JPH0748263A - Aldose reductase inhibitor - Google Patents

Abstract

PURPOSE:To obtain an aldose reductase inhibitor capable of preventing a complication of diabetes caused by accumulation of sorbitol or galactitol and useful for prophylaxis and/or treatment of retinopathy, cataract, nervous disorder and renal diseases by compounding a specific glucoside compound as an active component. CONSTITUTION:This inhibitor contains, as an active component, a glucoside compound expressed by formula I (formula II is cyclohexyl or 1-cyclohexenyl binding isopropyl or isopropenyl at 4-position or having cyclic bridge of dimethylmethano group between 4- and 1-positions; OR. is hydroxyl or group easily deriving hydroxyl). Further, the daily dose of the active component is preferably in the range of 1.0-10.0mg/kg in the case of oral administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aldose reductase inhibitor, and more particularly to an aldose reductase inhibitor containing a glucoside compound as an active ingredient, which is useful for treating various complications in diabetes. .

[0002]

2. Description of the Related Art Aldose reductase (hereinafter referred to as AR) is an enzyme that reduces aldoses such as glucose and galactose to polyols such as sorbitol and galactitol in a living body. It is the rate-limiting enzyme in the pathway. Sorbitol and galactitol produced by the action of this enzyme are accumulated in the lens, peripheral nerves, kidneys, etc. of diabetic patients and galactosemic patients, and as a result, diabetic complications such as retinopathy, cataract, neuropathy, and renal disease. It is known to cause disabilities. Therefore, by inhibiting the action of AR, it is possible to prevent or treat the onset of the above-mentioned diabetic complications.

In recent years, in order to prevent complications of diabetes due to the accumulation of sorbitol and galactitol, studies have been widely conducted to find compounds that inhibit the activity of aldose reductase from plants or microorganisms. For example, pentagalloyl glucose (Japanese Patent Laid-Open No. 63-104927) is already known to inhibit the activity of aldose reductase.

Therefore, the inventors have paid attention to the fact that glycosides and pseudo-oligosaccharides widely exist in the plant kingdom, and as a result of conducting a search for various plant components, a glucoside compound having a monoterpene contained in blue ginseng was found. It was found to have aldose reductase inhibitory activity. Furthermore, as a result of examining many compounds obtained by synthesis from known naturally occurring monoterpene alcohols, these monoterpenes, for example, menthol (Japanese Patent Publication No. 51-105) and terpineol (Japanese Patent Publication No. 58-183697). ) And borneol (Pharmaceutical magazine 103, 1133 (1983) Kaneda et al.) And the like as glucoside compounds having an aldose reductase inhibitory activity, and completed the present invention.

[0005]

According to the invention, the formula (I)

[0006]

[Chemical 3] (In the formula,

[0007]

[Chemical 4] Is a cyclohexyl or 1-cyclohexenyl group in which an isopropyl or isopropenyl group is bonded to the 4-position, or a dimethylmethano group is bridged cyclically between the 4-position and the 1-position, and OR ₁ is a hydroxyl group Alternatively, it represents a group which can be easily induced to a hydroxyl group. ) An aldose reductase inhibitor comprising a glucoside compound represented by (4) as an active ingredient is provided.

The glucoside compounds of the present invention are compounds derived from naturally occurring monoterpenes. As ring A in the compound (I) of the present invention, an isopropyl or isopropenyl group is bonded to the 4-position, or a dimethylmethano group is bridged cyclically between the 4-position and the 1-position. Examples include cyclohexyl or 1-cyclohexenyl substituted with a cyclohexyl or 1-cyclohexenyl group. Especially, as the ring A,

[0009]

[Chemical 5] Is preferred. Moreover, in the formula (I), a compound in which an O-glucoside is substituted at the 2-position or the 3-position is preferable.

In formula (I), the group which can be easily introduced into a hydroxyl group in OR ₁ is preferably a group which can be easily introduced into a hydroxyl group by hydrolysis in vivo, and examples thereof include a hydroxyl-protecting group. Examples of the hydroxyl-protecting group include those commonly used as a hydroxyl-protecting group in sugar chemistry, specifically, formyl, acetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, propyl, isopropyl, pivaloyl, benzoyl, p-nitrobenzoyl, p-phenylbenzoyl, ethoxycarbonyl, isobutyloxycarbonyl, benzyloxycarbonyl, p-nitrophenoxycarbonyl, 3-
Examples thereof include acyl type protecting groups such as benzoylpropionyl and benzoylformyl, and ether type protecting groups such as trimethylsilyl, dimethylethylsilyl, benzyl and p-methoxybenzyl. In addition, in the compound (I) of the present invention, each OR ₁ is not necessarily protected by the same protecting group, and may be protected by different protecting groups. However, it is preferable that all OR _1's are a hydroxyl group or an acetyl group.

