JPH0686436B2 - Novel hydantoin derivative and pharmaceutical composition containing the compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel hydantoin derivative and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient.

(Prior Art) Currently, sulfonylurea-based and biguanide-based drugs are generally used as oral hypoglycemic agents. However, these drugs often cause symptoms such as excessive hypoglycemia and lactic acidosis upon administration, and their side effects are a problem.

On the other hand, insulin products, which are well-known as antidiabetic agents,
Because of its nature, it can only be used as an intravenous injection, and the complexity and inconvenience of its application place a great burden on patients.

The present inventors are searching for compounds that have an effective, safer and orally administrable blood glucose lowering effect, and the hydantoin derivative of the present invention and a pharmaceutically acceptable salt thereof have an excellent blood glucose lowering effect, Moreover, they have found that they have low toxicity and extremely high safety, and completed the present invention.

(Problems to be Solved by the Invention) An object of the present invention is to provide a novel hydantoin derivative having a low side effect, low toxicity, and extremely safe oral hypoglycemic action, a pharmaceutically acceptable salt thereof, and a compound which is effective. It is to provide a pharmaceutical composition containing as an ingredient.

(Means for Solving Problems) The compound of the present invention is a novel hydantoin derivative represented by the following general formula (I).

(In the formula, X represents OH, R ₁ and R ₂ are the same or different and each represent hydrogen, an alkyl group having 6 to 20 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ₁ and R ₂ In the general formula (I), X is OH, and R ₁ and R ₂ are the same or different and each is hydrogen, an alkyl group, preferably hexyl, i- Hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl, stearyl, and other linear or branched alkyl groups having 6 to 20 carbon atoms, or cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
It represents a cycloalkyl group having 3 to 8 carbon atoms such as cycloheptyl and cyclooctyl.

Among the compounds of the present invention, particularly preferable compounds are as follows.

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-cyclohexyl-3-methylhydantoin 5-hydroxy-1,3-dicyclohexylhydantoin The hydantoin derivative of the present invention is a pharmaceutically acceptable compound represented by the general formula (I). Volatile salts, for example,
Examples thereof include alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium and magnesium, metal salts with other aluminum and silver, and salts with ammonia, organic amines and the like.

These salts can be prepared from the free hydantoin derivative of the present invention by a known method, or can be converted into each other.

When an optical isomer is present in the compound of the present invention,
The present invention includes any of its d1-form, d-form and 1-form.

Next, an example of the method for producing the compound of the present invention will be described.

(1) First, a normal esterification reaction is performed on glyoxylic acid. That is, alcohols or methyl cellosolve, etc., in an aprotic solvent such as benzene, toluene, xylene, carbon tetrachloride, etc. in the presence of an organic acid catalyst such as p-toluenesulfonic acid, camphorsulfonic acid, etc. for several hours while removing water produced. To room temperature to heating or reflux for 1 day. The resulting glyoxylic acid ester or O-alkylglyoxylic acid ester (glyoxylic acid ester alcoholate) is purified without isolation or in a suitable solvent, for example, water, acetic acid, alcohol such as butanol, or a mixed solvent thereof. , Room temperature to reflux 1
The compound of the present invention represented by the general formula (I) by reacting with N-alkylurea, N-cycloalkylurea, N, N'-dialkylurea or N, N'-dicycloalkylurea for a period of time to several days. Can be obtained.

The above reaction is carried out with glyoxylic acid, O-alkylglyoxylic acid ester (glyoxylic acid ester alcoholate), or α-ketocarboxylic acid such as pyruvic acid, N
-Alkylurea, N-cycloalkylurea, N, N'-dialkylurea, or N, N'-dicycloalkylurea can be used as the raw materials in the same manner.

(2) Further, the compound of the present invention can also be synthesized by the following ordinary N-alkylation reaction.

