JPH02304080A - 6h-dibenzo(b,d)pyran-6-one derivative, its production and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 to R8 are H, Cl, lower alkyl, lower alkoxy, formula II or formula III (M is H, alkali metal or ammonium) and at least one among R1 to R8 is formula II or formula III]. EXAMPLE:6H-Dibenzo[b,d]pyran-6-one-3-sulfuric acid ester potassium salt. USE:An aldose reducing enzyme inhibitor capable of preventing and treating complication of diabetes mellitus. PREPARATION:A hydroxy-6H-dibenzo[b,d]pyran-6-one derivative expressed by formula IV (X1 to X8 are H, Cl, lower alkyl, lower alkoxy or OH and at least one among X1 to X8 is OH) is subjected to sulfur esterification or glycolic acid etherification, or a substance subjected to the abovementioned esterification or etherification is reacted with a substance capable of producing alkali metal ion or ammonium ion.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides a novel 61I-dibenzo[
b, d] relating to pyran-6-one derivatives. .

[Conventional technology]

With the westernization of dietary habits, the number of people who think they have diabetes has increased dramatically in recent years, and there is an urgent need for treatment. Insulin and hypoglycemic agents have traditionally been widely used as antidiabetic drugs, but since diabetes is not just a simple abnormality of glucose metabolism41 but also a disease accompanied by various symptoms (Jf syndrome), these drugs alone are not sufficient. It is enough.

Accumulation of intracellular sorbyl through the polyol pathway, which is the metabolic pathway for glucose, is the cause of various complications in diabetes such as retinopathy, cataracts, neuropathy, and nephropathy. The enzyme that catalyzes the conversion between aldose and polystyrene, which is the first step in this polyol pathway, is called aldose reductase, and this enzyme is considered to be the rate-limiting enzyme in the polyol pathway. Aldose reductase■
By reducing the production and accumulation of sorbyl 1--3, it is possible to prevent and treat minor diabetic complications (R, G, 1-Dilmitsch, et al.: Niko England, 1-D-V- Null of Medicine (NeWEng,
JJled, ), 3081. 119-125
Page (1983): J, 11. Kinoshita et al.: Metabolism, Volume 28 (1)
, pp. 462-469 (1979)).

[Problems that the invention seeks to solve]

The present inventors conducted research on the aldose reductase inhibitory effect of various compounds, and found that a specific 611
The inventors have discovered that -dibenzo[b, a former pyran-6-one derivative, is effective as an aldose reduction inhibitor and have arrived at the present invention.

[Means to solve the problem]

The present invention specifically relates to the formula (I) (wherein R1, R2, R3, R4, R5゜R6, R
7, Re is a hydrogen atom, a chlorine atom, a lower alkyl group, a lower alkoxy group, or a formula (Ha, IIb) -O303M (IIa)-〇Cl-12
C02M (II b > (wherein, M is a hydrogen atom, an alkali metal atom, or an ammonia group)
611-dibenzo[b, dipyran-6-Δ
Derivatives of carbon dioxide, their production methods and uses. The compound of formula (Y) 1F is a new compound and can be produced as follows. J Nawara style (■).

(However, in the formula X1.X2.X3.X4.X5゜X8.X
7. X8 is a hydrogen atom, a chlorine atom, a lower alkyl group, a lower alkoxy group, or a hydroxy group, and x1 to x
At least one of 8 is a hydroxyl group) The hydroxy-6■-dibenzo[b,dl pyran-6-one derivative represented by It is obtained by the action of alkali metal ions or ammonium ions on a substance that has been converted or etherified. In this specification, the term "lower" means that the group to which this prefix is attached has 6 or less carbon atoms, preferably 4 or less.

The compound of formula (In), which is a raw material for the compound of the present invention, may exist as a natural component. For example, 3,4°8,9.
10-Pentahydroxydibenzo[b,(l]pyran-
6-one, Urolithin A and B (Urolithin
A, B), Autumn nari
ol>.

Autumn nariniol
), alterinariol (^1terinariol)
), Fleur r Nuisol (^1tenuisol)
, Noashiculifer
ol) etc. Also Bar 1-Ray (Hurtley)
) It can also be synthesized from (substituted)-2-pro7benzoic acid and polyhydroxybenzene such as resorcinol, 2-methylresorcinol, 4-chlorresorcinol, orcinol or 70loglucin by a condensation reaction (for example, F
arkaS,et,al,.

