JPH06116257A - Benzofuran derivative and its use - Google Patents

Abstract

PURPOSE:To obtain a new compound, having inhibitory action on the lipoxygenase activity, excellent in safety and useful as a preventing and a therapeutic agents for allergic and rheumatic diseases, psoriasis, etc. CONSTITUTION:The objective compound of formula I (R is H or hydroxyl group), e.g. 2-(1, 3-pentadienyl)-5-hydroxy-2,3-dihydroxybenzo[b]furan. Furthermore, this compound of formula I is obtained by using, e.g. a compound of formula II as a starting raw material and hydrolyzing the resultant compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzofuran derivative and its use, and more specifically, a benzofuran derivative having an inhibitory effect on 5-lipoxygenase activity, which is effective for the treatment and prevention of allergic diseases and various inflammations and the like. Regarding use.

[0002]

BACKGROUND OF THE INVENTION For allergic diseases such as bronchial asthma and various inflammations, histamine, serotonin, prostaglandin (PG), leukotriene (LT), thromboxane (TX), platelet activity. Many factors such as activating factor, lysolecithin, and various lymphokines are involved. Among these factors, PG and LT are involved.
Due to its number and diversity of physiological activities, spores play a particularly important role in allergic diseases and various inflammatory reactions.

When an abnormality occurs in the arachidonic acid metabolism system in the living body, overproduction or underproduction of arachidonic acid metabolites such as PG, LT, and TX occurs in the cells, which causes vascular permeability increase, Pathological conditions such as bronchoconstriction and promotion of platelet aggregation will appear, causing allergic diseases and various inflammations.

A large number of drugs that inhibit various enzyme actions involved in the arachidonic acid metabolic pathway have been developed as anti-inflammatory agents. For example, a nonsteroidal anti-inflammatory drug such as aspirin or indomethacin is mentioned as a drug exhibiting an anti-inflammatory effect by inhibiting cyclooxygenase activity and consequently suppressing PG production. However, these are PG
Although effective for system-related inflammation, it has no inhibitory effect on LT-induced inflammation.

As a potent mediator of bronchial asthma, a slow reacting substance of anaphylaxis (slow react).
ing substance of anaphyla
The existence of xis; SRS-A) has been revealed. This SRS-A is a mixture of CTC ₄ , LTD ₄ and LTE ₄ . In addition, LTB ₄ has a strong leukocyte attracting action and leukocyte activating action, and its involvement in inflammation is drawing attention. Therefore, compounds that inhibit the activity of 5-lipoxygenase, which is the initial enzyme in producing LT, are expected to be effective in the treatment and prevention of allergic diseases such as bronchial asthma and various inflammations. From such a viewpoint, compounds capable of inhibiting 5-lipoxygenase activity have been developed (for example, JP-A 1-213327).
6 gazette, WO91 / 07396 gazette).

However, some of these compounds are insufficient in their action or safety or have difficulty in their production.

Therefore, it has been desired to develop a compound which has excellent anti-allergic and anti-inflammatory effects as well as excellent safety.

[0008]

Means for Solving the Problems The inventors of the present invention have made extensive studies in view of such circumstances, and as a result, the compound (1) described later was
The inventors have found that they have excellent anti-allergic and anti-inflammatory effects and are highly safe, and have completed the present invention.

That is, the present invention is, firstly, the following general formula (1):

[0010]

[Chemical 2]

(In the formula, R represents a hydrogen atom or a hydroxyl group)
The present invention provides a benzofuran derivative represented by

Secondly, the present invention provides an antiallergic agent comprising a benzofuran derivative (1) as an active ingredient.

Thirdly, the present invention provides an anti-inflammatory agent containing a benzofuran derivative (1) as an active ingredient.

The benzofuran derivative (1) of the present invention includes four geometric isomers based on the two double bonds of the pentadienyl group and optical isomers based on the asymmetric carbon atom. .