That is, in a suitable solvent that does not inhibit the reaction, for example, in anhydrous alcohol or dimethyl sulfoxide, for example, in the presence of an organic base such as a lower alkyl amine or an alkali metal alkoxide or a base such as an alkyl metal hydroxide, for example, an alkyl halide, a cycloalkyl halide, etc. N-alkylation or N-cycloalkylation can be performed by reacting alkyl, dialkyl sulfuric acid such as dimethyl sulfuric acid, p-toluenesulfonic acid alkyl ester, p-toluenesulfonic acid cycloalkyl ester and the like. The above reaction can be carried out by reacting for several hours to several days at room temperature to appropriate heating.

The obtained compound of the present invention is subjected to distillation, chromatography,
Purified by ordinary means such as recrystallization, elemental analysis, melting point, 1
Identification was performed by R, NMR, UV, mass spectrum and the like.

The compound of the present invention can be made into a medicine by combining with a suitable medicinal carrier or diluent, and can be formulated by any ordinary method. It can be solid, semisolid, liquid or gas for oral or parenteral administration. Can be formulated into a dosage form such as tablets, capsules, powders, granules, powders, ointments, solutions, suppositories, injections, inhalants, aerosols and poultices.

In the formulation, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, and a compounding agent with another pharmaceutically active ingredient can be used. May be

In the preparation for oral administration, crystalline cellulose, as it is or together with suitable additives, for example, conventional excipients such as lactose, mannitol, corn starch and potato starch,
Cellulose derivatives, gum arabic, corn starch, gelatin and other binders, corn starch, potato starch, sodium carboxymethyl cellulose and other disintegrants, talc, magnesium stearate and other lubricants, other extenders, wetting agents, buffers , Tablets, powders, granules or capsules by appropriately combining preservatives, perfumes and the like, or ointment bases such as petrolatum, paraffin, plastibase, single ointment, single lead ointment, hydrophilic ointment, hydrophilic petrolatum, hydrophilic It can be made into an ointment by combining with a plasti base or the like.

Furthermore, the compound of the present invention can be mixed with various bases such as an emulsion base or a water-soluble base to produce a suppository.

As the injection, an aqueous solvent or a non-aqueous solvent, for example, a vegetable oil, a synthetic resin acid glyceride, a higher fatty acid ester, a solution of propylene glycol or the like, a suspension or an emulsion can be used, and in this case, a solubilizing agent if necessary, Ordinarily used additives such as an isotonicity agent, a suspending agent, an emulsifying agent, a stabilizer and a preservative may be added.

For use as an inhalant or aerosol, the compound of the invention is in the form of a liquid or fine powder in an aerosol container together with a gas or a liquid propellant and, if desired, a conventional auxiliary such as a wetting agent or a dispersant. To fill. The compound of the present invention may be in a non-pressurized dosage form such as a neprizer or atomizer.

As a poultice, it can be produced by mixing with peppermint oil, concentrated glycerin, kaolin and the like.

Although the desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc., in order to obtain the desired effect, it is generally 1 to 1000 mg, preferably 1 to 1000 mg, of the compound of the present invention to an adult per day. 5 to 600 mg can be orally administered, and a unit preparation containing an appropriate amount of the compound of the present invention can be administered 1 to several units per day.

In the case of parenteral administration (eg, injection), the daily dose is preferably at a dose level which is 3 to 1/10 of the above dose.

(Example) Below, the production example of the compound of this invention is shown by an Example.

Reference Example 1. Glyoxylic acid n-butyl ester monohydrate (15.0 g) and N-methylurea (7.4 g) were refluxed in an 80% aqueous acetic acid solution for 1 hour. After the reaction, the solvent was distilled off, a small amount of methanol was added, and the hardly soluble substance was filtered off. The residue crystallizes after the filtrate is dried to dryness under reduced pressure, but recrystallized from ethyl acetate to give 5-hydroxy-1-
10.4 g of white crystals of methylhydantoin (Compound 1) were obtained.

