JPH01250316A - Cholesterol-lowering agent - Google Patents

Abstract

PURPOSE:To obtain a cholesterol-lowering agent having excellently cholesterol lowering action, especially reducing total cholesterol value in blood, raising HDL-cholesterol value, comprising a naphthalene derivative or a salt thereof as an active ingredient. CONSTITUTION:A compound shown by the formula (ring A is benzene ring; R<1> and R<2> are -OR<5>, -NH-R<5>, etc., or one of R<1> and R<2> is -OR<5>, -NH-R<5>, etc., and the other is <=4C alkoxy; R<3> and R<4> are lower alkoxy or one of R<3> and R<4> is lower alkoxy and the other is H; R<5> is substituted lower alkyl, heterocyclic ring, cycloalkyl, etc.) or a salt thereof is contained, properly blended with ordinary additives such as excipient, binder, diluent, etc., and pharmaceutically manufactured by a conventional procedure to give the aimed substance. The substance can be prepared into a dosage form such as tablet, powder, capsule, granule, syrup, injection or suppository. A daily dose is 1.5-35mg/kg.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to an antilipemic agent containing a novel naphthalene derivative as an active ingredient.

(Prior art) Hyperlipidemia, especially hypercholesterolemia, is considered to be one of the main causes of arteriosclerosis, an adult disease. phenoxy)-2-methylpropanoic acid ethyl ester], propcol [chemical name: 4.4°-[(I-methylethylidene)bis(thio)]bis[2,6-bis(1,l-dimethylethyl)phenol] 〕〕Antilipidemic agents such as
It is used as a preventive agent.

Cholesterol is found in the blood as a very low density riboprotein (VL).
DL) cholesterol, low-density riboprotein (LDL) cholesterol, and high-density riboprotein (HDL) cholesterol, etc. Among these, VLDL and LDL promote the deposition of cholesterol on the arterial wall and cause arteriosclerosis. However, HDL has been shown to have the effect of preventing and treating arteriosclerosis by preventing the deposition of cholesterol on the arterial walls [Annals of Internal Medicine].
rnal Mediclne), Volume 90, No. 85~
91 (1979)], therefore, in the field of treatment and prevention of arteriosclerosis, the development of antilipidemic agents that reduce the amount of total cholesterol in the blood while at the same time increasing the amount of HDL-cholesterol. is desired.

(Structure and Effects of the Invention) The present invention provides an antilipidemic agent comprising a naphthalene derivative represented by the following general formula (1) and a pharmacologically acceptable salt thereof as an active ingredient, which has a different structure from conventionally known antilipemic agents. Concerning lipemic drugs.

(However, Ring A represents a substituted or unsubstituted benzene ring, R3 and R4 are both lower alkoxy groups, or one is a lower alkoxy group and the other is a hydrogen atom, Rs represents a substituted lower alkyl group, a heterocyclic group, a cycloalkyl group, an alkyl group having 5 or more carbon atoms, or an alkenyl group, and R6 and R't are the same or different, a hydrogen atom or a lower alkyl group ) The naphthalene derivative (I) and its pharmacologically acceptable salts, which are the active ingredients of the present invention, are both new compounds and have excellent antilipidemic effects, especially reducing blood total cholesterol. It has a desirable feature for the treatment and prevention of arteriosclerosis in that it lowers the HD L-cholesterol level and simultaneously increases the HD L-cholesterol level. For example, when a sample was administered to rats fed a diet containing cholesterol and sodium cholate to examine the effect of lowering serum cholesterol levels and increasing HDL-cholesterol levels, it was found that 1-(3,4- (dimethoxyphenyl)-2-methoxycarbonyl-3-(pentan-3-yloxycarbonyl)-4-hydroxy-6,7,8-)rimethoxynaphthalene has a serum cholesterol level lowering effect more than 4 times that of probucol. and showed an effect of increasing HDL-cholesterol level by 5 times or more.

Furthermore, naphthalene derivative (I) is highly safe when used in an effective amount without causing any side effects such as liver dysfunction (for example, fatty liver). For example, administering the above compound to mice at 100%
After oral administration of 1/kg and observation for 5 days, no deaths were observed and no weight suppression was observed.

