JP2876129B2 - 7-carboxymethoxy-4-phenylcoumarin derivatives and their preparation and use - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel 7-carboxymethoxy-4-phenylcoumarin derivative which is useful as a pharmaceutical.

[Conventional technology]

With the westernization of dietary habits, the number of diabetic patients has increased sharply in recent years, and treatment for them is urgently needed. Conventionally, insulin and hypoglycemic agents have been widely used as antidiabetic drugs, but since diabetes is a disease accompanied by various complications as well as a mere metabolic abnormality of metabolism, the above drugs alone are not sufficient. .

As a cause of various complications in diabetes such as retinopathy, cataract, neuropathy, and nephropathy, an enzyme that catalyzes the conversion between aldose-polyol, which is the first stage of the polyol pathway, which is the glucose metabolic pathway It is called aldose reductase and this enzyme is considered the rate-limiting step in the polyol pathway. By inhibiting this aldose reductase and reducing the production and accumulation of sorbitol, it is possible to prevent or treat diabetic complications as described above [RG Judylmish et al .: New England Journal of Medicine (New Eng. J. Med.), 308, 119-125 (198
3): JH Kinoshita, etc .: Metabolism, 28
Volume (1), pp. 462-469 (1979)].

[Problems to be solved by the invention]

The present inventors have conducted studies on the aldose reductase inhibitory activity of various compounds, and as a result, have found that a specific 7-carboxymethoxy-4-phenylcoumarin derivative is effective as an aldose reductase inhibitor. Reached.

(Means for Solving the Problems) The present invention provides a compound of the formula (I) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′
Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a di-lower alkylamino group, or a perfluoro-lower alkyl group), and contains the derivative as an active ingredient. Aldose reductase inhibitor and can be produced as follows.

Smooth expression (II) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′
Represents the same meaning as in the above formula (I).) 7-hydroxy-4-phenylcoumarin derivative represented by the following formula: In this specification, the term "lower" means that the group to which this term is attached has 6 or less, preferably 4 or less carbon atoms.

The compound of the formula (II) as a raw material of the compound of the present invention may exist as a natural component. For example, 7-hydroxy-4
-Phenylcoumarin is Bacillus typus
hosus) and Staphylococus aureus (Staphylococus)
aureus). Further, it can be synthesized from a substituted benzoyl acetate and a substituted resorudin by a Pechmann Condensation Reaction (for example, Mukerjee, et.al., Indian. JC
hem., 7,671. (1969)).

Synthesis of the compound of the formula (I) by etherifying the compound of the formula (II) with glycolic acid is carried out in a usual manner.
For example, reaction with potassium carbonate and ethyl bromoacetate in acetone gives an ester of the compound of formula (I).

The resulting ester of the compound of formula (I) is hydrolyzed with basicity and adjusted to around PH4 with a mineral acid to give a free acid, that is, the compound of formula (I), which is adjusted to around PH9 with an inorganic base. As a result, an inorganic salt of the compound of the formula (I) is obtained.

All of these can be isolated by a known method, for example, concentration to dryness or other methods, and purified by recrystallization or the like. The mineral acids used here include hydrochloric acid, sulfuric acid, phosphoric acid and the like, and the inorganic bases include alkali hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and ammonium hydroxide, sodium (bi) carbonate, ( Bi) potassium carbonate,
There are (bi) alkali carbonates such as (bi) ammonium carbonate.

The compounds of formula (I) are fairly stable in either acidic or alkaline solutions.

The aldose reductase inhibitor containing the compound represented by the formula (I) as an active ingredient can be used in the form of tablets, capsules, injections, powders, pills, granules, suppositories, and the like, using a commonly used carrier according to a conventional method. It may be used in eye drops and the like.

Next, the compound of the present invention, its production method and aldose reduction inhibitory action will be described in detail with reference to examples, but the present invention is not limited to the following examples. Note that the melting points of the products in each of the examples are uncorrected.

Reference example Production of compound of formula (II): Pechmann condensation Substituted resorudine and an equimolar amount of substituted benzoyl acetate are dissolved in ethanol, and hydrogen chloride gas is saturated under ice-cooling. After left overnight at room temperature, the precipitate flows into ice water, and the precipitated precipitate is collected and washed with water. After drying, it is recrystallized with a solvent.

Table 1 shows the physical property values of the compound of formula (II) thus obtained.

