JPS6245525A - Hypolipemic agent - Google Patents

Abstract

PURPOSE:To provide a hypolipemic agent containing a hydantoin derivative or its salt effective as a hypoglycemic agent and diuretic as an active component, having excellent hypolipemic activity and low toxicity, administrable safely for a long period and useful for the remedy of chronic diseases. CONSTITUTION:The objective agent contains at least one kind of the compound of formula (X is H or OR4; R1, R2, R3 and R4 are H, alkyl or cycloalkyl) or its salt as an active component. The especially preferable examples of the compound of formula are 5-hydroxy-1-methylhydantoin, 5-hydroxy-3- methylhydantoin, etc. The compound of formula is effective to significantly decrease the level of lipid such as triglyceride, free fatty acid, etc., in blood and is useful as a remedy for hyperlipemia accompanying to arterio-sclerosis, nephrose, hypertension, diabetes, etc., and a preventive for various circulatory diseases. Dose: preferably 5-600mg daily by oral administration.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention is directed to a hydantoin derivative represented by the following general formula (1) and having an excellent lipid-lowering effect, and a pharmaceutically acceptable salt thereof. The present invention relates to a lipid-lowering agent containing as an active ingredient.

(In the formula, X represents hydrogen or OR4, R1, R2, R3
, R4 are the same or different and each represent hydrogen, an alkyl group, or a cycloalkyl group 6) (Prior art) Blood contains triglyceride, cholesterol [1-yl, phospholipid, free fatty acid, etc.] Although lipids exist, abnormal increases and imbalances in these lipids cause various pathological conditions. That is, hyperlipidemia not only causes the formation of arteriosclerosis, but also exhibits various symptoms such as abnormal glucose metabolism, ischemic heart disease, and sudden onset.

The present inventors have discovered that the hydantoin derivatives of the present invention and their pharmaceutically acceptable salts have an excellent hypolipidemic effect, have low toxicity, and are highly safe, and have completed the present invention. .

(Problems to be Solved by the Invention) The object of the present invention is to provide a safe and medicinal lipid-lowering agent containing as an active ingredient a hydantoin derivative that has an excellent lipid-lowering effect, has low toxicity, and has few side effects. Our goal is to provide the following.

(Means for Solving the Problems) The lipid-lowering agent of the present invention contains as an active ingredient at least one of a hydantoin derivative represented by the following general formula (1) and a pharmaceutically acceptable salt thereof.

(In the formula, X represents hydrogen or OR4, R1, R2, R3
, R4 are the same or different and represent hydrogen, an alkyl group or a cycloalkyl group. ) In the above general formula (+), X is hydrogen or OR4, and R4 is hydrogen or an alkyl group, preferably methyl, ethyl, propyl, i-propyl, butyl, i-butyl, 5ec-butyl, t-butyl, pentyl. , i~pentyl, neo-pentyl, t-
pentyl, hexyl, i-hexyl, dimethylbutyl,
A linear or branched alkyl group having 1 to 20 carbon atoms such as heptyl, octyl, nonyl, decyl, stearyl, or a cycloalkyl group, preferably a carbon number such as cyclobutyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Represents 3 to 8 Schiff 1 core alkyl groups.

R1, R2 and R3 are the same or different and each represents hydrogen, an alkyl group, preferably methyl, ethyl, propyl, 1-propyl, butyl, 1-butyl, 5ec-butyl, (-butyl, pentyl, 1-pentyl, nco-hentyl, (-pentyl, hexyl, i-hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl, stearyl, etc., a straight chain or branched alkyl group having 1 to 20 carbon atoms, or a cycloalkyl group, preferably 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
represents a cycloalkyl group.

Among the compounds of the present invention, particularly preferred compounds 1 to 23 are as follows.

