JPH0656764A - Anti-atherogenic agent - Google Patents

Abstract

(57) [Summary] [Objective] A novel compound having functions of lowering LDL-cholesterol concentration and increasing HDL-cholesterol concentration and capable of becoming a highly safe anti-arteriosclerosis agent and the compound as an active ingredient An anti-atherogenic agent is provided. [Structure] 3,5-di-t-represented by the following general formula (I)
Anti-atherogenic agent containing butyl-4-hydroxybenzylthiourea derivative or a physiologically acceptable salt thereof as an active ingredient: Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, n represents an integer of 0 to 2.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 3,5-di-t-butyl-
The present invention relates to an anti-atherogenic agent containing a 4-hydroxybenzylthiourea derivative or a physiologically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Arteriosclerosis is one of the most common diseases at present and causes angina, myocardial infarction, cerebral infarction and the like. Hyperlipidemia is one of the causes of arteriosclerosis.

It is known that blood lipid levels, especially blood cholesterol levels, are closely related to arteriosclerosis. Blood cholesterol is classified into LDL (low density lipoprotein), HDL (high density lipoprotein), etc.
While L-cholesterol promotes cholesterol deposition on the arterial wall, HDL-cholesterol carries excess cholesterol from peripheral blood vessels back to the liver, preventing cholesterol deposition on the arterial wall. Thus, the ease with which cholesterol accumulates in the arterial wall depends on the total cholesterol concentration in serum and the ratio of LDL to HDL. Therefore, blood cholesterol levels, especially LDL
-An anti-arteriosclerotic agent that lowers cholesterol concentration and raises HDL-cholesterol is desired.

[0004] In general, antiarteriosclerotic agents are often taken for a long period of time, and therefore, high safety is required. However, existing drugs, such as clofibrate, have a high risk of causing side effects such as liver damage and are not sufficiently safe.

[0005]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned conventional drawbacks, and an object of the present invention is to reduce the LDL-cholesterol concentration in blood and to reduce the HD.
An object of the present invention is to provide a highly safe anti-atherosclerotic agent having a function of increasing L-cholesterol concentration.

[0006]

The anti-atherosclerotic agent of the present invention is 3,5-di-t-butyl- which is represented by the following general formula (I).
The active ingredient is a 4-hydroxybenzylthiourea derivative or a physiologically acceptable salt thereof:

[0007]

[Chemical 2]

Here, R ¹ is a hydrogen atom or a carbon number of 1 to
5 represents an alkyl group, and n represents an integer of 0-2.

Examples of the alkyl group having 1 to 5 carbon atoms for R ¹ include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group.

Specific examples of the compound represented by the general formula (I) include N- (3,5-di-t-butyl-4-hydroxybenzyl) -N'-phenylthiourea and N- (n-butyl). -N-
(3,5-di-t-butyl-4-hydroxybenzyl) -N '
-Phenylthiourea, N- (3,5-di-t-butyl-4-hydroxybenzyl) -N'-benzylthiourea and the like.

The above-mentioned isothiourea derivative (I) can react with a base or an acid to form a salt. Examples of the salt of the 3,5-di-t-butyl-4-hydroxybenzylthiourea derivative represented by the formula (I) include the following salts: (1) Alkali metal, alkaline earth metal, aluminum, etc. Salt with a metal; (2) ammonium salt; (3) methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, piperidine, morpholine, hexamethyleneimine, aniline, salt with an organic base such as pyridine; (4) formic acid, Acetic acid, trichloroacetic acid, maleic acid,
Salts with organic acids such as tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid; (5) Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; (6) Arginine, glutamic acid, Salts with amino acids such as ornithine.

The compound represented by the general formula (I) can be obtained by reacting the compound represented by the following formula (II) with the compound represented by (III):

[0013]

[Chemical 3]

Here, R ¹ is a hydrogen atom or a carbon number of 1 to 1.
5 represents an alkyl group.

