JP2000281656A - Phenylazole compound, its production and antihyperlipemia medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new phenylazole compound which can strongly lower the concentration of triglycerides and the concentration of cholesterol in blood in the same extents and is useful as an antihyperlipemia medice. SOLUTION: A compound of formula I [A is a (substituted) imidazolyl or (substituted) pyrazolyl; R1 is H, a 1-6C (halo)alkyl or (substituted) genzyl; R2, R3 are each H, OH, a halogen, a 1-6C (halo)alkyl, a 1-6C alkoxy or (substituted) phenyl; (m) is 0, 1, 2, 3 or 4; X is C(=0) or SO2; Y is CH2, O, S, C(=0), SO2, OCH2 or the like; (n) is 0 or 1; B is a (un)saturated heterocyclic group which contains one to four atoms of (substituted) N, O or the like], for example, [(4-imidazol-1-yl)phenyl]-N-(3-pyridyloxy)acetic acid amide. The compound of formula I can be produced, for example, by a method comprising subjecting a compound of formula II and a compound of formula III to a dehydrative condensation reaction in a solvent, if necessary, in the presence of a condensing agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a phenylazole compound, a method for producing the same, and an antihyperlipidemic drug.

[0002]

2. Description of the Related Art Serious heart diseases such as myocardial infarction are induced by hyperlipidemia, which is a major factor in atherosclerosis. For prevention of myocardial infarction, treatment of hyperlipidemia is important, and development of an antihyperlipidemic drug having excellent activity and safety is required.

[0003] As typical examples of such antihyperlipidemic drugs, pravastatin, simvastatin, clofibrate and the like are known. These drugs lower blood triglyceride levels or cholesterol levels and are already used in clinical settings.

By the way, various types of hyperlipidemia, such as a type having a high triglyceride (neutral fat) concentration in blood, a type having a high cholesterol concentration, and a type having both a high triglyceride concentration and a high cholesterol concentration in the blood, etc. There is.

[0005] However, many of the conventional drugs including the above-mentioned drugs mainly reduce either the blood triglyceride level or the cholesterol level, and reduce both the blood triglyceride level and the cholesterol level to the same extent. However, it may not be preferable depending on the type of hyperlipidemia.

[0006] Therefore, if a drug capable of lowering blood triglyceride concentration and cholesterol concentration to the same extent is developed, it will be effective as a therapeutic agent for the above-mentioned various types of hyperlipidemia and caused by arteriosclerosis. In particular, attention has been paid to the treatment and prevention of diseases such as ischemic heart disease, myocardial infarction, and cerebral infarction.

The following compounds are similar to the compounds of the present invention. (1) JP-A-55-69567 discloses the following compound (A)

[0008]

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Has been described as being useful as an antidepressant. (2) JP-A-2-1977839 discloses the following compound (B)

[0010]

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However, it is described that it is useful as a photofading inhibitor for organic coloring substances. (3) DE34007505 discloses the following compound (C)

[0012]

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Is useful as a therapeutic agent for arthritis. (4) EP 458037 discloses the following compound (D)

[0014]

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Have been described as platelet activating factor inhibitors. (5) EP324377 discloses the following compound (E)

[0016]

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Are described as antihypertensives. (6) Also, WO95 / 29163 discloses the following compound (F)

[0018]

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Has a cholesterol biosynthesis inhibitory activity.

However, a carbonylaminophenylazole compound having a hetero ring such as the compound of the present invention is not known.

[0021]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug which lowers triglyceride concentration and cholesterol concentration in blood to the same degree as compared with conventional drugs.

[0022]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that the blood triglyceride concentration and cholesterol concentration are reduced to a similar level as compared with conventional drugs. The present inventors have found a compound to be made, and have completed the present invention.

