JPS61257981A - Dibenz(b,e)oxepin derivative and antiallergic agent - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I {R<1> is (CH2)mOR<3> [R<3> is H, CH2CH(OH)CH2OCH2CH3, CH2CH(OAC)CH2OCH2CH3 or CH2OCH2CH2 OCH3; m is 1-4], CH(CH3)CH2OCR<3>, CH=CHCOOR<4> (R<4> is H or lower alkyl), (CH2)nCOOR<4> (n=1-3), etc.; R<4> is 4-lower alkylpiperazino group, 4-lower alkylhomopiperazino group or Y-(CH2)lNR<5>R<6> (Y is HN, O, etc.; R<5> and R<6> are lower alkyl; l is 5-6)}. EXAMPLE:11-( 2-Dimethylaminoethyl )thio-6, 11-dihydrodibenz[b,e]oxepin acetic acid methyl ester. USE:Useful as a drug having antiallergic action. PREPARATION:For example, a compound shown by the formula II is reacted with thionyl chloride and reacted with a compound shown by the formula III to give a compound shown by the formula Ia among compounds shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a dibenz(b,e)oxepin derivative and an antiallergic agent containing the same as an active ingredient.

Conventional technology Dibenz (b, e) oxepin derivatives include anti-inflammatory agents (JoMed, Chem, Vol. 21, p. 633, 1
US Pat. No. 4,282,36) or Methods for Use in Treating and Controlling Allergic Conditions
5) are known from the 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. 118/1989).

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 provides compounds of formula (I) [wherein R1 is (CH2)IIIOR' (wherein R
3 is a hydrogen atom, CH2Cl(0)1)C)120CH,
CH3,C)12CH(OAc)CH20C)IzCH
s or CHaOCf12CI'120CHs, and m represents an integer from 1 to 4. ), CH(C)Is)C
HzOR'' (in the formula, R3 represents the same meaning as above),
C) I=CHC0R4 (in the formula, R4 represents a hydrogen atom or a lower alkyl group), (C)I2) ncOOR
' (In the formula, R4 represents the same meaning as above, and n represents an integer from 1 to 3.), or CH(CH3)C0mouthR4(
In the formula, R4 represents the same meaning as above. ) and R2 is 4
-lower alkylpiperazino group, 4-lower alkylhomopiperazino group or Y-(CL) t NR' (in the formula,
Y represents NH, 0 or S, R5 and R6 represent the same or different lower alkyl groups, and t represents an integer of 2 to 5. ) represents. ) represented by dibenz (b, e
) Oxepin derivative [hereinafter referred to as compound (1). The same applies to compounds of other formula numbers] or a pharmacologically acceptable acid addition salt or metal salt thereof, and an antiallergic agent containing at least one of these compounds as an active ingredient.

The present invention will be explained in detail below.

In the definition of each group in formula (1), the lower alkyl group includes an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, etc. (4-lower alkylpiperazino group or 4-lower alkyl group). The same applies to the lower alkyl group of the alkyl homopiperazino group). Compound (I) includes all possible stereoisomers.

Compound (I) is produced by the following method.

Manufacturing method A (II) (I[[) (I
a) [In the formula, R7 is (CH2) ncOOR' (in the formula, n represents the same R6 meaning as above, and R6 represents a lower alkyl group) , R"lt represents the same meaning as above.), and R2 represents the same meaning as above. ] Compound (n) and 1-2 equivalents of thionyl chloride were mixed in methylene chloride, chloroform, benzene,
Toluene, ethyl ether, tetrahydrofuran, N,
The reaction is carried out in an inert solvent such as N-dimethylformamide at an appropriate temperature ranging from water cooling to room temperature for 30 minutes to 3 hours.

Next, in the reaction solution itself, or in the case where thionyl chloride was used in excess, excess thionyl chloride was distilled off, and the above-mentioned solvent was added as necessary, and 1-1 was added to compound (If).
Add 0 equivalents of the compound (DI) or its acid addition salt and, if necessary, 1-2 equivalents of a base such as triethylamine, and heat for 30 minutes at an appropriate temperature between water cooling and the boiling point of the solvent used.
Compound (Ia) is obtained by reacting for 10 minutes to 10 hours.