[0015]

[Chemical 4]

Here, n represents an integer of 0-2.

The compound represented by the general formula (I) is also obtained by heating the compound represented by the above formula (II) and the compound represented by the following formula (IV) together with carbon monoxide and sulfur under high pressure,
For example, it can be obtained by heating in an autoclave.

[0018]

[Chemical 5]

Alternatively, the compound represented by the general formula (I) is prepared by sulfiding a corresponding urea compound (a compound of the formula (I) in which thioxo is oxo) with a reagent such as diphosphorus pentasulfide. Can also be obtained.

The above 3,5-di-t-butyl-4-hydroxybenzylthiourea derivative used as an active ingredient of the anti-atherogenic agent in the present invention is Vests; Akad. Navuk.
B. SSR, Ser. Khim. Navuk, 1975 , 108-109 (1975); N
eftepererab. Neftekhim. 1981 , 15-16 (1981) and the like. In the literature, this compound has been shown to be useful as an antioxidant for jet fuels. However, it is not revealed in these references that this compound is useful for treating hyperlipidemia or arteriosclerosis.

The inventors of the present invention described above 3,5-di-t-butyl-4-
It was revealed for the first time that hydroxybenzylthiourea derivatives are useful as anti-atherogenic agents. This 3, 5
The -di-t-butyl-4-hydroxybenzylthiourea derivative and its physiologically acceptable salt are useful as anti-atherogenic agents and have extremely low toxicity to living bodies.
This is clear from the experimental example described later. This 3,5-
The preparation containing the di-t-butyl-4-hydroxybenzylthiourea derivative or a salt thereof can be administered orally or parenterally. 3,5-di-t
The -butyl-4-hydroxybenzylthiourea derivative or a salt thereof is used as a preparation containing a suitable carrier (excipient). Such preparations include tablets, capsules, fine granules, syrups, suppositories, ointments and injections. The carrier is an organic or inorganic solid or liquid capable of preparing a preparation suitable for oral or parenteral administration, and an inert pharmaceutical carrier material is usually used. They include, for example, crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable or animal fats, gums, polyalkylene glycols. The anti-arteriosclerotic agent of the present invention contains the 3,5-di-t-butyl-4-hydroxybenzylthiourea derivative and / or its salt in a proportion of 0.2 to 100%. This anti-arteriosclerotic agent contains other drugs (including anti-arteriosclerotic agent) unless the effects of the 3,5-di-t-butyl-4-hydroxybenzylthiourea derivative and / or its salt are reduced. May be contained. In this case, 3,5-di-
The t-butyl-4-hydroxybenzylthiourea derivative or its salt may not be the main component in the preparation.

The anti-atherosclerotic agent of the present invention is generally administered in a dose that achieves the desired action without side effects. The specific value depends on the degree of illness and age, and should be decided by the doctor.
The above-mentioned 3,5-di-t-butyl-4-hydroxybenzylthiourea derivative and / or its salt is 1 per adult per day.
It is administered in an amount such that it is between mg and 5 g, preferably between 3 mg and 1 g. The dose of the formulation containing the excipient is usually 10
It is mg to 10 g, preferably 20 mg to 5 g.

[0023]

EXAMPLES The present invention will be described below with reference to examples. Compounds 1, 2 and 3 in this Example are N-
(3,5-di-t-butyl-4-hydroxybenzyl) -N '
-Phenylthiourea, N- (n-butyl) -N- (3,5-di
-t-Butyl-4-hydroxybenzyl) -N'-phenylthiourea and N- (3,5-di-t-butyl-4-hydroxybenzyl) -N'-benzylthiourea.

Production Example 1 [Synthesis of Compound 1] 4.71 g of 3,5-di-t-butyl-4-hydroxybenzylamine and phenyl isothiocyanate 2.
70 g was stirred in benzene at room temperature overnight and then at 60 ° C. for 3 hours with heating. The reaction solution is filtered, and the filtrate is concentrated, purified by silica gel column chromatography (solvent: chloroform), and recrystallized using a mixed solvent of ethyl acetate-n-hexane to obtain the target compound 1.
17 g (yield 29%) was obtained.