・5-hydroxy-1-methylhydantoin ・5-hydroxy-3-methylhydantoin ・5-hydroquine-1
-Ethylhydantoin・5-hydroxy-1-butylhydantoin・5-methoxy-1-methylhydantoin・
5-Butoxy-3-methylhydantoin, 5-ethoxo I-methylhydantoin, 5-methoxy-3-methylhydantoin, 5-methoxy-1-cyclohexylhydantoin, 5-hydroxy-1,5-dimethylhydantoin, 5- Hydroxy-3,5-dimethylhydantoin, 5-hydroxy-1-hexylhydantoin, 5-hydroxy-1-decylhydantoin, 5-hydroxy-
1-stearylhydantoin, 5-hydroxy-1-cyclopentylhydantoin, 5-hydroxy-1-cyclohexylhydantoin, 5-hydroxy-1-(1,
3-dimethylbutyl)hydantoin・5-hydroxy-1-t-butylhydantoin・5
-Hydroxy-1,3-dicyclohexylhydantoin/5-methoxy-3-cyclohexylhydantoin/5
-Hydroxy-1-cyclohexyl-3-methylhydantoin/5-hydroxy-1,3-dimethylhydantoin/l
-Methylhydantoin The hydantoin derivatives of the present invention include pharmaceutically acceptable salts of the compound represented by the general formula (1), and include, for example,
Examples include salts with alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium and magnesium, other metal salts such as aluminum and silver, and salts with ammonia and organic amines.

These salts can be produced from the hydantoin derivatives of the present invention by known methods, or they can be converted into each other.

When optical isomers exist in the compound of the present invention,
The present invention includes any of the dl-integrated, d-integrated, and 1-integrated.

The above-mentioned hydantoin 3M N1 substance of the present invention and its production method have already been disclosed in Japanese Patent Application No. 59-241439,
It is known to have hypoglycemic and diuretic effects.

(Effect) Next, the acute toxicity and hypolipidemic effect of the compound of the present invention will be described.

A lysotifield-vircoxon method was used to determine the mortality rate of 7 days after administration of the test drug using 10 ddY male mice per group, and D50 was calculated as Jγ.

As a result, when the compounds of the present invention shown in the above examples were administered orally, intrastatically, intraperitoneally, or subcutaneously, 5.
Even when administered at doses of 000 mg/kg or more, no deaths were observed, and no transient symptoms were observed immediately after administration. Therefore, the LD5Q value of the compound of the present invention is 5. OOO
ng/kg or more. Furthermore, no changes were observed in any of the internal organs in the N (I) examination after the end of the experiment.

(2) Lipid lowering effect (1) Group of 10 male Wistar rats (body weight 2
10-250g) after 20 hours O,S%CMC-N
A The test drug dissolved or suspended in an aqueous solution was orally administered. Two hours later, the abdomen was opened under bendoparbital anesthesia, and a deep dish was inserted into the descending vena cava. The obtained blood was allowed to stand for 30 minutes to completely coagulate, and then centrifuged to collect serum.

Using the obtained serum, cpo-p-chlorophenol coloring method (R4chard W, 5payd et al.
, + C1inaC11nacalChe, vol.
24.1343 (197B)) and Acyl CoA 5ynthe
tase-Acyl CoA Oxidase method (S
Hilmizu S, et al, 8ioche
s.

Biophys, Res, Com+sun,, v
Free fatty acids (FFAs) were measured according to J.D. ol., 91.108 (1979)).

An example of the results is shown in Table 1.

Table 1 Control -33,5±2.9 0.51±0
．． 04 Compound 1 100 14.3±2.4
0.33±0.01C51) [35) Compound 2 100 15.3±2.4 0.
30±0.01 Compound 4 100 13.8±
0.9 0.28±0.04 Compound 23 100
18.5+1.8 0.29'-0,01(+
1) The lipid-lowering effect of the compound of the present invention is shown in rats in which hyperlipidemia was experimentally induced by streptocytosine administration.

Group of 10 male Wistar rats (body weight 200-
Streptocytosine (15mg) was injected from the tail vein into 260g
/kg) was administered. . After fasting from 24 to 48 hours after administration of streptocytosine, 0.5% CM
Compound 1 of the present invention dissolved in a C-Na aqueous solution was orally administered.

After 2 hours, serum was collected in the same manner as above (:), and TG
and FFA were measured.

An example of the results is shown in Table 2.