That is, the present invention relates to (a) a compound represented by formula (I)

[0024]

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(Wherein A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent. R ¹ is a hydrogen atom, a C _1-6 alkyl group, C
_{1-6 represents a} haloalkyl group or a benzyl group which may have a substituent. R ² and R ³ each independently have a hydrogen atom, a hydroxy group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group or a substituent. Represents a good phenyl group. m represents 0 or an integer of 1-4. However, when m represents an integer of 2 or more, -C (R ² ) (R ³ )-may be the same or different. X represents C (= O) or SO _2. Y is C
H ₂ , -Cr ¹ = Cr ^2- , O, S, C (= O), SO
₂ , OCH ₂ or NR ⁴ (where r ¹ , r ² and R ⁴
Is independently a hydrogen atom, a C _1-6 alkyl group,
Represents a C _1-6 haloalkyl group or a benzyl group which may have a substituent. ). n represents 0 or 1. B
Represents a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms which may have a substituent. Or a pharmaceutically acceptable salt thereof, represented by the formula (II):

[0026]

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Wherein A and R ¹ have the same meanings as described above, and a compound represented by the general formula (III):

[0028]

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(Where B, Y, R ² , R ³ , m and n
Represents the same meaning as described above. Wherein the compound represented by formula (I) is dehydrated and condensed.

[0030]

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(Where A, B, Y, R ¹ , R ² , R ³ ,
m and n represent the same meaning as described above. Method for producing compound represented by)

(C) a compound represented by the general formula (II) and a compound represented by the general formula (IV)

[0033]

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(Wherein B ′ is a saturated or unsaturated group containing 1 to 4 N, O or S atoms which may have a substituent which does not have a hydroxy group or an amino group as a substituent. Wherein R ^{2 ′} and R ^{3 ′} each represent R ² and R ³ which are not a hydroxy group, and X, Y,
m and n represent the same meaning as described above. Wherein the compound represented by the general formula (I-)
A method for producing the compound represented by 1), and

(D) An anti-hyperlipidemic composition comprising as an active ingredient one or more of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. Medicine.

In the compound represented by the above general formula (I) of the present invention, the optionally substituted imidazolyl group or the optionally substituted pyrazolyl group of A is, for example, any of the following groups

[0037]

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And the group represented by Among these A, 1-imidazolyl group, 1H-pyrazol-5-yl group, 1H-pyrazol-4-yl group, 1-methylpyrazol-5-yl group, 1-methylpyrazol-
A 3-yl group and a 1-benzylpyrazol-4-yl group are preferred.

In the above formula, R ⁵ and R ⁶ are each independently a hydrogen atom, a hydroxy group, a nitro group, a halogen atom such as fluorine, chlorine, bromine or iodine, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, or (substituted by a halogen atom such as fluorine, chlorine, bromine or iodine, or a C _1-6 alkoxy group such as methoxyethoxy, propoxy or isopropoxy group). may also be) C _1-6 alkyl groups, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
C _1-6 alkoxy group such as s-butoxy and t-butoxy group, or chloromethyldichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,
C such as 1-difluoroethyl and pentafluoroethyl groups
Represents _1-6 haloalkyl.

R ⁷ is a hydrogen atom, a C _1-6 alkyl group,
_{It represents a 1-6} haloalkyl group, a _C1-6 acyl group, a benzyl group which may have a substituent or the like. P is 0 or 1
The integer of -3 and q represent the integer of 0 or 1-2, respectively.

[0041] As C _1-6 alkyl group R ⁷ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t- butyl and the like, and C _1-6 haloalkyl group, Chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,
Examples of the C _1-6 acyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, and benzoyl.

Examples of the substituent of the benzyl group which may have a substituent include a nitro group, a halogen atom such as chlorine, bromine, fluorine and iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and s. -Butyl,
C _1-6 alkyl group such as t- butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. C _1-6
Examples thereof include an alkoxy group and a C _1-6 haloalkyl group such as chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, and pentafluoroethyl. Further, the benzyl group may have a plurality of the same or different substituents at arbitrary positions that can be substituted.

When R ⁷ is a hydrogen atom, the pyrazolyl group can have the tautomeric structure shown below.

[0044]

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As the saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms which may have a substituent for B, the following groups can be exemplified. In addition, there are no particular restrictions on the substitution positions of the following heterocycles and substituents. When each heterocyclic group has two or more substituents, the substituents may be the same or different.