The method for producing the compound (1-1) of the present invention will be described below. The compound (1-1) is produced, for example, according to the following reaction route.

[0016]

[Chemical 3]

First, tosyl chloride is added to hydroquinone monomethyl ether (2), and anhydrous K ₂ CO ₃ is used as a base in acetone to obtain a monotosyl compound (3). Then, by adding ethanethiol and AlCl ₃ as a Lewis acid in dichloromethane to cleave the methoxy group of (3) to obtain a monophenol body (4), (4) and allyl bromide are added in acetone. By using anhydrous K ₂ CO ₃ as a base at
Reaction is performed to obtain an allyl ether body (5).

The Claisen rearrangement reaction is applied to (5) to give an allylphenol derivative (6), and then the olefin moiety of (6) is reacted with m-chloroperbenzoic acid (m-CPBA) to cyclize (7). ) Get. Cyclization product (7) and N, N-dicyclohexylcarbodiimide (D
CC) and a so-called Moffat oxidation reaction to give an aldehyde (8), and then 2-butenylphosphonium bromide and NaH are added to (8) in tetrahydrofuran (THF) to form a diene. (9) is obtained. Furthermore, the target compound (1-1) is obtained by hydrolyzing (9) with KOH and methanol.
To get

The method for producing the compound (1-2) of the present invention will be described below. The compound (1-2) is produced, for example, according to the following reaction route.

[0020]

[Chemical 4]

First, 3,4-dihydroxybenzaldehyde (12) is reacted with benzyl bromide to obtain a dibenzyloxy derivative (13), and then (13) and m-C.
By reacting with PBA, a monophenol compound (1
After obtaining 4), (14) is reacted with dimethylamine and formaldehyde in this order to obtain an aminomethylphenol derivative (15).

Further, (15) is reacted with carbetoxymethyldimethylsulfonium bromide using anhydrous K ₂ CO ₃ as a base to obtain a cyclized compound (16), and then (16) and lithium aluminum hydride ( After obtaining a hydroxymethyl derivative (17) by reacting LAH), (17) is reacted with DCC to form an aldehyde derivative (1).
8) is obtained. Further, (18) is reacted with 2-butenyltriphenylphosphonium bromide to give a diene compound (1
9) is obtained, and the target compound (1-2) is obtained by debenzylating (19).

The benzofuran derivative (1) of the present invention is
5-lipoxygenase activity in the lachidonic acid cascade
Remarkable inhibitory effect on sex [50% inhibitory concentration (IC₅₀value is
10 ^-6M)] and its metabolite 5 (S)-
Hydroperoxyeicosatetraenoic acid (5-HPET
E), leukotriene, 5 (S) -hydroeicosate
It suppresses the generation of traenoic acid (5-HETE) and the like. Well
The compound (1) of the present invention was applied to a trachea specimen of a sensitized guinea pig.
Inhibits tracheal contraction caused by the addition of antigen
Anaphyla, which is a type of allergic reaction
It has an inhibitory action against xylem, and its action is WO91 /
In comparison with the benzofuran derivative described in JP 07396
It is stronger.

Further, since the toxicity in the toxicity test is extremely low, a drug containing the compound of the present invention as an active ingredient is used for allergic diseases such as bronchial asthma and rheumatic diseases,
It is useful for the treatment and prevention of psoriasis and various other inflammations.

A medicine containing the compound of the present invention as an active ingredient is used as it is or in the form of tablets, capsules, solutions, injections, suppositories, etc., using known carriers and excipients. It can be administered orally or parenterally. The dose varies depending on the subject, route, symptom and the like, but when administered to adult bronchial asthma, it is usually preferable to administer about 0.1 to 30 mg / kg body weight.

