JPS61152669A - Dibenzo(b,e)oxepine derivative and antiallergic agent - Google Patents

Abstract

NEW MATERIAL:Dibenzo[b,e]oxepine derivative of formula I {R<1> is H or methyl; one of R<2> and R<3> is COR<5> [R<5> is hydroxy, lower alkoxy, 1-(ethoxycarbonyloxy)ethoxy, or amino] or cyano and the other is H; R<4> is 4-methylpiperazino or Y-(CH2)nNR<6>R<7> (Y is NH, O or S; n is 2-4; R<6> and R<7> are H or lower alkyl)} or its salt. EXAMPLE:11-(4-Methylpiperazino)-6,11-dihydrodibenzo[b, e] oxepine-3-carboxylic acid methyl ester. USE:Useful as an anti-allergic agent. Administered preferably by oral administration or by injection. PREPARATION:The compound of formula Ia can be prepared according to the reaction formula, by reacting the compound of formula II [one of R<8> and R<9> is COR<10> (R<10> is lower alkoxy, etc.) and the other is H] with thionyl chloride in a solvent, and reacting the reaction product with the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to dibenz (b, e) oxepin derivatives and antiallergic agents containing these as active ingredients.

BACKGROUND OF THE INVENTION Dibenz(b,e)oxepin derivatives are known as anti-inflammatory agents (see J. Ned, Chem., vol. 21, p. 633, 1978) or for use in the treatment and control of allergic symptoms (U.S. Pat. 4.282.3
65) is known as prior art.

There is also an application filed by the present applicant regarding dibenz (b, e) oxepin derivatives and antiallergic agents containing these as active ingredients (Japanese Patent Application No. 118/009/1989).

Problems to be Solved by the Invention There is a constant need for compounds that have novel and useful antiallergic effects.

Means for Solving the Problems The present invention is based on the formula (1) [wherein R1 represents a hydrogen atom or a methyl group, and one of R2 and R3 is COR'' (wherein R5 represents a hydroxyl group, a lower alkoxy group, -(ethoxycarbonyloxy) represents an ethoxy group or an amino group) or a cyano group, the other represents a hydrogen atom, and R4 is a 4-methylpiperazino group or Y-(CHz)nNR'R'
(In the formula, Y represents NH, O and S, n represents 2.3 or 4, R6 and R1 are the same or different,
Represents a hydrogen atom or a lower alkyl group. ) represents. ]
Dibenz (b, e) oxepin derivatives represented by [hereinafter referred to as compound (I)]. Regarding compounds with other formula numbers.

] or its acid addition salt or metal salt, and an antiallergic agent containing at least one of these as an active ingredient.

The present invention will be explained in more detail below.

In the definition of each group in formula (1), examples of lower alkyl groups include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, and propyl groups. Further, examples of the lower alkoxy group include an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, a nidoxy group, and a propoxy group.

Compound (I) is produced by the following method.

Production method A [In the formula, R1 and R4 represent the same meanings as above, and one of R1 and R'' represents COR'' (in the formula, R111 represents a lower alkoxy group or an ami7 group) or a cyano group, and the other represents represents a hydrogen atom. ] Compound (n)
and 1 to 2 equivalents of thionyl chloride are reacted in an inert solvent such as methylene chloride, chloroform, benzene, toluene, ethyl ether, tetrahydrofuran, N,N-dimethylformamide, etc. from ice-cooling to room temperature for 30 minutes to 3 hours. . If thionyl chloride is used in excess, remove excess thionyl chloride from the reaction solution itself, add the solvent as necessary, and then add 1- to compound (n).
By adding 10 equivalents of compound (III) or its acid addition salt, and reacting for 30 minutes to 10 hours at an appropriate temperature between ice cooling and the boiling point of the solvent used, in the presence of a base such as triethylamine if necessary, the objective can be achieved. Compound (Ia>) is obtained.