Manufacturing method B (IV) (V) (Vl)
(Ib) (wherein R2 and R
8 represents the same meaning as above) for compound (■) 1-1.
5 equivalents of dialkylphosphonoacetic acid alkinope such as ethyl diethylphosphonoacetate etc. and 1-
After reacting with 1.5 equivalents of sodium hydride in an inert solvent such as ethyl ether, tetrahydrofuran, toluene, etc. under water cooling for 30 minutes to 1 hour, compound (IT)
is added and reacted at an appropriate temperature from water cooling to room temperature for 1 to 3 hours to obtain compound (V). Compound (V) and 0.5-1
The compound (
VT).

Compound (VI) was treated in the same manner as in Production Method A to obtain compound (Ib
).

Manufacturing method C (Ic) (Id) [wherein, R
2 represents the same meaning as above, R1 is R7 or CH=C
) ICOOR” (in the formula, R@ represents the same meaning as above), and R10 represents ((Jl*)ncOOH (in the formula,
n represents the same meaning as above. ) , CH(CH3)C0O
H or C1 (=C1lCOOH.) Compound (Ic) is dissolved in a solution of a base such as sodium hydroxide or potassium hydroxide in aqueous methanol or aqueous ethanol at an appropriate temperature between room temperature and the boiling point of the solvent used. Compound (Id) is obtained by holding and hydrolyzing the compound.

Examples include 2-tetrahydropyranyl group, 1-ethoxyethyl group, and 2-methoxyethyl group.

Compound (■) and 0.5-1 equivalent of lithium aluminum hydride are reacted in an inert solvent such as ethyl ether, tetrahydrofuran, toluene, etc. at an appropriate temperature between water cooling and the boiling point of the solvent used for 1-3 hours. Compound (■) is obtained by performing the following steps. Compound (■) and i -1,2 equivalents of sodium hydride were mixed in ethyl ether, tetrahydrofuran, and toluene.

After reacting for 1-2 hours in an inert solvent such as N,N-dimethylformamide at an appropriate temperature between room temperature and the boiling point of the solvent used, 1-3 equivalents of epichlorohydrin or shrimp were added to compound (■). Compound (IX) is obtained by adding bromohydrin and reacting at the same temperature for 1 to 3 hours. Compound (X) is obtained by refluxing compound (IX) in ethanol for 1 to 3 hours in the presence of a base such as potassium hydroxide or sodium hydroxide. Compound (X)
and an equivalent or excess amount, e.g. 1-5 equivalents, of acetic anhydride in pyridine, and if necessary, an inert solvent such as ethyl ether or tetrahydrofuran is added, and the mixture is heated at an appropriate temperature between water cooling and room temperature for 4-10 hours. Compound (X I '') is obtained by the reaction.

The compound (X I '') was prepared from room temperature in a solvent such as tetrahydrofuran, 4-dioxane, etc. containing water in the presence of a catalytic amount of an acid such as hydrochloric acid, sulfuric acid, p-)luenesulfonic acid, etc., and the boiling point of the solvent used was Compound (XII) is obtained by reacting for 3-6 hours at an appropriate temperature between
Compound (Ig
). Compound (Ig) is hydrolyzed at room temperature in a solvent such as methanol, ethanol, or tetrahydrofuran in the presence of a base such as potassium hydroxide or IJium hydroxide to obtain the target compound (Ih).

Production method F (■) (XTV)t4 (XV) (In the formula, R2, Rut R+3 and Z represent the same meanings as above.) Compound (■) obtained by production method E and 1-2 equivalents of methoxyethoxymethyl chloride and 1-4 equivalents of diisopropylethylamine in methylene chloride at room temperature.
Compound (XIV) is obtained by reacting for 3 hours.

Compound (XrV) in tetrahydrofuran containing water, 1
．． The compound (XV ).

Compound (Ih) is obtained by treating compound (XV) in the same manner as in production method A.

Unless otherwise specified, the isolation and purification of the compounds (including intermediates) obtained in the above-mentioned Production Methods A to F may be carried out by operations commonly used in organic synthesis reactions, such as filtration, organic solvents, such as ethyl acetate, methylene chloride, etc. extraction, drying, condensation, and, if necessary, purification by recrystallization or column chromatography.