Chem, Ber, 1974. Lice 3874-77
>, and a synthetic method by cyclization of benzoquinone carboxylic acid methyl ester and resorcinol monomethyl ether is also known (for example, P. Muel Ier, et.
at, , tlelv, Chim, Acta.

1979J lines 2833-40).

For sulfuric acid Nisderization of compounds of formula (III), conventional sulfating reagents are used, such as sulfonic acid, sulfuryl chloride, sulfur trioxide 1-rimedylamine complex.

Sulfamic acid, alkali pyrosulfate, etc. are used.

In order for the sulfuric acid esterification to proceed smoothly, the presence of a tertiary amine such as pyridine, dimethylaniline, or triethylamine is preferred.

Glycolic acid etherification is carried out in a conventional manner. For example, after reacting with an alkali and monohalogenoacetate, hydrolysis is performed.

By adjusting a sulfuric acid ester or a glycolic acid ether to a pH of around 5 with a mineral acid, each becomes a free acid, and by adjusting this to around ptta with an inorganic salt i, each becomes an inorganic salt base. All of these can be isolated by known methods such as concentration to dryness or other methods, and can be made into a single product by recrystallization or the like. The mineral acids used here include hydrochloric acid and sulfuric acid.

Examples include phosphoric acid, and inorganic bases include sodium hydroxide,
Alkaline hydroxides such as potassium hydroxide, lithium hydroxide, ammonium hydroxide, (heavy) sodium carbonate, (heavy)
There are alkali (heavy) carbonates such as potassium carbonate and ammonium (heavy) carbonate.

Among the compounds (I), sulfuric acid esters are susceptible to hydrolysis in neutral, especially acidic solutions, but are quite stable in alkaline solutions. Glycolic acid ethers are also quite stable in either acidic or alkaline solutions. These salts are generally water-soluble and also have a property of being considerably soluble in methanol.

The present invention also includes pharmaceuticals containing the compound represented by formula (I). Such medicines are prepared into tablets using conventional carriers and according to conventional methods.

Capsules, injections, powders, gunpowder, granules, and suppositories.

It may also be used as an i-drop.

Examples of the compound represented by formula (I>) and its starting material, the compound represented by formula (II), according to the present invention are as follows.

In addition, in Tables 1 and 2, the methyl group can be substituted with an ethyl group, a propyl group, a butyl group, etc.

Next, the compound of the present invention, its production method, and aldose reductase inhibitory effect will be explained in detail with reference to Examples, but the present invention is not limited to the following Examples.

Example (Production of Compound (III)... HLIrtley method) (Substituted) -2-proheptazonzoic acid 0.05 mol, resorcinol, 2-methylresorcinol, 4-chlorresorcinol,
0.1 mol of orcinol or phloroglycin, and N-
A mixture of 110 mff of NaOH was stirred and heated to dissolve,
After adding 5d of %Cu5Oa solution and refluxing for 1 to 5 hours,
Add ml of N-HC and reflux gently for 30 minutes. The cold precipitate was collected and sequentially added to water, 1% NaHCO3 solution,
Wash with water, recrystallize with ethanol or DMF and see Table 1A.
-K compound was obtained.

(Production of compound (I)) Example 1 (Table 2 "NO") Chlorsulfone under stirring with water cooling!122.330 (0,0
2 mol) into anhydrous pyridine 407 and after adding 3-hydroxy-68-dibenzo[b,dl pyran-6-one (Table 1 A >2.12(]' (o, 01 mol) , Stir and heat under reflux for 3 hours.The reaction solution is reduced to 1 m
Then add a small amount of ethyl alcohol and cool. After collecting the precipitate, dissolve the fruit in water and add N-KOI-1 to p118.
After adjusting the temperature, concentrate under reduced pressure at 45°C or lower. Water the residue
Recrystallized from ethyl alcohol to produce white crystals □ 611-
1.95 q of dibenzo[b,dl pyran-6-one=3-sulfuric acid-styrene potassium salt was obtained (Table 2, No. 1).

