JP2000281658A - Phenylazole compound and antihyperlipemia medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new phenylazole compound which can simultaneously lower the concentrations of triglycerides and cholesterol in blood in the same extents, has an action for inhibiting the production of lipid peroxides, and is useful as an antihyperlipemia medicine. SOLUTION: A compound of formula I [R1 is H or a 1-6C alkyl; R2, R3 are each H, methyl or methoxy, or R2 and R3 together form a ring; R4 is H or methyl; R5 is a (substituted) phenyl, (substituted) furyl, (substituted) thienyl or the like; A is a (substituted) imidazolyl or (substituted) pyrazolyl; Z is a band, CH=CH, C≡C or the like; (m) is 0 or 1; (k) is 0, 1 to 10], for example, N-[4-(imidazol-1-yl)phenyl]-4-phenyl-4-(3,5,6-trimethyl-1,4-benzoquino n-2-yl)butyric acid amide. The compound of formula I is produced, for example, by a method comprising reacting a carboxylic acid derivative of formula II with a halogenating agent and then reacting the obtained acid halide of formula III with an amine of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a phenylazole compound and an antihyperlipidemic drug containing the compound as an active ingredient.

[0002]

2. Description of the Related Art In recent years, it has been revealed that the production of lipid peroxide in a living body and the accompanying radical reaction have various adverse effects on the living body through membrane damage and cell damage. 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-61-4484.
0, Japanese Unexamined Patent Publication No.
5, EP345593, EP483772 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.

[0004] Serious heart diseases such as myocardial infarction are diseases induced by hyperlipidemia, which is 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 concentration of both is increased.

[0005] For the prevention of myocardial infarction, the treatment of hyperlipidemia is important, and there is a need for the development of an antihyperlipidemic drug having excellent activity and safety. Pravastatin (Pravastatin) is a typical example of such antihyperlipidemic drug.
in), Simvastatin,
Clofibrate drugs and the like are known.

[0006] However, these drugs are drugs that mainly reduce either the triglyceride or cholesterol level of blood lipids, and drugs that simultaneously and similarly reduce the triglyceride or cholesterol level of blood lipids. is not.

[0007] Accordingly, a drug which simultaneously and substantially reduces blood triglyceride and cholesterol and has an inhibitory effect on the production of lipid peroxide can be used for 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 the following imidazolylphenyl derivative (A) has cholesterol biosynthesis inhibitory activity.

[0009]

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(Wherein, X represents NH, O, S, CONH, etc., and A represents a phenoxy, phenylthio group, etc.)

[0011]

DISCLOSURE OF THE INVENTION The present invention relates to a phenylazole compound having an effect of simultaneously lowering blood triglyceride and cholesterol to the same extent as conventional drugs, and having an effect of suppressing the production of lipid peroxide. And an antihyperlipidemic drug containing the compound as an active ingredient.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above problems, and as a result, certain phenylazole compounds simultaneously and trivially reduce blood triglyceride and cholesterol, and The present inventors have found that they have a lipid peroxide production inhibitory action, and have completed the present invention. That is, the present invention relates to (a) general formula (1)

[0013]

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[0014] wherein, R ¹ represents a hydrogen atom or a C _1-6 alkyl group, R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group and, R ² And R ³ may together form a ring, R ⁴ represents a hydrogen atom or a methyl group, R ⁵ represents a phenyl group which may have a substituent, An optionally substituted furyl group, an optionally substituted thienyl group, an optionally substituted pyridyl group, an optionally substituted naphthyl group, Good indanyl group,
Represents a quinolyl group which may have a substituent or an isoquinolyl group which may have a substituent. A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent. Z is a bond or

[0015]

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(In the formula, n represents 0 or an integer of 1 to 6.) m is 0 or 1
Represents k represents 0 or an integer of 1-10. The phenylazole compound represented by or a pharmaceutically acceptable salt thereof, and

(B) 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.

In the compound represented by the general formula (1), R ¹ is a hydrogen atom or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,
represents a C _1-6 alkyl group such as t-butyl.

R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group. Also, R ² and R ³
Are combined to form * -CH ₂ CH ₂ CH _2- *, * -C
H ₂ CH = CH- *, * -CH = CHCH _2- *, *-
CH ₂ CH ₂ CH ₂ CH _2- *, * -CH = CHCH =
A 5- to 8-membered ring bonded to a benzene ring such as CH- * (* indicates that these groups are bonded to the benzene ring at the position where R ² and R ³ of the benzene ring are bonded); It may be formed.