In addition, the compound (IF) used as a starting material is U
eno et al., JoMed, Chem, vol. 19, 94
1 page (1976) HD, B., Autz et al., J.
, Med, Chem,, vol. 20.

67 pages (1977); D, E, Autz
et al., J.Med.Chem.

20, p. 1499 (1977), or phthalide, 0-)ruyl acid ester and the formula [wherein 1i15 is (CH2)ncOOR' (in the formula R
4 and n represent the same meanings as above. ) or CH(C
L) C0OR' (In the formula, R4 represents the same meaning as above.)
represents. ] can be easily produced by using the method described in the above literature as a raw material.

The compound (rl/) is a patent application filed by the applicant in 1979-279.
930<12/26) along with its manufacturing method.

In the compound (Ie>, RIl is CDOR' (in the formula R'
It has the same meaning as above. ) is JP-A-60-
28972 (2/14), along with its manufacturing method. For the compound (■), the R eye is C0OR” (
In the formula, R8 has the same meaning as above. ) is a compound (■)
is patent application No. 59-279931 (12/
26), and other compounds are the compounds described in Compound (U) or Compound (VI) with a catalytic amount of an acid such as sulfuric acid, ly-)luenesulfonic acid, etc. and a lower alcohol such as methanol or ethanol. It can be obtained by processing or by operations normally performed for the purpose of protecting hydroxyl groups in organic synthesis reactions.

In order to obtain a salt of compound (I), 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 compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, tartrate, and citrate. Examples include organic acid salts, and metal salts include alkali metal salts such as sodium salts and potassium salts.

Examples include 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 Next, the antiallergic effect and acute toxicity test of this compound are explained.

Anti-allergic effect test Anti-allergic effect was tested on rats for 48 hours homolo-go
us PCA (passive cutaneous
The results were investigated using the anaphylaxis test. In addition, experimental animals with a body weight of 180-22 mm were used to collect antiserum.
Wistar male rats weighing 0 g were used for the PCA test, and 1lister male rats weighing 120-140 g were used for the PCA test.

A) Preparation of anti-εIIA rat serum 5totland and 5hare method ((:a
nad, J.

Physiol, Pharmacol, 52.11
Anti-ovalbumin (EwA) by 14.1974)
Rat serum was prepared. In other words, if 1■ BWA is
uminumhydroxide gel 20g
and pertussis diphtheria tetanus combination vaccine Q, 5 m
g and administered subcutaneously to the paw of the rat 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-hour homologous PCA test on rats Using 3 rats per group, anti-[! WA rat serum 0
．． 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, the antigen εWA2ff
0.5ml of 1% Evans blue saline containing 1g/
100 g was administered into the tail vein. After 30 minutes, the animals were bled to death, the skin was peeled off, and the amount of dye leaked from the blue-stained area was measured.
Yama et al.'s method [M 1crob io 1゜[m
munol, 22.89 (1978)). That is, cut out the blue dyed part with scissors, put it in a test tube containing 1 ml of IN KOH, and incubate for 24 hours.
Incubated at 37°C for an hour. 0.6N phosphoric acid
Add 9+ml of acetone (5:13) mixture and shake, then
Centrifuge at 2500 rpm for 10 minutes, and remove 620μ of the supernatant.
The absorbance at m was measured, and the amount of leaked dye was quantified 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.

Inhibition rate (%) = Right, when the inhibition rate was 50% or more, the PCA inhibitory effect was considered positive, 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 dose (MBC). The results are shown in Table 4.

Acute Toxicity Test The compound of the present invention was administered orally (PO: 300 μ/kg) or intraperitoneally (IP: 100 mg/kg) to groups of 3 DD male mice weighing 20±1 g. 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 It has allergic effects and is useful as a medicine such as an anti-asthmatic agent.

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 Compound (I) or its acid addition salt as the active ingredient with a pharmacologically acceptable carrier. The carrier can take a wide variety of forms depending on the form of preparation desired for administration.

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 compositions in oral dosage forms. Oral liquid preparations, such as suspensions and syrups, can be prepared using water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, etc.
It can be manufactured using preservatives such as alkyl parahydroxybenzoates and flavors such as strawberry flavor and peppermint. Powders, capsules, and tablets contain excipients such as lactose, glucose, sucrose, and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl cellulose, It can be manufactured using a binder such as gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin, etc. 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 compound (1) is 1 to 20 mg/kg/day, and the administration frequency is preferably 3 to 4 times a day.