The compound of the present invention is represented, for example, by the following formula:

[0012]

[Chemical 6] (In the formula, symbols have the same meanings as above.) In the presence of silver carbonate in the compound represented by the formula (II), the compound represented by the formula (III)
It can be produced by reacting the compound of Furthermore, by subjecting the compound of formula (I) to alkaline hydrolysis, a compound (formula (I ′)) in which all R _{1 s of} formula (I) are hydrogen atoms can be introduced.

The above reaction utilizes the Konig-Knol reaction and is usually carried out in an organic solvent (eg, ethyl ether, dioxane, etc.) at a temperature slightly elevated from room temperature. After the reaction, the organic solvent is removed, the residue is subjected to, for example, silica gel column chromatography, the eluent is concentrated, and the concentrate is recrystallized to obtain the desired crystal.

The glucoside compound obtained by the above method is, specifically,

[0015]

[Chemical 7] 1β-D-glucoside having 1-menthol, carveol, or borneol as an aglycone, or tetraacetate of 1β-D-glucoside shown in is preferable.

In the above synthetic method, β is obtained when a D-glucopyranose derivative is used as the compound of formula (III).
An isomer is obtained, the corresponding α-isomer, β
Mixtures of-and α-isomers are also included in the compounds of the present invention. In addition, as the menthol, n-menthol, iso-menthol, neo-menthol, and neoiso-menthol 1-form and d-form are also included in the compound of the present invention. However, the compound of formula (I) of the present invention is
-Isomer is preferred and l-menthol is preferred.

The compound (I) of the present invention (particularly a compound in which OR ₁ is a hydroxyl group) inhibits aldose reductase present in human and non-human eye lenses, and therefore, for example, retinopathy due to diabetes, renal disease and It is a useful compound for complications such as neuropathy. The compound of the present invention is also suitable for healthy people as a health food for preventing diabetic complications. That is, the compound of the present invention is useful as a drug, a food additive, a health food, a feed additive for animals, and the like. For applications other than pharmaceuticals, natural extracts may be used without being purified.

The compounds of the invention are preferably administered orally. The compounds of the present invention are pharmaceutically acceptable excipients,
Pharmaceutically acceptable carrier for pharmaceuticals, non-toxic carrier or other additives, for example, binder (corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose etc. pre-gelatinized), extender (lactose, microcrystalline cellulose, calcium phosphate etc.) ), Lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), fillers (lactose, sugars, corn starch,
Formulation into granules, tablets, capsules, etc. by a known method as a composition containing calcium phosphate, sorbitol, glycine, etc.), disintegrant (potato starch, etc.), or wetting agent (sodium lauryl sulfate, etc.) You can In the case of producing these granules, tablets, capsules and the like, after being formulated into granules, tablets, capsules and the like by a known method, as an enteric coating substance, for example,
It is preferable to apply an enteric coating by a known method using benzoin, cellulose derivatives such as cellulose acetate phthalate, phenyl salicylate, methyl methacrylate / methacrylic acid copolymer and the like. Also,
These preparations may be mixed with, for example, known sweeteners, preservatives, dispersants, coloring agents or flavoring agents, and components such as antioxidants, preservatives or thickeners.

The dose of the compound of the present invention may be appropriately adjusted depending on the condition, age and the like.
0.1-20 mg / kg / day, preferably 1.0-1
It is 0.0 mg / kg / day.

[0020]

【Example】

1. Synthesis of l-menthyl β-D-glucopyranoside Tetraacetobromoglucose (64.9 mmol) 26.
7 g and 10.1 g (64.7 mmol) of 1-menthol are dissolved in 140 ml of ether, 15.0 g of silver carbonate is added with stirring at room temperature, and the mixture is stirred at the same temperature for 24 hours. After the reaction, silver carbonate is removed by filtration, and then the solvent is removed under reduced pressure to obtain a crude reaction oil.

