JPH0153646B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an inhibitor of aldose reductase (hereinafter abbreviated as AR) containing a hydantoin derivative as an active ingredient. Diabetic complications such as cataracts, retinopathy, and kidney disease are caused by the unnecessary and harmful accumulation of corresponding polyols converted from sugars by AR. For example, sugar cataracts occur when the AR present in the lens of the eye converts glucose, galactose, etc. into the corresponding sugar alcohol, and this converted sugar alcohol accumulates in the lens unnecessarily and harmfully, causing the lens to become cloudy. Occurs by doing. Therefore, in order to effectively prevent, alleviate, or treat the above complications, it is necessary to address the direct cause of the complications.
It is important to inhibit AR enzymatic activity as strongly as possible. Conventionally, many compounds such as arrestatin and sorbinil have been provided as active ingredients for AR enzyme activity inhibitors, but the reality is that their ability to inhibit AR activity is still not fully satisfied. The present inventors conducted intensive research using rat lens AR and bovine lens AR in order to obtain a product with a stronger ability to inhibit AR activity, and as a result, among the dozens of hydantoin derivatives included in the research subjects, 1-(phenylsulfonyl)hydantoin and CH ₃ , Br, Cl, CH ₃ O or NO ₂ in the ortho, meta or para position of the phenyl group of this compound
Mono-substituted products and their salts are extremely potent
They discovered that it has the ability to inhibit AR activity, leading to the completion of the present invention. That is, the present invention relates to an inhibitor containing as an active ingredient a hydantoin derivative having extremely strong ability to inhibit AR activity, which can be used for effective prevention of diabetic complications, and wherein the hydantoin derivative is a compound represented by the following general formula or It consists of its salts. (However, in the formula, R is H, CH ₃ , Br, Cl, CH ₃ O or
When R is _H , the compound represented by the above general formula basically contains 1-(phenylsulfonyl)hydantoin (hereinafter abbreviated as PSH), Mono- _substituted products _{( hereinafter} referred to as
For example, those in which CH ₃ is substituted at the ortho position are o-CH ₃
--abbreviated as PSH). In completing the present invention, the present inventors obtained dozens of hydantoin derivatives through chemical synthesis, all of which contain the same basic skeleton of hydantoin, but their ability to inhibit AR activity is limited. There were large differences depending on the type and number of bonding groups and the bonding position. The compound represented by the above general formula or its salt has the strongest ability to inhibit AR activity among them. For example, as will be described in detail later, PSH, p-CH ₃ -PSH, p-Br-PSH, p-Cl-
PSH, p-CH ₃ O-PSH and p-NO ₂ -PSH are
At a compound concentration (molar concentration, hereinafter abbreviated as M) that gives a 50% inhibition rate (hereinafter abbreviated as IC50) of enzyme activity, 1.06 × 10 ^-6 M and 1.00 × 10 ^-6M , 0.70×
^10-6 M, 0.92× ^10-6 M, 1.70× ^10-6 M, 1.12×
10 ^-6 M and 1.72× each for bovine lens AR.
^10-6 M, 0.88× ^10-6 M, 0.37× ^10-6 M, 0.86×
10 ⁻⁶ M, 1.48×10 ⁻⁶ M, and 1.00×10 ⁻⁶ M, all of which have strong ability to inhibit AR activity. PSH, which is the active ingredient of the inhibitor according to the present invention,
The synthesis method of the CH ₃ , Br, Cl, CH ₃ O or NO ₂ monosubstituted product at the ortho, meta or para position on the phenyl group of PSH is summarized as follows. PSH can be obtained by reacting phenylsulfonyl chloride and glycine to synthesize N-(phenylsulfonyl)glycine, then using rhodanammonium to form a thiohydantoin derivative, and further adding nitric acid for oxidation. p-CH ₃ -PSH is produced by reacting p-methylphenylsulfonyl chloride with glycine to form N-
It can be obtained by synthesizing [(p-methylphenyl)sulfonyl]glycine, then converting it into a thiohydantoin derivative using rhodanammonium, and then oxidizing it by adding nitric acid. In the following, each monosubstituted product described above can be obtained according to the synthesis method of p-CH ₃ -PSH. In addition, salts of these compounds such as Na and K can be easily obtained by conventional methods. Hydantoin derivatives consisting of the compound represented by the above general formula or salts thereof have a strong ability to inhibit AR activity, and the inhibitor according to the present invention containing this as an active ingredient is valuable for effectively preventing the above diabetic complications. expensive. Specifically, the hydantoin derivatives may be prepared using suitable carriers or vehicles used in the general formula, such as sterile water, vegetable oil, and non-toxic organic solvents, as necessary, as well as excipients, binders, lubricants, and coloring agents. , flavoring agents, emulsifiers, suspending agents, etc., in the form of tablets, powders, syrups, injection solutions, or ophthalmic solutions, and can be administered to patients either orally or parenterally. administered. As a general guideline, the dosage should be 100 mg or less of the hydantoin derivative per 1 kg of patient's body weight per day, but the appropriate amount is determined by the doctor depending on the patient's condition. Next, Tables 1 and 2 show the specific effects of the AR activity inhibiting ability of representative examples of hydantoin derivatives that are the active ingredients of the inhibitors according to the present invention. Table 1 shows three levels of compound concentration (M)
Table 2 shows the enzyme activity inhibition rate (%) of AR.
The concentration of the compound giving the IC50 (value in the table x 10 ^-6 M) is shown. In the table, Example 1 is PSH, and Example 2 is PSH.
-CH ₃ -PSH, 3 is p-Br-PSH, 4 is p
-Cl-PSH, 5 is p-CH ₃ O-PSH, 6 is o-NO ₂ -PSH, 7 is m-NO ₂ -PSH, 8 is
is p-NO ₂ -PSH, and Comparative Example 1 is hydantoin itself represented by the following chemical structural formula (1),
are other hydantoin derivatives represented by the following chemical structural formula (2), which were selected as research subjects of the present invention from among dozens of compounds obtained by chemical synthesis as having relatively similar chemical structures to PSH, Furthermore
RLAR is rat lens AR, BLAR is bovine lens.
It is AR. In addition, in each example in the table, Example 1
Except for PSH and the NO ₂ substituted products of Examples 6 to 8,
For each of the substituents in Examples 2 to 5, only those at the para position are representatively exemplified, but these substituents at the ortho or meta position are also applicable to the three types shown.
As with the NO ₂ substitutions, each has approximately the same inhibition rate of AR activity as the corresponding substitution at the para position. These AR activity inhibition rates (%) were obtained according to the method of Heyman et al. (Journal of Biological Chemistry, 240, 877,
(1965).

【table】

[Table] was zero or low, so analysis was omitted)

[Table] From the results in Tables 1 and 2, it is clear that the hydantoin derivative represented by the above general formula, which is the active ingredient of the inhibitor according to the present invention, has an extremely strong ability to inhibit AR activity. . Experimental Example The acute toxicity of the hydantoin derivatives of the present invention was investigated. 5 ICR male mice per group or
Compounds Nos. 1, 2, and 3 of the present invention were orally administered at 1 g/Kg each to ddY male mice, and observations were made up to 7 days later, and no deaths were observed.

【table】

【table】

Claims (1)

[Scope of Claims] 1. An aldose reductase inhibitor containing a hydantoin derivative consisting of a compound represented by the following general formula or a salt thereof as an active ingredient. (However, in the formula, R is H, CH ₃ , Br, Cl, CH ₃ O or
NO ₂ )