Mp: 135.0-136.0 ℃ IR (KBr): 3180,1750,1715,1446,1115,750cm -1 NMR (DMSO-d 6) δ = 2.72 (s, 3H), 4.98 (d, 1H, J = 8H
z), 6.88 (d, 1H, J = 8Hz), 10.74 (br.s, 1H) Reference Example 2. Glyoxylic acid was used as a starting material, and 5-hydroxy-3-methylhydantoin (as in Example 1 was used). Compound 2) was obtained.

Melting point: 115.5-116.5 ° C IR (KBr): 3350,1765,1700,1465,1068,823cm ^-1 NMR (DMSO-d ₆ ) δ = 2.80 (s, 3H), 5.16 (d, 1H, J = 8H
z), 6.72 (d, 1H, J = 8Hz), 8.61 (s, 1H) Reference Example 3. 19.0 g of glyoxylic acid monohydrate was placed in a 500 ml eggplant-shaped flask equipped with a Dean Stark device and 80 ml of It was dissolved in a mixed solvent of methyl cellosolve and 150 ml of toluene, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was refluxed overnight. After the reaction solution was concentrated to dryness under reduced pressure, 18.8 g of N-ethylurea was added without purification, and 160 ml of acetic acid and 40 ml of water were added.
Was added and dissolved, and the mixture was refluxed for 2 hours in an oil bath. After the reaction was completed, the reaction solution was concentrated to dryness, and acetic acid was removed by azeotropic distillation with toluene. After purification by silica gel column chromatography (ethyl acetate), it was recrystallized from ethyl acetate to obtain 23 g of 5-hydroxy-1-ethylhydantoin (Compound 3) as white crystals.

Melting point: 119.0-120.0 ° C IR (KBr): 3340,1778,1702,1470,1102cm ^-1 NMR (DMSO-d ₆ ) δ = 1.10 (t, 3H, J = 7Hz), 3.14 (dq, 1H,
J ₁ = 14Hz, J ₂ = 7Hz), 3.34 (dq, 1H, J ₁ = 14Hz, J ₂ = 7Hz) 5.09
(D, 1H, J = 9Hz), 6.88 (d, 1H, J = 9Hz), 10.74 (br.s, 1H) Similarly, the following compounds were obtained.

5-Hydroxy-1-butylhydantoin (Compound 4) Melting point: 94.0-95.0 ° C IR (KBr): 3330,1778,1704,1463,1080,750cm ^-1 NMR (DMSO-d ₆ ) δ = 0.89 (t, 3H) , J = 7Hz), 1.2-1.4 (m,
2H), 1.4-1.6 (m, 2H), 3.0-3.4 (m, 2H), 5.06 (d, 1H,
J = 8Hz), 6.88 (d, 1H, J = 8Hz), 10.71 (br.s, 1H) 5-methoxy-1-methylhydantoin (Compound 5) Melting point: 95.0-96.0 ° C IR (KBr): 3160,1764 , 1718,1442,1080cm ^-1 NMR (DMSO-d ₆ ) δ = 2.79 (s, 3H), 3.21 (s, 3H), 5.09
(S, 1H), 11.05 (br.s, 1H) 5-butoxy-3-methylhydantoin (Compound 6) Melting point: 37.0-39.0 ° C IR (KBr): 3300,2950,1780,1720,1462,1075cm ^-1 _{NMR (DMSO-d 6) δ} = 0.88 (t, 3H, J = 7Hz), 1.2-1.5 (m,
2H), 1.4-1.6 (m, 2H), 2.83 (s, 3H), 3.4-3.6 (m, 2
H), 5.21 (d, 1H, J = 2Hz), 8.84 (br.s, 1H) Reference Example 4 5.0 g of 5-hydroxy-1-methylhydantoin (Compound 1) was dissolved in 200 ml of anhydrous methanol to give 6.7 After adding g of triethylamine, 10.9 g (1.5 equivalents) of p-toluenesulfonic acid chloride was added, and the mixture was stirred at room temperature for 3 days.
After the reaction, the reaction solution was concentrated to dryness, a small amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated to dryness, and further purified by silica gel chromatography (ethyl acetate). The obtained crude crystals were recrystallized from a mixed solvent of ethyl acetate-hexane to give 5-methoxy-1-methyl hintoin (compound 5) as white crystals.
Obtained 3.8 g.

