JP2000290280A - Phenylazole compound, its production, and antihyperlipemic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new phenylazole compound capable of strongly and simultaneously reducing triglycerides and cholesterol in blood to the same extent and exhibiting suppressing actions on the production of lipid peroxides and useful as an antihyperlipemic agent. SOLUTION: This phenylazole compound is represented by formula I [A is immidazolyl or pyrazolyl; B is a group or the like represented by formula II (R2 and R3 are each H, cyano, hydroxy, a halogen, a 1-6C alkyl or the like; k is 0 or 1-15); D is chroman-2-yl or the like; R1 and R4 are each H or a 1-6C alkyl; m is 0 or 1], e.g. (±)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-N-[4- imidazol-1-yl)phenyl]carboxamide. The compound represented by formula I can be produced by subjecting a compound represented by formula III and a compound represented by formula IV to a dehydrating condensation. The compound represented by formula I having high safety and antioxidant actions can be expected for use as an antihyperlipemic agent, a therapeutic agent, etc., for arteriosclerosis and for suppressing action on the production of lipid peroxides.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a phenylazole compound, a method for producing the same, and an antihyperlipidemic drug containing the compound as an active ingredient.

[0002]

2. Description of the Related Art In recent years, it has become clear that the formation of lipid peroxide in a living body and the accompanying radical reaction have various adverse effects on the living body through membrane damage, cell damage and the like. Along with this, various attempts have been made to apply antioxidants and lipid peroxide production inhibitors to medicines, and antioxidants have been studied using these as basic skeletons.

[0003] As such a research report, for example, J. J.
Amer. Oil Chemist's Soc. , 51
200-203 (1974), JP-A-2-12197
No. 5, EP. No. 345593 and EP. 483
772 and the like. However, none of the drugs described in these publications has a weak effect or has side effects, and is not always practically satisfactory.

By the way, serious heart diseases such as myocardial infarction
It is a disease induced by hyperlipidemia, a major factor in atherosclerosis. Three types of hyperlipidemia are known: a type in which the concentration of triglyceride, which is a blood lipid, is increased, a type in which the concentration of blood cholesterol is increased, and a type in which the concentrations of both are increased. For prevention of myocardial infarction, treatment of hyperlipidemia is important, and development of an antihyperlipidemic drug having excellent activity and safety is required.

[0005] As typical examples of such antihyperlipidemic drugs, pravastatin, simvastatin, clofibrate and the like are known. However, these drugs are not drugs that simultaneously and to a similar extent reduce triglyceride and cholesterol levels in blood lipids.

[0006] Accordingly, a drug which simultaneously and substantially reduces blood triglyceride and cholesterol and has an inhibitory effect on the production of lipid peroxide is required for treating diseases such as ischemic heart disease, myocardial infarction and cerebral infarction caused by arteriosclerosis. Although attention has been paid particularly from the viewpoint of the treatment and prevention of, there has not yet been found any drug that satisfies these requirements.

As a compound similar to the compound of the present invention, WO
No. 95/29163 describes that an imidazolylphenyl derivative (a) shown below has cholesterol biosynthesis inhibitory activity.

[0008]

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Further, DE. No. 3,407,505 discloses the following compound (b) as a therapeutic agent for arthritis.

[0010]

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[0011]

DISCLOSURE OF THE INVENTION The present invention provides a drug which simultaneously and substantially reduces blood triglyceride and cholesterol and suppresses the production of lipid peroxide as compared with conventional drugs. The purpose is to do.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have simultaneously reduced blood triglyceride and cholesterol to the same extent, and have an effect of inhibiting the production of lipid peroxide. Find compounds,
The present invention has been completed. That is, the present invention
(A) General formula (1)

[0013]

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(In the formula, A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent. B represents any of the following groups.