Manufacturing method B I 1m [In the formula, R1 and R4 represent the same meanings as above, and RI 1
and R12, one of which is COR" (in the formula, R1s
represents a lower alkoxy group. ), and the other one represents a hydrogen atom; one of R13 and RI 4 represents a carboxyl group, and the other represents a hydrogen atom. ] Said manufacturing method A
The target compound (IC) is obtained by hydrolyzing the compound (Ib) obtained using the above method in aqueous methanol or aqueous ethanol solution of caustic soda or caustic potash at an appropriate temperature from room temperature to reflux.

Manufacturing method C [e; Width meter and R4 represent the same meanings as above, one of RIS and R16 represents a 1-(ethoxycarbonyloxy)ethoxycarbonyl group, and the other represents a hydrogen atom. ] Alkali metal of compound (IC) and 1-3 equivalents of carbonate α
-chlorodiethyl and N,N-dimethylformamide,
The target compound (Id) is obtained by reacting in an inert solvent such as tetrahydrofuran at an appropriate temperature from room temperature to 100°C for 1 to 5 hours in the presence of a catalytic amount of potassium iodide or sodium iodide as necessary. obtain.

Unless otherwise specified, the isolation and purification of the target compound in each of the above production methods may be carried out by operations commonly used in organic synthesis reactions, such as filtration, extraction with organic solvents such as ethyl acetate, methylene chloride, etc., drying, concentration, and subsequent steps as necessary. Depending on the situation, it can be carried out by recrystallization or purification by column chromatography. In addition, the compound (If) used as a starting material is, for example, a compound (n) in which either R8 or Ra represents COR" (in the formula, R1ff represents a lower alkoxy group), the present application Application filed on the same date as the present application by a person [Patent Application (7), Gibens (b.

[e] Method for producing oxepine derivatives], and for those containing a carboxamide group or cyano group, the method disclosed in U.S. Pat. ).

In order to obtain a salt of the target compound, if the target compound is obtained in the form of a salt, it may be purified as is, or if it is obtained in a free form, the salt may be produced by a conventional method.

Pharmaceutically acceptable acid addition salts of the target compound include inorganic acid salts such as hydrochloride, sulfate, and phosphate, and organic acids such as acetate, maleate, fumarate, tartrate, and citrate. Examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts and calcium salts.

Next, specific examples of the compounds of the present invention are shown in Table 1, their structures are shown in Table 2, and their physical and chemical properties are shown in Table 3.

Table 1 Table 2 Next, the antiallergic effect and acute toxicity test of this compound will be explained.

Anti-allergic effect test The anti-allergic effect was tested on rats for 48 hours.
spc^ (passive cutaneous a)
(naphlaxis) test. In addition, as experimental animals, the body weight should be 180 to 220 g for collecting antiserum.
One star male rat was used for the PCA test with a body weight of 1
WiStar male rats weighing 20-140 g were used.

A) Preparation of anti-εW Parat serum 5totland and 5hare method (Can
ad, J, Phys+ol.

Anti-ovalbumin rat serum was prepared by Pharmacol, 52.1114.1974). In other words, 1■ EWA is aluminum h
Hydroxide gel 2Qmg was mixed with 0.5ml of pertussis-diphtheria-tetanus combination vaccine and administered subcutaneously into the paws of rats in 4 divided doses.

After 14 days, blood was collected from the carotid artery, serum was separated, and -80
It was stored frozen at ℃. 48 hour homol of this antiserum
The titer of ogous PCA was 1:32.

B) 48 h ha of rats (Ilologous PC
^ Using 3 rats in test group 1, anti-EWA rat serum 0 diluted 8 times with physiological saline was applied to two areas on the back and inside where hair was removed.
．． Passive sensitization was performed by injecting 0.05 ml of each sample.

After 47 hours, the compound of the present invention or its solution (physiological saline or CMC solution) was orally administered, and 1 hour later, antigen lung^
1% Evans blue saline containing 2IIIg was added to 0.
After 30 minutes of administering 5 ml/100 g into the tail vein, the animals were exsanguinated to death, the skin was peeled off, and the amount of leaked dye was measured using the method of Katayama et al. [Microbioj
, Immunol.

22, 89 (1978)]. In other words, cut out the blue dyed part with scissors, IN KON 1m
1 in a test tube and incubate for 24 hours at 37°C.