R ⁵ is a phenyl group which may have a substituent, a substituent which may have a substituent (a furyl group such as 2-furyl or 3-furyl), or a substituent. Good (2-
A thienyl group such as thienyl and 3-thienyl), and may have a substituent (a pyridyl group such as 2-pyridyl, 3-pyridyl and 4-pyridyl), and may have a substituent (1- Naphthyl groups such as naphthyl and 2-naphthyl), an indanyl group which may have a substituent, and an optionally substituted group (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6 -Quinolyl, 7-quinolyl, 8-
A quinolyl group such as quinolyl) or a substituent (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-
Isoquinolyl groups such as isoquinolyl and 8-isoquinolyl)
Represents

A phenyl group, a furyl group, a thienyl group,
Examples of the substituent of the pyridyl group, naphthyl group, indanyl group, quinolyl group and isoquinolyl group include nitro group, cyano group, halogen atom such as chlorine, bromine, fluorine and iodine, methyl, ethyl, propyl, isopropyl, butyl and t-.
C _1-6 alkyl group such as butyl, methoxy, ethoxy, propoxy, C _1-6 alkoxy group isopropoxy, and the like, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, such as trifluoromethyl C _1- Examples thereof include C _1-6 alkoxycarbonyl groups such as ₆ haloalkyl groups, methoxycarbonyl, and ethoxycarbonyl groups.

These substituents may be substituted at any position on the ring, and the phenyl, furyl, thienyl, pyridyl, naphthyl, indanyl, quinolyl and isoquinolyl groups may be the same or different. It may be substituted with a plurality of different substituents.

A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent. As such imidazolyl group and pyrazolyl group,
For example, each group shown below can be mentioned.

[0024]

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Here, R ⁶ and R ⁷ each independently represent a hydrogen atom or a C _1-6 alkyl group which may have a substituent, and R ⁸ has a hydrogen atom and a substituent. _{Represents a} C _1-6 alkyl group or a C _1-6 acyl group which may be
Represents an integer of 0 or 1-3, and q represents an integer of 0, 1 or 2.

These A include 1-imidazolyl group, 1H-pyrazol-5-yl group, 1H-pyrazol-4-yl group, 1-methylpyrazol-5-yl group,
-A methylpyrazol-3-yl group and a 1-benzylpyrazol-4-yl group are preferred.

Examples of the C _1-6 alkyl group for R ⁶ , R ⁷ and R ⁸ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like. Further, the C _1-6 alkyl group may be substituted with a halogen atom such as chlorine, bromine, fluorine and iodine, or a C _1-6 alkoxy group such as a methoxyethoxy group.

Examples of the C _1-6 acyl group for R ⁸ include acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, benzoyl and the like.

When R ⁸ is a hydrogen atom, the pyrazolyl group can have the following tautomeric structure.

[0030]

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Z represents a bond or any of the groups shown in the above formula (5). Here, binding and, in the general formula ^{(1), -NR 1 C (} = O) may represent that it is bound (CH ₂₎ directly and _k.

The pharmaceutically acceptable salt of the compound represented by the above general formula (1) includes hydrochloric acid, sulfuric acid, nitric acid,
Salts of inorganic acids such as phosphoric acid, acetic acid, propionic acid, lactic acid,
Succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid,
Salts of organic acids such as nicotinic acid and heptagluconic acid can be mentioned.

[0033]

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)

[0035]

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(Where A, Z, R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ , k and m represent the same meaning as described above. )

That is, a carboxylic acid derivative represented by the general formula (3) is reacted with a halogenating agent such as thionyl chloride, phosphorus pentachloride, and oxalic acid dichloride to obtain an acid halide (4). The amide derivative represented by the general formula (1) can be obtained by reacting the acid halide (4) with an amine represented by the general formula (2) in an inert organic solvent in the presence of a base.

The solvent used for the reaction is not particularly limited as long as it is a solvent inert to the reaction. For example, diethyl ether, tetrahydrofuran (THF), 1.4-
Ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, acetonitrile, dimethylformamide (D
MF), dimethyl sulfoxide (DMSO), pyridine and the like can be used.