Similarly, the following compound was obtained.

5-Ethoxy-1-methylhydantoin (Compound 7) Melting point: 96.0-97.0 ° C IR (KBr): 3160,1765,1720,1443,1115cm ^-1 NMR (DMSO-d ₆ ) δ = 1.15 (t, 3H, J = 7Hz), 2.79 (s, 3
H), 3.43 (dq, 1H, J ₁ = 2Hz, J ₂ = 7Hz), 3.56 (dq, 1H, J ₁ = 2H
z, J ₂ = 7Hz), 5.08 (s, 1H), 11.00 (br.s, 1H) 5-methoxy-3-methylhydantoin (Compound 8) Melting point: 57.0-58.0 ° C IR (KBr): 3300,1760, 1715,1468,1082 cm ^-1 NMR (DMSO-d ₆ ) δ = 2.83 (s, 3H), 3.26 (s, 3H), 5.12
(D, 1H, J = 2Hz), 8.85 (br.s, 1H) MS: M ⁺ : 144m / z: 116,114,86,74,59 5-methoxy-1-cyclohexylhydantoin (Compound 9) Melting point: 121.0- 122.0 ℃ IR (KBr): 3175,3050,2940,2852,1780,1700,1430,1103,
768 cm ^-1 NMR (DMSO-d ₆ ) δ = 0.9-1.35 (m, 3H), 1.35-1.7 (m,
3H), 1.7-1.9 (m, 4H), 3.18 (s, 3H) 3.56 (tt, 1H, J ₁ =
3.6Hz, J ₂ = 12.0Hz), 5.25 (s, 1H), 11.0 (br.s, 1H) MS: M ⁺ : 212m / z: 197,182,169,131,103,98,82,67,60,55,41 Reference example 5 Add 214 g of methyl pyruvate to a 3 l eggplant-shaped flask,
155 g of N-methylurea was added. 800 ml of acetic acid and 200 ml of water were added and dissolved, and the mixture was refluxed for 2 hours and 30 minutes. After the reaction, the reaction solution was concentrated to dryness, toluene was added, and acetic acid was azeotropically removed. The obtained crude product was purified by silica gel chromatography (ethyl acetate and 5% methanol / chloroform) to obtain 95 g of 5-hydroxy-1,5-dimethylhydantoin (Compound 10).

Melting point: 122.0-123.0 ° C IR (KBr): 3340, 3200, 1780, 1765, 1720, 1440 cm ^-1 NMR (DMSO-d ₆ ) δ = 1.34 (s, 3H), 2.70 (s, 3H), 6.59
(S, 1H), 10.78 (s, 1H) MS: M ⁺ : 144m / z: 129,116,73,58,43 Similarly, 5-hydroxy-3,5-dimethylhydantoin (Compound 11) was obtained.

Melting point: (oil) NMR (DMSO-d ₆ ) δ = 1.37 (s, 3H), 2.81 (s, 3H), 6.50
(S, 1H), 8.63 (s, 1H) Example 1 21.0 g of glyoxylic acid benzyl ester / benzyl alcoholate and 10.0 g of N-hexylurea were refluxed in an 80% aqueous acetic acid solution for 1 hour and 30 minutes. After the reaction, the reaction solution was cooled and the reaction solution was concentrated to dryness under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1:
After purification in 1), it was recrystallized from benzene to obtain 7.4 g of colorless needle crystals of 5-hydroxy-1-hexyl hint-in (Compound 12).