Examples are shown below.

The physicochemical properties of the target compounds obtained in the Examples are shown in Table 3.

Example 1゜ 11-hydroxy-6,11-dihydrodibenz [b.

e] 6.0 g of oxepin-2-methyl acetate was dissolved in 15 Qml of methylene chloride, and 3.0 g of trifluoroacetic anhydride was added to the solution. (Add iml and stir at room temperature for 11 hours. Then 4.5 g of 2-dimethylaminoethanethiol hydrochloride
and a catalytic amount of boron trifluoride ethyl ether complex, and further stirred at room temperature for 2 hours.

The mixture was concentrated to dryness under reduced pressure, and 20 Qml of water and 4N aqueous hydrochloric acid were added to the residue to adjust the pH to 1.0. ether 10
After adding Qml and shaking, discard the organic layer. water layer l0
Adjust the pH to 13.0 using an aqueous N-sodium hydroxide solution. After adding 20 Qml of methylene chloride and shaking, the aqueous layer is discarded, and the organic layer is washed with water and saturated brine. After drying over anhydrous sodium sulfate, it is concentrated to dryness under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate: triethylamine = 40:10:1), and the main fraction was concentrated to dryness under reduced pressure to obtain an oily 1L- (2-dimethylaminoethyl)thio-6,11-dihydrodibenz [b.

e] Oxepin-2-methyl acetate (compound 1) 2.8 g
get.

Example 2゜ 11-hydroxy-6,11-dihydrodibenz [b.

e] 7.4 g of oxepin-2-methyl acetate was dissolved in 1001n+ of methylene chloride, and 2.8 g of thionyl chloride was dissolved under water cooling.
ml was added dropwise and stirred at room temperature for 1 hour. Concentrate to dryness under reduced pressure, dissolve the residue in 5 Qml of methylene chloride, and add 130 g of 1-methylbiperazine to 130 Qml of methylene chloride.
ml solution under water cooling. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified in the same manner as in Example 1 to obtain oily 1l-(4-methylpiperazino)-
6゜11-dihydrodibenz(b,e)oxepin-2
-Methyl acetate (compound 2 > 5.5 g are obtained.

Example 3゜By the same method as in Example 2, 11-hydroxy-6,
11-dihydrodibenz(b,e)oxepin = 7.4 g of 2-methyl acetate was chlorinated using 2.3 ml of thionyl chloride, and then N,N-dimethylethylenediamine 1
5g of oily 1l-(2-dimethylaminoethyl)amino-6,11-dihydrodibenz (b,e)
Oxepin-2-methyl acetate (compound 3) 8.7
get g.

Example 4 By the same method as in Example 2, 11-hydroxy-6,
3.8 g of 11-dihydrodibenz(b,e) oxepin-2-methyl acetate were chlorinated using 1.5+ ml of thionyl chloride and then reacted with 7.2 g of 2-dimethylaminoethanol to give an oily 1 l- (2-dimethylaminoethyl)oxy-6,11-dihydrodibenz (b
, e) Oxepin-2-methyl acetate (compound 4) 0.7
get g.

Example 5゜2-(11-methoxy-6,11-dihydrodibenz(
b, e) Methyl oxepin-2-yl)propionate
2.0 g and 1.4 g of 2-dimethylaminoethanethiol hydrochloride are dissolved in 5 Qml of methylene chloride, 0.5ml of boron trifluoride ethyl ether complex is added, and the mixture is stirred at room temperature for 3 hours. After adding ice chips and stirring for 30 minutes, it was concentrated under reduced pressure, and the residue was purified in the same manner as in Example 1 to obtain an oily 2-[:1l-(2-
1.9 g of methyl dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-yl]propionate (compound 5) is obtained.

Example 6 By the same method as in Example 2, 2-(11-hydroxy-6,11-dihydrodibenz(b,e)oxepin-
2.0 g of methyl 2-[11-(4
-methylpiperazino)-6,11-dihydrodibenz(
b, e) Methyl oxepin-2-yl]propionate (
2.0 g of compound 6) is obtained.