MP 284-286℃'□ IRνCo: 1740cm-1 RMR (DMSO-do >'7.20
<IH,ad> 7.30 (IH, d) 7.50~8.20 (3+7m') '8.40
(2nd day, dd) Example 2 (Table 2 No. 1) In place of the chlorosulfonic acid used in Example 1, 1.94 g (0.02 mol) of powdered sulfamic acid was added, and the mixture was stirred and heated under reflux for 3 hours. Thereafter, it was treated in the same manner as in Example 1, yielding a white crystal of 1.48 oJ. MP' and I of the obtained compound
R corresponded to the compound obtained in Example 1.

Example 3 (Table 2 No. 1)' In place of the chlorosulfonic acid used in Example 1, 5.10 (0.02 mol) of potassium pyrosulfate was added to give 1100
Stir at ℃ for 5 hours. After adding excess barium sulfate suspended in cold water to the residue concentrated under reduced pressure, carbon dioxide gas was introduced.
The deposited precipitate is removed and the furnace liquid is concentrated under reduced pressure. This was treated in the same manner as in Example 1 to obtain 1.37% potassium salt of the above ester.
I got g. The MP and IR of this compound were consistent with the compound obtained in Example 1.

Example 4 (Table 2 N0.1) Sulfur trioxide trimethylamine complex instead of chlorosulfonic acid used in Example 1 3. Add IIJ (0.02 mol) and stir at room temperature for 24 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 1.74 g of white crystals. The MP and IR of the obtained compound were consistent with the compound obtained in Example 1 = □ Example 5 (Table 2 No. 2) In Example 1, Table 1 A compound was mixed with 3-hydroxy-1-methyl-6 days. -dibenzo[b,dlpyran-6-one (Table 1 B> 2.26g (0.0tE)) was reacted, and 1-methyl-6■-dibenzo[b',d1pyran-6 -one-3-sulfate Nispur potassium salt (Table 2 No.
, 2>2.00g was obtained.

MP 297-298℃ 1RνCo: 1730cm-1□ NMR (DMSO=da) ”2.8(j
(31-I, S', -〇H3)7.20
(21-1, dd, aromaticH) 7.5
0-8.4. (41-1, m, arOmaticH
) Example 6 (Table 2 N0.3) In Example 1, the Δ compound in Table 1 was converted to 1,3-dihydroxy-
6■-dibenzo[b,dl pyran-6-one (Table 1 C
) 2.28111 (0.01 mol) and chlorosulfonic acid 3.500 (0.03 mol) and reacted to produce 61 dodibenzo[b,d]pyran-6-one-1,
3-disulfate potassium salt (Table 2 No. 3)
2.10 g was obtained.

MP 300°C or higher IR), ICO: 1720cm-1HMR (DMS
O-ds) 7.30 (21-1, dd, aromati
cH) 7.50-8.10 (2H, m, aroma
ticH) 8.30 (17 d d, ar
omaticl-1) 9.20 (IH, dd,
aromaticH) Example 7 (Table 2 N0.4) 1,3-dihydroxy-61-dibenzo[b,dl pyran-6-one (Table 1 C) 2.28 g (0.01 mol).

Adding 5.00 g (0.03 mol) of ethyl bromoacetate and 0.1 g of 1-lium iodide to a sodium oxide solution prepared from 657 absolute ethanol and 0.46 g (0.02 atoms) of sodium metal; Stir at high speed for 6 hours.

After cooling, it was filtered, and the residue obtained by concentrating the filtrate solution was recrystallized from ethanol to obtain the ethyl ester of compound 4 of formula (i).

Add this to 20d of 10% alcoholic potassium hydroxide and 1
After refluxing for an hour, 40r/1e of water was added and hydrochloric acid' [(1
Set aside and leave to cool. The deposited precipitate is extracted with an aqueous solution of hydrogen carbonate, and the extract is acidified with hydrochloric acid and allowed to cool.

When the precipitate obtained here was recrystallized from DMF-water, 6
-oxo-6-old-dibenzo[b,d]pyran-1,3-
Diyloxydiacetic acid (Table 2 No./l) 1.50
g was obtained.