This crude reaction oil was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5 /
Subjected to 1), the components were collected using the confirmation of the spot (Rf value about 0.3) by thin layer chromatography as an index, and the solvent was distilled off under reduced pressure to give a colorless oil. This oily substance was recrystallized from ether-petroleum ether to obtain 14.5 g of colorless powder of 1-menthyl β-D-glucopyranoside tetraacetate.

This is dissolved in 50 ml of methanol and 10%
50 ml of an aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was neutralized with glacial acetic acid, methanol was removed under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was concentrated under reduced pressure to give a colorless oil. This oily substance was recrystallized from chloroform-ether to obtain 6.8 g of 1-menthyl β-D-glucopyranoside as colorless powder.

Also, instead of using l-menthol,
Several compounds were obtained by using carveol and borneol. 1-menthyl β-D
Together with glucopyranoside:

[0024]

[Chemical 8] The tetraacetate of the glucoside compound obtained as an intermediate of the above compound is shown below.

[0025]

[Chemical 9]

2. Measurement of aldose reductase activity Six-week-old Wistar rats were killed under ether anesthesia, and the lens was immediately removed, and the temperature was set to -20 ° C.
It was saved at. The lens was homogenized with 0.1 M phosphate buffer (pH 7.0) containing 0.01 mM phenylmethylsulfonyl fluoride and 5 mM dithiothreitol, and centrifuged at 40,000 rpm for 30 minutes. Add 20% polyethylene glycol 6000 to the supernatant and mix 3
After stirring for 0 minutes, the mixture was centrifuged at 15,000 rpm for 30 minutes.
The supernatant thus obtained was used as a crude enzyme solution of aldose reductase. All the above operations were performed at 4 ° C, and the crude enzyme solution was stored at -20 ° C.

The measurement of aldose reductase activity is Kado
r. et al. [Biophys. Chem. , 8, 81-
85 (1978)]. That is, 50m
M phosphate buffer (pH 7.0), 0.2 mM NADP
H (reduced Nicotinamide Adenine Dinucleotide Phosp
hate Reduced Form; β-NADPH), the crude enzyme solution described above, and the compound obtained in the above specific example are dissolved in pure water or ethanol to a concentration of 1 × 10 ⁻⁴ to 1 × 10 ⁻⁶ M, respectively. Add each drug solution at 30 ℃
Pre-incubated for 30 minutes. The reaction is 1
Starting with the addition of 00 μM methylglyoxal, the decrease in absorbance at 340 nm was followed at 37 ° C., the tan θ value at that time was calculated, and the inhibition rate was calculated by the following formula. Inhibition rate (%) = [(B−A) / B] × 100 where A: tan θ value when the inhibitor is added B: tan θ value when the inhibitor is not added The results are shown in Table 1. As described above, the inhibitory activity was observed at the concentration of 1 × 10 ⁻⁴ M.

[0028]

[Table 1]

5. Formulation Example 10 parts by weight of l-menthyl β-D-glucopyranoside, 421.0 parts by weight of lactose and 50 parts by weight of potato starch were mixed well, and this was put in a fluidized bed granulator and the binder hydroxypropyl cellulose 18.75. 5 parts by weight of an aqueous solution was sprayed to obtain granules. Then, 20 parts by weight of disintegrant carboxymethyl cellulose calcium and 15 parts by weight of lubricant magnesium stearate were added and mixed. The obtained mixture was pressure-molded so that the weight of one tablet was 125 mg to obtain tablets. An enteric coated tablet was obtained by spraying a coating liquid having the following formulation on the tablet. Cellulose acetate phthalate 5.0 parts by weight 95% ethanol 47.5 parts by weight Acetic acid ethyl ester 47.5 parts by weight

[0030]

INDUSTRIAL APPLICABILITY The compound of the present invention can prevent or treat complications of diabetes due to the accumulation of sorbitol or galactitol, such as retinopathy, cataract, neuropathy and renal disorder.

Front page continuation (72) Inventor Hiroshi Tsuda 1-4-10 Wakihama-cho, Chuo-ku, Kobe City Japan Terpen Chemicals Co., Ltd.

Claims (1)

[Claims] 1. Formula (I): (In the formula, Is a cyclohexyl or 1-cyclohexenyl group in which an isopropyl or isopropenyl group is bonded to the 4-position, or a dimethylmethano group is bridged cyclically between the 4-position and the 1-position, and OR ₁ is a hydroxyl group Alternatively, it represents a group which can be easily induced to a hydroxyl group. ) An aldose reductase inhibitor comprising a glucoside compound represented by the formula (1) as an active ingredient.