Example 7 2.1 g of the compound obtained in Reference Example 2 was chlorinated using 9 ml of thionyl chloride Q in the same manner as in Example 2, and then reacted with 2.0 g of 1-methylpiperazine to obtain an oily 3-(11-(4-Methylpiperazino)-6,11-dihydrodibenz(b,e) ethyl oxepin-2-ylcoacrylate (compound?) 2.
Obtain 3 g.

Example 8゜1l-(2-dimethylaminoethyl)thio-6,11-
Dissolve 2.8 g of dihydrodibenz (b, e) oxepin-2-methyl acetate (compound 1) in 80 ml of ethanol, and add 0.6 g of sodium hydroxide to 2Q of water.
ml of solution and reflux for 1 hour.

Concentrate under reduced pressure, and add water 100011 and IN-hydrochloric acid aqueous solution to the residue to adjust p) to 15.5. The precipitated crystals were collected and dried by heating under reduced pressure to obtain 1l-(2-dimethylamineethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-acetic acid (compound 8) 2 .3
get g.

82.2 g of the obtained compound was added to Impropatool 3Qml.
1.1 ml of a 5.8M hydrogen chloride inpropatol solution was added under water cooling, and the mixture was stirred at room temperature for 1 hour. The crystals are collected and purified by recrystallization from acetonitrile to obtain 2.1 g of monohydrochloride of compound 8 (compound 8').

Example 9 In the same manner as in Example 8, 11-(4-methylpiperazino)-6,11-dihydrodibenz (b) was prepared.

e] Oxepin-2-methyl acetate (compound 2) 5.5 g
was hydrolyzed using 1.2 g of sodium hydroxide, and the resulting crude product was subjected to high porous polymer (HP-1O) column chromatography (eluent: methanol).

The main fraction is concentrated under reduced pressure and the residue is crystallized by stirring in isopropyl ether. The crystals were collected and dried by heating under reduced pressure to obtain 4.6 g of 1l-(4-methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-2-acetic acid (Compound 9). 94.5 g of the obtained compound was converted into a hydrochloride in the same manner as in Example 8 to obtain the dihydrochloride monohydrate of compound 9 (compound 9')4.
Obtain 5g.

Example 10 By the same method as in Example 8, 1l-(2-dimethylaminoethyl)-amino-6,11-dihydrodibenz(
b, e) Oxepin-2-methyl acetate (compound 3N, 2
g using 0.4 g of sodium hydroxide, and the reaction solution was subjected to the same isolation and purification steps as in Example 9 to obtain oily 1l-(2-dimethylaminoethyl)amino-6,11- Dihydrodibenz(b,e)oxepin-
1.1 g of 2-acetic acid (compound 10) is obtained. 101.0 g of the obtained compound was converted into a hydrochloride in the same manner as in Example 8, and compound 10 dihydrochloride 1.5 hydrate (compound 1
0') 1.0g is obtained.

Example 11゜By the same method as in Example 8, 1l-(2-dimethylaminoethyl)oxy-6,11-dihydrodibenz(b
, e) Oxepin-2-methyl acetate (compound 4) 0.7
g! Hydrolysis was carried out using 0.3 g of sodium hydroxide, and the reaction solution was subjected to the same isolation and purification steps as in Example 9 to obtain an oily 1l-(2-dimethylaminoethyl)oxy-6,11-dihydrodihydride. Benz[b,e]oxepin-
0.4 g of 2-acetic acid (compound 11) is obtained. 110.4 g of the obtained compound was converted into a hydrochloride by the same method as in Example 8, and compound 11 monohydrochloride monohydrate (compound 11') was obtained.
Obtain 0.3 g.

Example 12゜Methyl 2-(11-(2-dimethylaminoethyl)-thio-6,11-dihydrodibenz(b,e)oxepin-2-yltopropionate) was prepared in the same manner as in Example 8. Compound 5) 1.9g and sodium hydroxide 0.6
The reaction solution is adjusted to neutrality by hydrolysis using g. After standing at room temperature for 1 day, the precipitated crystals were collected and dried by heating under reduced pressure to obtain 2-(11-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz(b).
, e) Oxepin-2-isopropionic acid compound 12
)1. Obtain Tg.

12.1.5 g of the obtained compound is converted into a hydrochloride in the same manner as in Example 8 to obtain 1.5 g of 0.5 monohydrochloride of compound 12 (compound 12').