[0026]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

Example 1 2- (1,3-pentadienyl) -5-hydroxy-
2,3-Dihydroxybenzo [b] furan (Compound 1-
Production of 1) (a) Production of 4-methoxyphenyl-p-toluenesulfonate (3) Hydroquinone monomethyl ether (2) 24.83 g
(200 mmol), 38.13 g of tosyl chloride (20
0 mmol), 27.60 g (200 mmol) of anhydrous K ₂ CO ₃
Was added to 500 ml of acetone and heated under reflux for 6 hours, and then the reaction solution was filtered. The filtrate was evaporated under reduced pressure and the resulting material was extracted with ethyl acetate. After washing with 5% NaOH, saturated NaCl and water, it was dried over anhydrous MgSO ₄ . The crystals obtained by evaporation under reduced pressure were recrystallized from ethyl acetate and hexane to give 49.89 g of colorless crystals (yield 89.7%).
Got

Melting point: 68.6-69.2 ° C. ¹ H-NMR (90 MHz; CDCl ₃ / TMS) δ:
7.69 (2H, d, J = 8Hz), 7.30 (2H,
d, J = 8 Hz), 6.90 (2H, d, J = 9H)
z), 6.75 (2H, d, J = 9Hz), 3.76
(3H, s) 2.45 (3H, s)

(B) 4-hydroxyphenyl-p-tolu
Production of ensulfonate (4) AlCl under ice cooling₃64.60 g (484.5 mm
ol) to CH₂Cl₂ To the solution added to 200 ml,
All 160 ml and CH₂Cl₂ 160 ml mixed solution
And monotosyl compound (3) 44.95 g (161.5 mmo)
l) CH₂Cl₂ Add a solution dissolved in 160 ml and at 4 o'clock
The mixture was stirred while cooling with ice. 10% HC until the reaction solution becomes transparent
add l CH₂Cl₂Separate the layers and wash with saturated NaCl
And then anhydrous MgSO_FourAnd dried under reduced pressure. Got
Column chromatography of the oily substance (SiO₂， Heki
Purified with sun: ethyl acetate = 1: 1), colorless crystals 3
Obtained 8.88 g (yield 91.1%).

Melting point: 97.2-97.8 ° C. ¹ H-NMR (90 MHz; CDCl ₃ / TMS) δ:
7.69 (2H, d, J = 8Hz), 7.30 (2H,
d, J = 8 Hz), 6.68 (2H, d, J = 9H)
z), 5.01 (1H, s), 2.45 (3H, s)

(C) Preparation of 4-allyloxyphenyl-p-toluenesulfonate (5) 26.40 g (100 mmol) of monophenol body (4),
13.80 g (100 mmol) of anhydrous K ₂ CO _{3 and} 12.10 g (100 mmol) of allyl bromide were added to 5 parts of acetone.
The mixture was added to 00 ml and heated under reflux overnight. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated NaCl, dried over anhydrous MgSO ₄ , and then evaporated under reduced pressure. Column chromatography (SiO ₂ , CH
Purification with Cl ₃ : ethyl acetate = 9: 1) gave 22.48 g (yield 74.0%) of colorless crystals.

Melting point: 53.5-54.0 ° C. ¹ H-NMR (90 MHz; CDCl ₃ / TMS) δ:
7.69 (2H, d, J = 8Hz), 7.29 (2H,
d, J = 8 Hz), 6.90 (2H, d, J = 9H)
z), 6.75 (2H, d, J = 9 Hz), 5.50-
5.44 (1H, m), 5.36-5.19 (2H,
m), 4.51 (1H, t, J = 1.3Hz), 4.4
5 (1H, t, J = 1.3Hz), 2.44 (3H,
s)

(D) Preparation of 4-hydroxy-3-allylphenyl-p-toluenesulfonate (6) 19.98 g (65.6 mmol) of allyl ether compound (5)
Is dissolved in 40 ml of triglyme, and it is heated at 240 ° C (external temperature) for 5
Heated for hours. After allowing to cool, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous MgSO ₄ , evaporated under reduced pressure, and subjected to column chromatography (SiO ₂ , hexane: ethyl acetate =).
The product was purified by 2: 1) to obtain 10.13 g (yield 50.8%) of a yellow oily substance.

