JPS6267075A - Hydantoin derivative and aldose-reductase inhibitor containing said compound as active ingredient - Google Patents

Abstract

NEW MATERIAL:A hydantoin derivative expressed by formula I (R represents H or Cl) or salts thereof. EXAMPLE:1-(2,5-Dichlorophenylsulfonyl) hydantoin. USE:A strong aldose-reductase inhibitor, useful as an inhibitor against diabetic complications (for example, cataract, neuropathy, retinopathy and nephrosis), with low toxicity and usable by oral administration. PREPARATION:A substituted-phenylsulfonyl chloride expressed by formula II is reacted with glycine to obtain N-(substituted-phnylsulfonyl) glycine. Thus obtained compound is reacted with ammonium thiocyanate to form a thiohydantoin derivative. The derivative is further oxidized to obtain the compound expressed by formula I.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention relates to hydantoin derivatives represented by the general formula (I): (wherein R represents 1 or C1), salts thereof, and their active ingredients. The present invention relates to an inhibitor of aldose reductase (hereinafter abbreviated as AR).

Prior art> Diabetic complications such as cataracts, peripheral neuropathy, retinopathy, and nephropathy are caused by the unnecessary accumulation of corresponding polyols converted from carbohydrates by AR. Cataracts occur when AR in the crystalline lens of the eye converts gluten, lactose, etc. into the corresponding sugar alcohol.
This occurs because the converted sugar alcohol is unnecessarily deposited in the crystalline lens, changing the osmotic pressure, which damages the crystalline lens. Therefore, in order to effectively prevent, alleviate, or treat complications listed n;j, it is necessary to
It is important to inhibit the activity of R as strongly as possible.

<Problems to be Solved by the Invention> A large number of compounds such as arrestatin and turvinyl have been provided as AR activity inhibitors, but the reality is that their ability to inhibit AR activity is still not fully satisfied. However, there has been a desire for a compound that has an even stronger ability to inhibit AR activity.

Means for Solving Problems〉 The present inventors have previously discovered that mo/r11-substituted phenylsulfonylhydantoin derivatives have a strong ability to inhibit AR activity, and have developed a full-dose drug containing this compound as an active ingredient. Completed the invention of tase inhibitor (Patent application 1982-2135)
18).

In order to obtain a compound with even stronger ability to inhibit ΔR activity, the present inventors conducted an in vitro study using rat crystalline lenses.
In addition, as a result of intensive research on the effects of various compounds in v:vo by oral administration to streptocytosine diabetic rats, we found that among the dozens of compounds included in the research, hydantoin derivatives represented by general formula (I) and these The present inventors have discovered that salts of this compound have an extremely strong ability to inhibit ΔR activity, and have completed the present invention.

The present invention relates to a hydantoin derivative represented by the general formula (in which R represents H or CI), a salt thereof, a method for producing the same, and a compound containing these compounds as an active ingredient. The hydantoin derivatives and salts thereof of the present invention, which inhibit AR activity, have a strong ability to inhibit AR activity, and can be used to effectively prevent diabetic complications.

The hydantoin derivative of the present invention can be produced as follows. General formula (■): (However, in the formula, R is I]
or CI) is reacted with glycine to synthesize N-(iFi-substituted phenylsulfonyl)glycine, and then ammonium thiocyanate is used to synthesize a thiohydantoin conductor, and further, for example, By oxidizing with nitric acid, a hydantoin conductor represented by general formula (I) can be produced.

As the salts, for example, sodium salts, potassium salts, ammonium salts, magnesium salts and the like are useful and can be easily obtained by conventional methods.

In completing the present invention, the present inventors synthesized dozens of hydantoin derivatives having the basic skeleton of hydantoin. There were large differences depending on the bonding position. The hydantoin derivatives represented by the general formula (I) and their salts have the strongest ability to inhibit °R activity among these compounds.

Next, the ability of the hydantoin derivatives of the present invention to inhibit AR activity will be demonstrated through experimental examples.

Experimental Example 1 Hayman et al.'s method [S, Hayman and J, H
KinosbiLa, J., Biol, Chem,, 2
4 0 , 0.4 according to 8 7 7 (I965) 1
M ammonium sulfate, 10+MDL-glyceraldehyde, 0.16 MNΔDPH and 0.010-0.0
0.1 M phosphoric acid tl street solution containing 1 Gu AR (pt1
6.2) Add a 10 μm hydantoin derivative solution to 0.1 ml, and check the decrease in absorbance at 3400 μm with Gill 7
Measured with an Ord Model 250 Spectro 7r) meter.

The AR used in this experiment was based on the method of Cador et al. [P
, F., Kador and N.E., 5barpl.
esS+Biophys, Chew, 8. 81(
After extraction from rat lens by I978, the method of Inagaki et al. [K.

InaHaki et al, Arch+Bio
chem, Biophys, +216.337 (I
982)] was used.

The results are shown in the 1tSi table.

Table 1 Experimental Example 2 Effect on diabetic rats body weight 230-250. Diabetic rats were prepared by intraperitoneally injecting streptocytosine into male Wistar rats at a rate of Song/kg.

Hydantoin derivative of the present invention or comparative compound 50 mg/k11/day on the day of streptocytosine administration
was orally administered, and on the 16th day, the rats were sacrificed, the crystalline lens and sciatic nerve were removed, and the method of donation (Chemical &
The amount of sorbitol was determined by squamography according to the journal Harwaceutical Bulletine+, 1985).