0.6N! Add 9 parts of a phosphoric acid/acetone (5:13) mixture, shake, centrifuge at 2500 rpm for 10 minutes, measure the absorbance in 620 μl of the supernatant, and quantify the amount of leaked dye using a calibration curve prepared in advance. . The average value of the two locations was taken as the value for one individual, and the inhibition rate for each individual was calculated using the following formula.

Suppression rate (%) = Inhibition rate of 50% or more was considered positive for PCA suppression effect, and the minimum dose at which a positive case was observed in at least one out of three animals was defined as the minimum effective amount (MEO). The results are shown in Table 4.

Acute toxicity test The compound of the present invention was administered orally (po: 300 mg/k
g) or intraperitoneally (ip: 100 μ/kg). The mortality situation was observed 7 days after administration, and the MLD (minimum mortality dose) value was determined. The results are shown in Table 4.

Table 4 As is clear from Table 4, compound (1) and its pharmacologically acceptable acid addition salts and metal salts have antiallergic effects and are useful as pharmaceuticals.

Compound (I) can be used in various pharmaceutical forms for administration purposes in view of its pharmacological action.

The pharmaceutical composition of the present invention can be prepared by homogeneously mixing an effective amount of the free form or acid addition salt of Compound (I) as the active ingredient with a pharmaceutically acceptable carrier.

The carrier will depend on the form of preparation desired for administration.
It can take a wide range of forms. These pharmaceutical compositions are desirably in unit dosage form suitable for administration orally or by injection. Any useful pharmacologically acceptable carrier can be used in preparing the compositions in oral dosage forms. For example, oral I-M preparations such as suspensions and syrups may contain water, sugars such as sucrose, sorbitol, and fructose, polyethylene glycols, propylene glycols, oils such as sesame oil, olive oil, soybean oil, etc. It can be manufactured using preservatives such as alkyl parahydroxybenzoate, and flavors such as strawberry flavor and peppermint tomato. Powders, tablets, capsules, and tablets contain excipients such as lactose, glucose, sucrose, and mannitol, starch, and disintegrants such as sodium alginate.
Lubricants such as magnesium, stearate, and talc, polyvinyl alcohol 1. It can be manufactured using binders such as citroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, and the like. Tablets and capsules are the most useful oral dosage units because of their ease of administration. Solid pharmaceutical carriers are used in the manufacture of tablets and capsules. Injectable solutions can also be prepared with carriers consisting of saline solutions, glucose solutions, or mixtures of saline and glucose solutions. The effective dose of the compound represented by general formula (1) is 1
〜20■/kg/day, and the number of administrations is 3 times a day.
~4 times is preferred.

Examples and reference examples are shown below.

In addition, the physicochemical properties of the target compounds obtained in the examples are as follows.
shown in the table.

Reference example 4-Bromo-2-methyl-11-oxo-6,11'-
Dihydrodibenz (b,e) 135.0 g of oxepin and 11145.8 g of cyanide are suspended in 700 ffil of N,N-dimethylformamide and refluxed for 8.5 hours.

Ferric chloride hexahydrate 180.0g, concentrated hydrochloric acid 44.5m
1 and 1.5 l of water were added, and the mixture was stirred at 70°C for 30 minutes. After cooling, the mixture is extracted twice with chloroform (1) and 01 (Ol). The organic layer was washed with water, dried over anhydrous sulfuric acid and concentrated under reduced pressure. The obtained crude crystals were heated and dissolved in toluene 3001111, activated carbon was added and stirred, and hot filtration was performed.
- Add hexane 1501111 and precipitate crystals at room temperature. The crystals were collected by filtration and dried under reduced pressure to obtain 2-methyl-11
83.2 g of -oxo-6,11-dihydrodibenz(b,e)oxepin-4-carbonitrile are obtained.

Melting point: 181-182℃ IR (Br tablet): 2240.1640.147
0.1305cm-'NMR (CDCj!3.δppm
): 2.37 (s, 3H), 5.33 (s,
2B>, 7.35-7.80 (m, 6H) Elemental analysis value Cls Hr r N As Ox (%) CHN Calculated value 77.09 4.45 5.62 Theoretical value 76.88 4.19 5.46 2-methyl-11-oxo-6,1 thus obtained
65.0 g of 1-dihydrodibenz(b,e)oxepin-4-carbonitrile was dissolved in 75% sulfuric acid 1. The suspension was suspended in Ol and stirred at 80°C for 2.5 hours. After cooling, ice water 6.0
1 and stir for 30 minutes. The resulting crystals are filtered, washed with water, and then dried by heating under reduced pressure.