Examples Production of compound of formula (I) 6-ethyl-7-hydroxy-4- (3-isopropyloxyphenyl) coumarin [Table 1 (II-42)] 4.
7 g (0.0145 mol), 2.6 g (0.0145 mol) of ethyl bromoacetate, 0.2 g of potassium iodide and 2.0 g of anhydrous potassium carbonate are added to 200 ml of acetone, and the mixture is heated under reflux with stirring for 4 hours. After cooling, the insolubles are separated, and the residue obtained by evaporating the solvent is dissolved in ether. This ether solution is water, 5%
Wash with NaOH aqueous solution and water in this order, and dry the ether layer with anhydrous sodium sulfate. The solvent is distilled off and the residue obtained is treated on a silica gel column. 4.5 g of ethyl 6-ethyl-4- (3-isopropyloxyphenyl) coumarin-7-yloxyacetate is obtained by chloroform fractionation.

4.5 g of the above ester is added to 60 ml of ethanol and 5% NaOH aqueous solution
Add to 20 ml of the mixture and heat to reflux for 30 minutes. After cooling, the insolubles are separated and the solution is acidified with hydrochloric acid. The precipitated precipitate was recrystallized from acetone-benzene to give 6-ethyl-4-.
4.0 g of (3-isopropyloxyphenyl) coumarin-7-yloxyacetic acid [Table 2 (I-42)] is obtained.

Further, a compound of the formula (I) shown in Table 2 was obtained from the compound of the formula (II) shown in Table 1 in the same manner as described above. Their physical properties and aldose reductase inhibitory activity are also shown in Table 2.

Aldose reductase inhibitory action A 7-week-old male Wistar strain rat was sacrificed under ether anesthesia, and the lens was immediately removed. Lens
1.0 mM 2-mercaptoethanol and 1.0 mM NADP (oxidized form
100 mM sodium-potassium-phosphate buffer containing nicotinamide adenine dinucleotide phosphate (pH6.8)
Was homogenized. Then, the mixture was centrifuged at 12,000 rpm for 15 minutes, and the supernatant was used as a sample for measuring aldose reductase activity. All the above procedures were performed at 4 ° C and the sample was -80.
Stored at ° C.

Aldose reductase activity is measured by KADOA
The method was carried out according to the method described above (see Biophysical Chemistry 8 (1978) 81-85). That is, 0.1 mM NADP as coenzyme
H (reduced nicotinamide adenine dinucleotide phosph
ate) and 100 mM sodium-potassium-phosphate buffer containing 2.0 mM DL-glyceraldehyde as substrate (pH 6.
2) To 970 μl, 10 μl of various concentrations of the compound of the present invention was added, and then 20 μl of the above-mentioned sample was added, and the reaction was carried out at 25 ° C. Using a control lacking only the substrate, the decrease in absorbance at 340 nm was measured for 200 seconds. In addition, instead of adding the sample solution, only the solvent was added, and the reaction was performed in the same manner as described above. The absorbance was measured using UV-260 (manufactured by Shimadzu Corporation). As a result, the inhibitory activity against aldose reductase was 1 × 10 ⁻⁸ (M), as shown in Table 2, and the inhibitory activity (IC ₅₀ ) was observed.

Acute toxicity Acute toxicity test by oral administration of the compound of formula (I) obtained in each of the above examples was performed using ddv mice (body weight: 23 to 25 g). I couldn't.

〔The invention's effect〕

As is clear from the above results, the 7-carboxymethoxy-4-phenylcoumarin derivative of the present invention has an aldose reductase inhibitory effect and is useful as a highly safe therapeutic drug for diabetes.

Continued on the front page (72) Inventor Megumi Terashima 92 Kamitomi, Toyama City, Toyama Prefecture (72) Inventor Akio Suzui 2-42-302, Miyauchicho, Amagasaki City, Hyogo Prefecture (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 311/00-311/74 REGISTRY (STN) CA (STN)

Claims (3)

(57) [Claims] (1) Formula (I) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′
Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a di-lower alkylamino group, or a perfluoro-lower alkyl group). 2. Formula (II) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′
Represents the same meaning as in the above formula (I). 7-carboxymethoxy-4 represented by the above formula (I), wherein a 7-hydroxy-4-phenylcoumarin derivative represented by the following formula is etherified with glycolic acid. -Preparation of phenylcoumarin derivatives. 3. An aldose reductase inhibitor comprising a 7-carboxymethoxy-4-phenylcoumarin derivative represented by the above formula (I) as an active ingredient.