JPH07121935B2 - Dihydrobenzofuranone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a dihydrobenzofuranone derivative useful as a drug.

More specifically, the present invention provides a compound of general formula useful as a therapeutic agent for gastric and duodenal ulcer. (In the formula, R ¹ is a hydrogen atom, R ² is a hydrogen atom, a lower alkyl group, a cycloalkyl group or a pyridylalkyl group, or —NR ¹ R ² is integrated into a piperidino group, a morpholino group or 4-position may be substituted 1
-Forms a piperazinyl group, and the substituent is a lower alkyl group which may have a hydroxyl group, a lower alkoxycarbonyl group or the like), and provides a dihydrobenzofuranone derivative.

[Conventional technology]

As the dihydrobenzofuranone derivative as in the present invention,
Some compounds are already known. For example, in the Journal of Pharmaceutical Sciences (J.Pharm.Sci.) Vol. 69, p. 164 (1980), an intermediate for the production of a metabolite of a compound having an inhibitory action on platelet aggregation and an anti-inflammatory action is described. The compound represented by is reported.

In addition, Japanese Patent Laid-Open Publication No. 58-135877 discloses a general formula for anti-inflammatory, analgesic and antipyretic agents. (Wherein R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are a hydrogen atom or a lower alkyl group, R ¹³ is a hydrogen atom or a halogen atom, and n is 0 or 1) It has been reported.

Furthermore, published patent gazette, Sho 59-31511, published patent gazette,
54-98752, 55-2623, 55-64582, 5
5-147271, 56-5473, 56-154477 and 56-154478 have general formulas having gastric secretion inhibitory action, anti-inflammatory action, analgesic action, etc. (In the formula, ring A represents a benzene ring or a naphthalene ring,
The benzene ring or naphthalene ring is a lower alkyl group, nitro group, halogen atom, optionally substituted amino group, optionally substituted hydroxyl group, acyl group, sulfamoyl group, carboxyl group, lower alkoxycarbonyl group, substituted Optionally substituted carbamoyl group, optionally substituted ureido group, optionally substituted thioureido group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, optionally substituted aminomethyl group, cyano Group, which may be substituted with at least one or more of a group and a phenyl group) have been reported.

[Problems to be Solved by the Invention]

The present inventors have conducted studies to find a compound that is effective against stress-induced ulcers and has few side effects. As a result, certain dihydrobenzofuranone derivatives are effective against experimental ulcers, particularly stress ulcers, and have low toxicity. ,
The present invention was found to be useful as a therapeutic agent for gastric and duodenal ulcers of mammals including humans, and has completed the present invention.

The present invention is based on such knowledge.

[Means for Solving the Problems]

The dihydrobenzofuranone derivative represented by the above general formula (I) of the present invention shows a remarkable inhibitory effect on restraint water immersion stress ulcer in rats, has low toxicity, and is useful as a therapeutic agent for gastric and duodenal ulcers. is there.

The compounds of the general formula (I) of the present invention are novel compounds of the formula A carboxylic acid or a reactive functional derivative thereof represented by the general formula It can be produced by reacting with an amine represented by the formula (R ¹ and R ² in the formula have the same meanings as described above).

The compound of formula (II) used as a starting material in the present production method is also a novel compound and can be produced as follows. That is, by reacting methyl 5-formylsalicylate and malonic acid, the formula A cinnamic acid derivative represented by the following formula is produced, and after esterification, it is reacted with α-bromo-γ-butyrolactone in the presence of a base such as potassium carbonate to give a compound of the formula A compound represented by The resulting compound is then treated with a base such as 1,8 in the presence of an inorganic salt such as sodium chloride.
-The compound can be produced by treating with diazabicyclo [5.4.0] -7-undecene and then hydrolyzing the ester.

The compound of the general formula (I) of the present invention has a geometric isomer due to a double bond, but in the present invention, it is not limited to E-form, Z-form or a mixture thereof.

The compound of the general formula (I) of the present invention has a geometric isomer due to a double bond, but in the present invention, it is not limited to E-form, Z-form or a mixture thereof.