The obtained crude crystals were purified by recrystallization from 1.81 toluene to obtain 2-methyl-11-oxo-6,11-dihydrodibenz (b, e) oxepin-4-carboxamide 50
．． Obtain 8 g.

Melting point: 193-195℃ IR (KBr tablet): 3460.1640.15
90.1570.1435゜1260cm-' NMR(DMSOJi, δPI)m): 2.3
2(s, 3H), 3.58(brs.

2H), 5.213(s, 2H), 7.25-7.
93 (Tan, 6H) Elemental analysis value Cr * H + s N
As O3 (%) C) (N Calculated value ?1.9Q 4.90 5.24 Actual value 71.83 4.71 5.0 2-methyl-11-oxo-6, obtained as in 11-
10.0 g of dihydrodibenz (b, e) oxepine-4-carboxamide is suspended in 11 Qml of ethanol, 0.85 g of sodium borohydride is added, and the mixture is stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and 10% of water was added to the residue.
After adding Qml and stirring, the crude crystals are collected by filtration. The crude crystals were purified by recrystallization from 70 Qml of ethanol to obtain 11-hydroxy-2-methyl-6,11-dihydrodibenz (
b, e) Oxepin-4-carboxamidro, 7 g are obtained.

Melting point: 176-179°C IR (KBr tablet): 3440.1640.1570
．． 1440.1210cm-'NMR (mouth MSO-d6
．． δpl)Il+): 2.22(s, 3
H), 4.52 (brs.

3H), 5.29 and 5.57 (q, 2H, 80 type), 5.92 (s, IH), 7.12-7
．． 40 (m, 6) 1) Elemental analysis value C+ s H+ s
N O3 (%) HN Calculated value 71.36 5.61 5.20
Actual value? 1.15 5.48 5.08
Example 1 11-Hydroxy-6,11-dihydrodibenz [b.

e] 6.8 g of methyl oxepin-3-carboxylate was suspended in 100 ml of methylene chloride, and 5.8 g of methyl oxepin-3-carboxylate was suspended in 100 ml of methylene chloride.
．． Add 9g dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated to dryness under reduced pressure, and methylene chloride 100II11 was added to the residue to dissolve it. A solution of 25 g of N-methylpiperazine dissolved in 30 IIll of methylene chloride was immersed in water-cooling, and the mixture was stirred at room temperature for 2 hours.
Stir for an hour. After adding 10 ports a+1 of methylene chloride and washing with water, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent
By subjecting the main fraction to ethyl acetate:triethylamine=10:1) and concentrating the main fraction, methyl 1l-(4-methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-3-carboxylate (compound 1) Obtain 6.2g.

11.5 g of the compound thus obtained was added to 15a+1
1.3 ml of an 8.2M hydrogen chloride-itubrobanol solution was added to the solution, and the mixture was allowed to stand at room temperature.

The resulting crystals were collected by filtration and dried under reduced pressure to obtain compound 1-2.
1.8 g of hydrochloride X hydrate (compound 1') is obtained.

Example 2. -7° Compound 2-7 and compounds 2' and 3' were prepared in the same manner as in Example 1 except that the compounds listed in Table 5 were used as raw materials.
, 4', 6' and 7' are obtained.

The results are shown in Table 5.

Example 8゜ 11-hydroxy-6,11-dihydrodibenz [b.

e] 6.8 g of methyl oxepin-3-carboxylate was dissolved in IO Qml of methylene chloride, and 5.9 g of thionyl chloride was added dropwise under water cooling, followed by stirring at room temperature for 2 hours. It was concentrated to dryness under reduced pressure, and the residue contained 7.1 g of 2-dimethylaminoethanethiol hydrochloride and 14 g of N,N-dimethylformamide.
Add 0101 and stir at 120°C for 3 hours. After concentrating to dryness under reduced pressure, 10 Qml of water was added, followed by 4N hydrochloric acid to adjust the pH to 1 and dissolve the soluble materials. After washing with 30 ml of ether, a 4N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12. Extract with 200 ml of ether, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent
Ethyl acetate:triethylamine=10:1) and concentrated the main fraction to give methyl 1l-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz (b,el oxepin-3-carboxylate) ( 7.7 g of compound 8) was obtained.