[0046]

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[0047]

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[0048]

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(In the above formula, Z represents NR ⁹ , S or O, and R ⁸ represents a hydroxy group, a nitro group, a halogen atom,
C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6
Represents a haloalkyl group or a phenyl group which may have a substituent, and R ⁹ represents a hydrogen atom, a C _1-6 alkyl group,
_{Represents a 1-6} haloalkyl group or a benzyl group which may have a substituent, and R ¹⁰ represents a hydroxy group, a halogen atom,
_{Represents a} C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group or a phenyl group which may have a substituent, and R ¹¹ represents a hydroxy group, oxo, a halogen atom,
_{Represents a 1-6} alkyl group, a C _1-6 alkoxy group or a C _1-6 haloalkyl group, and represents R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷
And R ¹⁸ represent a hydrogen atom, a hydroxy group, a nitro group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-6 haloalkyl group;

A is an integer of 0 or 1 to 3 and b is 0 or 1 to
C is 0 or an integer of 1 to 4 d is 1 or 2 e
Represents 0, 1 or 2, f represents 0 or an integer of 1 to 6, g represents 0 or an integer of 1 to 7, h represents an integer of 0 or 1 to 9, respectively. A line passing through two of the condensed rings indicates that any of the rings may be substituted.

Of these heterocycles B1 to B35,
B2, B3, B4, B8, B22 and B23 are particularly preferred.

R ¹ is a hydrogen atom, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoro It may have a C _1-6 haloalkyl group such as methyl, 1-fluoroethyl, 1,1-difluoroethyl, pentafluoroethyl group, or a substituent at any position of the benzene ring (benzyl, α- A benzyl group such as methylbenzyl, α, α-dimethylbenzyl, α-ethylbenzyl, α, α-diethylbenzyl).

Examples of the substituent of the benzyl group include a nitro group, a halogen atom such as chlorine, bromine, fluorine and iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl. C _1-6
C _1-6 alkoxy group such as alkyl group, methoxy, ethoxy, propoxy, isopropoxy, butoxy group, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, pentafluoro Examples thereof include a C _1-6 haloalkyl group such as an ethyl group.

R ² and R ³ each independently represent a hydrogen atom, a hydroxy group, a halogen atom such as chlorine, fluorine, bromine or iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t - C _1-6 alkyl group such as butyl group, methoxy, ethoxy, propoxy, isopropoxy, C _1-6 alkoxy group or a butoxy group, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,1
-C such as difluoroethyl and pentafluoroethyl groups
Represents a _1-6 haloalkyl group or a phenyl group which may have a substituent at any position of a benzene ring.

Examples of the substituent of the phenyl group include a halogen atom such as nitro group, chlorine, bromine, fluorine and iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl. C
_1-6 alkyl group, methoxy, ethoxy, propoxy, isopropoxy, C _1-6 alkoxy group such as butoxy group, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl And a C _1-6 haloalkyl group such as a pentafluoroethyl group.

The above-mentioned substituents (benzyl group and phenyl group) may have a plurality of the same or different substituents.

X represents C (＝ O) or SO ₂ . Y
Is CH ₂ , -Cr ¹ = Cr ^2- , O, S, C (=
O), SO ₂ , OCH ₂ or NR ⁴ , and r ¹ , r ²
And R ⁴ are each independently a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
s- butyl, C _1-6 alkyl groups a t- butyl group and the like, methoxy, ethoxy, propoxy, isopropoxy, C _1-6 alkoxy group or a butoxy group, or a chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl Methyl, 1-fluoroethyl, 1,1-difluoroethyl,
Represents a C _1-6 haloalkyl group such as a pentafluoroethyl group.

The pharmaceutically acceptable salts of the compounds represented by formula (I) include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and acetic acid, propionic acid, lactic acid and succinic acid. And salts of organic acids such as tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid.

[0059]

BEST MODE FOR CARRYING OUT THE INVENTION Next, main production methods of the compound of the present invention will be described below.

