JPH0742274B2 - 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): And a salt thereof and an inhibitor of aldose reductase (hereinafter abbreviated as AR) containing them as an active ingredient.

<Prior Art> Cataracts, 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, the AR present in the lens of the eye converts glucose, galactose, etc. into a corresponding sugar alcohol, and the converted sugar alcohol is unnecessarily accumulated in the lens to increase the osmotic pressure, which causes the lens to penetrate into the lens. It happens by giving an obstacle. Therefore, in order to prevent, reduce or treat effectively the above-mentioned complications, it is essential to inhibit the activity of the direct cause, AR, as strongly as possible.

<Problems to be Solved by the Invention> Conventionally, a large number of compounds such as arrestatin and sorbin are provided as AR activity inhibitors, but the reality is that their AR activity inhibiting ability cannot be sufficiently satisfied. A compound having a more effective AR activity inhibiting ability has been desired.

<Means for Solving Problems> The present inventors have previously found that a halogen-substituted phenylsulfonylhydantoin derivative has a strong AR activity-inhibiting ability, and invented an aldose reductase inhibitor containing this compound as an active ingredient. Completed (JP-A-58-109418, JP-A-62-67075).

As a result of intensive studies on the effects of various compounds to obtain a compound having a more effective AR activity inhibiting ability, the present inventors have found that 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. The present invention has the general formula (I): A hydantoin derivative represented by the following, a salt thereof, a method for producing the same, and an AR activity inhibitor containing these compounds as active ingredients. The hydantoin derivative of the present invention and its salt are potent.
It has the 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): The naphthalene sulfonyl chloride represented by is reacted with glycine to synthesize naphthalene sulfonyl glycine, which is then converted into a thiohydantoin derivative using ammonium thiocyanate, and further oxidized with nitric acid to give a compound represented by the general formula (I). The hydantoin derivatives represented can be prepared.

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.

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

Experimental example 1 Method by Heyman [S. Hayman and JH Kinoshita, J. Bio
l. Chem., 240.877 (1965)], 0.4 M ammonium sulfate, 10 mM DL-glyceraldehyde, 0.16 mM NADPH.
0.1M phosphate buffer (pH 6.
2) Add 10 μl of hydantoin derivative solution to 1.0 ml,
The decrease in absorbance at 340 nm was measured with a Guilford model 250 spectrophotometer.

The AR used in this experiment was the method of Cader et al. [PF
Kador and NESharpless, Biophys.Chem., 8.81 (197
8) ”from the rat lens and then the method of Inagaki et al. [K. Inagaki et al. Arch. Biochem. Biophys., 216,
337 (1982)] was used to obtain the AR. The results are shown in Table 1.

Experimental 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 4th day of streptozotocin administration, the hydantoin derivative of the present invention or the comparative compound 50 mg / kg / day was orally administered, and 16
On day one, the rat was sacrificed and the lens and sciatic nerve were removed, and Okuta et al. (Chemical & Pharmaceutical).
The amount of sorbitol was determined by gas chromatography according to Al Bulletine, 33 , 2990-2995 (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.

Experimental Example 3 The hydantoin derivative of the present invention was examined for acute toxicity. The compound 500 of the present invention was added to 10 male ICR mice per group.
Oral administration of ˜600 mg / kg was observed for 1 week, but no abnormality was 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.

The hydantoin derivative of the present invention is a generally used suitable carrier or medium, for example, sterilized water or vegetable oil, if necessary, a harmless organic solvent, etc., and is used as an excipient, a binder, a lubricant, a coloring agent. , A flavoring agent, an emulsifying agent, a suspending agent, etc. are appropriately selected and combined, and used as an inhibitor of AR activity in the form of tablets, powders, syrups, injectable solutions or eye drops, and administered to patients either orally or parenterally To be done. As a tentative guideline, the dose is 50 mg or less per day of the patient's body weight converted to 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 1) Synthesis of α-naphthalenesulfonyl glycine 15 g (0.11 mol) of anhydrous potassium carbonate was dissolved in 40 ml of purified water, and 8.0 g (0.11 mol) of glycine was added and dissolved. To this, α-naphthalene sulfonyl chloride 20g (0.09m
ol) was added and the mixture was heated at 40 to 50 ° C. for 10 minutes, and further heated in a boiling water bath for 30 minutes. After cooling, add 2N hydrochloric acid to add acidity (pH2-
In 3), the resulting precipitate was collected by filtration.

Yield 21.5g Yield 95.0% 2) Synthesis of 1- (α-naphthalenesulfonyl) -2-thiohydantoin α-Naphthalenesulfonyl glycine 10g (0.04mol) in anhydrous pyridine 3.5ml, dried ammonium thiocyanate
After adding 6.6 g (0.09 mol) and 12.2 ml of acetic anhydride, the mixture was heated with stirring in a boiling water bath for 30 minutes. 60 ml after cooling
Purified water was added and the mixture was ice-cooled, and the resulting precipitate was collected by filtration.

Yield 10.5g Yield 78% 3) Synthesis of 1- (α-naphthalenesulfonyl) hydantoin 100 ml of 50% (v / v) nitric acid was added to 12.4 g (0.041 mol) of 1- (α-naphthalenesulfonyl) -2-thiohydantoin, heated in a boiling water bath for 90 minutes, and the precipitate formed after ice cooling was collected by filtration. did.

Yield 1.8 g Yield 15.5% Melting point 210-214 ° C. Example 2.1) Synthesis of β-naphthalenesulfonylglycine Anhydrous potassium carbonate (7.6 g, 0.05 mol) was dissolved in purified water (20 ml), and glycine (4.1 g, 0.05 mol) was added and dissolved. To this, β-naphthalene sulfonyl chloride 10g (0.04m
ol) was added, 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 (pH2-
In 3), the resulting precipitate was collected by filtration.

Yield 11.2g Yield 92% 2) Synthesis of 1- (β-naphthalenesulfonyl) -2-thiohydantoin β-Naphthalenesulfonyl glycine 11.4 g (0.04 mol) in anhydrous pyridine 3 ml, dried ammonium thiocyanate
After adding 6.6 g (0.09 mol) and 9 ml of acetic anhydride, the mixture was heated with stirring in a boiling water bath for 30 minutes. After cooling, 80 ml of purified water was added and the mixture was ice-cooled, and the resulting precipitate was collected by filtration.

Yield 10.6g Yield 80% 3) Synthesis of 1- (β-naphthalenesulfonyl) hydantoin To 13.2 g (0.04 mol) of 1- (β-naphthalenesulfonyl) -2-thiohydantoin, 100 ml of 50% (v / v) nitric acid was added,
After heating for 90 minutes in a boiling water bath and cooling with ice, the precipitate formed was collected by filtration.

Yield 2.6g Yield 21% Melting point 215-220 ℃

Claims (5)

[Claims] 1. A hydantoin derivative represented by the following general formula (I) and salts thereof. 2. The compound according to claim 1, which is 1- (α-naphthalenesulfonyl) hydantoin and salts thereof. 3. The compound according to claim 1, which is 1- (β-naphthalenesulfonyl) hydantoin and salts thereof. 4. General formula (II): In the step of reacting naphthalenesulfonyl chloride represented by and glycine to produce naphthalenesulfonylglycine, reacting the obtained compound with ammonium thiocyanate to obtain a thiohydantoin derivative, and oxidizing the derivative. General formula (I): A method for producing a hydantoin derivative represented by. 5. General formula (I): A prophylactic / therapeutic agent for diabetic complications, which comprises a hydantoin derivative represented by the following formula or a salt thereof as an active ingredient.