The compound of the general formula (I) of the present invention shows an anti-ulcer action with a suppression rate of about 30 to 70% by oral administration of 100 mg per 1 kg of body weight in a restrained water immersion stress ulcer experiment using Wistar male rats. In an acute single-dose acute toxicity test in ICR male mice, a strong toxic effect was not observed even at a dose of 1000 mg / kg body weight, and it is extremely useful as a therapeutic agent for stomach and duodenal ulcer of mammals including humans. .

When the compound of the general formula (I) of the present invention is used as an agent for treating ulcer, it may be administered in various dosage forms as it is or after being mixed with an appropriate pharmaceutical additive.

Examples of such dosage forms include powders, granules, fine granules, tablets, capsules, syrups, liquids, suppositories, and other oral administration agents and parenteral administration agents.

In addition, the optimal dose for actual treatment is appropriately determined according to the patient's age, body weight, sex, degree of symptoms, etc.
In the case of parenteral administration, the daily dose for adults is from 1 mg to 1000 mg and is divided into 1 to several divided doses.

〔The invention's effect〕

The compound represented by the general formula (I) of the present invention is about 30 to 70 by oral administration of 100 mg per kg body weight in a restrained water immersion stress ulcer experiment using male Wistar rats (8 weeks old).
Shows a suppression effect of about%.

In addition, the compound of the general formula (I) of the present invention has low toxicity and IC
Almost no deaths are observed even when 1000 mg / kg body weight is orally administered to R male mice (6 to 7 weeks old).

As described above, the compound represented by the general formula (I) of the present invention has a strong anti-stress ulcer action and low toxicity, and is therefore useful as a therapeutic agent for stomach and duodenal ulcer of mammals including humans.

〔Example〕

The contents of the present invention will be described in more detail with reference to the following reference examples and examples.

The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 52.2 g of methyl 5-formylsalicylate was dissolved in 200 ml of pyridine, 36.2 g of malonic acid and 3 ml of aniline were added, and the mixture was mixed at 60 ° C. for 16 hours.
After stirring for an hour, the mixture was heated to reflux for 1 hour. After cooling, the reaction solution was added to ice-dilute hydrochloric acid with stirring, and the precipitated crystals were collected by filtration and washed with water,
There was obtained 43.4 g of 4-hydroxy-3-methoxycarbonylcinnamic acid having a melting point of 234-236 ° C.

Elemental analysis value: (as C ₁₁ H ₁₀ O ₅ ) C% H% Calculated value 59.46 4.54 Measured value 59.20 4.39 IR (KBr): ν _CO 1670 cm ⁻¹ NMR (DMSO-d ₆ ) δ: 3.91 (3H, s ), 6.39 (1H, d, J = 15.9Hz), 7.02 (1H, d,
J = 8.8Hz), 7.55 (1H, d, J = 15.9Hz), 7.87 (1H, dd, J =
2.2and8.8Hz), 8.01 (1H, d, J = 2.2Hz), 10.77 (1H, s),
12.25 (1H, br) 4-Hydroxy-3-methoxycarbonylcinnamic acid 41.0
To g, 700 ml of methanol and 30 ml of concentrated sulfuric acid were added, and the mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, ice water was added, the mixture was extracted with chloroform, washed successively with water, an aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give 4-hydroxy-3 having a melting point of 92 to 94 ° C.
34.5 g of methyl methoxycarbonylcinnamate was obtained.