Melting point: 183-184 ° C. ¹ H-NMR (δ: CDCl ₃ ): 1.35 (18H, s), 4.75 (2H, d, J = 4.5
Hz), 5.15 (1H, s), 6.20 (1H, s, br), 7.05 (2H, s), 7.
15 ~ 7.50 (5H, m), 7.85 (1H, s, br).

Production Example 2 Synthesis of Compound 2 18.75 g of 3,5-di-t-butyl-4-hydroxybenzaldehyde and 5.85 of n-butylamine
g was refluxed in benzene for 2 hours. The reaction solution was concentrated and ethanol was added. This was cooled to 0 ° C., 3.02 g of sodium borohydride was added thereto, and the mixture was reacted at room temperature overnight. This was cooled to 0 ° C., water was added, and extraction with chloroform was performed. The extract was washed successively with water and saturated brine, and then purified by silica gel column chromatography (solvent: chloroform).

4.2 g of the product obtained was dissolved in a mixture of 80 ml of n-hexane and 20 ml of benzene and the solution obtained was added dropwise to 1.95 ml of phenyl isothiocyanate while stirring. The reaction solution was stirred at room temperature for 4 hours. After concentration, the residue was purified by silica gel column chromatography (solvent: chloroform). Concentrate it, dissolve in pentane,
It was left at room temperature overnight. The precipitated solid was collected by filtration, washed with pentane, and dried. Recrystallization was performed using a mixed solvent of n-hexane-benzene to obtain 0.55 g of the desired compound 2 (yield 9%).

Melting point: 97-98 ° C. ¹ H-NMR (δ: CDCl ₃ ): 0.95 (3H, t, J = 4.5Hz), 1.45 (18H,
s), 1.75 (4H, m), 3.85 (2H, m), 4.80 (2H, s), 5.25 (1
H, s), 7.10 (3H, s), 7.25 (5H, m).

(Production Example 3) [Synthesis of Compound 3] 1.2 g of 3,5-di-t-butyl-4-hydroxybenzylamine and 0.7 of benzyl isothiocyanate
3 ml and 50 ml of benzene were dissolved, and the mixture was stirred overnight at room temperature and then reacted at 60 ° C. for 3 hours on an oil bath. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform, the fractions containing the target substance were collected, and the solvent was distilled off under reduced pressure. The residue was recrystallized using a mixed solvent of benzene and hexane to give the target compound 3
0.66 g (yield 34.7%) was obtained.

Melting point: 129-132 ° C. ¹ H-NMR (δ: CDCl ₃ ): 1.38 (18H, s), 4.45 (2H, d, J = 5H
z), 4.65 (2H, d, J = 5Hz), 5.22 (1H, s), 6.10 (2H, br),
7.11 (2H, s), 7.27 (5H, s).

Example 1 100 g of compound 1 and 55 g of lactose
And a mixture of 41 g of dried potato starch was kneaded with 20 ml of water, extruded through a 16 mesh screen, dried at 40 ° C. and granulated. Then, uniformly mix with 4 g of magnesium stearate and tablet into tablets by a conventional method (200
A tablet containing 100 mg of Compound 1 per mg) was obtained.

Example 2 A tablet containing 100 mg of Compound 2 per tablet (200 mg) was obtained in the same manner as in Example 1 except that Compound 2 was used instead of Compound 1 of Example 1. It was

Example 3 196 g of granules obtained by the same method as in Example 1 was mixed with 4 g of magnesium stearate, and 200 mg each was filled into a No. 2 hard capsule, and 100 mg of Compound 1 was added per capsule. Hard capsules containing in proportion were obtained.