MP 293-296℃ IRνco: 1750cm-1 HMR (DMSO-da) 4.80 (21-!, S, -0-CH2-Go
>4.90 (21-1,8,-0-CH2-Go>
6.60 (21-1, S, aromaticl-
1) 7.40-8.00 (2[-1,m, aro
matic)-1) 8.20 (IH, dd,
aromaticH>9.20 (III, dd
, aromaticH>Example 8 (Table 2 No. 5
) In Example 1, the compound of Table 1 A was
,9-dimethoxy-611-dibenzo[b,d7pyran-6-one (Table 1 D) Reacted in place of 2.72 g (0.01 mol)! , 8.9-dimethoxy-61]-
Dibenzo[b,dl pyran-6-one-3-sulfate potassium salt (Table 2 No. 5 > 2.05 (II
I got it.

MP 300'C or more I Rl/Co: 1700cm-1HMR (DMS
O-ds) 3.90 (31-1,S, 0-CH3)4.
00 (3H,S,0-CH3>7.10-8.
30 (51-l, m, aromaticH) example
9 (Table 2 No. 6) White crystals of 8,9-dimethoxy-6H-dibenzo [b, d] were obtained by the same treatment as in Example 8 using N-NaOH instead of N-K 0f-1. Pyran-6-one-3-Fa acid ester sodium-lium salt (Table 2 No. 6
) 1.90g was obtained. MP, IR, and NMR are the same as in the previous example.

Example 10 (Table 2 N0.7) By treating in the same manner as in Example 8 using dilute ammonia water instead of N-K OH, pale yellow crystals of 8,9-dimethoxy-6■-dibenzo[b, dl Pyran-6-one-3-sulfate ester ammonia cum salt 1.72 (J (No. 0.7 in Table 2)) was obtained. IR and NMR were the same as in the previous example.

Example 11 (Table 2 N0.8) In Example 7, the compound C in Table 1 was converted to 3-hydroxy-8,9
-dimethoxy-6H-dibenzo[b, former pyran-6-one (first compound listed > 2.72 g (o, 01 mol)
, ethyl bromoacetate 2.50 (1 (0,015 mol),
Sourium iodide ~ Thulium, 05g and absolute ethanol 3
5d and metal] ~ 0.23g of lium (0.01 atom)
8,9-dimethoxy-6-oxo-68-dibenzo[b,d]pyran-3-yloxyacetic acid (Table 2 No.).

8) 1.66g was obtained.

MP, 201-211℃ IR))co: 1760.1740cm-1HM
R(DMSO-66) 3.90 (3H,S, 0-C)-1s >4
．． 00 (3H,S,0-CH3)4.80
(2H,S,O-CH2-Go)6.70-8.2
0 (5H, m, aromaticl-1>Example 12
(Table 2 N0.9) In Example 1, the compound A of Table 1 was converted to 3-hydroxy-8,9
-dimethoxyni-1-medyru-6H-dibenzo [b, dl
8,9-dimethoxy-1-methyl-6-dibenzo[b,dl pyran-6-one-3 −
Sulfate ester potassium salt (Table 2 No. 9 > 2.2
5g was obtained. , MP 271-273°C I Rvco: 1700 cm-1 HMR (DMSO-do) 2.90 (3H,S, C-Cl-13>3.
90 (3H,S,0-CH3)4.00
(3H,S, 0-CH3)7.10 (2H
, dd, aromaticl-1) 7.70
(2H, dd, aromatic) l) Example 13 (Table 2 No. 10) 'In Example 11, the first compound was converted to 3-hydroxy-8,9-dimethoxy-1-
Reacted in place of methyl-611-dibenzo[b,dl pyran-6-one (Table 1 E> 3.10 g (0.01 mol)) to form 8,9-lame-1-xy-1-methyl-6-oxo- 61-dibenzo [b.

d” pyran-3-yloxyacetic acid (Table 2 N0.10)
1.85g was obtained.