Elemental analysis value: (as C ₁₂ H ₁₂ O ₅ ) C% H% Calculated value 61.01 5.12 Measured value 60.91 5.00 IR (KBr): ν _CO 1705,1675 cm ⁻¹ NMR (CDCl ₃ ) δ: 3.80 (3H, s ), 3.98 (3H, s), 6.34 (1H, d, J = 15.9H
z), 7.00 (1H, d, J = 8.8Hz), 7.62 (1H, d, J = 15.9Hz),
7.64 (1H, dd, J = 2.2and8.8Hz), 8.01 (1H, d, J = 2.2H
z), 10.98 (1H, s) 33.0 g of methyl 4-hydroxy-3-methoxycarbonylcinnamate was dissolved in 150 ml of 2-butanone, and potassium carbonate 3
After adding 2.8 g and 15.5 ml of α-bromo-γ-butyrolactone, the mixture was heated to reflux with stirring for 3 hours, further 6.0 ml of α-bromo-γ-butyrolactone was added, and heated to reflux for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluting solvent: chloroform / ethyl acetate = 50/1) and then recrystallized from methylene chloride-diethyl ether to give a melting point of 96-98 ° C. 3-methoxycarbonyl-4- (tetrahydro-2-oxo-3
39.8 g of methyl (furyloxy) cinnamate was obtained.

Elemental analysis value: (as C ₁₆ H ₁₆ O ₇ ) C% H% Calculated value 60.00 5.03 Actual value 59.90 4.94 IR (KBr): ν _CO 1770,1710 cm ⁻¹ NMR (CDCl ₃ ) δ: 2.55 to 2.85 (2H, m), 3.80 (3H, s), 3.90 (3H, s), 4.
35 ~ 4.45 (1H, m), 4.55 ~ 4.65 (1H, m), 5.01 (1H, t, J =
7.1Hz), 6.39 (1H, d, J = 15.9Hz), 7.31 (1H, d, J = 8.8H)
z), 7.63 (1H, dd, = 2.2and8.8Hz), 7,64 (1H, d, J = 15.9)
Hz), 7.99 (1H, d, J = 2.2Hz) 38.0 g of methyl 3-methoxycarbonyl-4- (tetrahydro-2-oxo-3-furyloxy) cinnamate was added to N, N-
Dissolve in 380 ml of dimethylformamide, sodium chloride
8.4g and 1,8-diazabicyclo [5.4.0] -7-undecene
93 μl was added, and the mixture was stirred at 150 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate, diluted hydrochloric acid,
The extract was washed successively with water, an aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from chloroform-hexane to give 3- [3-oxospiro [benzofuran-2 (3H), 1'-cyclopropane] -5-yl having a melting point of 175 to 177 ° C. ]
19.4 g of methyl acrylate was obtained.

Elemental analysis value: (as C ₁₄ H ₁₂ O ₄ ) C% H% Calculated value 68.85 4.95 Measured value 68.60 4.78 IR (KBr): ν _CO 1700 cm ^-1 NMR (CDCl ₃ ) δ: 1.55 to 1.8 (4H, m ), 3.81 (3H, s), 6.41 (1H, d, J = 1
5.9Hz), 7.19 (1H, d, J = 8.8Hz), 7.71 (1H, d, J = 15.9H
z), 7.79 (1H, dd, J = 2.2and8.8Hz), 7.88 (1H, d, J = 2.2
Hz) 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] methyl acrylate 18.1
Ethanol 500 ml and 2N sodium hydroxide aqueous solution 78 g
ml was added, and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was washed with methylene chloride, 78 ml of 2N hydrochloric acid was added to the aqueous layer, the precipitated crystals were collected by filtration and washed with water, and the melting point was 21
6-218 ° C 3- [3-oxospiro [benzofuran-2
(3H), 1'-Cyclopropane] -5-yl] acrylic acid
13.4g was obtained.

Elemental analysis value: (as C ₁₃ H ₁₀ O ₄ ) C% H% Calculated value 67.82 4.38 Measured value 67.59 4.32 IR (KBr): ν _CO 1710,1685 cm ⁻¹ NMR (DMSO-d ₆ ) δ: 1.35 to 1.65 (2H, m), 1.7 to 1.95 (2H, m), 6.58 (1H,
d, J = 15.9Hz), 7.40 (1H, d, J = 8.8Hz), 7.68 (1H, d, J =
15.9Hz), 8.03 (1H, d, J = 1.7Hz), 8.13 (1H, dd, J = 1.7a
nd8.8Hz), 12.37 (1H, br-s) Example 1 3- [3-oxospiro [benzofuran-2 (3H), 1 '
40 ml of dry benzene and 2.2 ml of thionyl chloride were added to 1.40 g of -cyclopropane] -5-yl] acrylic acid, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and a solution of this residue in dry methylene chloride (15 ml) was added dropwise to a solution of triethylamine (1.7 ml) and piperidine (0.9 ml) in dry methylene chloride (15 ml) under ice-cooling, and then the mixture was stirred at room temperature for 16 hours. did.
The reaction solution was washed successively with diluted hydrochloric acid, a nest, an aqueous solution of sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol-diethyl ether to give 1- [3
-[3-oxospiro [benzofuran-2 (3H), 1'-
1.35 g of cyclopropane] -5-yl] acryloyl] piperidine was obtained.