¹ H-NMR (90 MHz; CDCl ₃ / T
MS) δ: 7.68 (2H, d, J = 8Hz), 7.2
9 (2H, d, J = 8 Hz), 6.78 to 6.60 (3
H, m), 6.08 to 5.66 (1H, m), 5.35.
(1H, s), 5.16 to 4.90 (2H, m), 3.
31 (1H, t, J = 1.3 Hz), 3.24 (1H,
t, J = 1.3 Hz), 2.44 (3H, s)

(E) 5-p-toluenesulfonyloxy-
2,3-dihydroxybenzo [b] furan-2-methano
Of the allylphenol body (6) 5.343 g (17.6 mmo)
l) to CHCl₃In addition to 100 ml, m-chloroperbenzoic
Acid (m-CPBA) 6.04 g (35 mmol) was added, and
After stirring at the temperature for 2 hours, the mixture was heated to reflux overnight. Ethyl acetate
Extraction with 10% NaHSO₃Removes peracid and saturates
NaHCO₃, Washed with saturated NaCl, anhydrous MgS
O_FourDried in. Evaporate under reduced pressure and column chromatography
ー (SiO ₂, Hexane: ethyl acetate = 1: 1)
Purified, 3.57 g of yellow oil (yield 63.1%)
Got

¹ H-NMR (90 MHz; CDCl ₃ / T
MS) δ: 7.71 (2H, d, J = 8Hz), 7.3
1 (2H, d, J = 8 Hz), 6.92 to 6.88 (1
H, m), 6.59 to 6.58 (1H, m), 5.01
Up to 4.78 (1H, m), 3.83 to 3.66 (2H,
m), 3.195 to 3.00 (2H, m), 2.45
(3H, s), 1.82 (1H, brs)

(F) 5-p-toluenesulfonyloxy-
Preparation of 2,3-dihydroxybenzo [b] furan-2-aldehyde (8) 3.47 g (10.8 mmol) of cyclized product (7) was added to DMSO5.
To a solution dissolved in 5 ml, 8.926 g (43.4 mmol) of N, N-dicyclohexylcarbodiimide (DCC) and 5.5 ml of 1.0 MH ₃ PO _{4 /} DMSO were added, and the mixture was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was filtered through Celite.
After washing with saturated NaCl, it was dried with anhydrous MgSO ₄ .
It was distilled off under reduced pressure. Column chromatography (SiO ₂ ,
Ethyl acetate: PhH = 1: 1, hexane: ethyl acetate =
2: 1 and hexane: ethyl acetate = 1: 1) and purified by changing the developing solvent in this order, and colorless oily substance 1.46 g
(Yield 42.6%) was obtained.

¹ H-NMR (90 MHz; CDCl ₃ / T
MS) δ: 9.81 (1H, d, J = 1.0 Hz),
7.70 (2H, d, J = 8Hz), 7.31 (2H,
d, J = 8 Hz), 6.93 to 6.89 (1H, m),
6.71 to 6.58 (2H, m), 5.17 to 4.50
(1H, m), 3.43 to 3.02 (2H, m), 2.
45 (2H, s)

(To) 2- (1,3-pentadienyl)-
Preparation of 5-p-toluenesulfonyloxy-2,3-dihydroxybenzo [b] furan (9) 2-butenyltriphenyl-phosphonium bromide (10) 2.73 in 70 ml of tetrahydrofuran (THF).
g (6.87 mmol) dissolved in 60% NaH
0.275 g (6.87 mmol) was added, and the mixture was stirred at room temperature for 15 minutes, and the aldehyde compound (8) 1.4 was added to 30 ml of THF.
What melt | dissolved 6g (4.58 mmol) was added, and it stirred at room temperature overnight. Then, saturated NH ₄ Cl was added, the mixture was extracted with ethyl acetate, washed with saturated NaCl, dried over anhydrous MgSO ₄ , and evaporated under reduced pressure. Column chromatography (S
Purification with iO ₂ , hexane: ethyl acetate = 5: 1) gave 0.653 g (yield 40.0%) of a colorless oily substance.