[0015]

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(Wherein R ² and R ³ each independently represent a hydrogen atom, a cyano group, a hydroxy group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl A C _2-6 alkynyl group, a C _2-6 alkenyloxy group, a C _2-6 alkynyloxy group, a C _1-6 acyloxy group or a C _3-6 cycloalkyl group, and k is 0 or 1-15. Further, when k is 2 or more, R ² and R ³ may be the same or different from each other.) D is chroman-2- which may have a substituent Yl group, 2,3-dihydrobenzofuran-2-yl group which may have a substituent, thiochroman-2-yl group which may have a substituent, 2 which may have a substituent , 3
-Represents a dihydrobenzothiophen-2-yl group or a 1,3-benzoxatiol-2-yl group which may have a substituent. R ¹ and R ⁴ each independently represent a hydrogen atom or a C _1-6 alkyl group which may be substituted. m
Represents 0 or 1. Or a pharmaceutically acceptable salt thereof.

(B) General formula (2)

[0018]

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Wherein A and R ¹ have the same meanings as described above, and a compound represented by the general formula (3):

[0020]

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Wherein B, D, R ⁴ and m have the same meanings as described above, wherein the compound represented by the general formula (1) is dehydrated and condensed.

[0022]

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(Where A, B, D, R ¹ R ⁴ and m are
Represents the same meaning as above. A method for producing the compound represented by

(C) a compound represented by formula (2) and a compound represented by formula (4):

[0025]

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(Wherein B ′ has the same meaning as B)
D ′ represents the above D having a substituent protected by an acyl group. Wherein the compound is represented by the general formula (1-1):

[0027]

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(Wherein A, B ', D' and R ¹ have the same meanings as described above), and

(D) An anti-hyperlipidemic drug comprising, as an active ingredient, one or more of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof. It is.

Examples of the imidazolyl group optionally having a substituent of A or the pyrazolyl group optionally having a substituent in the compound represented by the general formula (1) include the following. Groups.

[0031]

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[0032] Here, R ^5, R ⁶ each independently represent a hydrogen atom or an optionally substituted C _1-6 alkyl group, R ⁷ is a hydrogen atom, a C ₁ substituted _-6
Represents an alkyl group or a C _1-6 acyl group. N is 0
Or p represents an integer of 1-3, and p represents an integer of 0 or 1-2, and when n or p is 2 or more, R ⁵ and R ⁶ may be the same or different.

Examples of the C _1-6 alkyl group for R ⁵ , R ⁶ and R ⁷ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups. Further, these C _1-6 alkyl groups may be substituted with halogen atoms such as chlorine, bromine, fluorine, iodine and the like.

Examples of the C _1-6 acyl group for R ⁷ include an acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, benzoyl group and the like.

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

[0036]

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In the above formula, B represents any of the following groups.

[0038]

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Here, R ² and R ³ each independently represent a hydrogen atom, a cyano group, a hydroxy group, a halogen atom such as chlorine, fluorine, bromine or iodine, methyl, ethyl,
A C _1-6 alkyl group such as propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl or a halogen atom such as chlorine, bromine, fluorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, etc. C
_A C _1-6 alkyl group which may be substituted with a _1-6 alkoxy group, etc.)

C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups, ethenyl, 1-propenyl, 1-methylvinyl, allyl, 1-
Methylallyl, C _2-6 alkenyl groups such as 2-butenyl, ethynyl, 1-propynyl, 2-propynyl C _2-6 alkynyl group such as, ethenyloxy, 1-propenyloxy, 1-methylvinyl, allyloxy, 1 −
C _2-6 such as methylallyloxy and 2-butenyloxy groups
Alkenyloxy group, ethynyloxy, 1-propynyloxy, C _2-6 alkynyloxy groups such as 2-propynyloxy group, acetoxy group, propionyloxy group, C _1-6 acyloxy group such as Buchirirokishi group, cyclopropyl,
Represents a C _3-6 cycloalkyl group such as cyclobutyl, cyclopentyl, and cyclohexyl group.

[0041] Incidentally, k is an integer of 0 or 1-15, and when k is 2 or more, but R ² and R ³ are present in plural, the plurality of R ² and R ^3, in each of the same They may be different.

D is a chroman-2-yl group which may have a substituent, a 2,3-dihydrobenzofuran-2-yl group which may have a substituent, or a group which has a substituent. A thiochroman-2-yl group, a 2,3-dihydrobenzothiophen-2-yl group which may have a substituent,
Or a 1,3-benzoxathiol-2-yl group which may have a substituent. As such D, for example,
The following groups can be mentioned.