Elemental analysis value: (as C ₁₈ H ₁₉ NO ₃ ) C% H% N% Calculated value 72.71 6.44 4.71 Measured value 72.61 6.51 4.80 IR (KBr): ν _CO 1700, 1645 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.5 ~ 1.8 (10H, m), 3.55 ~ 3.75 (4H, m), 6.90 (1H,
d, J = 15.4Hz), 7.17 (1H, d, J = 8.8Hz), 7.66 (1H, d, J =
15.4Hz), 7.75 (1H, dd, J = 1.7and8.8Hz), 7.92 (1H, d, J
= 1.7 Hz) Example 2 3- [3-oxospiro [benzofuran-2 (3H), 1 ′
-Cyclopropane] -5-yl] acrylic acid (0.60 g) and morpholine (0.23 ml) were used and treated in the same manner as in Example 1 and then recrystallized from benzene to give 4- [3- [3] having a melting point of 259 to 262 ° C. -Oxospiro [benzofuran-2 (3
H), 1'-Cyclopropane] -5-yl] acryloyl] morpholine (0.62 g) was obtained.

Elemental analysis value: (as C ₁₇ H ₁₇ NO ₄ ) C% H% N% Calculated value 68.22 5.72 4.68 Measured value 68.52 5.84 4.70 IR (KBr): ν _CO 1705,1645 cm ⁻¹ NMR (CDCl ₃ ) δ: 1.55 ~ 1.85 (4H, m), 3.6 ~ 3.8 (8H, m), 6.84 (1H, d,
J = 15.4Hz), 7.18 (1H, d, J = 8.2Hz), 7.72 (1H, d, J = 1)
5.4Hz), 7.76 (1H, dd, J = 2.2and8.2Hz), 7.92 (1H, d, J
= 2.2 Hz) Example 3 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] acrylic acid 0.90 g and 2- (1-piperazinyl) ethanol 0.61 g,
After reacting in the same manner as in Example 1 and treating in substantially the same manner, purification by silica gel flash column chromatography (eluting solvent: chloroform / ethanol = 30/1), recrystallization from chloroform-benzene, and melting point 191-194 ° C. 2 -[4
-[3- [3-oxospiro [benzofuran-2 (3
H), 1'-Cyclopropane] -5-yl] acryloyl] -1-piperazinyl] ethanol (1.01 g) was obtained.

Elemental analysis value: (as C ₁₉ H ₂₂ N ₂ O ₄ ) C% H% N% Calculated value 66.65 6.48 8.18 Measured value 66.86 6.56 7.88 IR (KBr): ν _CO 1705,1645 cm ⁻¹ NMR (CDCl ₃ ) δ : 1.5 to 1.9 (4H, m), 2.3 to 2.75 (7H, m), 3.55 to 3.9 (6
H, m), 6.87 (1H, d, J = 15.4Hz), 7.18 (1H, d, J = 8.8H
z), 7.70 (1H, d, J = 15.4Hz), 7.76 (1H, dd, J = 1.6and8.
8Hz), 7.92 (1H, d, J = 1.6Hz) Example 4 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] acrylic acid 0.60 g and 1-piperazinyl ethyl acetate dihydrochloride 0.64 g were used,
The reaction and the treatment were conducted in substantially the same manner as in Example 1, purified by silica gel flash column chromatography (eluting solvent: benzene), and recrystallized from methylene chloride-hexane to give [4- [3] having a melting point of 131 to 133 ° C. -[3-Oxospiro [benzofuran-2 (3H), 1'-cyclopropane] -5-yl] acryloyl] -1-piperazinyl]
0.35 g of ethyl acetate was obtained.