Melting point: 96.0-97.0 ° C IR (KBr): 3360,3140,2950,1780,1760,1710,1475,1097,
755 cm ^-1 NMR (DMSO-d ₆ ) δ = 0.85 (t, 3H, J = 6.6 Hz), 1.24 (s, 6
H), 1.3-1.6 (m, 2H), 3.09 (ddd, 1H, J ₁ = 5.9Hz, J ₂ = 8.2H
z, J ₃ = 14.0Hz), 3.25 (ddd, 1H, J ₁ = 7.3Hz, J ₂ = 8.2Hz, J ₃ = 1
4.0Hz), 5.04 (d, 1H, J = 8.8Hz), 6.84 (d, 1H, J = 8.8Hz),
10.7 (br.s, 1H) MS: M ⁺ : 200 m / z: 129,116,89,85,58,41,30 Similarly, the following compounds were obtained.

5-Hydroxy-1-decylhydantoin (Compound 13) Melting point: 100.0-101.0 ° C IR (KBr): 3350,2920,2855,1780,1760,1710,1470,1100,
755 cm ^-1 NMR (DMSO-d ₆ ) δ = 0.85 (t, 3H, J = 6.6 Hz), 1.23 (s, 14)
H), 1.3-1.6 (m, 2H), 3.08 (ddd, 1H, J ₁ = 5.9Hz, J ₂ = 8.1H
z, J ₃ = 13.9Hz), 3.24 (dt, 1H, J ₁ = 7.7Hz, J ₂ = 13.9Hz), 5.0
3 (d, 1H, J = 8.8Hz), 6.84 (d, 1H, J = 8.8Hz), 10.7 (br.s,
1H) MS: M ⁺ : 256m / z: 129,116,99,85,69,58,41,30 5-hydroxy-1-stearylhydantoin (Compound 14) Melting point: 112.0-114.0 ° C IR (KBr): 3320,2910 , 2850,1780,1760,1710,1480,1095,
750 cm ^-1 NMR (DMSO-d ₆ ) δ = 0.84 (t, 3H, J = 6.6Hz), 1.23 (s, 30
H), 1.4-1.6 (m, 2H), 3.08 (ddd, 1H, J ₁ = 6.1Hz, J ₂ = 7.9H
z, J ₃ = 14.0Hz), 3.24 (dd, 1H, J ₁ = 6.4Hz, J ₂ = 14.0Hz), 5.0
3 (d, 1H, J = 8.8Hz), 6.82 (d, 1H, J = 8.8Hz), 10.68 (br.
s, 1H) MS: M ⁺ : 368m / z: 352,296,129,113,101,69,57,43,30 5-hydroxy-1-cyclopentylhydantoin (Compound 15) Melting point: 139.0-141.0 ° C IR (KBr): 3320,2950,2870 , 1778,1715,1470,1078,763cm
_{^{-1 NMR (DMSO-d 6)}} δ = 1.3-1.9 (m, 8H), 4.00 (tt, 1H, J 1
= 8.1Hz, J ₂ = 8.1Hz), 5.11 (d, 1H, J = 8.8Hz), 6.79 (d, 1H,
J = 8.8Hz), 10.70 (br.s, 1H) MS: M ⁺ : 184m / z: 155,117,99,89,84,67,56,41,27 5-hydroxy-1-cyclohexylhydantoin (Compound 16) Melting point: 176.0-178.0 ° C IR (KBr): 3310,2920,2850,1770,1700,1450,1115,753cm
_{^{-1 NMR (DMSO-d 6)}} δ = 0.9-1.4 (m, 3H), 1.4-1.9 (m, 7
H), 3.51 (tt, 1H, J ₁ = 4.0Hz, J ₂ = 11.8Hz), 5.10 (d, 1H, J =
8.8Hz), 6.76 (d, 1H, J = 8.8Hz), 10.7 (br.s, 1H) MS: M ⁺ : 198m / z: 155,117,82,67,56,41,27 5-hydroxy-1- (1,3-Dimethylbutyl) hydantoin (Compound 17) Melting point: 148.0-149.0 ° C IR (KBr): 3250,2950,1762,1700,1445,1100cm ^-1 NMR (DMSO-d ₆ ) δ = 0.7-1.0 ( m, 6H), 1.1-1.2 (m, 3
H), 1.2-1.7 (m, 3H), 3.8-4.0 (m, 1H), [5.06 (d, J
= 8.8Hz), 5.10 (d, J = 8.8Hz); total1H], [6.78 (d, J
= 8.8Hz), 6.80 (d, J = 8.8Hz); total1H], 10.72 (br.s, 1
H) MS: M ⁺ : 200m / z: 143,100,72,44,43,41 5-hydroxy-1-t-butylhydantoin (Compound 18) Melting point: 189.0-190.5 ° C IR (KBr): 3230,2965,1760 , 1710,1436,1230,1080cm ^-1 NMR (DMSO-d ₆ ) δ = 1.37 (s, 9H), 5.14 (s, 1H), 6.78
(Br.s, 1H,), 10.47 (br.s, 1H) MS: M ⁺ : 172m / z: 157,84,58,41 5-hydroxy-1,3-dicyclohexylhydantoin (Compound 19) Melting point: 148.0 -149.0 ° C IR (KBr): 3275,2930,2850,1766,1700,1678,1450,1112,
760 cm ^-1 NMR (DMSO-d ₆ ) δ = 0.9-1.4 (m, 6H), 1.4-1.8 (m, 12
H), 1.8-2.0 (m, 2H), 3.54 (tt, 1H, J ₁ = 4.0Hz, J ₂ = 11.0H
z), 3.69 (tt, 1H, J ₁ = 3.8Hz, J ₂ = 12.0Hz), 5.09 (s, 1H),
6.82 (br.s, 1H) MS: M ⁺ : 280m / z: 237,199,181,155,117,99,83,67,55,41 Reference Example 6 Glyoxylic acid methyl ester / methyl alcoholate 75
0 mg and 920 mg of N-cyclohexylurea were refluxed for 1 hour in 50 ml of a mixed solution of acetic acid: methyl alcohol (4: 1). After cooling, the solvent was distilled off and the residue was purified with a silica gel column. The obtained crude crystals were recrystallized from benzene to obtain 420 mg of colorless needle crystals of 5-methoxy-3-cyclohexylhydantoin (Compound 20).