¹ H-NMR (90 MHz; CDCl ₃ / T
MS) δ: 7.71 (2H, d, J = 8Hz), 7.3
1 (2H, d, J = 8 Hz), 6.92 to 6.89 (1
H, m), 6.57 to 6.55 (2H, m), 6.51
~ 5.16 (5H, m), 3.49-2.77 (2H,
m), 2.45 (3H, s), 1.84 to 1.74 (3
H, m)

The above compound (10) was produced by the following method. 2.7 g of crotyl bromide (200 mm
ol) and triphenylphosphine 5.24 g (20 mmo
l) was added to anhydrous benzene and heated to reflux overnight with stirring. The white powder that precipitated was collected by filtration and washed with benzene and ether. After drying under reduced pressure, 6.90 g of white powder
(Yield 86.8%) was obtained.

Melting point: 240.1 to 241.3 ° C. ¹ H-NMR (90 MHz; CDCl ₃ / TMS) δ:
8.03 to 7.50 (15H, m), 6.17 to 5.8
0 (1H, m), 5.41 to 5.03 (1H, m),
4.89-4.60 (2H, m), 1.69-1.54
(3H, m)

(H) 2- (1,3-pentadienyl)-
Preparation of 5-hydroxy-2,3-dihydroxybenzo [b] furan (1-1) Diene compound (9) 100 mg (0.28 mmol) in MeOH
5 ml of 5N KOH / MeOH (1 ml) and H ₂ O (2 ml) were added, and the mixture was heated under reflux for 1 hour and evaporated under reduced pressure. 10% H
After adding Cl to acidify, it was extracted with ethyl acetate and saturated N
Wash with aCl. It was dried over anhydrous MgSO ₄ and evaporated under reduced pressure. Purification by column chromatography (SiO ₂ , hexane: ethyl acetate = 2: 1) gave colorless crystals (45 mg, yield 78.6%).

Melting point: 71.3 to 71.9 ° C. ¹ H-NMR (90 MHz; CDCl ₃ / TMS) δ:
6.71 to 6.60 (3H, m), 6.49 to 5.12
(3H, m), 4.44 (1H, s), 3.48-2.
79 (2H, m), 1.85 to 1.73 (3H, m)

Example 2 2- (1,3-pentadienyl) -5,6-hydroxy-2,3-dihydroxybenzo [b] furan (Compound 1
-2) (a) 3,4-dibenzyloxybenzaldehyde (1
Production of 3) 3,4-dihydroxybenzaldehyde (12) 20 g
(145 mmol) and benzyl bromide 49.6 g (29
(0 mmol) was stirred in acetone at 80 ° C. for 6 hours. After cooling, the reaction solution was filtered, the filtrate was poured into water and extracted with diethyl ether. The organic layer is washed with brine and washed with Na ₂ SO ₄ · 10H
_It was dried at 20. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a hexane-ethyl acetate mixed solvent to obtain 44 g of pale yellow needle crystals (melting point: 84 to 85 ° C). (Yield 95.
4%).

(B) Preparation of 3,4-dibenzyloxyphenol (14) 18 g (5) of compound (13) was added to 200 ml of ethyl acetate.
6.5 mmol) and m-CPBA 15 g (86.7 mmol)
Was dissolved and mixed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium hydrogen carbonate solution and brine, and dried over Na ₂ SO ₄ / 10H ₂ O. The solvent was distilled off under reduced pressure and then dissolved in 50 ml of THF. To this solution was added 50 ml of 15% sodium hydroxide solution with stirring. After 30 minutes, add 15% hydrochloric acid solution to this solution at 0 ° C. to pH 2
It was added until it became, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over Na ₂ SO ₄ / 10H ₂ O. After the solvent was distilled off under reduced pressure, the crude product was precipitated in a hexane-chloroform mixed solvent and collected. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 14.2 g of compound (14) (yield 82.0%). The melting point of the recrystallized product from hexane / ethyl acetate was 99-100 ° C.