[0043]

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In the above formula, * represents an asymmetric carbon atom, X represents an oxygen atom or a sulfur atom, and q represents 1 or 2.
^{Further, R 8, R 9, R} 12, R 13 and R ¹⁴ each independently represent a hydrogen atom or a C _1-6 alkyl group, R ^10,
R ¹¹ each independently represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group.

The above R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³
And the C _1-6 alkyl group for R ¹⁴ includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
-Butyl, t-butyl and the like. _Examples of the C _1-6 alkoxy group for R ¹⁰ and R ¹¹ include methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.

G is preferably OR ¹⁵ or NHR ¹⁶
And R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or a C _1-6 acyl group. here,
_Examples of the C _1-6 acyl group for R ¹⁵ and R ¹⁶ include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and a benzoyl group which may have a substituent. Examples of the substituent of the benzoyl group include a halogen atom such as fluorine, chlorine, and bromine substituted at an arbitrary position of a benzene ring, a C _1-6 alkyl group such as methyl and ethyl groups, a methoxy, ethoxy, and isopropoxy group. C _1-6 alkoxy group, nitro group, cyano group and the like.

R ¹ and R ⁴ are each independently a hydrogen atom, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, or (chlorine, bromine , A halogen atom such as fluorine and iodine, and a C _1-6 alkyl group which may be substituted with a C _1-6 alkoxy group such as methoxy, ethoxy, propoxy and isopropoxy groups.

The pharmaceutically acceptable salt of the compound represented by the general formula (1) includes hydrochloric acid, sulfuric acid, nitric acid,
Examples thereof include salts of inorganic acids such as phosphoric acid and salts of organic acids such as acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid, and heptagluconic acid. These salts can be easily produced by ordinary synthetic chemistry techniques.

[0049]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention represented by the general formula (1) can be produced, for example, as follows.

Production method 1

[0051]

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(Where A, B, D, R ¹ , R ⁴ and m
Represents the same meaning as described above. )

That is, the amide derivative represented by the general formula (1) is obtained by subjecting the carboxylic acid derivative represented by the general formula (3) and the amine represented by the general formula (2) to dehydration condensation by a conventional method. Things.

This dehydration condensation reaction can be carried out in the presence of a suitable condensing agent. In this case, as the condensing agent, for example, 1,3-dicyclohexylcarbodiimide, 1-
(3-dimethylaminopropyl) -3-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,
2-dihydroquinoline or the like can be used.

In this reaction, N-
By allowing hydroxysuccinimide, 1-hydroxybenzotriazole, and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine to coexist, the reaction can proceed more quickly.

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, tetrahydrofuran (THF) and 1.4-dioxane, benzene, toluene, xylene and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, dimethylformamide (DM
F), dimethylsulfoxide (DMSO), pyridine and the like. The reaction proceeds smoothly at −15 ° C. to about the boiling point of the solvent, preferably at 0 to 80 ° C.

Among the carboxylic acid derivatives represented by the general formula (3), the compound in which m is 0 can be prepared by a known method described in a literature [for example, Collection Czechoslo].
v. Chem. Commun. , 24 , 1689-16
94 (1959); Amer. Oil Chemi
sts'Soc. , 51 , 200-203 (197)
4). Org. Chem. , 54 , 561-569
(1989); Med. Chem. , 33, 149
1-1496 (1990), WO 97/49388, etc.].

The carboxylic acid derivative represented by the general formula (3) wherein m is 1 can be produced, for example, according to the following reaction formula.

[0059]

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(Wherein B, D and R ⁴ have the same meanings as described above.) That is, the carboxylic acid derivative represented by the general formula (6) and the amine represented by the general formula (5) are The amide compound represented by the general formula (7) is obtained by performing dehydration condensation in the same manner as in Production Method 1. Next, the ester of the general formula (7) is hydrolyzed by a known method to obtain a carboxylic acid derivative represented by the general formula (8).

Of the compounds represented by the general formula (2), 4
-(4-Aminophenyl) pyrazol can be prepared by known methods described in the literature [for example, Indian J. Am. Chem. , 26
B, 616-619 (1987)].

Production Method 2 Among the compounds of the present invention, a compound wherein m = 0 and B has a substituent protected by an acyl group can be produced according to the following reaction formula.