As the base used in the reaction, for example,
Amines such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and inorganic bases such as sodium hydrogencarbonate, 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.

(Production method 2)

[0041]

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That is, the carboxylic acid derivative represented by the general formula (3) and the amine represented by the general formula (2) are dehydrated and condensed by a conventional method to give the amide derivative represented by the general formula (1). Obtainable.

The dehydration-condensation reaction is not particularly limited as long as it is a commonly used method, but a method using a condensing agent is more preferable. Examples of such a condensing agent include 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, and the like. it can.

Further, N-hydroxysuccinimide, 1
-Hydroxybenzotriazole, 3,4-dihydro-
When 3-hydroxy-4-oxo-1,2,3-benzotriazine coexists in the reaction system, the reaction may proceed more quickly.

The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction. Examples thereof include ethers such as diethyl ether, THF, 1.4-dioxane, benzene, toluene, xylene and the like. Aromatic hydrocarbons, dichloromethane, chloroform, 1,2-
Examples include halogenated hydrocarbons such as dichloroethane, acetonitrile, DMF, DMSO, pyridine and the like. The reaction temperature is from −15 ° C. to about the boiling point of the solvent, preferably from 0 to 80 ° C.

(Production Method 3) Among the compounds of the present invention, the compound wherein Z is a quinone ring derivative can also be produced by the method shown in the following reaction formula.

[0047]

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(Where A, B, R ¹ , R ¹⁷ , R ¹⁸ , R ¹⁹
And Y represent the same meaning as described above. That is, in the same manner as in the above production method 1 or 2, the general formula (5)
After producing the amide compound represented by the formula, a quinone derivative represented by the general formula (1-2) can be produced by reacting with an oxidizing agent.

The oxidizing agent used in this reaction includes, for example, silver oxide and cerium ammonium nitrate. When silver oxide is used, the reaction is carried out at -10 ° C to 30 ° C in the presence of nitric acid in a water-containing organic solvent such as water-dioxane or water-acetonitrile. When cerium ammonium nitrate is used, for example, cerium ammonium nitrate alone or cerium ammonium nitrate and pyridine-2,6-dicarboxylic acid N-oxide, pyridine in a water-containing organic solvent such as water-methanol or water-acetonitrile. -5 ° C in the presence of 2,4,6-tricarboxylic acid or pyridine-2,6-dicarboxylic acid.
The reaction is performed at 20 ° C.

The carboxylic acid derivative represented by the general formula (3) can be prepared by a known method described in the literature (for example, JP-A-61-44).
No. 840, J.P. Org. Chem. , 54 , 330
3-3310 (1989); Med. Chem. ,
32 , 2214-2221 (1989), Chem. P
harm. Bull. , 30 , (8) 2797-281
9 (1982)).

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

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 is determined from IR, NMR, MS and the like.

The compound (1) of the present invention and the starting compounds (3) and (4) have several optically active substances (for example,
Some are based on the asymmetric carbon to which R ⁵ is attached. ) And tautomers may exist, all of which are within the scope of the present invention.

Examples of the compounds of the present invention obtained as described above are shown in Table 1. Note that z ₁ to z used in the Z column of the table are used.
The meaning of the symbol ₉ is as follows.

[0055]

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[0056] Also, as used in m & R ⁴ column of the table, R1～R1
6 symbols, and were used in column G, the meaning of the symbols h ₁ to h ₃ is,
Each is as follows.

[0057]

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[0058]

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[0059]

[Table 1001]

[0060]

[Table 1002]

[0061]

[Table 1003]

[0062]

[Table 1004]

[0063]

[Table 1005]

[0064]

[Table 1006]

[0065]

[Table 1007]

[0066]

[Table 1008]

[0067]

[Table 1009]

[0068]

[Table 1010]

[0069]

[Table 1011]

[0070]

[Table 1012]

[0071]

[Table 1013]

[0072]

[Table 1014]

[0073]

[Table 1015]

[0074]

[Table 1016]

[0075]

[Table 1017]

[0076]

[Table 1018]

[0077]

[Table 1019]

[0078]

[Table 1020]

[0079]

[Table 1021]

[0080]

[Table 1022]

[0081]

[Table 1023]

[0082]