(C) 2-dimethylaminomethyl-4,5
-Production of dibenzyloxyphenol (15) 11.0 g (35.9 mmol) THF of compound (14)
(50 ml) 50% Dimethylamine 3 with stirring
1.6 g (0.36 mol) and 50 ml of water are added. Then, 29.1 g of 37% formaldehyde (0.36 mol /
Water (50 ml) was gradually added at room temperature, and the mixture was stirred for 2 hours and allowed to stand overnight. The mixture was extracted with ethyl acetate and the extract washed with brine. The ethyl acetate layer was dried over Na ₂ SO ₄ · 10H ₂ O, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 1).
0: 1) and purified as a light brown powdery compound (15) 9.39
g was obtained (yield 72.0%). Recrystallization from hexane gave colorless crystals (melting point 58-59 ° C).

(D) Ethyl 5,6-dibenzyloxy-
Production of 2,3-dihydrobenzo [b] furan-2-carboxylate (16) Carbetoxymethyl dimethylsulfonium bromide 2.06 g (9 mmol) and potassium carbonate 1.24 g (9
A mixture of mmol / 10 ml N, N'-dimethylformamide) was stirred at room temperature for 5 hours. Compound (1
5) Add 1.09 g (3 mmol), and add 4 at 60-70 ° C.
Stir for hours. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate and then washed with brine. The ethyl acetate layer was added to Na ₂ SO ₄
The extract was dried over 10H ₂ O, evaporated under reduced pressure, and the residual oily substance was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain compound (16) as a pale yellow oily substance. Hexane was added to this and the obtained crystal was collected by filtration to obtain 0.72 g (melting point 68 to 69 ° C.) (yield 59.3%).

(E) 5,6-dibenzyloxy-2,3-
Dihydrobenzo [b] furan-2-methanol (17)
Production of lithium aluminum hydride (LAH; 1g / 10ml)
1.93 g (4.7) of compound (16) in a suspension of (THF).
7 mmol / 20 ml THF) was gradually added under ice cooling.
After 0.5 hours, 1 ml of water, 1% of 15% sodium hydroxide solution
ml, water 3 ml, and magnesium sulfate were slowly added in this order, and the mixture was stirred at room temperature for 0.5 hours. The mixed solution was filtered, and the solvent of the filtrate was evaporated under reduced pressure to obtain 1.63 g of the compound (17) as a colorless oily substance (yield 94.3%).

(F) 5,6-dibenzyloxy-2,3-
Dihydrobenzo [b] furan-2-aldehyde (18)
3.12 g (8.61 mmol) of compound (17) and 7.10 g (34.4 mmol / 4) of dicyclohexylcarbodiimide
0 ml DMSO (dimethyl sulfoxide)
e)) A solution of 1 MH ₃ PO _4/4 ml DMSO was stirred at room temperature for 3 hours. The reaction mixture was added to 50 ml of chloroform and filtered. The filtrate was mixed with ethyl acetate and washed with brine. The ethyl acetate layer was dried over Na ₂ SO ₄ · 10H ₂ O and evaporated under reduced pressure to give a pale yellow oily substance. This oily substance was purified by silica gel column chromatography (ethyl acetate: chloroform = 9: 1) to give the compound (1
1.82 was obtained as a colorless oily substance (1.92 g, yield 61.
8%).

(To) 2- (1,3-pentadienyl)-
Production of 5,6-dibenzyloxy-2,3-dihydrobenzo [b] furan (19) Sodium hydride 102 mg (4.25 mmol), 2-butenyl triphenylphosphonium bromide 1.0 g
A mixture of (2.55 mmol / 10 ml THF) at room temperature 1
Stir for 5 minutes and add 610 mg of compound (18) (1.
69 mmol / 5 ml THF) was added. After stirring the reaction mixture at room temperature for 5 hours, 10 ml of saturated ammonium chloride was added,
It was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na ₂ SO ₄ · 10H ₂ O, and evaporated under reduced pressure to give a pale yellow oily substance. This was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1),
Compound (19) as a slightly yellowish oily substance 27
7 mg was obtained (yield 41.1%).