Elemental analysis value: (as C ₂₁ H ₂₄ N ₂ O ₅ ) C% H% N% Calculated value 65.61 6.29 7.29 Measured value 65.31 6.32 7.09 IR (KBr): ν _CO 1750,1710,1645 cm ^-1 NMR (CDCl ₃ ) Δ: 1.29 (3H, t, J = 7.1Hz), 1.5 to 1.8 (4H, m), 2.55 to 2.
75 (4H, m), 3.27 (2H, s), 3.65 ~ 3.9 (4H, m), 4.21 (2
H, q, J = 7.1Hz), 6.86 (1H, d, J = 15.4Hz), 7.18 (1H, d, J
= 8.8Hz), 7.69 (1H, d, J = 15.4Hz), 7.76 (1H, dd, J = 2.
2and8.8Hz), 7.91 (1H, d, J = 2.2Hz) Example 5 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] acrylic acid 0.70 g and cyclohexylamine 0.42 ml were reacted and treated in the same manner as in Example 1, and then recrystallized from benzene-hexane to give N-cyclohexyl having a melting point of 206 to 208 ° C. -3- [3
0.75 g of -oxospiro [benzofuran-2 (3H), 1'-cyclopropane] -5-yl] acrylamide was obtained.

Elemental analysis value: (as C ₁₉ H ₂₁ NO ₃ ) C% H% N% Calculated value 73.29 6.80 4.50 Measured value 73.41 6.92 4.36 IR (KBr): ν _NH 3260 cm ⁻¹ ν _CO 1715,1650 cm ⁻¹ NMR ( CDCl ₃ ) δ: 1.1 to 2.1 (14H, m), 3.85 to 4.0 (1H, m), 5.50 (1H, d,
J = 7.7Hz), 6.33 (1H, d, J = 15.4Hz), 7.161H, d, J = 8.8H
z), 7.63 (1H, d, J = 15.4Hz), 7.74 (1H, dd, J = 2.2and8.
8Hz), 7.87 (1H, d, J = 2.2Hz) Example 6 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] acrylic acid 0.75 g and 2-pyridylmethylamine 0.36 g were reacted in the same manner as in Example 1 and treated in substantially the same manner, then recrystallized from benzene, melting point 178-180 ° C. 3- [3-oxospiro [benzofuran-2 (3H), 1'-cyclopropane] -5
-Yl] -N- (2-pyridylmethyl) acrylamide
0.82 g was obtained.

Elemental analysis value: (as C ₁₉ H ₁₆ N ₂ O ₃ ) C% H% N% Calculated value 71.24 5.03 8.74 Measured value 71.29 5.01 8.43 IR (KBr): ν _NH 3260 cm ⁻¹ ν _CO 1705,1665,1650 cm _{^{-1 NMR (CDCl 3) δ:}} 1.5~1.85 (4H, m), 4.71 (2H, d, J = 5.0Hz), 6.52 (1
H, d, J = 15.9Hz), 7.1 to 7.4 (4H, m), 7.6 to 7.8 (3H, m),
7.86 (1H, d, J = 2.2Hz), 8.56 (1H, d, J = 5.0Hz) Example 7 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] acrylic acid (0.80 g) and 3-pyridylmethylamine (0.42 ml) were reacted in the same manner as in Example 1 and treated in a similar manner, and then recrystallized from methylene chloride-diethyl ether to give the melting point. 161-164 ℃ 3
-[3-oxospiro [benzofuran-2 (3H), 1'-
0.79 g of cyclopropane] -5-yl] -N- (3-pyridylmethyl) acrylamide was obtained.