[Table 1024]

[0083]

[Table 1025]

[0084]

[Table 1026]

[0085]

[Table 1027]

[0086]

[Table 1028]

[0087]

[Table 1029]

[0088]

[Table 1030]

[0089]

[Table 1031]

[0090]

[Table 1032]

[0091]

[Table 1033]

[0092]

[Table 1034]

[0093]

[Table 1035]

[0094]

[Table 1036]

[0095]

[Table 1037]

[0096]

[Table 1038]

[0097]

[Table 1039]

[0098]

[Table 1040]

[0099]

[Table 1041]

[0100]

[Table 1042]

(Antihyperlipidemic agent) The compound of the present invention is useful as an antihyperlipidemic agent because it reduces blood triglyceride and cholesterol to the same extent. Also,
Since the compound of the present invention has an antioxidant action and a lipid peroxide production inhibitory action, it can prevent the occurrence and progress of arteriosclerotic lesions by preventing oxidative degeneration of LDL.
It can be a therapeutic agent for arteriosclerosis.

Further, 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 aggravated due to 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 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 that can be formulated in an accurate dose and can be easily administered.

The composition contains a conventional pharmaceutical carrier or excipient and the compound of the general formula (1) alone or as one kind of active ingredient. Components, carriers, adjuvants and the like can be included.

The pharmaceutically acceptable composition is 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 has the general formula (1)
Or 5 to 75% by weight of a compound or a pharmaceutically acceptable salt thereof, and the remainder is a suitable pharmaceutical excipient.

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 phosphate, sodium saccharin, talc, cellulose ether derivative,
It is formed by adding glucose, gelatin, sucrose, citrate, propyl gallate and 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, diluents such as lactose, sucrose and dicalcium phosphate, for example, disintegrants such as croscarmellose sodium or a derivative thereof, and lubricating agents such as magnesium stearate Binders may be included, for example, binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose ether derivatives.

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 0.5% of the compound of general formula (1) or a pharmaceutically acceptable salt thereof.
It is preferable to disperse and formulate up to 50% by weight.

The liquid composition that can be administered as a medicament comprises 0.5 to 50% by weight of one or more of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof, and an optional pharmaceutical adjuvant. Is dissolved in a carrier such as water, saline, dextrose aqueous solution, glycerol, ethanol, etc.
It can be manufactured by performing a treatment such as dispersing to form a solution or suspension.

The pharmaceutical compositions of the present invention may optionally 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.

The actual manufacture of such dosage forms may be effected in a conventional manner, for example, as described in Remington's Pharmac.
medical Sciences, 18th edition, Mack
Publishing Company, Easto
n, Pennsylvania, 1990 and the like.

Generally, one or more of the compounds of general formula (1) or pharmaceutically acceptable salts thereof will depend on the individual and the pathological condition characterized by the hypercholesterolemia being treated. Administered in a therapeutically effective amount which varies. Usually, the therapeutically effective daily dose is
About 0.14 mg to about 14.3 mg of the compound of the general formula (1)
/ Day, preferably about 0.7 m / kg body weight
g to about 10 mg / day, most preferably about 1.4 mg to about 7.2 mg / kg 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 range from about 10 mg to about 1.0 g per day, preferably one day. About 50 mg to about 700 mg, most preferably about 100 mg to about 500 mg daily.

[0116]

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

Reference Example 1 Production of 3- (4-nitrophenyl) pyrazole

[0118]

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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 3- (4-aminophenyl) pyrazole

[0121]

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3- (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, diluted with a sodium hydroxide aqueous solution to make the mixture strongly alkaline, and extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 8.1 g of the desired product.

Example 1 N- [4- (imidazol-1-yl) phenyl] -4
-Phenyl-4- (3,5,6-trimethyl-1,4-
Production of benzoquinone-2-yl) butyric acid amide (compound 1)

[0124]

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0.71 g of 1- (4-aminophenyl) imidazole, 1.25 of 4-phenyl-4- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) butyric acid
g, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.85 g) and 1-hydroxybenzotriazole (0.68 g) were dissolved in DMF (8 ml), and triethylamine (0.7 ml) was added thereto and the mixture was allowed to stand at room temperature overnight. Stirred. The reaction solution was poured into ice water, and the precipitate was collected by filtration. The obtained crude product was dissolved in chloroform-methanol, washed with brine, 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 obtain 0.82 g of the desired product (amorphous).

