JPH068281B2 - Hydantoin derivative and aldo-reductase inhibitor containing the same as active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention has the general formula (I): (In the formula, R represents H or C1), a hydantoin derivative, a salt thereof, and an aldose reductase containing them as an active ingredient (hereinafter abbreviated as AR).
Inhibitor of

<Prior Art> Cataract, peripheral neuropathy, retinopathy, nephropathy and the like as diabetic complications arise from unnecessary accumulation of corresponding polyols converted from sugar by AR. For example, in sugar cataract, AR existing in the lens of the eye converts glucose, galactose, etc. into a corresponding sugar alcohol,
The converted sugar alcohol accumulates unnecessarily in the lens and changes in osmotic pressure, which is caused by damage to the lens. Therefore, in order to prevent, reduce or treat the above-mentioned complications effectively, it is important to inhibit the activity of the direct cause, AR, as strongly as possible.

<Problems to be Solved by the Invention> Conventionally, many compounds such as arrestatin and sorbin are provided as AR activity inhibitors, but in reality, their AR activity-inhibiting ability cannot be sufficiently satisfied. Therefore, a compound having a stronger ability to inhibit AR activity has been desired.

<Means for Solving Problems> The present inventors have previously found that a mono-substituted phenylsulfonylhydantoin derivative has a strong ability to inhibit AR activity, and have made an invention of an aldose reductase inhibitor containing this compound as an active ingredient. Completed (Japanese Patent Application No. 56-21351)
8).

In order to obtain a compound having a stronger AR activity-inhibiting ability, the present inventors orally administered to a streptozotocin diabetic rat in vitro using a rack lens,
As a result of diligent research on the effects of various compounds in vivo, it was found that among the tens of compounds included in the study, the hydantoin derivative represented by the general formula (I) and salts thereof have extremely strong AR activity inhibiting ability. The present invention has been completed and the present invention has been completed.

(In the formula, R represents H or C1) A hydantoin derivative, a salt thereof, a method for producing the same, and an AR activity inhibitor containing the compound as an active ingredient. INDUSTRIAL APPLICABILITY The hydantoin derivative of the present invention and a salt thereof have a strong ability to inhibit AR activity and can be used for effective prevention of diabetic complications.

The hydantoin derivative of the present invention can be produced as follows. General formula (II): (In the formula, R represents H or C1) and glycine is reacted with a substituted phenylsulfonyl chloride to synthesize N- (substituted phenylsulfonyl) glycine, and then thiohydantoin derivative is prepared using ammonium thiocyanate. In addition, the hydantoin derivative represented by the general formula (I) can be produced by further oxidizing, for example, nitric acid.

As the salt, for example, salts such as sodium salt, potassium salt, ammonium salt and magnesium salt are useful and can be easily obtained by a conventional method.

Upon completion of the present invention, the present inventors have synthesized several tens of types of hydantoin derivatives having a basic skeleton of hydantoin. The ability of these hydantoin derivatives to inhibit AR activity is determined by the type and number of binding groups and the binding position. There was a big difference. The hydantoin derivative represented by the general formula (I) and a salt thereof have the strongest AR activity inhibiting ability among these compounds.

Next, the ability of the hydantoin derivative of the present invention to inhibit AR activity will be shown by Examples.

Example 1 Method of Hayman et al. [S. Hayman and JH Kinoshita, J. Bio
l. Chem., 240.877 (1965)].
4M ammonium sulfate, 10 mM DL-glyceraldehyde, 0.16 mM NADPH and 0.01-
0.1 M phosphate buffer containing 0.016 uAR (pH 6.
2) Add 0.1 µl of the hydantoin derivative solution to 0.1 ml and decrease the absorbance at 340 nm by Guilford.
Measured with a model 250 spectrophotometer.

The AR used in this experiment was the method of Cador et al. [P. F. Kador and N. E. Sharpless, Biophys.Che
m., 8.81 (1978)] and then extracted from the rat crystal, followed by the method of Inagaki et al. [K. Inagaki et al. Arch,
Biochem. Biophys., 216, 337 (1982)].

The results are shown in Table 1.

Example 2 Effect on diabetic rats Male Wistar rats weighing 230-250 g were intraperitoneally injected with streptozotocin at a rate of 50 mg / kg to prepare diabetic rats.

From the day of streptozotocin administration, the hydantoin derivative of the present invention or the comparative compound 50 mg / kg / day was orally administered, and 1
On day 6, the rat was sacrificed to remove the lens and sciatic nerve,
The amount of sorbitol was determined by gas chromatography according to Okuda's method (Chemical & Pharmaceutical Bulletine, submitted, 1985).

As controls, normal rats (non-diabetic rats) and diabetic rats to which the hydantoin derivative was not administered (denoted as controls) were used.

The results are shown in Table 2.

Example 3 The hydantoin derivative of the present invention was examined for acute toxicity. The compound of the present invention (500 to 600 mg / kg) was orally administered to 10 male ICR mice per group and observed for 1 week. No abnormalities were observed.