Preferred examples of the naphthalene derivative (r) which is an active ingredient of the present invention include - In formula (1), ring A is an unsubstituted benzene ring, or 1 to 3 selected from lower alkoxy groups and halogen atoms. a benzene ring substituted with groups or atoms or alkylenedioxy groups, R
5 is a sulfur-containing, nitrogen-containing or oxygen-containing heteromonocyclic group, phenyl group, cycloalkyl group, lower alkylthio group, lower alkoxy group, lower alkoxy group substituted with a lower alkoxy group,
A lower alkyl group substituted with a group selected from a mono- or di-lower alkylamino group, a hydroxyl group, and a hydrogen atom; a sulfur-containing, nitrogen-containing, or oxygen-containing heteromonocyclic group; a cycloalkyl group; a carbon number of 5 or more Examples include alkyl groups: or alkenyl groups.

Among these, compounds having particularly preferable pharmacological effects include a benzene ring in which ring A is substituted with three lower alkoxy groups, R3 and R4 are lower alkoxy groups, R5 is a nitrogen-containing or oxygen-containing heteromonocyclic group, phenyl a lower alkyl group substituted with a group selected from the group consisting of a cycloalkyl group, a lower alkylthio group, a lower alkoxy group, a lower alkoxy group substituted with a lower alkoxy group, a di-lower alkylamino group, and a hydroxyl group; a nitrogen-containing heteromonocyclic group Examples include an alkyl group; an alkyl group having 5 or more carbon atoms; or an alkenyl group.

In the present invention, lower alkyl groups, alkyl groups having 5 or more carbon atoms, alkenyl groups, cycloalkyl groups, lower alkoxy groups, and alkylenedioxy groups include alkyl groups having 1 to 4 carbon atoms, and alkyl groups having 5 to 10 carbon atoms, respectively. alkyl group,
Alkenyl group having 2 to 10 carbon atoms, cycloalkyl group having 4 to 8 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 1 to 2 carbon atoms
Examples of sulfur-containing, nitrogen-containing or oxygen-containing heteromonocyclic groups include:
Examples include 5- to 6-membered sulfur-containing, nitrogen-containing, or oxygen-containing heteromonocyclic groups such as thienyl group, pyridyl group, furyl group, and morpholino group.

In addition, naphthalene derivative (1) which is an active ingredient of the present invention
Examples of pharmacologically acceptable salts include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), quaternary ammonium salts (
(tetramethylammonium salt, tetraethylammonium salt, etc.) can be preferably mentioned. Also - formula (
In 1), when at least one of R1 and R1 is a group containing one or more nitrogen atoms, the naphthalene derivative (1) can also be used as an acid addition salt, such as an inorganic acid addition salt. Suitable examples include addition salts (hydrochloride, hydrobromide, sulfate, etc.) and organic acid addition salts (formate, acetate, p-toluenesulfonate, methanesulfonate, etc.).

The dosage of the naphthalene derivative (1) or its pharmacologically acceptable salt depends on the type and severity of the disease, the age, weight, and condition of the patient, but the dosage is usually 1.
, 5-35 mg/kg, especially 5-25 mg/k
Preferably, it is g.

Furthermore, naphthalene derivative (I) or a pharmacologically acceptable salt thereof can be administered either orally or parenterally, but oral administration is particularly preferred.

When administered orally, it can be administered as a solid preparation such as a tablet, powder, capsule, or granule, which may contain conventional excipients, binders, diluents, lubricants, and disintegrants. ,
It may also contain additives such as wetting agents. It can also be orally administered as a liquid preparation such as an aqueous or oily suspension, solution, syrup, or elixir. On the other hand, when administered parenterally, it can be used as an injection, suppository, etc.

The naphthalene derivative (1) and its pharmacologically acceptable salts of the present invention have an excellent antilipidemic effect, and are particularly characterized by increasing HDL-cholesterol levels while lowering total blood cholesterol levels. Therefore, it can be used for the treatment and prevention of hyperlipidemia (eg, hypercholesterolemia), arteriosclerosis (eg, atherosclerosis, Mönckeberg's arteriosclerosis), and the like.