Table 2 Untreated rats - 51 ±2 0.52±
0.02 control -98±9 0.77±0
．． 04 Compound 1 10 60±5 0.
30±0.03100 49±60.22±0.02 (Effect of the invention) As is clear from the results of the above pharmacological tests, not only untreated rats but also rats in which hyperlipidemia was experimentally induced, The compounds of the present invention significantly lowered blood lipids such as triglycerides and free fatty acids.

Therefore, the compound of the present invention is a lipid-lowering agent useful for treating hyperlipidemia associated with arteriosclerosis, nephrosis/hypertension, diabetes, obesity, and various other diseases, and for preventing various diseases of the circulatory system. The compound of the present invention has low toxicity, few side effects, and can be administered orally, so it can be used safely over a long period of time, and is particularly advantageous for treating chronic diseases.

The compound of the present invention can be combined with a suitable pharmaceutical carrier or diluent to form a medicament, and can be formulated by any conventional method to form a solid, semisolid, liquid or gaseous form for oral or parenteral administration. Dosage forms such as tablets, capsules, powders, granules, powders, soft formulas, liquids, liquids, etc.
It can be formulated into main propellants, inhalers, aerosols, vapors, and poultices.

For formulation, the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, the compounds of the present invention may be used alone or in appropriate combinations, and they may be used in combination with other pharmaceutically active ingredients. It can also be used as a medicine.

For oral preparations, crystalline cellulose, cellulose derivatives, gum arabic, corn starch may be used as is or with appropriate additives, such as evaporated milk TIN, mannitol, corn starch, and dill starch. , binders such as gelatin, corn starch,
Disintegrants such as potato starch and sodium carboxyl methyl cellulose, talc, lubricants such as Mag 21 Noum Stearate, other thickeners, wetting agents, buffers, preservatives, fragrances, etc. are appropriately combined to form tablets, powders, etc. Form into granules or capsules, or combine with ointment bases such as petrolatum, paraffin, plus 1000 base, single ointment, lead ointment, hydrophilic ointment, hydrophilic petrolatum, hydrophilic plus 1000 base, etc. It can be done.

Furthermore, the compounds of the present invention can be mixed with various bases, such as emulsion bases or water-soluble bases, to produce planed products.

The injection may be a solution or suspension in an aqueous or non-aqueous solvent, such as vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, etc. In this case, solubilizing agents and isotonizing agents may be added as necessary. Commonly used additives such as additives may also be added.

For use as an inhaler or aerosol, the compounds of the invention can be placed in an aerosol container in the form of a liquid or microbodies, together with a gaseous or liquid propellant, and optionally with the usual excipients such as wetting agents or dispersing agents. Fill inside. The compound of the present invention may be administered in a non-pressurized dosage form such as a nebulizer or an atomizer.

Poultices can be produced by mixing with peppermint oil, concentrated glycerin, kaolin, etc.

The desired projection form of the compound of the present invention varies depending on the subject to be administered, the shape, the method of administration, the intercostal space, etc., but in order to obtain the desired effect, the compound of the present invention should be administered to adults on -i.
It is possible to administer 1 to 1000 mg, preferably 5 to 600 mg per day, and the compound of the present invention can be administered in an appropriate dosage form (1 to several units per day) of the compound of the present invention.

In the case of daily administration F5 (for example, injection), -L'' administration ψ is preferably at a level of 3 to 1/10 of the above-mentioned dose.

(Example) Prescription examples of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below.

Prescription example 1. (Tablet) Lactose +30
Corn starch 40 total 280
Buttocks Prescription Example 2, (Capsule) Compound of the Invention 50 Milk Zero Tang 25
0 total 300 N Prescription example 3. (Injection) Sodium chloride Appropriate amount 1- Prescription example・t, (planing)

Claims (1)

[Claims] (1) A hypolipidemic agent containing at least one hydantoin derivative represented by general formula (I) and a pharmaceutically acceptable salt thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents hydrogen or OR_4, R_1, R_2
, R_3, and R_4 are the same or different and each represents hydrogen, an alkyl group, or a cycloalkyl group. )