JP2907646B2 - Antihyperlipidemic and anti-atherosclerotic agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel anti-hyperlipidemic agent and an anti-atherosclerotic agent, and more particularly, to an anti-hyperlipidemic agent having a blood cholesterol lowering effect and an effect of inhibiting macrophage foaming. The present invention relates to an anti-atherosclerotic agent having

[0002]

2. Description of the Related Art As the standard of living improves, dietary habits containing a high calorie and high cholesterol diet are increasing. Furthermore, aging of the population is added to this, and hyperlipidemia and arteriosclerotic diseases caused by the hyperlipidemia are rapidly increasing, which is a major social problem. As pharmacotherapy for hyperlipidemia and arteriosclerosis, blood lipids are mainly reduced,
At present, there is no drug that can be expected to regress the atherosclerotic lesion itself. Atherosclerosis is a characteristic lesion of intimal hyperplasia and lipid accumulation in blood vessels, and as a drug therapy, drugs that lower blood lipids are used as described above, but recent biochemical findings It has been known that foaming of macrophages plays a central role in the formation of atherosclerotic lesions, and it is expected that suppressing this can regress arteriosclerotic lesions themselves.

[0003]

SUMMARY OF THE INVENTION The present invention relates to an acyl Co
An object of the present invention is to provide a novel drug with low toxicity, which can reduce blood cholesterol and suppress macrophage foaming by inhibiting the activity of A cholesterol acyltransferase (so-called ACAT) and intracellular cholesterol transport. It is assumed that.

[0004]

Means for Solving the Problems The inventors of the present invention have continued their studies to achieve this object. As a result, certain benzimidazole compounds have an ACAT inhibitory action and an intracellular cholesterol transport inhibitory action and are excellent. The inventors have found that they have a blood cholesterol lowering effect and also have a macrophage foaming suppressing effect, and have completed the present invention.
That is, the present invention is an invention of an antihyperlipidemic agent and an anti-atherosclerotic agent comprising a compound represented by the following formula I, II or III or a pharmaceutically acceptable salt thereof as an active ingredient.

[0005]

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[Wherein, R ₁ represents a hydrogen atom, an alkyl, aryl, mercapto, alkylthio, alkenylthio, arylthio, or heterocyclic thio group; R ₂ represents a hydrogen atom or an alkyl group (provided that alkyl R ₃ and R ₄ are each independently a hydrogen atom, a halogen atom, a nitro group, R ₅ O—, R ₅ CONH—, R ₅ NHC.
_{O -, (R 5) 2} NCO-, R 5 SO 2 NH-, R 5 N
HSO ₂ —, R ₅ OCO—, R ₅ COO— or R ₅ N
HCONH- represents _{(R 5} represents an alkyl or aryl group); _{R 6} represents a divalent group. In the above formulas I-III, preferred compounds are those represented by the formula I, among which the following formula IV

[0007]

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[Wherein, R ₁ represents a hydrogen atom, an alkyl, mercapto, or alkylthio group; R ₃ represents a hydrogen atom, a halogen atom, a nitro group, R ₅ O—, R ₅ CONH;
—, R ₅ NHCO—, R ₅ NHSO ₂ — or R ₅ SO
₂ NH- (R ₅ represents an alkyl group). Are particularly preferred. Hereinafter, the present invention will be described in detail.

In the formulas I, III and IV, the alkyl group represented by R ₁ is an alkyl group having 1 to 18 carbon atoms (eg, methyl, ethyl, butyl, octyl, dodecyl, octadecyl group), preferably Examples include the alkyl groups of Formulas 1 to 8 (e.g., methyl, ethyl, butyl, and octyl groups), including both linear and branched cases. Examples of the aryl group include a phenyl and naphthyl group, and a phenyl group is particularly preferable. As the alkyl group of the alkylthio group, an alkyl group having 1 to 18 carbon atoms (eg, methyl, ethyl, butyl, octyl, dodecyl, octadecyl group), preferably an alkyl group having 1 to 8 carbon atoms (eg, methyl, Ethyl, butyl, octyl group), and includes both linear and branched cases.
The alkenyl group of the alkenylthio group has 2 to 2 carbon atoms.
18 alkenyl groups (e.g., allyl, 2-octadecenyl group). Examples of the aryl group of the arylthio group include phenyl and naphthyl groups, and a phenyl group is particularly preferable. Further, examples of the hetero ring of the heterocyclic thio group include a pyridine ring and a hexahydropyrimidine ring, and a 2 or 4-pyridine ring is particularly preferable. Each of the alkyl, aryl, alkylthio, alkenylthio, arylthio and heterocyclic thio groups represented by R ₁ may have a substituent, in which case the substituent may be a halogen atom, an alkyl, an aryl, an alkoxy, ,
Aryloxy, acylamino and nitro groups. Preferred groups represented by R ₁ include a hydrogen atom, an alkyl, a mercapto, and an alkylthio group, and specific examples include a methyl, butyl, mercapto, and methylthio group.