The naphthalene derivative (1) which is an active ingredient of the present invention is, for example, an aldehyde compound represented by the formula (A)- (wherein, rings A, R' and R4 have the same meanings as above) or a dialkyl acecoolate thereof. and an acetylene compound represented by the general formula % formula % [) (where R1 and R1 have the same meanings as above) and an organic acid (for example, formic acid,
It can be produced by reacting it with acetic acid, p-toluenesulfonic acid, methanesulfonic acid) or an inorganic acid (for example, hydrochloric acid, sulfuric acid) under cooling to heating.

Alternatively, the naphthalene derivative (1) can be combined with [B') the aldehyde compound (U) or its dialkyl acecoolate and the general formula (% formula %) (however, R- represents a lower alkoxy group, and R2 has the same meaning as above) After reacting with the acetylene compound represented by
is hydrolyzed by a conventional method to form the general formula (where OR' represents an optionally protected hydroxyl group, rings A, R'', R'
and R4 have the same meanings as above. ) A 3-naphthoic acid compound represented by the formula % is prepared, and the compound and a compound represented by the general formula % formula % ( ) (wherein R1 has the same meaning as above) are mixed with a conventional condensing agent (for example, (a mixture of a diazendicarboxylic acid diester compound and triphenylphosphine, a mixture of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, etc.), and if necessary, removing a protecting group from the product. You can also.

In addition, in the compound (Vl), when R1 or R1 is a hydroxy group-substituted alkoxy group or a hydroxy group-substituted alkylamino group, the reaction may be carried out while protecting these hydroxy groups.

Experimental example (serum cholesterol level lowering effect and HDL-cholesterol level increasing effect) 1 SD male and female rats body weight: 140-200 g, 5 animals per group) were given cholesterol at 2 w/w% and sodium cholate at 0.5 w. /w%-containing feed was freely available for 4 days. Thereafter, the control group was given the above-mentioned feed, and the sample-administered group was given a feed containing the above-mentioned feed mixed with the test compound listed in Table 1 below at a ratio of 100%. Three days later, the rats were anesthetized with ether, their weight was measured, and blood was collected from the abdominal aorta. After leaving the blood at room temperature for 1 hour, it was centrifuged to obtain serum, and the amount of serum cholesterol was determined by an enzymatic method [Clinical Chemistry (CIin, Chem, )].
, Vol. 20, p. 470 (1974)]. On the other hand, the amount of HDL-cholesterol in the serum is
After LDL- and LDL-cholesterol were precipitated and removed using dextran sulfate [Canadian Journal of Biochemistry (Ca'n, J.

Biochem), Vol. 47, p. 1043 (1969)], and was measured by the above enzymatic method. Based on these experimental results, the serum cholesterol lowering effect and HDL-cholesterol increasing effect of the test compound were determined according to the following formula.

□ The experimental results are shown in Table 1 below.

Table 1 In addition, in the above experiment, blood was collected, the liver was quickly removed, the weight was measured, and the relative weight (weighed weight ix 100/body weight) was determined by combining it with the results of the previous body weight measurement, and the average of the sample administration group. When the relative weight was compared with that of the control group, the group administered with the test compound listed in Table 1 did not show a substantial increase in the weight.

Production Example 1 (1) 5.1 g of n-hexyl alcohol and 10.48 g of triphenylphosphine were added to 40 g of tetrahydrofuran.
m1 and cooled to -20°C. A solution of 2.24 g of acetylene dicarboxylic acid and 6.7 g of diazenedicarboxylic acid diethyl ester in 30 ml of tetrahydrofuran was added dropwise to the solution over 15 minutes while stirring, and the mixture was stirred at room temperature for 2 hours. The solvent is distilled off from the reaction solution under reduced pressure, hexane is added to the residual aroma, and insoluble matter is filtered off. After concentrating the filtrate, the residual aroma was subjected to silica gel chromatography [solvent: hexane-ethyl acetate (4:1)] to obtain 3.8 g of acetylene dicarboxylic acid di-n-hexyl ester as a pale yellow oil.

NMR (CDCli) δ: 0.8-2.0 (m.

