (as C ₂₃ H ₁₇ N ₂ O ₃ F ₃ ) C (%) H (%) N (%) F (%) Theoretical value 64.79 4.02 6. 0.57 13.37 Experimental value 64.12 4.02 6.69 13.08 Mass spec (m / z): 426 (M ⁺ ) (EI) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.72 (1H, d, J = 4.40 Hz), 6.1
4 (1H, d, J = 4.40Hz), 6.74 (1H,
t, J = 2.44 Hz), 6.78 (1H, brs),
6.81 (1H, dd, J = 2.44, 8.30H
z), 6.84 (1H, dd, J = 2.44, 8.30)
Hz), 6.98 (1H, brs), 7.03 (2H,
d, J = 8.30 Hz, 7.18 (2H, d, J =
8.79 Hz), 7.41 (2H, d, J = 8.30H
z), 7.42 (1 H, t, J = 8.30 Hz), 7.
43 (2H, d, J = 8.79Hz), 11.87 (1
H, brs) Example 18 1-Imidazolyl-1- [4- obtained in Example 17
[3- (4-Trifluoromethylphenoxy) phenoxy] phenyl] methanol (0.39 g) in a solution of trifluoroacetic acid (10 ml) in ice-cooled triethylsilane (0.21).
3 g was added, and the mixture was stirred at 45 ° C. for 14 hours. After the reaction,
Ethyl acetate was added, washed with aqueous sodium carbonate solution, water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography, and chloroform-methanol (99:
1) From the elution part, 0.179 g (yield 48%) of 2- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] imidazole was obtained.

[0126] Mass spectrum (m / z): 410 (M ⁺ ) (EI) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 3.95 (2H, s), 6.71-6.73 ( 1
H, m), 6.79-6.90 (4H, m), 7.01.
(2H, d, J = 8.79Hz), 7.18 (2H,
d, J = 8.79 Hz), 7.26 (2H, d, J =
8.30 Hz), 7.41 (1H, t, J = 8.30H
z), 7.73 (2H, d, J = 8.79Hz), 1
1.8 (1H, brs) Example 19 a) Methanol solution (60 m) of 5.6 g of 1,3-bis (4-formyl-2-fluorophenoxy) benzene.
To l) are added 3.1 g of hydroxyamine hydrochloride, 3.9 g of sodium acetate, and 5 ml of water, and the mixture is heated under reflux for 12 hours. Allow to cool naturally to room temperature and filter the precipitated crystals. In addition, the crystals were added to water (100 ml) and ethanol (50 m
1,3-bis [2-
5.0 g of fluoro-4- (hydroxyiminomethyl) phenoxy] benzene was obtained.

Mass spectrum (m / z): 384 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 6.71-6.81 (4H, m), 7.13- 7.
64 (8H, m), 11.38 (2H, br) b) 1,3-bis [2-fluoro-4- (hydroxyiminomethyl) phenoxy] benzene 5.0 g in an ethanol solution (50 ml) in an argon atmosphere. Below, at 0 ° C., borane-pyridine complex 3.9 ml, 10% hydrochloric acid 5 m
1 and then stirred at the same temperature for 15 minutes. After adding 20 ml of cold water and stirring for 30 minutes, the solvent is distilled off under reduced pressure. 20 ml of saturated potassium carbonate water and 100 ml of chloroform were added to the residue, the organic layer was separated, and the aqueous layer was chloroform (20 ml x
Back-extract in 3). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3-fluoro-4- [3-[(2-
Fluoro-4-hydroxyiminomethyl) phenoxy]
Phenoxy] benzylhydroxylamine (2.0 g) was obtained as a crude product.

C) 3-Fluoro-4- [3-[(2-
Fluoro-4-hydroxyiminomethyl) phenoxy]
1.34 ml of ethoxycarbonyl isocyanate is added to a tetrahydrofuran solution (15 ml) of 2.0 g of phenoxy] benzylhydroxylamine at 0 ° C. under an argon atmosphere and stirred for 30 minutes. Then, 2.8 ml of 1N sodium hydroxide aqueous solution is added, and the mixture is stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, 1N hydrochloric acid (15 ml) and ethyl acetate (50 ml) were added to the residue to separate the organic layer,
The aqueous layer is back extracted with ethyl acetate (10 ml x 3). The organic layers are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform:
By refining with methanol = 95: 5), 1-
[(2-Fluoro-4-hydroxyiminomethyl) phenoxy] -3- [2-fluoro-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] 700 mg of benzene was obtained.

Mass spectrum (m / z): 456 [(M +
H) ⁺ ]] FAB / Pos Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.68 (2H, s), 6.69-6.75 (3)
H, m), 7.20-7.27 (3H, m), 7.34.
-7.39 (2H, m), 7.46 (1H, d, J = 8
Hz), 7.59 (1H, d, J = 12 Hz), 8.1
6 (1H, s), 11.41 (1H, br) Example 20 a) Methanol solution (50 ml) of 8.0 g of 1,3-bis (3-chloro-4-formylphenoxy) benzene.
To this, 4.0 g of hydroxyamine hydrochloride, 5.1 g of sodium acetate and 5 ml of water are added, and the mixture is heated under reflux for 12 hours.
The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (hexane: sodium acetate = 2:
By purifying in 1), 3.7 g of 1,3-bis [3-chloro-4- (hydroxyiminomethyl) phenoxy] benzene was obtained.