Next, in formulas I to III, the alkyl group represented by R ₂ is an alkyl group having 1 to 12 carbon atoms (for example, methyl, butyl, hexyl, octyl,
Dodecyl group), preferably an alkyl group having 1 to 6 carbon atoms (eg, methyl, butyl, hexyl group),
Both linear and branched cases are included. The alkyl group represented by R ₂ may have a substituent, and examples of the substituent in this case include aryl, amino, and acylamino groups. However, this excludes the case where the substituent is a hydroxyl group. Preferred groups represented by R ₂ include a hydrogen atom and an alkyl group having 1 to 6 carbon atoms, with a hydrogen atom being particularly preferred.

[0011] Formula I, the alkyl group R ₄ in R ₃ and the formula I is represented by R ₅ in the case where a group containing R ₅ in II and IV, alkyl group having 1 to 20 carbon atoms (e.g., A methyl, butyl, octyl, dodecyl, octadecyl group), preferably an alkyl group having 4 to 18 carbon atoms (eg, methyl, butyl, octyl, dodecyl, octadecyl group). Including. Examples of the aryl group include a phenyl and naphthyl group, and a phenyl group is particularly preferable. The alkyl and aryl groups represented by R ₅ may have a substituent, and examples of the substituent include a halogen atom, an alkyl, an aryl, an acylamino, and an aryloxy group. Preferred groups represented by R ₃ and R ₄ include the groups containing R ₅ described above, that is, R ₅ O— and R ₅ C
_{ONH-, R 5 NHCO-, R 5} SO 2 NH-, R 5 N
HSO ₂ —, R ₅ OCO—, R ₅ COO— or R ₅ N
Each group can be mentioned the HCONH-, in particular, R _3, a group represented by R ₄ is _{R 5 O-, R 5 CONH-,} R 5 NH
CO-, R ₅ NHSO ₂ — or R ₅ SO ₂ NH— is preferable, and specific examples thereof include octyloxy, hexadecyloxy, dodecanoyloxy, dodecylcarbamoyl, octylsulfonylamino, dodecylsulfamoyl and the like. Is mentioned.

In the formulas II and III, the divalent group represented by R ₆ includes — (CH ₂ ) _n —, —O (C
_{H 2) n O -, -} HNCO (CH 2) n CONH -, -
HNSO ₂ (CH ₂ ) _n SO ₂ NH—, etc. (n is 1 to 10
And particularly preferably 2)
Diradical is, n is a 2~8 - _{(CH 2) n} - and -HN
CO _{(CH 2)} a n CONH-. R _{1 to} R described above
₆ , any of the substituents has 4 carbon atoms
The above compounds are preferred, and in particular, the carbon number of at least one substituent other than R ₂ is from 4 to 20, more preferably,
It is preferable to have 8 to 18. Formula I, II or I
Examples of the pharmaceutically acceptable salt of the compound represented by II include hydrochloride, hydrobromide, nitrate, sulfate, toluenesulfonate and the like, with hydrochloride being particularly preferred. Hereinafter, specific examples of the compounds included in the present invention will be described, but the present invention is not limited to these compounds.

[0013]

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[0014]

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[0015]

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[0016]

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[0017]

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[0018]

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[0019]

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[0020]

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[0021]

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[0022]

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[0023]

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[0024]

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[0025]

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[0026]

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[0027]

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Next, a method for synthesizing these compounds will be described. The benzimidazole ring is generally reacted with o-phenylenediamines and carbon disulfide under basic conditions to form 2-mercaptobenzimidazoles or o-phenylenediamines with carboxylic acid esters or carboxylic acids under acidic conditions. By reacting with the acid orthoester, 2-alkyl and arylbenzimidazoles are synthesized.