(Production Method 1) When X is C (= O)

[0061]

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(Where A, B, Y, R ¹ , R ² , R ³ ,
m and n represent the same meaning as described above. )

The amide derivative represented by the general formula (I-2) can be obtained by subjecting an amine represented by the general formula (II) and a carboxylic acid represented by the general formula (III) to dehydration condensation by a conventional method. Can be.

The conditions for the dehydration-condensation reaction are not particularly limited as long as they are generally performed, but a method using a condensing agent is preferred.

In this case, as the condensing agent, for example, 1,
3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide,
-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline and the like can be used.

In this reaction, N-hydroxysuccinimide, 1-hydroxybenzotriazole,
3,4-dihydro-3-hydroxy-4-oxo-1,
When 2,3-benzotriazine coexists, the reaction proceeds more rapidly.

The reaction solvent is not particularly limited as long as it is a solvent inert to the reaction. For example, diethyl ether,
Ethers such as tetrahydrofuran (THF) and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, chloroform;
Halogenated hydrocarbons such as dichloroethane, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine and the like can be used. The reaction temperature is from −15 ° C. to about the boiling point of the solvent, preferably from 0 to 80 ° C.

Among the amine compounds represented by the general formula (II), 4- (4-aminophenyl) pyrazole can be obtained by a known method described in the literature [for example, Indian J. Am. Che
m. , 26 B, can be produced according to 616-619 (1987)].

(Production Method 2)

[0070]

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(Wherein A, Y, R ¹ , m and n have the same meanings as described above, and B ′ is the above-mentioned heterocycle B having no hydroxy group or amino group as a substituent, R ² ′ , R ³ '
Represents R ² and R ³ which are not a hydroxy group and an amino group, respectively. )

Among the compounds of the present invention, compounds wherein R ² and R ³ are not a hydroxy group or an amino group are represented by the general formula (II)
And an acid chloride or a sulfonyl chloride represented by the general formula (IV) in an inert organic solvent in the presence of a base.

The reaction solvent is not particularly limited as long as it is a solvent inert to the reaction. Examples thereof include ethers such as diethyl ether, THF and 1,4-dioxane, and aromatic solvents such as benzene, toluene and xylene. Hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, D
MSO or the like can be used.

The base used is, for example,
Examples include amines such as triethylamine, pyridine, and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and sodium hydroxide. be able to. The reaction temperature is from −15 ° C. to about the boiling point of the solvent, preferably from 0 to 80 ° C.

The acid chloride or the sulfonyl chloride represented by the general formula (IV) can be produced by a conventional method using a corresponding carboxylic acid compound by using a halogenating agent such as thionyl chloride, phosphorus pentachloride or the like.

(Production Method 3) The carboxylic acid represented by the general formula (III), which is an intermediate of the above production method, can be produced by the following method.

I) R ² = R ³ = H, m = n = 1, Y =
For compounds that are O, S, NR ⁴

[0078]

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(Wherein B has the same meaning as described above;
Y ′ represents O, S or NR ⁴ , and R ⁴ has the same meaning as described above. )

The compound represented by the general formula (VII) can be obtained by reacting the alcohol represented by the general formula (VI) with methyl bromoacetate in an inert solvent in the presence of a base.

The reaction solvent is not particularly limited as long as it is a solvent inert to the reaction. Examples thereof include ethers such as diethyl ether, THF and 1,4-dioxane, and aromatic solvents such as benzene, toluene and xylene. Hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ketones such as acetone and methyl ethyl ketone, acetonitrile, DMF, DMSO and the like can be used.

Examples of the base used include sodium hydride, sodium carbonate, potassium carbonate, silver oxide and the like. The reaction temperature is about −15 ° C. to about the boiling point of the solvent,
Preferably it is 0-80 degreeC.

Then, the obtained compound represented by the general formula (VII) is hydrolyzed in the presence of a base to obtain a carboxylic acid represented by the general formula (III-1).