MP 221-231℃ I Rvco: 1746.1718cm-1 Example 14
(Table 2 N0.11) In Example 11, the first compound was 3-hydroxy-8,
9-dimethoxy-4-methyl-61dodibenzo [b, d
pyran-6-one (Table 1 F) 3.10 g (0,
8,9-lame-1-xy-4-medy-6-oxo-61-dibenzo (b.

d1 pyran-3-yloxyacetic acid (Table 2 N0.11)
1.35g was obtained. □ MP 267-272℃ I Rvco: 1734.1718cm-1 example 15
(Table 2 N0.12) In Example 11, the first compound was 3-hydroxy-8,
9-dimethoxy-2-chloro-6[1-dibenzo[b,
dl pyran-6-one (Table 1 G > 3.289 (0
, 01 mol) and reacted with 8.9-dimethoxy-
2-chloro-6-oxo-68-dibenzo (b.

d1 pyran-3-yloxyacetic acid (Table 2 N0.12)
2.46(] was obtained.

MP 286-296°9 T Rν (0: 1744.1716Cm-1 Example 16
(Table 2 N0.13) In Example 6, the compound C in Table 1 was converted into 1,3-dihydroxy-
8,9-Dimethoxy-6■-dibenzo[b,dl pyran-6-one (Table 1 H > 2.88(] (00,0
React with 1 mol of 8,9-dimethoxy-611
-dibenzo[b,dl pyran-6-one-1,3-disulfate potassium salt (Table 2 No. 13> 2.1
3g was obtained.

MP 300℃ or higher IRνCo: 1740cm-1 HMR (DMSO-do) 3.90 (3H,S,0-CH3) 4.00
(3H,S, 0-Ct-h)7
．． 00~8.30 (4H, m, aromaticH
>Example 17 (Table 2 No. 14) In Example 16, N-NaO was used instead of N-KOl-1.
By using H and treating in the same manner as □, white crystal 8
,9-dimethoxy-6[1-dibenzo[b,dl pyran-6-one-1,3-disulfate ester sodium salt (No. 14 in Table 2) 2.11 g was obtained. M.P., I.R.

NMR is the same as before.

Example 18 (Table No. 2, Table 15) In Example 16, diluted ammonia water was used instead of N-KOH, and by the same treatment as in Example 17, pale yellow crystals of 8,9-dimethoxy-' 6H-dibenzo [b, d
1.85 g of J pyran-6-one-1,3-'disulfate ammonium salt (No. 15 in Table 2) was obtained.

MP, IR, and NMR are the same as in the previous example.

Example 19 (Table 2 N0.16) In Example 7, the compound C in Table 1 was converted into 1,3-dihydroxy-
8,9-Dimethoxy-6■-dibenzo[b,dlpyran-6-one (Table 1 H.) 2.88 g (0.01 mol) was replaced with 6-oxo-8,9-dimethod. ”
Nidi-6-dibenzo[b,dlpyran-1,3-diyl-A-sidiacetic acid (Table 2 No. 16) 1.32
I got q.

MP 300°C or higher (2IR)
)co: 1778.1742cm-1HMR(DM
SCI-d6) 3.90 (31-1,S, 0-CI-h)
4.00 (3H,S, 0-CI-
13>4.80 (2H,S, 0-C
H2-Co)4.85 (2i-1,S, 0-
C1-(2-Co)6.5-8.7 (41-(, m,
aromaticl-1) Example 20 (Table 2 N0.1
7) In Example 11, the first compound was 3-hydroxy-8,
9,10-N~rimethoxy-611-dibenzo[b,d
] Pyran-6-one (Table 1 Compound 1> 3.02g
Reaction in place of (o, oi mol), 8.9.10-1
~rimethoxy-6-oxo-6H-dibenzo [b, dl
Pyran-,3-,--yloxyacetic acid (Table 2 No.
17) Obtain 1.66g.

MP 206~210°CI Rν
C□: 1750. 1718cm-1 example 21
(Table 2 N0.18> In Example 11, the compound shown in the first table was
4-methyl-8.9.10-, -1-rimethyl-6ft-dibenzoIf), d]pyran-6-Δ' (
Table 1, ) Compound) 3.16 g (0,01-E/L, )
Reacted instead v,a,9,1o-1~rimethoxy4-methyl-6,-,-fu1xo-6i1-dibenzo[b,dlpyran-3-yloxyacetic acid (Table 2 N
o, 18> Obtained 1.82 g.

MP 224-231℃ IRνCo: 1754.1734cm-1 Example 22
(Table 2 No. 0.19) In Example 7, the compounds of Table 1 G were added to 1,3-dihydro
b.

d] Reacted in place of pyran-6-one (Table 1 K),
8,9.10-Trime1~nidocy 6-oxy-6-
Oxo-61 dodibenzo [b, former biran-1,3-diyloxydi acid resistant (Table 2 No. 19) 1.77 g
I got it. .