Synthesis Example 1 Synthesis of 2-methyl-5-nitrobenzimidazole (5) 15.3 g of 3,4-diaminonitrobenzene was added to acetic anhydride 6
The mixture was added to 4 ml of concentrated hydrochloric acid and 2 ml of concentrated hydrochloric acid and heated under reflux for 3 hours. After cooling, the precipitated crystals were dispersed in a 10% aqueous sodium hydroxide solution and collected by filtration. The crystals were recrystallized from aqueous ethanol to obtain 6 g of the compound (5) as crystals. Melting point 220-221 ° C Elemental analysis Actual value (%) C: 54.42, H: 4.03, N: 23.62 Calculated value (%) C: 54.23, H: 3.98, N: 23. 72

Synthesis Example 2 Synthesis of 1,8-bis (5-nitrobenzimidazol-2-yl) octane (6) 10.8 g of o-phenylenediamine and 10.1 g of sebacic acid
Was added to 120 ml of 4N hydrochloric acid, and the mixture was refluxed for 6 hours. After cooling, the crystals were collected by filtration and washed with a 1N aqueous sodium carbonate solution until the solution became alkaline. The crystals are collected by filtration and dried.
Dissolve in 5 ml and 3.8 g of potassium nitrate while stirring under ice-cooling
Was added in small portions. After stirring for 2 hours under ice cooling, the mixture was poured into ice water and the crystals were washed with a 1N aqueous sodium carbonate solution until the crystals became alkaline. Recrystallized from aqueous ethanol,
3.4 g of compound (6) crystals were obtained. 135-137 ° C Elemental analysis Found (%) C: 60.62, N: 19.25, H: 5.41 Calculated (%) C: 60.54, N: 19.26, H: 5. 54

Synthesis Example 3 Synthesis of 2-mercapto-5-methoxybenzimidazole (13) 2.6 g of 3,4-diaminoanisole and 70 ml of ethanol
And 15 ml of carbon disulfide were added, and 1.5 g of sodium hydroxide dissolved in 5 ml of water was added. After heating on a hot water bath for 3.5 hours, the mixture was ice-cooled and filtered, and the mother liquor was distilled off under reduced pressure. Ethanol was added to dissolve the residue, and insolubles were removed.
Crystallize from aqueous methanol to give the desired compound (13)
2.0 g were obtained. Melting point: 254 to 255 ° C Elemental analysis: measured value (%) C: 53.06, H: 4.52, N: 15.27 Calculated value (%) C: 53.33, H: 4.44, N: 15. 56

Synthesis Example 4 Synthesis of 2-benzylthiobenzimidazole (7) 15 g of 2-mercaptobenzimidazole and 16.5 g of benzyl bromide were dissolved in 50 ml of ethanol, and the mixture was heated and refluxed in a water bath for 5 hours. Collect the crystals obtained after cooling,
Recrystallization from ethanol gave 18 g of compound (7). Melting point 185-186 ° C Elemental analysis Actual value (%) C: 69.59, H: 5.30, N: 11.74 Calculated value (%) C: 69.99, H: 5.03, N: 11. 66

Synthesis Example 5 5-Dodecanoylamino-2-
Synthesis of mercaptobenzimidazole (8) 5 g of 5-amino-2-mercaptobenzimidazole was dissolved in 50 ml of pyridine, and 7.95 g of dodecanoyl chloride was added dropwise under ice cooling. After stirring at room temperature for 3 hours,
The crystals precipitated by pouring into ice water were collected by filtration and recrystallized from aqueous methanol to give 10.9 g of compound (8). Melting point 266-267 ° C Elemental analysis Actual value (%) C: 66.38, H: 8.54, N: 11.34 Calculated value (%) C: 65.71, H: 8.36, N: 12. 10

Synthesis Example 6 Synthesis of 2-morpholinomethylbenzimidazole (36) 1 g of 4N hydrochloric acid and 142 g of chloroacetic acid were added to 108 g of o-phenylenediamine, and the mixture was heated under reflux for 1.5 hours.
After standing overnight, the mixture was diluted with 2 liters of water, neutralized with dilute aqueous ammonia, and the precipitated crystals were collected by filtration to obtain 113 g of 2-chloromethylbenzimidazole. 10 g of the obtained 2-chloromethylbenzimidazole and 10.5 g of morpholine
Was dissolved in 75 ml of alcohol and heated under reflux for 3 hours. After cooling, ether was added, the precipitated crystals were separated by filtration, and the filtrate was washed with water and saturated with hydrogen chloride gas to precipitate an oil. When a small amount of alcohol was added thereto, it crystallized. The crystals were collected by filtration and recrystallized from alcohol to obtain 2.5 g of compound (36). 235-236 ° C Elemental analysis Found (%) C: 49.48, H: 5.88, N: 14.27 Calculated (%) C: 49.66, H: 5.91, N: 14. 48 Other exemplary compounds can be synthesized according to the above examples. The melting points of the obtained crystals are listed below.