Elemental analysis value: (as C ₁₉ H ₁₆ N ₂ O ₃ ) C% H% N% Calculated value 71.24 5.03 8.74 Measured value 71.51 4.90 8.49 IR (KBr): ν _NH 3230 cm ^-1 ν _CO 1695,1665 cm ^-1 NMR (CDCl ₃ ) δ: 1.5 to 1.85 (4H, m), 4.61 (2H, d, J = 5.5Hz), 6.42 (1
H, d, J = 15.4Hz), 6.45 (1H, br-s), 7.16 (1H, d, J = 8.8H
z), 7.29 (1H, dd, J = 4.9and7.7Hz), 7.65 ~ 7.8 (3H,
m), 7.84 (1H, d, J = 2.2Hz), 8.52 (1H, d, J = 4.9Hz), 8.
59 (1H, s) Example 8 3- [3-oxospiro [benzofuran-2 (3H), 1 ′
After adding 10 ml of dry benzene and 1.1 ml of thionyl chloride to 0.70 g of -cyclopropane] -5-yl] acrylic acid, 2
Heated to reflux for hours. The reaction solution was concentrated to dryness under reduced pressure, and a solution of this residue in dry dioxane (2 ml) was added dropwise to a mixed solution of 25% aqueous ammonia (3 ml) and dioxane (1 ml) under ice-cooling stirring, followed by reaction for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added, the mixture was extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethanol to give 3- [3-oxospiro [benzofuran-2 (3H), 1'-cyclopropane] -5-yl] acrylamide having a melting point of 220 to 221 ° C. Obtained 0.53 g.

Elemental analysis value: (as C ₁₃ H ₁₁ NO ₃ ) C% H% N% Calculated value 68.11 4.84 6.11 Actual value 68.01 4.81 5.78 IR (KBr): ν _NH 3380,3200 cm ^-1 ν _CO 1700,1660 cm ^-1 NMR (CDCl ₃ ) δ: 1.5-1.8 (4H, m), 5.56 (2H, br-s), 6.43 (1H, d, J =
15.4Hz), 7.18 (1H, d, J = 8.8Hz), 7.68 (1H, d, J = 15,4H
z), 7.77 (1H, dd, J = 1.7and8.8Hz), 7.90 (1H, d, J = 1.7)
Hz) Example 9 3- [3-oxospiro [benzofuran-2 (3H), 1 '
-Cyclopropane] -5-yl] acrylic acid (0.60 g) and a 40% aqueous solution of methylamine (0.4 ml) were used for the same reaction and treatment as in Example 8, followed by recrystallization from ethanol.
N-methyl-3- [3-oxospiro [benzofuran-2 (3H), 1'-cyclopropane] -5 having a melting point of 228 to 230 ° C.
-Yl] 0.53 g of acrylamide was obtained.

Elemental analysis value: (as C ₁₄ H ₁₃ NO ₃ ) C% H% N% Calculated value 69.12 5.39 5.76 Measured value 68.89 5.25 5.58 IR (KBr): ν _NH 3350 cm ⁻¹ ν _CO 1690,1665 cm ⁻¹ NMR ( CDCl ₃ ) δ: 1.5 to 1.85 (4H, m), 2.96 (3H, d, J = 4.9Hz), 5.67 (1
H, br-s), 6.36 (1H, d, J = 15.4Hz), 7.16 (1H, d, J = 8.8H
z), 7.65 (1H, d, J = 15.4Hz), 7.75 (1H, dd, J = 1.7and8.
8Hz), 7.87 (1H, d, J = 1.7Hz)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/495 31/535 Examiner Shoei Hoshino (56) Reference JP-A-1-246274 (JP , A) Pharmaceutical Journal, 109 (4), 241-2 (1989) Pharmaceutical Journal, 109 (4), 232-40 (1989)

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ is a hydrogen atom, R ² is a hydrogen atom, a lower alkyl group, a cycloalkyl group or a pyridylalkyl group, or —NR ¹ R ² is integrated into a piperidino group, a morpholino group or 4-position may be substituted 1
A dihydrobenzofuranone derivative which forms a piperazinyl group and the substituent is a lower alkyl group which may have a hydroxyl group, a lower alkoxycarbonyl group or the like).