¹ H-NMR of compound 1 (CDCl ₃ , δ ppm): 1.9 (s, 6H), 2.05 (s, 3H), 2.4-2.8 (m, 4H), 4.4 (t, 1H), 7.1
(s, 1H) 7.2-7.3 (m, 9H), 7.65 (d, 2H), 7.8 (s, 1H), 8.25 (s, 1H)

Example 2 4-phenyl-4- (3,5,6-trimethyl-1,4
Example 1 except that 7-phenyl-4- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) heptanoic acid was used in place of -benzoquinone-2-yl) butyric acid.
N- [4- (imidazol-1-yl)
[Phenyl] -7-phenyl-4- (3,5,6-trimethyl-1,4-benzoquinon-2-yl) heptanoic amide (Compound 2) was produced.

¹ H-NMR of compound 2 (CDCl ₃ , δ ppm): 1.2-1.8 (m, 6H), 1.95 (s, 3H), 2.0 (s, 3H), 2.05 (s, 3H), 2.1-
2.4 (m, 4H), 4.3 (t, 1H), 7.7.2-7.4 (m, 9H), 7.65 (d, 2H), 7.75 (s, 1H), 7.
8 (s, 1H)

Example 3 N- [4- (imidazol-1-yl) phenyl] -3
-(3,5,6-trimethyl-1,4-benzoquinone-
Production of 2-yl) propionamide

[0130]

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1.91 g of 2,5-dimethoxy-3,4,6-trimethylphenylpropionic acid, 1.35 g of 1- (4-aminophenyl) imidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 1.63 g of hydrochloride, 1-hydroxybenzotriazole
30 g and 1.3 ml of triethylamine in DMF 30
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 dissolved in chloroform. After washing the chloroform solution with saturated saline, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is crystallized from chloroform-diethyl ether to give N- [4- (imidazol-1-yl) phenyl] -3- (2,5-dimethoxy-3,4,6-trimethylphenyl) propionic acid 2.89 g of the amide were obtained.

The resulting N- [4- (imidazole-1-
Yl) phenyl] -3- (2,5-dimethoxy-3,
4,6-Trimethylphenyl) propionamide 1.
01 g and pyridine-2,6-dicarboxylic acid 1.30 g
Was suspended in a mixed solvent of 18 ml of acetonitrile and 4 ml of water. The mixture was cooled to 0 ° C. and stirred,
A mixed solution of 4.24 g of cerium ammonium nitrate in 5 ml of water and 5 ml of acetonitrile was added dropwise, and after the addition was completed, the mixture was further stirred for 30 minutes. The precipitated crystals were collected by filtration, and methanol
After dissolving in a mixed solvent of chloroform, the solution was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: chloroform / methanol = 20).
/ 1) to give 0.89 g of the desired product. Melting point: 1
45-150 ° C dec.

Embodiment 4

[0134]

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In the same manner as in Example 3, N- [4- (imidazol-1-yl) phenyl] -5- (3,5,6-
Trimethyl-1,4-benzoquinon-2-yl) pentanoic acid amide was prepared. mp. 140-143 ° C

Next, examples of the compound of the present invention as a medicine will be described. Example 5 Oral (10 mg tablet) Compound of the present invention 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

Compound 1 was prepared so as to have the above composition.
Was uniformly mixed with 50 g of lactose, 407 g of lactose and 100 g of constarch using a fluidized granulation coating apparatus (manufactured by Okawara Seisakusho Co., Ltd.). In addition, 1
200 g of a 0% hydroxypropylcellulose aqueous solution was sprayed and granulated. After drying, the mixture was passed through a 20-mesh sieve.
Magnesium stearate (3 g) was added, and a rotary tableting machine (manufactured by Hata Iron Works Co., Ltd.) was used to make a tablet of 120 mg per tablet using a 7 mm × 8.4 R mortar and punch.