[0035]

Table 1 化合物 Compound No. Melting point (° C) Compound No. Melting point (° C) ) ───────────────────────────────── (1) 195 to 200 (HCl salt) (2) 200 to 203 (3) 133 to 135 (HBr salt) (4) 167 to 170 (5) 220 to 221 (6) 135 to 137 (7) 190 to 191 (8) 226 to 267 (9) 266 to 268 (10) 275 -276 (11)> 300 (12)> 280 (13) 254-255 (14) 128-129 (15) 95-97 (16) 106-108 (17) 181-183 (18) 119-123 (20) ) 84-87 (21) 183-186 (23) 250-252 (24) 214-217 (25) 200 (decomposition) (26) 284- 86 (27) 230-232 (28) 132-134 (29) 217 (decomposition) (30) 243-245 (31) 143-144 (32)> 250 (33) 124-125 (34) 218-220 ( 35) 215 to 217 (HCl salt) (36) 235 (decomposition, HCl salt) (37) 162 to 164 (38) 215 to 216 (39) 202 to 203 (42) 230 to 231 (43) 155 to 156 ( 44) 163-164 (45) 146 (decomposition) (46) 197-199 (47) 54-56 (48) 60-63 (49) 82-85 (50) 188-191 (51) 209-212 ─────────────────────────────────

The medicament of the present invention may contain one or more compounds of the above formulas I to III, and is a known and compatible antihyperlipidemic agent conventionally used in the art. It may be used in combination with an anti-atherosclerotic agent. Examples of such conventionally used antihyperlipidemic or anti-atherosclerotic agents include melinamide, probucol, mevalotin and the like. Administration of the agent of the present invention is oral administration, injection (mainly intramuscular, intravenous, subcutaneous)
And the like, and is formulated into a dosage form according to each administration method. It can be used as an oral preparation such as tablets, powders, granules, capsules, syrups, emulsifiers, suspensions and solutions, injections, and the like. In addition, the composition can be prepared by mixing an appropriate carrier or diluent and an appropriate physiologically active substance according to the dosage form.

Preferred examples of pharmaceutical carriers or diluents which can be used in combination with the compounds of the formulas I to III in the medicament according to the invention are glucose; saccharose; lactose; ethyl alcohol; glycerin; mannitol; sorbitol; Diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, other polyethylene glycols; mono-saturated fatty acids such as glyceryl trilaurate, glyceryl monostearate, glyceryl tristearate and glyceryl distearate; Di and triglycerides; pectin; starch; corn starch; alginic acid; xylose; talc; Oils and fats such as castor oil, corn oil, wheat malt oil, sesame oil, cottonseed oil, sunflower oil and cod liver oil; gelatin; lecithin; silica; cellulose; methylhydroxypropylcellulose, methylcellulose, hydroxyethylcellulose; cellulose derivatives such as carboxymethylcellulose calcium. 12-22 such as calcium stearate, calcium laurate, magnesium oleate, calcium palmitate, calcium behenate and magnesium stearate;
Magnesium or calcium salts of fatty acids having the following carbon atoms: cyclodextrins; for example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, Dihydroxypropyl-β-cyclodextrin, carboxymethylethyl-β-cyclodextrin and dimethyl-β-cyclodextrin; emulsifiers;
2, especially saturated and unsaturated fatty acids having 10 to 18 carbon atoms and monohydric aliphatic alcohols such as glycol, glycerin, diethylene glycol, pentaerythritol, ethyl alcohol, butyl alcohol, octadecyl alcohol (for example, 1 such as alkanol) ~ 20
Or esters with polyhydric alcohols or silicones such as dimethylpolysiloxane; and pyrogen-free distilled water.

The dosage of the drug of the present invention varies depending on the type of disease, age, weight, degree of symptoms, administration route, etc. of the disease. 500 mg, preferably 0.2 to 10
An amount in the range of 0 mg is suitable.