81.5 g of the compound was dissolved in 15 ml of Impropatol, 0.8 liter of 8.2M hydrogen chloride Impropatol solution was added, and the mixture was concentrated to dryness under reduced pressure. The crude crystals of the residue are purified by recrystallization using Improper Tools to obtain 1.5 g of monohydrochloride of compound 8 (compound 8').

Example 9. -13° Compound 9-12.27 and Compound 9 were prepared in the same manner as in Example 8 except that the compounds listed in Table 6 were used as raw materials.
', 10', 11' are obtained.

The results are shown in Table 6.

Example 14゜1l-(2-dimethylaminoethyl)thio-6,11-
2.0 g of methyl dihydrodibenz[b,e]oxepine-3-carboxylate (compound 8) is dissolved in 201'nl of an IN-sodium hydroxide 60% ethanol aqueous solution and refluxed for 1 hour. After cooling, concentrate under reduced pressure and add 3Qml of water to the residue.
Add and dissolve, and adjust to p) 15 by adding 4N hydrochloric acid.

After stirring at room temperature for 1 hour, the resulting crystals were collected by filtration and dried under reduced pressure by heating to give 1l-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-
1.7 g of 3-carboxylic acid (compound 13) is obtained.

131.5 g of the obtained compound was added to 15 m of Improper Tools.
8.2M hydrogen chloride inpropertool solution Q
, and concentrated to dryness under reduced pressure. The residue is purified by recrystallization from ethanol to obtain 1.3 g of compound 13 monohydrochloride 3/4 hydrate (compound 13').

Example 15. -18゜Example 14 except that the compounds listed in Table 7 were used as raw materials.
Compound 14-17 and compound 15 were prepared by the same method as
', 16' and 17' are obtained. The results are shown in Table 7.

Example 19゜1l-(2-dimethylaminoethyl)thio-6,11-
3.1 g of ethyl dihydrodibenz (b, e) oxepine-4-carboxylate (compound 9) was dissolved in a 60% aqueous IN sodium hydroxide ethanol solution and refluxed for 1 hour. After cooling, it was concentrated under reduced pressure, and 50 ml of water was added to the residue to dissolve it. Add 4N hydrochloric acid to adjust the pH to 5, and concentrate under reduced pressure. The residue is subjected to high porous polymer (IP-10) column chromatography (eluent: methanol) and the main fraction is concentrated. Add Improper Tool to the residue and crystallize it 1
2.4 g of l-(2-dimethylaminoethyl)thio-6,11 dihydrodibenz (b, e) oxepine-4-carboxylic acid compound 18) is obtained.

This is suspended in 3 Qml of Improper Tool, and 2 ml of 8M hydrogen chloride Improper Tool solution is added.

The mixture was concentrated to dryness under reduced pressure, and the residue was purified by recrystallization from Improper Tools to obtain 1.7 g of compound 18 dihydrochloride quarter hydrate (compound 18').

Example 20. -23゜Example 19 except that the compounds listed in Table 7 were used as raw materials
Compound 19-22 and compound 19'-2 in the same manner as
We get 2'. The results are shown in Table 7.