(H) 2- (1,3-pentadienyl)-
5,6-dihydroxy-2,3-dihydrobenzo [b]
Production of furan (1-2) A stirred solution of 950 mg of compound (19) (2.38 mmol / 8)
9.5 ml of dimethyl sulfide and boron trifluoride etherate (6 ml) were added to 20 ml of dichloromethane at -20 ° C. The reaction mixture was stirred at -20 ° C for 3 hours and then gradually warmed to room temperature. After 1 hour, 15 ml of water was added and the mixture was extracted with 15 ml of ethyl acetate. The organic layer was washed successively with saturated sodium hydrogen carbonate solution and brine, and then Na ₂ SO ₄ · 10H.
Dry over ₂ O and evaporate the solvent under reduced pressure to leave a reddish oil. This was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain a crystalline solid. The target compound (1-2) was obtained by recrystallizing this solid from a mixed solvent of ethyl acetate-hexane.
162 mg of crystals of mp. (Melting point 129-130 ° C) were obtained (yield 31.2%). The ¹ H-NMR spectrum (internal standard TMS) of the compound (1-2) is shown in FIG.

Experimental Example 1 (5-lipoxygenase activity inhibitory action) RBL-1 cells (Rat Basophilic Le
UKEMIA, purchased from Dainippon Pharmaceutical Co., Ltd.) 2.5 × 10 ⁷ cells were washed twice with 0.1 M Tris-hydrochloric acid buffer (pH 7.5) and then disrupted by sonication. Ultracentrifugation is performed at 100,000 × g for 90 minutes, and the supernatant is used as a 5-lipoxygenase enzyme solution.
μl and 0.1 M Tris-HCl buffer (pH 7.5) 1.7
5 ml, arachidonic acid 100 μM, CaCl ₂ 1 ml, AT
P (adenosine triphosphate) 1 mM and the compound of the present invention (1-
1) and (1-2) (final concentration is 10 μM, 3.0 μM
, 1.0 μM, 0.3 μM and 0.1 μM)
Each of the reaction liquids consisting of is reacted at 37 ° C for 10 minutes. The reaction is stopped by adding 50 μl of 1N HCl and the mixture is extracted with 6 ml of ethyl acetate. The extract was concentrated under reduced pressure, the method of this concentrate Amano et al (vitamins, 5
9 , 211-219 (1985)) and quantify 5-HETE with a UV detector. The concentration of the compound of the present invention that inhibits 5-lipoxygenase activity by 50% (IC ₅₀ ) is represented by the concentration of the compound of the present invention that inhibits the production of 5-HETE by 50% as compared with the control group. The results are shown in Table 1.

[0054]

[Table 1]

As is clear from the results shown in Table 1, the compounds of the present invention have a remarkable inhibitory action on 5-lipoxygenase activity.

Experimental Example 2 (Contractile Inhibitory Action on Sensitized Guinea Pig Isolated Trachea) Ovalbumin (OVA) of 50 mg / ml physiological saline was used.
Male guinea pigs (Hartley) were intraperitoneally and subcutaneously administered once at 1 ml / body, and after 2 to 3 weeks, the trachea was removed and used for the experiment. The isolated trachea was cut into a spiral shape and suspended in a Magnus tube (10 ml, 31 ° C.) connected to an isotonic transducer with a load of 1.0 g to record the change in tension. To eliminate the action of prostaglandins, indomethacin (indo)
The Magnus tube was filled with Krebs solution containing methacin; 1.4 × 10 ⁻⁶ M). Histamine (10 μg / ml) was added to the Magnus tube to contract the trachea, and the maximum tension at that time was measured, and the value was taken as the standard tension of each trachea sample. Next, pyrilamine (7 × 10 ^-6 M), which is an antihistamine
Was added to the Magnus tube to remove the effect of histamine, and then compound (1-1) (20 μM) or compound (1-
2) (10 μM or 20 μM) was added, and the antigen (O
VA) (10 μg / ml) was added, and the contraction of the trachea induced by OVA was measured by tension over time. OVA
The inhibition rate of the compound (1-1) and the compound (1-2) on the contraction of the trachea caused by
Two points were calculated at the maximum contraction and 60 minutes after the addition of OVA. The results are shown in Table 2.