Example 4 A hard capsule containing 100 mg of Compound 3 per capsule was obtained in the same manner as in Example 3 except that Compound 3 was used instead of Compound 1 of Example 3. .

Example 5 Compound 1 10.0 g Lactose 85.0 g Crystalline cellulose 4.5 g Magnesium stearate 1.5 g The above ingredients were mixed well and 100 mg of Compound 1 per 1 g.
To obtain a powdered powder.

(Example 6) A compound 2 was used in place of the compound 1 of Example 5, and a powder containing 100 mg of the compound 2 per 1 g was obtained in the same manner as in Example 5.

(Experimental Example 1) Using compounds 1 to 3 obtained in Production Examples 1 to 3 as test compounds, the antiarteriosclerotic action (antihyperlipidemic action) was examined by the following method using Wistar rats. It was

Wistar male rats (6 animals per group, average weight)
150 g) was allowed to freely take a high-cholesterol feed (feed containing 1.5% cholesterol, 0.5% cholic acid and 5% olive oil (CA-1; manufactured by CLEA Japan, Inc.)) for 7 days, and 2.5 w / v of the test compound was further added. % Of gum arabic solution in these rats at a rate of 3 ml / kg body weight,
Gavage was administered 4 times on days 4, 5, 6 and 7. After the final administration of the test compound, it was fasted overnight, and blood was collected from the lower aorta under ether anesthesia on the 8th day, and serum was obtained by centrifugation.

Serum total cholesterol (T-C) and HDL-cholesterol (HDL-C) were calculated as T
C kit-K (Nippon Shoji) and HDL-C kit-N
It was measured using the enzymatic method of (Nippon Shoji). TC and HD
The difference from L-C was calculated and used as the sum of VLDL (Very Low Density Lipoprotein) -cholesterol and LDL-cholesterol. Each value was also obtained for the control group to which only the aqueous solution of gum arabic was administered, and the change rate was calculated for each value by the following formula.

[0040]

[Equation 1]

The above results are shown in Table 1. In Table 1, the total cholesterol amount (T-C) was decreased, the HDL-cholesterol amount (HDL-C) was increased, and the VLDL-cholesterol amount and LDL were all administered when any of the compounds 1, 2 and 3 was administered. -The sum of cholesterol
It was shown that the
It can be seen that the 5-di-t-butyl-4-hydroxybenzylthiourea derivative shows an excellent anti-atherogenic effect.

[0042]

[Table 1]

Experimental Example 2 Using compounds 1 to 3 as test compounds, acute toxicity was examined by the following method using ICR mice.

Using ICR female mice (body weight 20 to 25 g), the number of mice was 6 per group. Test compounds 1 to 3 were suspended in a 2.5% aqueous solution of gum arabic and orally administered at a rate of 0.1 ml / 10 g body weight. The general symptoms were observed for 2 weeks after the administration, the number of dead mice / the number of test mice was calculated, and the 50% lethal dose (LD ₅₀ ) (mg / kg) was estimated. As a result, compound 1
No deaths were observed in the cases of ~ 3 when administered at a rate of 500 mg / kg. From this, the LD _{50 of} compounds 1-3 is
It was estimated to be 500 mg / kg or more and was found to have low toxicity.

[0045]

According to the present invention, 3,5-di-t-butyl-4- having antihyperlipidemic action and antiarteriosclerotic action as described above
An anti-atherogenic agent containing a hydroxybenzylthiourea derivative or a salt thereof as an active ingredient is provided. The compound used for the anti-arteriosclerotic agent of the present invention has the effect of particularly lowering the blood level of LDL-cholesterol and increasing the blood level of HDL-cholesterol. Furthermore, this compound has very little toxicity and is safe.

Claims (1)

[Claims] 1. A 3,5-di-formula represented by the following general formula (I):
Anti-arteriosclerotic agent containing t-butyl-4-hydroxybenzylthiourea derivative or a physiologically acceptable salt thereof as an active ingredient: Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, n represents an integer of 0 to 2.