[0063]

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(In the formula, A, B ', D' and R ¹ have the same meanings as described above.)

That is, the carboxylic acid derivative represented by the general formula (3 ') is obtained by using a halogenating agent such as thionyl chloride, phosphorus pentachloride, oxalic acid dichloride to obtain an acid chloride (4), and then obtaining the acid chloride (4). The acid chloride is reacted with an amine represented by the general formula (2) 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, pyridine, or the like can be used.

As the base used in the reaction, 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 is carried out at -15 ° C to about the boiling point of the solvent, preferably at 0 to 80 ° C.

In the present invention, after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment. The structure of the compound of the present invention can be determined from IR, NMR, MS and the like.

The compound (1) of the present invention and the starting compounds (3) and (5) may have several optically active forms and tautomers. These are all included in the scope of the present invention.

(Antihyperlipidemic Drug) The compound of the present invention is useful as an antihyperlipidemic drug because it strongly reduces blood triglyceride and cholesterol levels to the same extent. In addition, since the compound of the present invention has an antioxidant effect and an inhibitory effect on lipid peroxide production, it can prevent the occurrence and progression of arteriosclerotic lesions by preventing oxidative degeneration of LDL, and can be used as a therapeutic agent for arteriosclerosis. It is also useful as a therapeutic agent for various diseases based on oxidative action, for example, senile dementia disease, heart disease, cancer, diabetes, digestive disease, burn, eye disease, kidney disease and the like.

Furthermore, in ischemic organ diseases such as stroke and myocardial infarction, various active oxygens are generated at the time of blood reperfusion at the ischemic site, and tissue damage is exacerbated by cell membrane destruction due to lipid peroxidation. The compound of the present invention having an antioxidant effect can prevent tissue damage at an ischemic lesion by removing various active oxygens and lipid peroxides, and can be a therapeutic drug for ischemic organ damage.

When the compound of the present invention is administered as these medicaments, the compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof in a pure form or a drug having similar utility Can be carried out in any of the accepted modes of administration.

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 compositions also include a conventional pharmaceutical carrier or excipient and one or more active ingredients of the formula (I)
Embedded image but may further contain other drugs, pharmaceutical ingredients, carriers, adjuvants and the like.

The pharmaceutically acceptable composition comprises a compound of the general formula (1) or a pharmaceutically acceptable salt thereof.
The seed or two or more are present in amounts from 1 to 99% by weight, and from 99 to 1% by weight of a suitable pharmaceutical excipient, depending on the intended mode of administration. The composition preferably contains 5 to 75% by weight of one or more of the compound of formula (1) or a pharmaceutically acceptable salt thereof, with the balance being suitable pharmaceutical excipients. .

The preferred route of administration is oral, using a convenient daily dosage standard adjusted according to the degree of hyperlipidemia to be treated. Such compositions for oral administration include:
One or more of the compound of general formula (1) or a pharmaceutically acceptable salt thereof, and any commonly used excipients, such as pharmaceutical mannitol, lactose, starch, gelatinized starch, stearin Magnesium acid, sodium saccharin, talc, cellulose ether derivatives,
It is formed by adding glucose, gelatin, sucrose, citrate, propyl gallate and the like.

Such compositions are used in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained-release preparations, suppositories and the like.

In the case of such a composition, diluents such as lactose, sucrose and dicalcium phosphate, for example, disintegrants such as croscarmellose sodium or a derivative thereof, for example, magnesium stearate and the like Lubricants such as binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose ether derivatives and the like 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%) with a compound of the general formula (1) or a pharmaceutically acceptable salt of 0.5 to 50.
It is preferable to formulate the drug by dispersing the weight%.

The liquid composition which can be administered as a medicament comprises 0.5 to 50% by weight of one or more of the compound of the formula (1) or a pharmaceutically acceptable salt thereof, and an optional medicament adjuvant. , Water, saline, dextrose aqueous solution, glycerol, ethanol or the like, and then dissolving or dispersing the same in a carrier to form a solution or suspension.

The pharmaceutical compositions of the present invention may, if desired, contain small amounts of auxiliary substances, such as wetting agents, emulsifying agents, pH buffering agents,
Antioxidants and the like, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene and the like can also be added.