22H), 4.15 (t, 4H) (2) Main island 3.8g, 2-(3,4-dimethoxy-α-
hydroxybenzyl)-3,4,5-)rimethoxybenzaldehyde dimethyl acetal 6g and acetic acid 6ml
The mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, the residual aroma was subjected to silica gel chromatography [solvent: hexane-ethyl acetate (2:1)], the solvent was distilled off from the eluate, and the resulting residual aroma was recrystallized from methanol. 1-(3,4-dimethoxyphenyl)-2,
3-bis(n-hexyloxycarbonyl)-4-hydroxy-6,7,8-tritoxynaphthalene 5.2g
is obtained as colorless needles.

M, p, 67°C Production Example 2 (1) Dissolve 266 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal in 95 ml of benzene, and add to the solution. Acetylene dicarboxylic acid dimethyl ester 9
5+++1 and p-toluenesulfonic acid archihydrate 300
After cooling the reaction solution, the solvent was distilled off under reduced pressure, and 600 sl of methanol was added to the residual aroma.
Leave at 0°C overnight. By filtering the precipitated crystals and recrystallizing them from ethyl acetate, 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)=4-
Hydroxy-6,7,8-trimethoxynaphthalene 20
2 g are obtained as colorless prismatic crystals.

M, p, 178-179 °C (2) Add 100 ml of anhydrous petroleum ether to 7.0 g of sodium hydride (61.4% mineral oil dispersion),
After stirring, the petroleum ether is removed from the mixture. 50 ml of dimethylformamide was added to the mixture, cooled to 0°C, and while stirring, 72.9 g of the compound obtained in (1) above was added.
A solution of 500 ml of dimethylformamide was added over 200 minutes, and the mixture was stirred at room temperature for 1 hour. The mixture was heated to 0° again.
After cooling to C and adding 18 g of methoxymethyl chloride dropwise over 155 minutes, the reaction solution was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, and 700ml of ethyl acetate was added to the residual aroma.
1 was added to form a solution, washed with water, dried, the solvent was distilled off under reduced pressure, the residual aroma was washed with hexane, and recrystallized from a mixture of ethyl acetate and hexane to obtain 1-(3,4-dimethoxyphenyl)-2, 3-bis(methoxycarbonyl)-4
78 g of -methoxymethoxy-6,7,8-tritoxynaphthalene are obtained as colorless needles.

M, p, 93°C (3) 14.2g of the main island was dissolved in 420+*l of dioxane, and a solution of 16g of potassium hydroxide dissolved in a mixture of 601ml of water and 120ml of methanol was added to the solution at 10°C.
It takes 00 minutes to drip. After the mixture has been left at room temperature for 36 hours, the solvent is removed under reduced pressure and the residual aroma is dissolved in 800 ml of water. Hydrochloric acid (26.8 ml of 35% hydrochloric acid) was added to the solution while stirring with water cooling.
diluted with 100w+1 water) and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residual aroma was recrystallized from a mixture of ethyl acetate and hexane to obtain 1-(3,4-dimethoxyphenyl)-2.
-methoxycarbonyl-4-methoxymethoxy-6,7
, 8-trimethoxy-3-naphthoic acid (10.5 g) was obtained as a colorless prism product.

M, p, 114°C (decomposed) (4) Main island 2.6g, n-hexyl alcohol 0°56
g and triphenylphosphine 1.37 g are dissolved in 2 On+1 tetrahydrofuran, and a solution of 0.96 g of diazendicarboxylic acid diethyl ester in 5 ml of tetrahydrofuran is added dropwise to the solution over 5 minutes while stirring and cooling with water. After stirring the mixture at room temperature for 3 hours, the solvent was distilled off under reduced pressure. 1-(3,4-
dimethoxyphenyl)-2-methoxycarbonyl-3=
2.5 g of (n-hexyloxycarbonyl)-4-methoxymethoxy-6,7,8-tritoxynaphthalene are obtained as a pale yellow oil.

(5) Add 20 ml of trifluoroacetic acid and 2 ml of water to 2.5 g of Honjima, and stir at room temperature for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure, and the residual aroma was dissolved in 100 ml of ethyl acetate. After washing and drying the solution, the solvent is distilled off under reduced pressure, the residual aroma is subjected to silica gel chromatography (solvent: chloroform), and the residual aroma obtained by distilling off the solvent from the eluate is recrystallized from isopropyl ether. 1-(3,
4-dimethoxyphenyl)-2-methoxycarbonyl-
3-(n-hexyloxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene l.