As a reaction solvent, water or a hydroalcoholic solvent such as water-methanol or water-ethanol can be used, and as a base, an inorganic base such as sodium hydroxide or potassium hydroxide can be used. The reaction is
It proceeds smoothly at 0-100 ° C.

The compound of the general formula (VII) can also be produced by the following method.

[0086]

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(Wherein B ′ has the same meaning as described above;
Hal represents a halogen atom. )

That is, a compound represented by the general formula (VII) is obtained by reacting a halide represented by the general formula (VIII) with methyl hydroxyacetate in an inert solvent in the presence of a base. Can be.

Solvents that can be used in the reaction include:
For example, diethyl ether, THF, ethers such as 1,4-dioxane, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, chloroform,
Halogenated hydrocarbons such as 1,2-dichloroethane, D
MF, DMSO, or the like can be used.

As the base, sodium hydride, sodium carbonate, potassium carbonate and the like can be used. The reaction proceeds smoothly at 0 to 100 ° C.

The carboxylic acid represented by the general formula (III-1) can be prepared by a method known in the literature, for example, as described in J. Am. Org. Che
m. , 55 2908-2913 (1990); M
ed. Chem. , 14 (8) 758-766 (197)
It can be produced by the method described in 1) and the like.

In the present invention, after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment.

The compound (1) of the present invention and the starting compounds (3) and (5) may have some optically active isomers and tautomers, all of which are within the scope of the present invention. include. The structure of the compound of the present invention is IR, NMR
And MS and the like.

(Antihyperlipidemic agent) The compound of the present invention is useful as an antihyperlipidemic agent. The method of administration may be in any form acceptable for the administration of the compound of the above general formula (I) or a pharmaceutically acceptable salt thereof in pure form or a drug having similar utility. It can be carried out.

For example, oral, nasal, parenteral, topical, transdermal or rectal, solid, semisolid, lyophilized powder or liquid dosage forms such as tablets, suppositories, pills, soft and hard capsules, Powders, liquids, suspensions, aerosols and the like can be preferably formulated in an appropriate dosage form which can be prescribed in an accurate dose and can be easily administered.

The composition contains a conventional pharmaceutical carrier or excipient, and the compound represented by the above formula (I) alone or as one of the active ingredients. Components, carriers, adjuvants and the like can be included.

Generally, depending on the intended mode of administration,
A pharmaceutically acceptable composition comprises 1 to 99% by weight of one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutical excipient. The composition contains 99 to 1% by weight.

The composition preferably contains 5 to 75% by weight of one or more of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, with the balance being appropriate. Pharmaceutical excipients.

When administered with medicaments, the preferred method of administration is oral, using a simple daily dosage standard prepared according to the degree of hyperlipidemia to be treated.

Such a composition for oral administration comprises one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and any commonly used excipient. For example, pharmaceutical mannitol, lactose, starch,
Gelatinized starch, magnesium stearate, sodium saccharin, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate,
It can be produced by adding propyl gallate or the like.

Such a composition is used in the form of a solution, suspension, tablet, pill, capsule, powder, sustained-release preparation, suppository and the like.

In the case of such a composition, for example,
Lactose, sucrose, diluents such as dicalcium phosphate, for example, disintegrants such as croscarmellose sodium or derivatives thereof, for example, lubricating agents such as magnesium stearate, for example, starch, gum arabic, polyvinylpyrrolidone, gelatin, A binder such as a cellulose ether derivative can be included.

In the case of suppositories, a carrier that slowly dissolves in the body, for example, polyoxyethylene glycol or polyethylene glycol (PEG), for example, PEG1000
(96%) or PEG 4000 (4%), and the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is dispersed in 0.5 to 50% by weight to form a formulation.

The liquid composition that can be administered as a medicament comprises 0.5 to 50% by weight of one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and 0.5 to 50% by weight. Pharmaceutical adjuvants in water, saline, dextrose aqueous solution, glycerol, ethanol and other carriers
It can be manufactured by dissolving, dispersing, or other treatments to form a solution or suspension.