Pharmacological Test (1) Inhibition Test of Macrophage Foaming Using In Vitro Mouse Peritoneal Macrophages The neck of a 15-week-old ICR mouse female (manufactured by Nippon SLC) was cut and exsanguinated. (Nissui Pharmaceutical) was injected. After removing the abdomen, this was promptly collected and centrifuged at 1,000 rpm for 5 minutes to collect peritoneal macrophages. Next, the collected peritoneal macrophages were subjected to GIT.
The cells were suspended in a medium (manufactured by Wako Pure Chemical Industries) and seeded on a 24-well microplate. After culturing at 37 ° C under 5% CO ₂ for 2 hours, the medium was changed to Dulbecco's modified Eagle MEM medium (Nissui Pharmaceutical). Further, at 37 ° C., 5% CO ₂
After culturing for 16 hours under the conditions, the following substances were added in the following order.

Test Compound—Dissolved in DMSO (manufactured by Wako Pure Chemical Industries) A 1 mM solution was prepared and used as a stock solution. This stock solution was appropriately diluted and 5 μl was added to one well (500 μl). Liposomes PC / PS / DCP / CHOL. = 50/50/10 /
75 (nmol) PC: Phosphatidylcholine (Funakoshi) PS: Phosphatidylserine (Funakoshi) DCP: Dicetyl phosphate (Funakoshi) CHOL. : Cholesterol (manufactured by Sigma) ³ H-oleic acid (manufactured by Amersham Japan) After further culturing at 37 ° C. and 5% CO ₂ for 16 hours,
The lipid fraction was extracted with chloroform and methanol. The extracted lipid fraction is developed by TLC (developing solvent: hexane:
Ether: acetic acid = 70: 30: 1), CE (cholesteryl ester) and TG (triglyceride) were scraped off and a liquid scintillation counter (Packard BH
The radioactivity was measured at -22). The cholesteryl ester formation rate was calculated from the ratio with the control. Table 1 shows the results.

[0041]

[Table 2] Compound No. Dose CE production rate (%) TG production rate (%) ───────────────────────────────── (3) 5 μM 69 89 (5) 5 μM 67 89 (6) 5 μM 8.061 (7) 5 μM 61 91 (8) 5 μM 42 106 (10) 5 μM 69 129 (12) 5 μM 52 102 (20) 5 μM 49 62 (21) 5 μM 64 93 (23) 5 μM 56 119 (27) 5 μM 5178 (28) 5 μM 53 164 (30) 5 μM 51 91 (34) 5 μM 50 108 (42) 5 μM 61 96 (43) 5 μM 45 98 (47) 5 μM 5598 ──────────────────────────

From Table 1, it is clear that these compounds do not significantly reduce the TG generation rate, that is, they have low toxicity and significantly suppress the CE generation rate. That is, these compounds do not show high toxicity to macrophages,
It significantly suppresses macrophage foaming.

(2) Blood lipid lowering effect of high cholesterol feed diet rabbits A New Zealand white rabbit female weighing about 2 kg was fed a high cholesterol feed (100 g / day / animal: ORC-4 + 0.5% cholesterol + 0.5% oriental yeast). 5%
Olive oil) for 7 days, and hypercholesterolemia was obtained. Subsequently, the animals were reared on the same amount of high cholesterol diet, and the test compound (8) 10
0 mg / kg / day / animal was mixed in the feed and administered continuously for 7 days.
On the other hand, three rabbits per group were bred only with the same amount of high cholesterol feed as a control group. Once a week, a small amount of blood was collected from the parotid vein and the total blood cholesterol level was measured (Iatripo TC: used by Jatron). The blood total cholesterol lowering rate was 25% in comparison with the control (3 birds) not receiving the drug. Thus, it was revealed that the test compound (8) has an excellent blood cholesterol lowering effect.

(3) Blood lipid lowering effect in normal feed diet rabbits New Zealand white rabbit females weighing about 2 kg were bred for 7 days on ordinary feed (100 g / day / animal: ORC-4: Oriental Yeast Co., Ltd.). . Subsequently, the animals were bred with the same amount of a normal diet, and 100 mg / kg / day / animal of the test compound (8) was mixed with the feed and administered continuously for 7 days to 3 animals per group (test group). In addition, three rabbits in one group of the same rabbit were bred only with the same amount of the normal diet, and used as a control group. Once a week, a small amount of blood was collected from the parotid vein to measure the total blood cholesterol. (Iatripo TC: manufactured by Yatron Co., Ltd.) The blood total cholesterol lowering rate was expressed as a ratio to the control (3 birds) not receiving the drug, which was 2%.
It was 0%. Thus, it was revealed that the test compound (8) has an excellent blood cholesterol-lowering effect not only in the cholesterol-loaded diet rabbit but also in the normal diet rabbit.