Such a preparation can be prepared by a conventional method, for example,
Remington's Pharmaceutical
l Sciences, 18th edition, Mack Publi
shing Company, Easton, Penn
It can be produced according to the description taught in Sylvania, 1990 and the like.

One or more of the compounds of general formula (1) or pharmaceutically acceptable salts thereof depends on the individual and the pathological condition characterized by the hypercholesterolemia to be treated. Is administered in a therapeutically effective amount which varies. Usually, a therapeutically effective daily dose will be about 0.14 mg to about 14.3 mg / kg of the compound of formula (1) per kg of body weight, preferably about 0.7 mg to about 10 mg / kg of body weight, Preferably, from about 1.4 mg / kg to about 7.2 mg / kg of body weight per day.

For example, when administered to a human weighing 70 kg, the dose of the compound of general formula (1) or a pharmaceutically acceptable salt thereof may be about 10 mg to about 1.0 g per day, preferably one day. About 50 mg to about 700 mg, more preferably about 100 mg to about 500 mg per day.

[0085]

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

Example 1 (±)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) -N- [4- (imidazol-1-yl) phenyl] carboxamide (Compound No. 1
Production of -1)

[0087]

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(±) -6-hydroxy-2,5,7,8
-Tetramethylchroman-2-carboxylic acid 4.0 g, 4
-Aminophenylimidazole 2.82 g, 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.4 g), 1-hydroxybenzotriazole (2.72 g), and triethylamine (2.5 ml) were added to DMF.
The mixture was added to 30 ml and stirred at room temperature for 20 hours. The reaction solution was poured into ice water, the precipitate was collected by filtration, and the obtained crystals were extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was crystallized from chloroform-ether to give 3.85 g of the desired product. mp. 229-231 ° C

Example 2 (±)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) -N- [4- (pyrazole-
5-yl) phenyl] carboxamide (Compound No. 2-
Production of 1)

[0090]

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(±) -6-hydroxy-2,5,7,8
1.0 g of tetramethylchroman-2-carboxylic acid, 4
0.70 g of -aminophenylpyrazole, 0.85 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.68 g of 1-hydroxybenzotriazole and 0.63 ml of triethylamine were added to DM
F8ml and stirred at room temperature for 20 hours. The reaction solution was poured into ice water, the precipitate was collected by filtration, 10 ml of a 1N aqueous sodium hydroxide solution and 10 ml of ethanol were added, and the mixture was refluxed for 1 hour. After cooling, the mixture was neutralized with 1N-hydrochloric acid and extracted with chloroform. After washing with saturated saline, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 3) to give the title compound (0.1%).
53 g were obtained. mp. 215-218 ° C

Example 3 (±) -2-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) -N-methylcarbonylamino] -N- [4- (imidazole- Production of 1-yl) phenyl] acetamide (Compound No. 1-8)

[0093]

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(±) -6-hydroxy-2,5,7,8
2.0 g of tetramethylchroman-2-carboxylic acid, 1.36 g of sarcosine ethyl ester hydrochloride, 1- (3-
1.70 g of dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1.36 g of 1-hydroxybenzotriazole and 2.5 ml of triethylamine were added to DMF1
The mixture was added to 5 ml and stirred at room temperature for 20 hours. The reaction solution was poured into ice water, the precipitate was collected by filtration, and the obtained crystals were extracted with chloroform-methanol. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

After the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 3), the obtained intermediate was added to a 1N aqueous solution of sodium hydroxide (15 ml) and ethanol (15 ml), and the whole volume was refluxed for 1 hour. After cooling, the mixture was adjusted to pH 1 with hydrochloric acid and extracted with chloroform-methanol. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.51 g of a crude product.