The pharmaceutical composition of the present invention may contain, if desired, a small amount of auxiliary substances, such as wetting agents, emulsifiers, pH buffers, antioxidants, etc., for example, citric acid, sorbitan monolaurate, triethanol Amine oleate, butylated hydroxytoluene and the like can also be added.

The actual method for producing such dosage forms is conventional, for example, from Remington's Pharm.
Aceutical Sciences, 18th edition, Ma
ckPublishing Company, East
on, Pennsylvania, 1990 and the like.

In general, one or more of the compounds of general formula (I) or pharmaceutically acceptable salts thereof may be administered to an individual and to a pathological condition characterized by the hypercholesterolemia to be treated. It is administered in a therapeutically effective amount that varies depending on the condition.

Usually, a therapeutically effective daily dose will be about 0.14 mg to about 14.3 m / kg of body weight of a compound of formula (I).
g / day, preferably about 0.7 g / kg body weight.
mg to about 10 mg / day, more preferably about 1.4 mg to about 7.2 mg / kg of body weight. For example,
When administered to a human weighing 70 kg, the dose range of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is from about 10 mg to about 1.0 g, preferably 1 mg / day, preferably 1 mg / day.
About 50 mg to about 700 mg per day, more preferably about 100 mg to about 500 mg per day.

[0109]

Next, the present invention will be described more specifically with reference to examples.

Example 1 [(4-Imidazol-1-yl) phenyl)]-N-
(3-pyridyloxy) acetic acid amide (Compound No. 2-4)
7) Manufacturing

[0111]

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5 g of 3-hydroxypyridine was added to DMF50
The resulting solution was dissolved in ice-cold water, and 2.1 g of sodium hydride was added little by little under ice cooling. After all of the addition, the reaction was allowed to warm to room temperature and stirred for an additional 30 minutes. Thereafter, the mixture was ice-cooled again, and 8.1 g of methyl bromoacetate was added little by little. After completion of the addition, the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into ice-cold water and extracted with ethyl acetate. After the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform: methanol = 2).
0: 3) to give 1.7 g of methyl 2- (3-pyridyloxy) acetate.

1.7 g of the methyl 2- (3-pyridyloxy) acetate obtained above was added to 10 ml of methanol.
And 2.5 mol / l sodium hydroxide aqueous solution 10m
and stirred at 60 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 3 by adding 1.0 mol / l hydrochloric acid. The precipitated white crystals were collected by filtration, and the obtained crystals were washed with water and air-dried to obtain 0.6 g of 2- (3-pyridyloxy) acetic acid.

Next, 0.6 g of 4- (imidazol-1-yl) phenylamine, 0.72 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 0.58 g of 1-hydroxybenzotriazole and (3-
0.6 g of pyridyloxy) acetic acid was added to 10 ml of DMF, and 0.6 g of triethylamine was further added, followed by stirring at room temperature for 15 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and ethyl acetate, and then air-dried to give the target compound [4- (imidazol-1-yl) phenyl] -N- ( 0.14 g of 3-pyridyloxy) acetic acid amide was obtained. mp. 174 ° C

Example 2 [4- (Imidazol-1-yl) phenyl] -N-
(2-pyridyloxy) acetic acid amide (Compound No. 2-4)
5) Manufacturing

[0116]

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5 g of 2-hydroxypyridine and 24 g of silver (I) oxide were added to 150 ml of DMF, 20 g of methyl bromoacetate was added with stirring, and the mixture was stirred at room temperature for 2 hours.
The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (chloroform-chloroform: methanol =
Purification by 100: 1) gave 1 g of methyl 2- (2-pyridyloxy) acetate.