(4) Acute toxicity test The compound (8) was suspended in a 0.5% Tween 80 solution and orally administered to a group of six 8-week-old ddy mice, and acute toxicity was observed for one month. As a result, the LD50 value of the compound was 1000.
mg / kg or more. This indicates that the compounds of the present invention have low toxicity.

[0046]

Example 1 Tablet Preparation of a Tablet Containing 25 mg of Compound (8) Compound (8) 10 g Corn starch 40 g Microcrystalline cellulose 45 g Carboxymethylcellulose calcium 4 g Light anhydrous silicic acid 500 mg Magnesium stearate 500 mg A total of 100 g is uniformly mixed. , Compression molded with a tableting machine, one tablet 2
50 mg tablets were obtained. One tablet contains Compound (8) 2
It contains 5mg, and take 5-30 tablets a day in several divided doses for adults.

Example 2 Preparation of capsule containing 40 mg of compound (8) 20 g of compound (8) 79.5 g of cornstarch 500 mg of light anhydrous silicic acid 500 mg A total of 100 g is uniformly mixed, and 200 mg thereof is filled in a capsule. To give a capsule. This capsule contains 40 mg of compound (8) per capsule, and 1 to 20 capsules per day for an adult is divided into several doses.

Example 3 Preparation of granules containing 100 mg of compound (8) in 1 g of granules Compound (8) 10 g 40 g of corn starch 10 g of 10% hydroxypropylcellulose ethanol solution 50 g A total of 100 g was uniformly mixed and kneaded. Thereafter, the mixture was granulated by an extrusion granulator and dried to obtain granules. 1 g of the granule contains 100 mg of the compound (8), and is used in an adult once a day.
Take ８8 g in several divided doses.

[0049]

According to the present invention, the present invention has an excellent blood cholesterol lowering effect and a macrophage foaming suppressing effect,
A long-term administrable drug having low toxicity and excellent therapeutic effect on hyperlipidemia and arteriosclerosis is provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 A61K 31/535 C07D 235/12 C07D 235/12 235/14 235/14 235/16 235/16 235/28 235 / 28 403/12 231 403/12 231 235 235 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 235/00 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. An anti-hyperlipidemic or anti-atherosclerotic agent comprising a compound represented by the following formula I, II or III or a pharmaceutically acceptable salt thereof as an active ingredient. Embedded image Wherein R ₁ is a hydrogen atom, alkyl, aryl, mercapto, alkylthio, alkenylthio, arylthio,
R ₂ represents a hydrogen atom or an alkyl group (however, the alkyl group is not substituted with a hydroxyl group); R ₃ and R ₄ each independently represent a hydrogen atom or a halogen atom , a nitro _{group, R 5 O-, R 5 CONH-} , R 5 NHC
O—, (R ₅ ) ₂ NCO—, R ₅ SO ₂ NH—, R ₅ N
HSO ₂ —, R ₅ OCO—, R ₅ COO— or R ₅ N
HCONH- (R ₅ represents an alkyl or aryl group) represents; R ₆ is _{- (CH 2) n -,} - O (CH 2) n O -, - H
NCO (CH ₂ ) _n CONH-, -HNSO ₂ (C
_{H 2) n SO 2 NH- (} n represents an integer of 1 to 10). ] 2. The anti-hyperlipidemic and anti-atherosclerotic agent according to claim 1, wherein the active ingredient is a compound represented by the formula I. 3. The anti-hyperlipidemic and anti-atherosclerotic agent according to claim 2, wherein the compound represented by the formula I is a compound represented by the following formula IV. Embedded image [Wherein, R ₁ represents a hydrogen atom, an alkyl, a mercapto, or an alkylthio group; R ₃ represents a hydrogen atom, a halogen atom, a nitro group, R ₅ O— or R ₅ CONH—, R ₅ N
_{HCO-, R 5 NHSO 2 -,} R 5 SO 2 NH- (R 5
Represents an alkyl group). ]