6 g are obtained as colorless needles.

M, p, 119-120''C Production Examples 3 to 7 (1) Compounds listed in Table 2 below are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 1-(1).

Table 2 (2) Compounds listed in Table 3 below are obtained by treating the product in (1) above in the same manner as in Production Example 1-(2) or Production Example 2-(1).

Table 3 It is.

NMR(CDCl2)δ: 0.5-2.0(m,
2011), 3.14 (s.

311), 3.74(s, 311), 3.
78 (s, 3H), 3.81 (s, 3H)
, 3.93(s, 311), 4.2-4.
6 (+++ 1ll), 4.9~5゜2 (n+,
1ll), 6.70(s, 311),
7.52 (s, IH), 12.40 (s,
III) Production Examples 8 to 11 The corresponding raw material compounds were prepared in Production Example 1-(2) or Production Example 2-(1).
) to obtain the compounds listed in Table 4 below.

Table 4 Book: The NMR data of these compounds are as follows.

Production Example 8; NMR(CDCI:l)δ:1.15(L,
611), 3.3-4.0 (n+.

1611), 3.79 (s, 31), 3.89
(s, 311), 4.10 (t.

211), 4.45 (t, 211), 6.7~
7.0 (m, 311), 7.3~7.6 Cm,
311), 8.2-8.5 (m, III),
12.11 (s, LH) Production Example 10: NMR(CDCI:I) δ:1.13 (t,
6+1), 3.1-4.2 (n+.

1811), 3.65 (s, 311), 3.7
6 (s, 311), 3.87 (s.

311), 3.95 (s, 311), 4.43
(t, 211), 6.6-6.9 (m+ 411)
, 7.59 (s, l1l), 12.02 (s
, III) Production Example 11: NMR (CDCI) δ: 1.15 (t,
6u), 1.39 (t, 3+I).

1.45 (t, 311), 3.87 (
s, 3H), 3.3-4.4 (m.

2211), 4.43 (t, 211),
6.6-7.7 (a+, 611), 12
゜01 (s, 1tl) Production Examples 12 to 27 The corresponding raw material compounds were prepared in Production Example 1-(2) or Production Example 2-(1).
) and then treated in the same manner as in Production Example 2-(2) to (5) to obtain the compounds listed in Table 5 below.

(However, in Production Example 23 below, 2,3-isopropylidene dioxypropanol was used as the raw material compound (Vf) instead of n-hexyl alcohol.

In this raw material compound, the impropylidene group used as a protecting group for two adjacent hydroxyl groups is treated with trifluoroacetic acid to form a naphthalene derivative (1) Table 5 Book *: The IR data of the compound of Production Example 17 is as follows. It is.

ujoL IRv (cm-'): 1735, 1655゜1
590.1520 Production Example 2 days (1) 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4-methylenedioxybenzaldehyde dimethyl acecool and acetylene dicarboxylic acid dimethyl ester Production Example 1-(2) Or, by treating in the same manner as in Production Example 2-(1), 1-(3,4-dimethoxyphenyl)-
2,3-bis(methoxycarbonyl)-4-hydroxy-7,8-methylenedioxynaphthalene is obtained.

M, p, 228-229'C (2) Main island and methoxymethyl chloride production example 2-(2) and (3)
1-(3,4-dimethoxyphenyl)-2-methoxycarbonyl-4-methoxymethoxy-
7,8-methylenedioxy-3-naphthoic acid is obtained.

M, p, 222"C (3) By treating Honjima and 2-chloro-n-propyl alcohol in the same manner as in Production Example 2-(4) and (5), 1-(3,4-dimethoxyphenyl) -2-methoxycarbonyl-3-(2-chloro-n-propyloxycarbonyl)-4-hydroxy-7,8-methylenedioxynaphthalene is obtained.

M, p, 187-189°C Production Example 29 (1) 1-(3,4-dimethoxyphenyl)-2,3-
Bis(methoxycarbonyl)-4-hydroxy-6,7
, 8-trimethoxynaphthalene and benzyl chloride in the same manner as in Production Example 2-(2) and (3) to produce 1-(3,4-dimethoxyphenyl)-2-methoxycarbonyl-4-benzyloxy- 6,7,8-trimethoxy-3-naphthoic acid is obtained.