Next, this was hydrolyzed in the same manner as in Example 1 to obtain 0.6 g of 2- (2-pyridyloxy) acetic acid. Further, the obtained 2- (2-pyridyloxy) acetic acid was dehydrated and condensed with 4- (imidazol-1-yl) phenylamine in the same manner as in Example 1 to obtain [4- (imidazol-1-yl). ) Phenyl]-
0.1 g of N- (2-pyridyloxy) acetic acid amide was obtained. mp. 110 ° C

Reference Example 1 Production of 5- (4-nitrophenyl) pyrazole

[0120]

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15 g of 4-nitroacetophenone and N, N
-A mixture of 54 g of dimethylformamide dimethyl acetal was refluxed for 1 hour. After cooling the reaction solution, the precipitated crystals were collected by filtration (yield 13.5 g). The obtained crystals were added to a solution of 4.62 g of hydrazine hydrate in 150 ml of ethanol, 0.15 g of p-toluenesulfonic acid hydrate was added, and the mixture was refluxed for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and ether was added for crystallization to obtain 10.1 g of the desired product.

Reference Example 2 Production of 5- (4-aminophenyl) pyrazole

[0123]

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To 100 ml of ethanol, 10.1 g of 5- (4-nitrophenyl) pyrazole and 35.7 g of stannous chloride hydrate were added. There, concentrated hydrochloric acid 25.5ml
Was added dropwise, and after the addition was completed, the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, the mixture was made strongly alkaline with water and a 20% aqueous sodium hydroxide solution, and extracted with chloroform. After the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 8.1 g of the desired product.

Tables 1 and 2 show typical examples of the compounds of the present invention including the above Examples. In each table, A
And B are represented by symbols. The meanings of the symbols are as follows.

[0126]

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[0127]

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[0128]

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[0129]

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[0130]

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[0131]

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[0132]

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[0133]

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[0134]

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[0135]

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[0136]

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[0137]

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[0138]

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[0139]

[Table 101]

[0140]

[Table 102]

[0141]

[Table 103]

[0142]

[Table 104]

[0143]

[Table 105]

[0144]

[Table 106]

[0145]

[Table 107]

[0146]

[Table 108]

[0147]

[Table 109]

[0148]

[Table 110]

[0149]

[Table 111]

[0150]

[Table 201]

[0151]

[Table 202]

[0152]

[Table 203]

[0153]

[Table 204]

[0154]

[Table 205]

[0155]

[Table 206]

[0156]

[Table 207]

[0157]

[Table 208]

[0158]

[Table 209]

[0159]

[Table 210]

Next, examples of the compound of the present invention as a pharmaceutical preparation will be described.

Example 3 Oral (active ingredient 10 mg tablet) Compound of compound No. 1-150 10 mg Lactose 81.4 Constarch 20 Hydroxypropylcellulose 4 Carboxymethylcellulose calcium 4 Magnesium stearate 0.6合計 Total 120mg

Compound No. 1-150 (corresponding to the numbers in the above table, the same applies hereinafter) 50 g of the compound, 407 g of lactose and 100 g of constarch were applied using a fluidized granulation coating apparatus (manufactured by Okawara Seisakusho Co., Ltd.). , Mixed uniformly. This was granulated by spraying 200 g of a 10% aqueous solution of hydroxypropylcellulose. After drying, the mixture was passed through a 20-mesh sieve, and 20 g of calcium carboxymethylcellulose and 3 g of magnesium stearate were added thereto.
7 mm × 8 with a rotary tableting machine (manufactured by Hata Iron Works).
Using a 4R mortar, a tablet of 120 mg per tablet was prepared. This tablet is a tablet having the above composition.

[0163]

Next, it will be shown that the compounds of the present invention have excellent pharmacological activity.

Pharmacological Test Example 1 Influence of Cholesterol-Loaded Hamsters on Serum Lipids A powder feed containing 1% cholesterol and 10% coconut oil was allowed to be taken freely by Syrian hamsters (Std: Syrian, male, 4 weeks old) for 3 weeks. 0.1% hydrochloric acid solution or 1
% Polyethylene Hardened Castor Oil (NIKKOL HCO-
60) Each test compound was dissolved or suspended in the solution, and orally administered once a day in the last week for 5 days. The solvent was orally administered to a control group.

Next, 2 to 4 hours after the last administration, blood was collected from the abdominal vena cava under anesthesia with pentobarbital, and the serum was separated. Next, the serum total cholesterol value and the serum triglyceride value were measured by an automatic biochemical measurement device using a measurement kit, and the serum lipid lowering rate was calculated from the measured value of each group according to the following formula.