The obtained crude product, 4-aminophenylimidazole (1.41 g), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.71) were obtained.
g, 1.36 g of 1-hydroxybenzotriazole and 1.26 ml of triethylamine were added to 16 ml of DMF, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into ice water, the precipitate was collected by filtration, and the obtained crystals were extracted with chloroform-methanol. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 3),
1.02 g of the desired product was obtained. (amorphous)

¹ H-NMR (CDCl ₃ , δ ppm):
1.7 (s, 3H), 1.75 (m, 1H), 2.05 (s, 3H), 2.2 (s, 3H), 2.25 (s, 3
H), 2.5-2.9 (m, 3H), 3.45 (s, 3H), 3.75 (d, 1H), 4.4 (d, 1H),
7.1 (s, 1H), 7.2-7.3 (m, 3H), 7.7-7.8 (m, 3H)

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

[0099]

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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 dissolved in 150 ml of ethanol, and hydrazine hydrate 4.62 was obtained.
g and 0.15 g of p-toluenesulfonic acid hydrate were added, and the mixture was further refluxed for 1 hour. The solvent was distilled off under reduced pressure, and ether was added for crystallization to obtain 10.1 of the desired product.
g was obtained.

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

[0102]

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5- (4-nitrophenyl) pyrazole 1
0.1 g was dissolved in 100 ml of ethanol, 35.7 g of stannous chloride hydrate was added thereto, and 25.5 ml of concentrated hydrochloric acid was added dropwise with further stirring. After the addition was completed, the reaction mixture was refluxed for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, a diluted aqueous solution of sodium hydroxide was added to make the mixture alkaline, and the mixture was extracted with chloroform. After washing with a saturated saline solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 8.1 g of the desired product.

Tables 1 to 3 show typical examples of the compounds of the present invention, including the above Examples. The symbol h ₁ in the following table
~h ₁₃ represent the following meanings.

[0105]

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[0106]

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[0107]

[Table 101]

[0108]

[Table 102]

[0109]

[Table 103]

[0110]

[Table 104]

[0111]

[Table 105]

[0112]

[Table 201]

[0113]

[Table 202]

[0114]

[Table 203]

[0115]

[Table 301]

[0116]

[Table 302]

[0117]

[Table 4]

Next, a production example of a preparation containing the compound of the present invention will be described. Example 4 Oral (active ingredient 10 mg tablet) Compound of compound No. 1-1 10 mg Lactose 81.4 mg Constarch 20 mg Hydroxypropylcellulose 4 mg Carboxymethylcellulose calcium 4 mg Magnesium stearate 0.6 mg合計 Total 120mg

To obtain the above composition, 50 g of the compound of Compound No. 1-1 (Table 1), 407 g of lactose and 100 g of constarch were used in a fluid granulation coating apparatus (manufactured by Okawara Seisakusho Co., Ltd.). And 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, 120 mg tablets were obtained per tablet.

[0120]

Next, various test examples show that the compound of the present invention has 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. Next, 0.1% hydrochloric acid solution or 1% polyethylene hardened castor oil (NIKKOL
Each test compound was dissolved or suspended in an HCO-60) solution and orally administered once a day for the last week for 5 days. The solvent was orally administered to the control group. Next, the last administration 2
４4 hours later, blood was collected from the abdominal vena cava under pentobarbital anesthesia, and the serum was separated. Then, using a measurement kit for serum total cholesterol level and serum triglyceride level,
It was measured by an automatic biochemical measurement device, and the serum lipid lowering rate was calculated from the measured value of each group according to the following formula.

[0122]

(Equation 1)

The results are shown in Table 5.

[0124]

[Table 5]

Pharmacological Test Example 2 Anti-Lipid Peroxide Activity In Vitro The method of Malvy et al. (Malvy, C., et a.)
l. , Biochemical and Biophi
local Research Communicat
ions. , 95 , 732-737 (1980), the lipid peroxide activity in rat liver microsomes was measured. That is, 500 μM cysteine and 5 μM ferrous sulfate were added to rat liver microsomes, heated, and malonaldehyde generated by decomposition of lipid peroxide was measured by the thiobarbituric acid method. 50% inhibitory concentration (IC
₅₀ values). The results are shown in Table 6.