M, p, 172'C (decomposition) (2) 1.4 g of ice crystals, 183 mg of isobutylamine and 336 mg of 1-hydroxybenzotriazole are dissolved in 15 n+l of tetrahydrofuran. 570 μl of dicyclohexylcarbodiimide was added to the solution while stirring while cooling with water.
Stir at the same temperature for 2 hours and at room temperature for 12 hours. The solvent was distilled off from the reaction solution, 50 ml of acetone was added to the residual aroma, and insoluble materials were filtered off. The solvent was distilled off from the filtrate, the residual aroma was subjected to silica gel chromatography [solvent: chloroform-acetone (20:1)], the solvent was distilled off from the eluate, and the resulting residual aroma (pale yellow oil) was extracted with methanol. Dissolve in 30a+1 and add 200μ of palladium-carbon to make 3kg
/crA in a hydrogen atmosphere for 2 hours. The catalyst was filtered off from the reaction solution, and the residual aroma was recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 1-(3,4-dimethoxyphenyl)-2-methoxycarbonyl-3-isobutylcarbamoyl-4-hydroxy-6. , 1.1 g of 7,8-1-rimethoxynaphthalene are obtained as colorless crystals.

M, p, 135-137°C Production Examples 30 and 31 The corresponding starting compounds were treated in the same manner as in Production Example 29 to obtain the compounds listed in Table 6 below.

Table 6

Claims (1)

[Claims] 1. General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ (However, ring A represents a substituted or unsubstituted benzene ring, and R^
1 and R^2 both have the formula: -OR^5, -NH-R^5
Or ▲There are mathematical formulas, chemical formulas, tables, etc. ▼, or one of the groups is the formula: -OR^5, -NH-R^5
Or ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ indicates that the other is an alkoxy group with 4 or less carbon atoms, and R^3 and R^4 are both lower alkoxy groups, Or, one is a lower alkoxy group and the other is a hydrogen atom, and R^5 is a substituted lower alkyl group, a heterocyclic group, a cycloalkyl group, an alkyl group having 5 or more carbon atoms, or an alkenyl group. , R^6 and R^7 are the same or different and represent a hydrogen atom or a lower alkyl group. ) An antilipemic agent comprising a naphthalene derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2. Ring A is an unsubstituted benzene ring, or a benzene ring substituted with 1 to 3 groups or atoms selected from lower alkoxy groups and halogen atoms, or alkylene dioxy groups, R^5 is sulfur-containing, Selected from a nitrogen-containing or oxygen-containing heteromonocyclic group, a phenyl group, a cycloalkyl group, a lower alkylthio group, a lower alkoxy group, a lower alkoxy group substituted with a lower alkoxy group, a mono- or di-lower alkylamino group, a hydroxyl group, and a halogen atom The antilipemic agent according to claim 1, which is a lower alkyl group substituted with a group containing: a sulfur-containing, nitrogen-containing or oxygen-containing heteromonocyclic group; a cycloalkyl group; an alkyl group or alkenyl group having 5 or more carbon atoms. 3. A benzene ring in which ring A is substituted with three alkoxy groups having 1 to 4 carbon atoms, R^3 and R^4 are alkoxy groups having 1 to 4 carbon atoms, and R^5 is a 5- to 6-membered nitrogen-containing group. or an oxygen-containing heteromonocyclic group, a phenyl group, a cycloalkyl group having 4 to 8 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkoxy group substituted with an alkoxy group having 2 to 8 carbon atoms; an alkyl group having 1 to 4 carbon atoms substituted with a group selected from a group, a dialkylamino group having 2 to 8 carbon atoms, and a hydroxyl group; a 5- to 6-membered nitrogen-containing heteromonocyclic group; The antilipemic agent according to claim 2, which is a cycloalkyl group; an alkyl group having 5 to 10 carbon atoms; or an alkenyl group having 2 to 10 carbon atoms. 4. The antilipemic agent according to claims 1 to 3, which is a therapeutic/preventive agent for hypercholesterolemia or arteriosclerosis.