Example 24 2.6 g of 1l-(4-methylpiperazino)-6,11-dihydrodibenz(b,e) methyl oxepin-3-carboxylate (compound 1) was added to IN sodium hydroxide 6
Dissolve in 0% ethanol aqueous solution 3Qa+1 and reflux for 1 hour. Concentrate to dryness under reduced pressure, and the residue contains 3.4 g of α-chlorodiethyl carbonate, 0.1 g of sodium iodide, and N,N
- Add 39 ml of dimethylformamide and hold at 80-90°
Stir for 5 hours. After cooling, the mixture was concentrated to dryness under reduced pressure, 5 Qml of water was added to the residue, and 4N hydrochloric acid was further added to adjust the pH to 2 to dissolve the soluble portion. After washing with ether 20+01,
The pH was adjusted to 10 by adding 4N aqueous sodium hydroxide solution, and the mixture was extracted with 5 Qml of ether. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform:methanol = 10:1), the main fraction was concentrated, and 1l-(4-methylpiperazino)-6,1
1-(ethoxycarbonyloxy)ethyl 1-dihydrodibenz(b,e)oxepin-3-carboxylate
“2.7 g (compound 23) is obtained.
232.6 g of one compound was added to a solution of 0.7 g of fumaric acid dissolved in 1,201 ml of amethane, and after stirring at room temperature, the mixture was reduced to a reduced line, and isopropanol was added to the residue, and after stirring at room temperature, By filtration, 2.9 g of compound 23 hepmarate A hydrate (compound 23') is obtained.;Example 25.-27゜The same procedure was carried out except that the compounds listed in Table 8 were used as raw materials. Example 24
Compound 24-26 and compound 24'-2 in the same manner as
Get 6'. The results are shown in Table 8.

Example 28゜11-hydroxy-2-methyl-6,11- as a raw material
Compound 28 was prepared in the same manner as in Example 1, except that 0.65 g of dihydrodibenz(:b,e)oxepin-2-carboxamide and 2.1 g of 2-dimethylaminoethanol were used.
Obtain 0.50 g.

Table 5 Raw materials Product names 4 Compounds used Yield (g
(g) 1-Hydroxy-6,11-dihydrodibenz (b, e) Oxepin 4.8-Ethyl carboxylate 25.64-methylpiperazine 8.51-hydroxy-2-methyl-111-dihydrodibenz (b, e) 3.9Hixebine-4-carboxylic acid di-34,11-J-methylpiperazine 12.91-Hydroxy-6,11-dihydrodibenz[b,e]oxepin-4,2-6
Table 7 Table 8 Table Example 29. Tablets having the following composition are prepared using a conventional tablet method.

1l-(4-methylpiperazino)-6,11-dihydrodibenz (b, e) oxepine-4-carboxylic acid dihydrochloride hydrate (compound 2') 30 ■ Lactose 60 ■ Potato starch 30 ■ Polyvinyl alcohol 2 ■Magnesium stearate 1■ Talal pigment
Micro-amount Example 30. A powder having the following composition was prepared by a conventional method.

11-(N,N-dimethylaminoethyl)thio-6,
11-dihydrodibenz(b,e)oxepin-9-carboxylic acid hydrochloride quarter hydrate (compound 16') 0mg Lactose 270 ■Example 3
1. Syrup A syrup having the following composition was prepared by a conventional method.

1l-(2-dimethylaminoethyl)thio-6,11-
Dihydrodibenz (b, e) oxepine-4-carboxylic acid ethyl fumarate (compound 10') 300 ■ Refined white sugar 40 g Methyl paraoxybenzoate 40 ■ Propyl paraoxybenzoate 10 mg Strawberry flavor 0.1 cc Add water to this total amount 1
00cc.

Effects of the Invention Compound (1) and its acid addition salts and metal salts have antiallergic effects.

Claims (2)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents a hydrogen atom or a methyl group, and R^
Either one of 2 and R^3 is COR^5 (R^
5 represents a hydroxyl group, a lower alkoxy group, a 1-(ethoxycarbonyloxy)ethoxy group, or an amino group. ) or represents a cyano group, the other represents a hydrogen atom, and R^4
is 4-methylpiperazino group or Y-(CH_2)_
nNR^6R^7 (in the formula, Y represents NH, O or S, n represents 2, 3 or 4, and R^6 and R^7 represent the same or different hydrogen atom or lower alkyl group. ) represents. ] Dibenz [b, e]
An oxepin derivative [hereinafter referred to as compound (I)] or a pharmacologically acceptable acid addition salt or metal salt thereof. (2) An antiallergic agent containing Compound (I) or a pharmacologically acceptable acid addition salt or metal salt thereof as an active ingredient.