Example 13 By the same method as in Example 8, methyl 2-m-(4-methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-2-yl]propionate (compound 6
) 2.0 g was hydrolyzed using 0.6 g of sodium hydroxide, the reaction solution was adjusted to pH 6.0, and left for 1 day. By collecting the precipitated crystals and heating and drying them under reduced pressure, 2-oi-(4-methylpiperazino)-6
,11-dihydrodibenz(b,e)oxepin-2-
Obtain 6 g of isopropionic acid (compound 13N).

131.5 g of the obtained compound is converted into a hydrochloride in the same manner as in Example 8 to obtain 1.7 g of dihydrochloride monohydrate of compound 13 (compound 13').

Example 14 By the same method as in Example 8, 3-(11-(4-methylpiperazino)-6,11-dihydrodibenz(b,
e) 2.2 g of ethyl oxepin-2-ylcoacrylate
By hydrolyzing with 0.7 g of sodium hydroxide, 3-(11-(4-methylpiperazino)-6
, 11-dihydrodibenz [b, e) Oxepin-2-
1.6 g of ylcoacrylic acid (compound 14) is obtained.

141.4 g of the obtained compound was converted into a hydrochloride salt by the same method as in Example 8, and the dihydrochloride dihydrate of compound 14 (
Compound 14'>1.6 g is obtained.

Example 15゜1l-(2-dimethylaminoethyl)thio-6,11-
10.9 g of ethyl dihydrodibenz[b,e]oxepin-2-carboxylate was dissolved in 15 Q of tetrahydrofuran.
ml, add 0.8 g of lithium aluminum hydride, and stir at room temperature for 1 hour. A small amount of water was added, the resulting inorganic salts were removed, and the p solution was concentrated to dryness under reduced pressure to give 1 liter of oil.
9.0 g of -(2-dimethylaminoethyl)thio-2-hydroxymethyl-6,11-dihydrodibenz(b,e)oxepin (compound 15) is obtained.

151.5 g of the obtained compound was dissolved in acetone (50 ml), 0.6 g of fumaric acid was added, and the mixture was stirred at 50° C. for 1 hour. After cooling, the precipitated crystals are harvested and dried under reduced pressure and heat to obtain 1.3 g of compound 15 monofumarate hemihydrate (compound 15').

Example 16 In the same manner as in Example 15, 11-(4-methylpiperazino)-6,11-dihydrodibenz (b) was prepared.

e] 8.6 g of ethyl oxepine-2-carboxylate was reduced using 0.6 g of lithium aluminum hydride, and the obtained product was recrystallized and purified using a mixed solvent of tetrahydrofuran and ethyl acetate to obtain 2- Hydroxymethyl-11-(4-methylpiperazino)-6,11-
Obtain 4.0 g of dihydrodibenz (b, eel oxepin (compound 16)).

Example 17゜By the same method as in Example 15, 1l-(2-diethylaminoethyl)amino-6,11-dihydrodibenz[
b, e: ]] Oxepine-2-carboxylic acid ethyl 16
g with lithium aluminum hydride to give oily 1 l-(2-diethylaminoethyl)amino-2-hydroxymethyl-6,11-dihydrodibenz(b,e)oxepin (compound 17)0. Obtain 76g.

The obtained 0.71 g of Compound 17 is converted into a hydrochloride salt in the same manner as in Example 8 to obtain 0.73 g of the dihydrochloride of Compound 17 (Compound 17').

Example 18 In the same manner as in Example 15, 11-(4-methylpiperazino)-6,11-dihydrodibenz (b) was prepared.

e] Oxepin-2-acetic acid dihydrochloride (compound 9') 2
．． By reducing 0g with 0.4g of lithium aluminum hydride, oily 2-(2-hydroxyethyl)-11-(4-methylpiperazino)-6,11-
Dihydrodibenz (b, a) oxepin (compound 18)
Obtain 0.9g.

180.8g of the obtained compound was transferred to Impropatool 30m.
Dissolve 8M hydrogen chloride inproper tool solution in 5.8
ml and stirred for 1 hour, the precipitated crystals were collected, washed with isopropyl ether, and dried under reduced pressure with heat to obtain compound 18.
0.8 g of the dihydrochloride di-eternal hydrate (compound 18') was obtained.