[0057]

[Table 2]

As is clear from the results shown in Table 2, the compounds of the present invention have a remarkable tracheal contraction inhibitory action. According to the present experimental system, both compound (1-1) and compound (1-2) were found to suppress the tracheal contraction more strongly than the benzofuran derivative described in WO91 / 07396. It was

Experimental Example 3 (Single-dose toxicity test in mice) As test animals, 5-week-old male ICR mice (purchased from Charles River Japan) were used. Compounds (1-1) and (1-2) were prepared to 6 mg / ml with 66.7% polyethylene glycol, 40 mg / kg was administered to 5 animals, 60 mg / kg was administered to 1 animal, and a single intravenous injection from the tail vein was performed. Was administered. After the administration, the general condition / mortality was observed and the body weight was measured, and the dead animals were immediately sacrificed, and the surviving animals were sacrificed 13 days after the administration, and necropsy was performed.

In compound (1-1), 60 mg / kg
In the administration example, the subject died 1 minute after administration. In the case of 40 mg / kg administration, all cases survived until 13 days after administration. From the above, the LD ₅₀ value of compound (1-1) was estimated to be less than 60 mg / kg. Regarding the change in body weight, normal weight gain was shown over 13 days after administration. Regarding autopsy, no clear change was observed in either dead or surviving cases.

In compound (1-2), 60 mg / kg
In the administration example, death occurred 6 minutes after administration. In the case of 40 mg / kg administration, 2 cases died 1 day and 2 days after administration, respectively.
From the above, the LD ₅₀ value of compound (1-2) is estimated to be 40 mg / kg or more. Regarding the change in body weight, the body weight decreased or suppressed to increase until 7 days after administration. After 7 days, the degree of increase in body weight was greater than that in the control group, and after 13 days, there was no difference from the control group. Regarding autopsy, in the case of death, dark redness due to congestion of lung hardness was observed in both the 60 mg / kg administration group and the 40 mg / kg administration group. In all surviving cases, no change was observed in the organs of the whole body.

[0062]

The benzofuran derivative of the present invention has a remarkable 5-lipoxygenase activity inhibitory action, and also has excellent anti-allergic and anti-inflammatory actions, and allergic diseases such as bronchial asthma and rheumatic diseases, It is useful as a therapeutic / preventive drug for psoriasis and various other inflammations.

[Brief description of drawings]

FIG. 1 is a drawing showing a ¹ H-NMR spectrum of a compound (1-2) of the present invention.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiro Sato 540, Narita, Odawara, Kanagawa Prefecture Meiji Dairy Industry Health Science Research Institute (72) Inventor, Itaro 540, Narita, Odawara, Kanagawa Prefecture Meiji Dairy Industry Health Science Research Institute (72) Inventor Yoshihiro Yoshiyama 540 Narita, Odawara, Kanagawa Prefecture Meiji Dairy Health Science Institute

Claims (3)

[Claims] 1. The following general formula (1): (In the formula, R represents a hydrogen atom or a hydroxyl group), a benzofuran derivative. 2. An anti-allergic agent comprising the benzofuran derivative according to claim 1 as an active ingredient. 3. An anti-inflammatory agent comprising the benzofuran derivative according to claim 1 as an active ingredient.