[0166]

(Equation 1)

Table 3 shows the results.

[0168]

[Table 301]

[0169]

[Table 302]

[0170]

[Table 303]

Pharmacological Test Example 2 Repeated Oral Toxicity The compound of Compound No. 1-150 was suspended in a 1% polyethylene-hardened castor oil (NIKKOL HCO-60) solution and administered to 6 rats / group (male SD) in a group. 100 daily
Oral administration was performed at a rate of mg / kg for 7 days. As a result, no death or other toxic symptoms were observed.

As described above, the compound of the present invention has a blood lipid-lowering effect, in particular, a blood triglyceride concentration and a cholesterol concentration, which have the same effect.
It is useful as a therapeutic agent for hyperlipidemia, arteriosclerosis, myocardial infarction, cerebral infarction, etc.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/437 A61K 31/437 31/4439 31/4439 31/4709 31/4709 31/4725 31/4725 31 / 497 31/497 31/498 31/498 31/506 31/506 31/519 31/519 31/522 31/522 C07D 231/12 C07D 231/12 C 231/20 231/20 Z 401/12 401/12 403/12 403/12 405/12 405/12 409/12 409/12 417/12 417/12 471/04 104 471/04 104A 473/04 473/04 491/048 491 / 048 491/052 491/052 (72) Inventor Kunito Ito 345 Takada, Odawara-shi, Kanagawa Japan Soda Co., Ltd.Odawara Research Laboratory Co., Ltd. (72) Inventor Nobuhiro Umeda 345 Odawara-shi, Kanagawa Pref. Reference) 4C063 AA01 BB07 CC22 CC25 CC28 CC34 CC54 CC75 CC76 CC79 CC81 CC82 CC92 CC94 CC97 DD04 DD06 DD12 DD14 DD15 DD22 DD25 EE01 4C065 AA03 CC01 DD01 EE02 HH03 JJ01 JJ03 KK02 LL01 PP03 4C086 AA01 AA02 AA03 AA04 BC36 BC38 BC41 BC42 BC52 BC74 CB05 CB07 CB22 GA02 GA04 GA07 GA08 GA09 GA12 MA01 MA04 NA14 ZA36 ZA45 ZC33

Claims (4)

[Claims] 1. A compound of the general formula (I) (In the formula, A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent.
R ¹ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group or a benzyl group which may have a substituent. R ² and R ³ each independently have a hydrogen atom, a hydroxy group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group or a substituent. Represents a good phenyl group. m represents 0 or an integer of 1-4. When m represents an integer of 2 or more, -C
(R ² ) (R ³ )-may be the same or different. X
Represents C (＝ O) or SO ₂ . Y is CH ₂ , -C
r ¹ = Cr ² −, O, S, C (= O), SO ₂ , OCH
₂ or NR ⁴ (where r ¹ , r ² and R ⁴ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group or a benzyl which may have a substituent (s)) Represents a group). n represents 0 or 1. B represents a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms which may have a substituent. Or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula (II) (Wherein A and R ¹ have the same meanings as described above) and a compound represented by the general formula (III): (Wherein B, Y, R ² , R ³ , m and n have the same meanings as described above), wherein the compound represented by the general formula (I) is dehydrated and condensed. 4] (Where A, B, Y, R ¹ , R ² , R ³ , m and n are
Represents the same meaning as above. )). 3. A compound represented by the general formula (II) and a compound represented by the general formula (IV): (Wherein B ′ represents an N, O or S atom which may have a substituent that is not a hydroxy group or an amino group;
Pieces comprising a heterocyclic group, saturated or unsaturated, R 2 ^'and R
^{3 ′} represents R ² and R ³ which are not hydroxy groups, respectively, and X, Y, m and n have the same meaning as described above. Wherein the compound is represented by the general formula (I-1): A method for producing a compound represented by the formula: 4. An antihyperlipidemic drug comprising as an active ingredient one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.