Melting point: 135.0-137.0 ° C IR (KBr): 3320, 2915, 2850, 1768, 1710, 1422, 1105 cm ^-1 NMR (DMSO-d ₆ ) δ = 0.9-1.4 (m, 3H), 1.4-1.8 (m, Four
H), 1.8-2.1 (m, 3H), 3.22 (s, 3H), 3.70 (tt, 1H, J ₁ =
4.0Hz, J ₂ = 14.0Hz), 5.09 (s, 1H), 8.80 (br.s, 1H) MS: M ⁺ : 182m / z: 131,99,60,55,41 Example 2 2.0g of 5 -Hydroxy-1-cyclohexylhydantoin, methanol containing 600 mg sodium methoxide 30 m
melted in l. After 20 minutes, 0.7 ml of methyl iodide was added dropwise and the reaction was continued at a reaction temperature of 50 ° C. for 1 hour. The solvent was distilled off and the residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 1). The obtained crude crystals were recrystallized from benzene to obtain colorless needle crystals of 5-hydroxy-1-cyclohexyl-3-methylhydantoin (Compound 21) (500 mg).

Melting point: 140.0-141.0 ° C IR (KBr): 3360,2940,2802,1770,1700,1445,1070,762cm
_{^{-1 NMR (DMSO-d 6)}} δ = 0.9-1.4 (m, 3H), 1.4-1.9 (m, 7
H), 2.81 (s, 3H), 3.55 (tt, 1H, J ₁ = 4.0Hz, J ₂ = 11.8Hz),
5.16 (d, 1H, J = 8.8Hz), 6.82 (d, 1H, J = 8.8Hz) MS: M ⁺ : 212m / z: 169,131,82,67,56,41,27 Obtained.