[0126]

[Table 6]

Pharmacological Test Example 3 Anti-Lipid Peroxide Activity In Vivo The effects of the compounds of the present invention on the amount of hepatic lipid peroxide production and liver damage in rats administered with carbon tetrachloride were examined. That is, SD male rats (6 weeks of age), 5 rats per group, were orally administered with olive oil and an equivalent mixture of carbon tetrachloride at a rate of 1 ml / kg (0.5 ml / kg as carbon tetrachloride). 24 hours after carbon tetrachloride administration, the liver was removed and Uc was removed.
Hiyama et al. (Uchiyama, M., et. al.)
al. , Analytical biochemis
try. , 86 , 271-278 (1978), the amount of hepatic lipid peroxide production was measured by the thiobarbituric acid method. In addition, serum enzyme activity (GOT, GPT) was measured as an indicator of liver damage due to carbon tetrachloride.

Next, each test compound was dissolved or suspended in a 0.1% hydrochloric acid solution or olive oil, and orally administered three times 1 hour before, 3 hours and 6 hours after carbon tetrachloride administration. The above-mentioned solvent was orally administered to a normal rat group and a control group. From the measured values of each group, the lipid peroxide production inhibition rate and liver injury inhibition rate were calculated according to the following formula.

[0129]

(Equation 2)

[0130]

(Equation 3)

Table 7 shows the results.

[0132]

[Table 7]

Pharmacological Test Example 4 Repeated Oral Dose Toxicity The compound of Compound No. 1-1 was suspended in a 1% polyethylene-hardened castor oil (NIKKOLHCO-60) solution and administered to 6 rats / group (male SD) for 1 day. 100mg / k
Oral administration was performed at a rate of g for 7 days. As a result, no death or other toxic symptoms were observed.

As described above, the compound of the present invention has high safety and reduces blood triglyceride concentration and cholesterol concentration to the same extent, and is therefore useful as an antihyperlipidemic drug.

Further, since the compound of the present invention has an antioxidant effect and an inhibitory effect on the production of lipid peroxide, it can prevent the development and progression of atherosclerotic lesions by preventing oxidative degeneration of LDL. It can be a therapeutic agent.

Further, since the compound of the present invention has an excellent antioxidant effect, it is possible to prevent tissue damage at ischemic lesions by removing various active oxygens and lipid peroxides, and to prevent ischemic organ damage. Can be a therapeutic drug.

Further, according to the production method of the present invention, the compound represented by the general formula (1) can be produced industrially advantageously.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 411/12 C07D 411/12 (72) Inventor Seiichi Uchida 345 Takada, Odawara-shi, Kanagawa Japan Soda Research Co., Ltd. In-house (72) Inventor Tadayuki Seibu 345 Takada, Odawara-shi, Kanagawa Foda-term in Nippon Soda Co., Ltd.Odawara Research Laboratories (reference)

Claims (4)

[Claims] 1. A compound of the general formula (1) (In the formula, A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent.
B represents any of the groups shown below. Embedded image (Wherein, R ² and R ³ are each independently a hydrogen atom,
Cyano group, hydroxy group, halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, C _2-6 alkenyl group, C
_2-6 alkynyl group, C _2-6 alkenyloxy group, C _2-6
Alkynyloxy group, C _1-6 acyloxy group or C _3-6
Represents a cycloalkyl group, and k represents an integer of 0 or 1-15. When k is 2 or more, R ² and R ³
May be the same or different. D is an optionally substituted chroman-2-yl group, an optionally substituted 2,3-dihydrobenzofuran-2-yl group, or an optionally substituted substituent. Thiochroman-2-yl group, 2,3 which may have a substituent
-Represents a dihydrobenzothiophen-2-yl group or a 1,3-benzoxatiol-2-yl group which may have a substituent. R ¹ and R ⁴ each independently represent a hydrogen atom or a C _1-6 alkyl group which may be substituted. m
Represents 0 or 1. Or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula (2) Wherein A and R ¹ have the same meanings as described above, and a compound represented by the general formula (3): (Wherein B, D, R ⁴ and m represent the same meaning as described above), which is characterized by dehydration-condensation with a compound represented by the following general formula (1): (Wherein A, B, D, R ¹ , R ⁴ and m represent the same meaning as described above). 3. A compound represented by the general formula (2) and a compound represented by the general formula (4): (Wherein, B ′ represents the same meaning as B, and D ′ represents D having a substituent protected by an acyl group). And the general formula (1-1) (Wherein, A, B ′, D ′ and R ¹ have the same meanings as described above). 4. An anti-hyperlipidemic drug comprising as an active ingredient one or more of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.