As controls, normal rats (non-diabetic rats) and diabetic rats to which no hydantoin derivatives were administered (control rats) were used as controls.
−r) was used.

The results are shown in table ff12.

Table 2 Experimental Example 3 Acute toxicity of the hydantoin derivatives of the present invention was investigated. 500 to 600 mg/kg of the compound of the present invention was orally administered to 10 ICR male mice per group and observed for 1 week, but no abnormalities were observed.

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

The hydantoin derivatives of the present invention can be prepared using commonly used suitable carriers or media such as sterile water, oils and fats, as well as non-toxic organic solvents, excipients, binders, lubricants, colorants, etc.
It can be used as an AR activity inhibitor in the form of tablets, powders, syrups, injections, eye drops, suppositories, plasters, inhalants, etc. by appropriately selecting and combining masturbating agents, emulsifying agents, suspending agents, etc. , administered to patients either orally or parenterally. As a tentative guideline, the dosage of the compound of the present invention is less than the amount of the hydantoin derivative per 1 kg of the patient's body weight per day, but it can be increased or decreased depending on the patient's condition. The manufacturing method will be specifically illustrated using a demon example.

Example 1 1) For the synthesis of 2.5-dichlorophenylsulfoylglycine, 17 g (0,12+ol) of anhydrous potassium carbonate was mixed with 5 ml of purified water.
011 and glycine 9.311 (0,12-of
) was added and dissolved. To this, 25 g (0.10 wol) of 2,5-dichlorophenylsulfonyl chloride was added, and after heating at 40 to 50°C for 10 minutes, the mixture was further heated in a boiling water bath for 1 hour. After cooling, add 2N hydrochloric acid to make it acidic (pH 2).
~3), and the resulting precipitate was collected by filtration.

Collection i 28.1. Yield 97.0%2) 1
Synthesis of -(2,5-dichlorophenylsulfonyl)-2-thiohydantoin 2.5-dichlorophenylsulfonylglydine 11.5
g (0.04 mol), anhydrous birinone 3.31, dry ammonium thiocyanate 6.1. (0,081mo
After adding 8.2 ml of acetic anhydride and 8.2 ml of acetic anhydride, the mixture was heated in a boiling water bath for 30 minutes with stirring. After cooling, purified water of No. 801 was added and cooled, and the resulting precipitate was collected by filtration.

Yield: 7.4 g Yield: 56.3%3) 1-
Synthesis of (2,5-dichlorophenylsulfonyl)hydantoin 1-(2,5-dichlorophenylsulfonyl)-2-thiohydantoin 13.3g (0,041-01) 1 piece 5
Add 100 ml of 0% (v/v) nitric acid and boil for 9 hours in a boiling water bath.
After heating for 0 minutes and cooling with water, the resulting precipitate was collected by filtration.

Yield jfl 5.1g Yield 40.2% Melting point 22
G-230℃ Example 2゜1) 2,4.5-)'J dichlorophenylsulfonyl glycine synthesis 1+; 1 5.9 g (0.04 mol) of anhydrous potassium carbonate was dissolved in 30 tsuru of purified water, 30 g of glycine .5g (0,04II
lol) was added and dissolved. To this, 2,4.5-)
Lichlorophenylsulfonylchlora 4 F 10g (0
, 036 mol) was added and heated at 60-70°C for 10 minutes, and then further heated in a boiling water bath for 40 minutes. After cooling, 2N hydrochloric acid was added to make it acidic (pH 2 to 3), and the resulting precipitate was collected by filtration.

Yield [11g Yield 95.9% 2) Synthesis of 1-(2,4,5-)dichlorophenylsulfonyl)-2-thiohydantoin 214.5-Trichlorophenylsulfonylglycine 6.3g (0,02
After adding 2.51 mol of birinone anhydride, 3.08 (0.04 mol) of dry ammonium thiocyanate and 4 ml of acetic anhydride, the mixture was heated in a boiling water bath with stirring for 30 min.
Heated for minutes. After cooling, purified water of No. 601 was added and cooled, and the resulting precipitate was collected by filtration.

Yield 3.5g Yield 48.6% 3) Synthesis of 1-(2,4,5-)lichlorophenylsulfonyl)hydantoin 1-(2,4,5-)lichlorophenylsulfonyl)-
2-Thiohydantoin 15. Add 50% (V/V) nitric acid 1,001 to
After heating for 0 minutes and cooling with water, the resulting precipitate was collected by filtration.

Yield: 1.7g Yield: 12.4% Melting heat 232-235℃ Patent applicant Mochiu1 Pharmaceutical Co., Ltd. (1 person) Mi...

Claims (1)

[Claims] 1. Hydantoin derivatives and salts thereof represented by the following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (I) (However, R in the formula represents H or Cl) 2 , general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (However, in the formula, R represents H or Cl) A substituted phenylsulfonyl chloride represented by the formula (R represents H or Cl) is reacted with glycine to form N-( Method 3 for producing hydantoin derivatives, which comprises a step of producing substituted phenylsulfonyl)glycine, a step of reacting the obtained compound with ammonium thiocyanate to obtain a thiohydantoin derivative, and a step of oxidizing the derivative. ): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) An aldose reductase inhibitor whose active ingredient is a hydantoin derivative or its salts represented by (in the formula, R represents H or Cl)