MP 245- to 255°C IRνCO: 1736.1668 cm-1 = 25- (Aldose reductase inhibitory effect) 7-week-old Wistar male rats were
.

The animal was sacrificed under ether anesthesia, and the crystalline lens was immediately removed.

The crystalline lens was heated with 1.0 ml of 2-mercaptoethanol and 1.0 mM NADP (oxidized nicotina
mide adenine nucleotide
Homogenization was performed in a 100 mM sodium-potassium-phosphate buffer (pH 6, 8) containing phosphate). The mixture was then centrifuged at 12,000 rl) m for 15 minutes, and the supernatant was used as a sample for aldose reductase activity measurement. All the above operations were performed at 4°C, and the specimen was kept at 180°.
Saved in C.

The activity of aldose reductase can be measured using KADO (KADO).
A) The method of et al. (Biophysical Chemis
try 8 (1978) 81-85). In other words, 0.1mM NAD 1 (
Reduced nicO1inamide adenine di
2. nucleotide phosphate) and substrate. OmM DL-glyceraldehyde in 100mM thulium-phosphate buffer
)H6,2) To 970 μg, 10 gg of solutions of various concentrations of the compound of the present invention were added, and then 20 μ°C of the above specimen was added, and the reaction was carried out at 25°C. As a control, only the substrate was lacking and the decrease in absorbance was measured at 340n+n for 200 seconds. In addition, instead of adding the sample solution, only the solvent was added, the reaction was carried out in the same manner as described in 1-, and the control value was used as the control value 3. The absorbance was measured using UV-26
0 (manufactured by Shimadzu Corporation) was used. As a result, the J8 inhibitory activity against aldose reductase was as shown in Table 3.
-8M) was observed.

Table 3 (Acute Toxicity) 6■-dibenzo[b,dlpyran-
Acute oral administration tests of 6-one derivative samples were conducted using Wistar rats, and it was found that L.
Dso was all greater than lo/ko.

〔Effect of the invention〕

As is clear from the above results, the 61-dibenzo[b,dl pyran-6-one derivative of the present invention has aldose reductase inhibitory activity and is useful as a highly safe drug for treating diabetic complications.

Applicant: Toyo Fufulmar Co., Ltd. Daiso Co., Ltd.

Claims (3)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [However, in the formula, R_1, R_2, R_3, R_4, R_5
, R_6, R_7, and R_8 are hydrogen atoms, chlorine atoms, lower alkyl groups, lower alkoxy groups, or formulas (IIa, IIb) -OSO_3M (IIa) -OCH_2CO_2M (IIb) (However, in the formula, M is a hydrogen atom, an alkali metal atom or an ammonium group), and R_1
~R_8, at least one is a group represented by either formula (IIa, IIb)] A 6H-dibenzo[b,d]pyran-6-one derivative represented by the following. (2) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (However, in the formula, X_1, X_2, X_3, X_4, X_5
, X_6, X_7, X_8 are a hydrogen atom, a chlorine atom, a lower alkyl group, a lower alkoxy group, or a hydroxy group, and at least one of X_1 to X_8 is a hydroxy group) Hydroxy-6H represented by - Perform sulfuric acid esterification or glycolic acid etherification of the dibenzo[b,d]pyran-6-one derivative, or act on the esterified or etherified substance with a substance that generates alkali metal ions or ammonium ions. 6H-dibenzo [ represented by the above formula (I), which is characterized by
b, d] Method for producing pyran-6-one derivative. (3) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [However, in the formula, R_1, R_2, R_3, R_4, R_5
, R_6, R_7, and R_8 are hydrogen atoms, chlorine atoms, lower alkyl groups, lower alkoxy groups, or formulas (IIa, IIb) -OSO_3M (IIa) -OCH_2CO_2M (IIb) (However, in the formula, M is a hydrogen atom, an alkali metal atom or ammonium group), and at least one of R_1 to R_8 is a group represented by either formula (IIa, IIb)] ] An aldose reductase inhibitor containing a pyran-6-one derivative as an active ingredient.