[0138]

Next, it will be shown that the compounds of the present invention have excellent pharmacological activity. Pharmacological Test Example 1 Effect of Cholesterol-Loaded Hamster on Serum Lipid First, Syrian hamster (Std: Syrian,
(Male, 4 weeks old) were allowed to freely take a powder feed containing 1% cholesterol and 10% coconut oil for 3 weeks. Then, 0.1% hydrochloric acid solution or 1%
Polyethylene-hardened castor oil (NIKKOL HCO-6
0) Each test compound was dissolved or suspended in the solution, and orally administered once a day for 5 days in the last week.

Further, only a solution having the same composition as described above without containing the test compound was orally administered to the control group of hamsters.

Next, 2 to 4 hours after the final administration, each hamster in each test group and control group was anesthetized with pentobarbital, and blood was collected from the inferior abdominal vena cava to separate serum. Then, the serum total cholesterol level and serum triglyceride level were measured with an automatic biochemical measurement device using a measurement kit,
The serum lipid lowering rate was calculated from the measured value of each group according to the following formula.

[0141]

(Equation 1) Table 2 shows the results.

[0142]

[Table 2]

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, 734-737, 1980)
The lipid peroxide activity in rat liver microsomes was measured in accordance with the above. That is, 500 μl of rat liver microsomes
M cysteine and 5 μM ferrous sulfate were added, and the mixture was heated. Malonaldehyde generated by decomposition of lipid peroxide was measured by the thiobarbituric acid method. The 50% inhibitory concentration (IC ₅₀ value) of the compound of the present invention was determined, and the results are shown in Table 3.

[0144]

[Table 3]

Pharmacological Test Example 3 Anti-Lipid Peroxide Activity In Vivo The effects of the compound 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, using a group of 5 male SD rats (6 weeks old),
2 ml / kg of carbon tetrachloride in a mixture of olive oil and an equal volume
(1 ml / kg as carbon tetrachloride). 24 hours after carbon tetrachloride administration, the liver was removed and
(Uchiyama M, et. al.)
al. , Analytical biochemis
try. , 86 , 271-278 (1978)), and the amount of hepatic lipid peroxide production was measured by the thiobarbituric acid method. In addition, serum enzyme activity (GOT, GTP) was measured as an indicator of liver damage due to carbon tetrachloride.

Next, a solution in which each test compound was dissolved or suspended in a 0.1% hydrochloric acid solution or olive oil was orally administered 1 hour before, 3 hours and 6 hours after carbon tetrachloride administration, a total of three times. The above-mentioned solvent alone 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.

[0147]

(Equation 2)

[0148]

(Equation 3) Table 4 shows the results.

[0149]

[Table 4]

As described above, the compound of the present invention has excellent pharmacological activity to reduce blood triglyceride and cholesterol to the same extent and is highly safe, and therefore, is useful as an antihyperlipidemic drug. Useful.

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 occurrence and progress of arteriosclerotic lesions by preventing oxidative degeneration of LDL. It can be a therapeutic agent for arteriosclerosis.

Further, since the compound of the present invention has an excellent antioxidant effect, by removing various active oxygens and lipid peroxides, it is possible to prevent tissue damage at ischemic lesions, It can be a treatment for disorders.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 405/14 C07D 405/14 409/12 409/12 409/14 409/14 (72) Inventor Seiichi Uchida 345 Takada, Odawara-shi, Kanagawa Japan Soda Co., Ltd.Odawara Research Laboratories (72) Inventor Yumi Horikoshi 345 Takada, Odawara-shi, Kanagawa Japan Soda Co., Ltd. BC38 GA02 GA04 GA07 GA12 MA01 MA04 NA14 ZA45 ZC33

Claims (2)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a hydrogen atom or a C _1-6 alkyl group, R ² and R ³ each independently represent a hydrogen atom, a methyl group or a methoxy group, and R ² and R ^{3 May} form a ring together with R ⁴ represents a hydrogen atom or a methyl group, and R ⁵ represents a phenyl group which may have a substituent, A good furyl group, a thienyl group which may have a substituent, a pyridyl group which may have a substituent,
A naphthyl group which may have a substituent; an indanyl group which may have a substituent; a quinolyl group which may have a substituent; or an isoquinolyl group which may have a substituent. A represents an imidazolyl group which may have a substituent or a pyrazolyl group which may have a substituent.
Z is a bond or the following: (N represents 0 or an integer of 1 to 6). m represents 0 or 1. k represents 0 or an integer of 1 to 10. Or a pharmaceutically acceptable salt thereof. 2. 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.