5-Hydroxy-1,3-dimethylhytotoin (Compound 22) Melting point: (colorless oil) IR (KBr): 3300,3000,1776,1715,1195,703cm ^-1 NMR (CDCl ₃ ) δ = 3.02 (s , 6H), 5.14 (s, 1H), 5.25 (b
rs, 1H) MS: M ⁺ : 144m / z: 127,116,88,59,42 The compound of the present invention is produced by each of the above-mentioned production methods, and the production method is not limited by the above-mentioned Examples. Absent.

Formulation examples of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below.

Formulation Example 1. (Tablets) Composition per tablet (mg) Compound of the present invention 100 Lactose 130 Corn starch 40 Magnesium stearate 10 Total 280 mg Formulation Example 2. (Capsules) Composition per capsule (mg) The present invention Compound 50 Lactose 250 Total 300 mg Formulation example 3. (Injection) Composition per ampoule (mg) Compound of the present invention 10 Sodium chloride Appropriate amount Distilled water for injection Appropriate amount 1 ml Formulation example 4 (Ointment) Composition weight (G) Compound of the present invention 1 Emulsion wax 30 White petrolatum 50 Liquid paraffin 20 Total 101 g Formulation example 5. (Suppository) Component per unit (mg) Compound of the present invention 20 Cocoa butter 1980 Total 2000 mg (action) The pharmacological action of the compound of the present invention will be described.

(1) Acute toxicity Using 10 male ddy mice per group, 7 after administration of the test drug
The LD ₅₀ was calculated from the daily mortality using the Richfield-Wilcoxone method.

As a result, when the compound of the present invention shown in the above Example was orally, intravenously, intraperitoneally, or subcutaneously administered, in any case, 5,00
No deaths were observed at 0 mg / kg or more, and no transient symptoms immediately after administration were observed. Therefore, the LD ₅₀ value of the compound of the present invention is 5,000 mg / kg or more. Furthermore, no change was observed in each organ of the internal organs even after autopsy after the end of the experiment.

(2) Blood glucose lowering effect A group of 10 male Sprague-Dawley rats weighing about 250 g
Used as an animal. Rats were tested for the hypoglycemic effect of the test drug after fasting for 18 hours by the method of Dulin, W L et al., Proc.
c.Expl.Med., 107 , 245 (1961)] was modified and measured.
That is, in order to prevent a decrease in blood glucose level due to fasting in rats, 0.5 ml / 100 g of 20% glucose aqueous solution was subcutaneously administered to the skin on the back of the rat, and immediately thereafter, the test drug was orally administered. Two hours later, the abdomen was opened under pentobarbital anesthesia, and blood was collected from the descending vena cava. The obtained blood was left to stand for 30 minutes for complete coagulation and then centrifuged to collect serum. Blood glucose was measured by the mutarotase GOD method using the obtained serum.

An example of the results is shown in Table 1.

(Effect of the Invention) As is clear from the results of the above-mentioned pharmacological test, the compound of the present invention exhibits an excellent blood glucose lowering action. That is, even when administered in large amounts, without excessively lowering the blood glucose level, it has an excellent feature of always keeping the subject in a state close to the normal value, and is extremely useful as a drug for improving an abnormal hyperglycemic state. It is very useful. Further, the compound of the present invention is as described above.
Since it is low-toxic and extremely safe, it can be administered continuously for a long period of time, and it can be administered as an oral agent. Therefore, it can be used not only for the treatment of diabetes but also for various diseases caused by it.
For example, it is an extremely useful drug for the treatment of vascular disorders such as diabetic arteriosclerosis, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic microangiopathy.

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Claims (2)

[Claims] 1. A hydantoin derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. (In the formula, X represents OH, R ₁ and R ₂ are the same or different and each represents hydrogen, an alkyl group having 6 to 20 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ₁ and R 2; _{One of the two} represents a group other than hydrogen.) 2. A hypoglycemic agent containing as an active ingredient at least one of a hydantoin derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. (In the formula, X represents OH, R ₁ and R ₂ are the same or different and each represents hydrogen, an alkyl group having 6 to 20 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ₁ and R 2; _{One of the two} represents a group other than hydrogen.)