Since the hydantoin derivative of the present invention has a strong ability to inhibit AR activity and has low toxicity, the drug containing the hydantoin derivative of the present invention as an active ingredient is useful for effectively preventing the diabetic complication.

Suitable carriers or media generally used for the hydantoin derivative of the present invention, such as sterilized water and oils and fats, non-toxic organic solvents and the like, excipients, binders, lubricants, colorants,
Oral combination with a flavoring agent, an emulsifying agent, a suspending agent, etc., as an inhibitor of AR activity in the form of tablets, powders, syrups, injections, eye drops, suppositories, ointments or inhalants, and oral Alternatively, the drug is parenterally administered to a patient. The dosage is, as a rough guide, 50 mg or less per day of the patient's body weight in terms of the hydantoin derivative, but it can be increased or decreased depending on the patient's condition. Next, the method for producing the compound of the present invention will be specifically shown by Examples.

Example 1 1) Synthesis of 2,5-dichlorophenylsulfonylglycine 17 g (0.12 mol) of anhydrous potassium carbonate was added to 50 m of purified water.
It was dissolved in 1 and 9.3 g (0.12 mol) of glycine was added and dissolved. To this, 25 g (0.10 mol) of 2,5-dichlorophenylsulfonyl chloride was added, and 40-
After heating at 50 ° C. for 10 minutes, it was further heated in a boiling water bath for 1 hour. After cooling, 2N hydrochloric acid was added to make the solution acidic (pH 2-3), and the resulting precipitate was filtered.

Yield 28.1 g Yield 97.0% 2) 1- (2.5-dichlorophenylsulfonyl) -2
-Synthesis of thiohydantoin 2,5-dichlorophenylsulfonylglycine 11.5
g (0.04 mol) to anhydrous pyridine 3.3 ml, dried ammonium thiocyanate 6.1 g (0.081 mol)
Then, 8.2 ml of acetic anhydride was added, and the mixture was heated in a boiling water bath for 30 minutes while stirring. After cooling, 80 ml of purified water was added and the mixture was ice-cooled, and the resulting precipitate was filtered.

Yield 7.4 g Yield 56.3% 3) Synthesis of 1- (2,5-dichlorophenylsulfonyl) hydantoin 50% to 13.3 g (0.041 mol) of 1- (2,5-dichlorophenylsulfonyl) -2-thiohydantoin
(v / v) 100 ml of nitric acid was added, and the mixture was heated in a boiling water bath for 90 minutes, cooled with ice and the precipitate formed was filtered.

Yield 5.1 g Yield 40.2% Melting point 226-230 ° C Example 2. 1) Synthesis of 2,4,5-trichlorophenylsulfonylglycine 5.9 g (0.04 mol) of anhydrous potassium carbonate was added to purified water 3
It was dissolved in 0 ml, and 3.5 g (0.041 mol) of glycine was added and dissolved. To this, 10 g (0.036 mol) of 2,4,5-trichlorophenylsulfonyl chloride
Was added, and the mixture was heated at 60 to 70 ° C. for 10 minutes, and further heated in a boiling water bath for 40 minutes. After cooling, add 2N hydrochloric acid to add acidity (pH
2-3) and the resulting precipitate was filtered.

Yield 11 g Yield 95.9% 2) Synthesis of 1- (2,4,5-trichlorophenylsulfonyl) -2-thiohydantoin 2,4,5-Trichlorophenylsulfonylglycine 6.3 g (0.02 mol) was added to anhydrous pyridine 2.5 ml and dried ammonium thiocyanate 3.0 g (0.04 mol).
l) and 4 ml of acetic anhydride were added and then heated for 30 minutes in a boiling water bath with stirring. After cooling, 60 ml of purified water was added and ice-cooled, and the resulting precipitate was filtered.

Yield 3.5 g Yield 48.6% 3) Synthesis of 1- (2,4,5-trichlorophenylsulfonyl) hydantoin 1- (2,4,5-trichlorophenylsulfonyl)-
2-thiohydantoin 5 in 15.0 g (0.04 mol)
100 ml of 0% (v / v) nitric acid was added, the mixture was heated in a boiling water bath for 90 minutes, and after cooling with ice, the precipitate formed was filtered.

Yield 1.7 g Yield 12.4% Melting point 232-235 ° C

Claims (3)

[Claims] 1. A hydantoin derivative represented by the following general formula (I) and salts thereof. (However, in the formula, R represents H or C1) 2. General formula (II): (Wherein R represents H or C1), a step of reacting a substituted phenylsulfonyl chloride represented by the formula with glycine to produce N- (substituted phenylsulfonyl) glycine, the obtained compound and ammonium thiocyanate A process for producing a hydantoin derivative, which comprises a step of reacting to give a thiohydantoin derivative, and a step of oxidizing the derivative. 3. General formula (I): A prophylactic / therapeutic agent for diabetic complications comprising a hydantoin derivative represented by the formula (wherein R represents H or C1) or a salt thereof as an active ingredient.