Mass spectrum (m / z): 416 [(M-
H) ^- ] FAB / Neg nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 6.72-7.05 (10H, m), 7.65 (2)
H, m), 8.14 (2H, br) b) 1,3-bis [3-chloro-4- (hydroxyiminomethyl) phenoxy] benzene (3.7 g) in an ethanol solution (50 ml) under an argon atmosphere. At 0 ° C
Add 2.7 ml of borane-pyridine complex and 5 ml of 10% hydrochloric acid, and stir at the same temperature for 4 hours. Add 20 ml of cold water 3
After stirring for 0 minutes, the solvent is evaporated under reduced pressure. 20 ml of saturated potassium carbonate water and 100 ml of chloroform were added to the residue,
After separating the organic layer, the aqueous layer is chloroform (20 ml x 3).
Back extract with. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-chloro-4- [3-[(4-aminomethyl-3-chloro) phenoxy. ] Phenoxy] benzylhydroxyamine 2.5 g of crude product was obtained.

C) 2-chloro-4- [3-[(4-aminomethyl-3-chloro) phenoxy] phenoxy] benzylhydroxyamine 2.5 g in a tetrahydrofuran solution (30 ml) at 0 ° C. under an argon atmosphere. , 1.5 ml of ethoxycarbonyl isocyanate is added, and the mixture is stirred for 30 minutes. Further, 2.4 ml of a 1N sodium hydroxide aqueous solution is added, and the mixture is stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, 10 ml of 1N hydrochloric acid and 50 ml of chloroform were added to the residue, the organic layer was separated, and the aqueous layer was back-extracted with chloroform (10 ml × 3). The organic layers are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 96: 4) to give 1- [2-chloro-4- [3- [3-chloro-4-[(3,5- 1.4 g of dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] phenoxy] benzyl] -3-ethoxycarbonylurea were obtained.

Mass spectrum (m / z): 588 [(M-
H) ^- ] FAB / Neg nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.19 (3H, t, J = 7Hz), 4.11 (2
H, q, J = 7 Hz), 4.81 (2H, s), 5.1
7 (2H, s), 6.81 (1H, m), 6.88 (2
H, m), 7.06-7.09 (2H, m), 7.22
(2H, m), 7.44 (1H, d, J = 8Hz),
7.46 (1H, d, J = 8Hz), 7.49 (1H,
d, J = 8 Hz), 7.56 (1H, d, J = 8 Hz) Hereinafter, Tables 1 and 2 show the chemical structural formulas and physicochemical properties of the compounds obtained by the above reference examples, and Tables 3 to 6 show the above. The chemical structural formulas of the compounds obtained in the examples are listed below.

[0133]

[Table 1]

[0134]

[Table 2]

[0135]

[Table 3]

[0136]

[Table 4]

[0137]

[Table 5]

[0138]

[Table 6]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 233/60 103 103 233/64 103 233/78 249/12 508 257/04 B 263/44 277 / 34 285/08 (72) Inventor Takayuki Suzuki 2-5-9 Ninomiya Ninomiya Tsukuba 223, Tsukuba, Ibaraki Prefecture 223 (72) Inventor Kenichi Onda 2-5-9 Ninomiya Nukunomiya, Tsukuba, Ibaraki Prefecture 407 (72) Tsukuba ) Inventor Toru Kontani 3-24-3, Matsushiro, Tsukuba, Ibaraki 4-603 (72) Inventor Osamu Noshiro 6-15-9 Nagayama, Ryugasaki, Ibaraki

Claims (8)

[Claims] 1. A heterocyclic derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (Each symbol in the above formula has the following meaning. A ring group: imidazolyl group, tetrazolyl group, R ^1: a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a nitro group, a carboxyl group, lower alkoxycarbonyl group, the formula -CH ₂ -NHCONH-COOR
⁵ In a group represented by or a group of the formula ^{-CH = N-OH, R 2} , R 3: same or different and each represents a hydrogen atom or a halogen atom, R ^4: a hydrogen atom or a hydroxyl group, R ^5: a hydrogen atom or a lower alkyl Group, X: oxygen atom, sulfur atom or group represented by formula -NH-, Y: nitrogen atom or A group represented by: n: 0 or 1) 2. The A ring group is a tetrazolyl group.
The heterocyclic derivative described or a pharmaceutically acceptable salt thereof. 3. A ring group has the formula: The heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is an oxygen atom and Y is a nitrogen atom. 4. R ¹ is a hydrogen atom, a lower alkyl group, a trifluoromethyl group, a nitro group, a carboxyl group, a lower alkoxycarbonyl group, or a formula —CH ₂ —NHCONH—C.
The heterocyclic derivative or a salt thereof according to any one of claims 1 to 3, which is a group represented by OOR ⁵ or a group represented by the formula -CH = N-OH. 5. The heterocyclic derivative according to claim 4, wherein R ¹ is a trifluoromethyl group, or a pharmaceutically acceptable salt thereof. 6. 2- [4- [3- (4-trifluoromethylphenoxy) phenoxy] benzyl] -1,2,4
-Oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof. 7. 5- [4- [3- (4-Trifluoromethylphenoxy) phenoxy] benzyl] tetrazole or a pharmaceutically acceptable salt thereof. 8. 2- [4- (3-Benzyloxyphenoxy) benzyl] -1,2,4-oxadiazolidine-
3,5-dione or a pharmaceutically acceptable salt thereof.