Example 19゜1.5 g of the compound obtained in Reference Example 7 was chlorinated using 5 ffll of thionyl chloride Q in the same manner as in Example 2, and then reacted with 1.3 ml of 1-methylbiperazine to give an oily 2- (2-acetoxy-3-ethoxypropyloxy)methyl-11-(4-methylpiperazino)
-6,11-dihydrodibenz (b.

e] Oxepin (compound 22N, 3 g was obtained.

Example 20° 1.3 g of the compound obtained in Example 19 was dissolved in a mixed solvent of 3 Q ml of tetrahydrofuran and 5% potassium hydroxide-methanol solution, and stirred at room temperature for 30 minutes. 2N-
After neutralizing the reaction solution by adding an aqueous hydrochloric acid solution, it is concentrated under reduced pressure. Add 50 Qml of methylene chloride and 30 Qml of water to the residue.
After adding ml and shaking, discard the aqueous layer. After drying the organic layer with anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure.
A crude product is obtained.

This was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate: triethylamine = 10:
10:1) and the main fraction was concentrated under reduced pressure to obtain oily 2-(3-ethoxy-2-hydroxypropyloxy)methyl-11-(4-methylpiperazino)-6.
, 11-dihydrodibenz(b,e)oxepin (Compound 19) 0.9 g is obtained.

190.9 g of the obtained compound was dissolved in 3 Q ml of acetone, 0.23 g of fumaric acid was added, and the mixture was stirred at room temperature for 2 hours. The residue was concentrated to dryness under reduced pressure, and the residue was crystallized by tritinylation with isopropyl ether, which was collected and dried by heating under reduced pressure to obtain compound 19 monofumarate monohydrate (compound 19') 0.9g
get.

Example 21゜2.0 g of the compound obtained in Reference Example 9 was chlorinated using thionyl chloride 0.7a+1 in the same manner as in Example 2, and then 2-dimethylaminoethanethiol hydrochloride 3
．． 0g to form an oily 1l-(2-dimethylaminoethyl)thio-2-methoxyethoxy-methoxymethyl-6,11-dihydrodibenz(b,e)oxepin (
2.5 g of compound 20) is obtained.

201.1 g of the obtained compound is treated in the same manner as in Example 19 using 0.31 g of fumaric acid to obtain 0.9 g of 1 fumarate of compound 20 (compound 20').

Example 22゜I obtained in Reference Example 9 by the same method as Example 21
f-Hydroxy-2-(2-methoxyethoxy)methoxymethyl-6,11-dihydrodibenz(b,e) 1.4 g of oxepin was chlorinated using 0.5 ml of thionyl chloride, and then 1-methylpiperazine 21+11 Oily 2-(methoxyethoxymethoxymethyl)-11-(4-methylbiperazino)-
0.8 g of 6,11-dihydrodibenz(b,e)oxepin (compound 21).

210.8 g of the thus obtained compound is treated in the same manner as in Example 19 using 0.23 g of fumaric acid to obtain 0.7 g of fumarate hemihydrate (compound 21').

Example 23 In the same manner as in Example 1, 2.5 g of methyl 3-(11-hydroxy-6,11-dihydrodibenz(b,e)oxepin-2-yl)propionate and 1 g of trifluoroacetic anhydride were prepared. .5111 From 1.8 g of 1,2-dimethylaminoethanethiol hydrochloride and a catalytic amount of boron pentafluoride ethyl ether complex, 3-(11-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz( b, e) 2.8 g of methyl oxepin-2-yl]propionate (compound 23) are obtained.

Example 24 By the same method as in Example 2, 3-[11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-
2-yl]methyl propionate 2.5 g 1 Thionyl chloride Q, Qml and N-methylbiperazine 4.2 g to 3
- 2.7 g of methyl (11-(4-methylpiperazino)-6,11-dihydrodibenz(b,e''l oxepin-2-yl)propionate (compound 24) are obtained.

Example 25 By the same method as in Example 1, 4-(11-hydroxy-6,11-dihydrodibenz(b,e)oxepin-
4-(11-(2- methylaminoethyl)thio-6,11-dihydrodibenz(b,e]oxepin-2-yl]butyrate (compound 25) 2.
Obtain 5 g.

Example 26゜Methyl 3-(11-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-yl)furopionate (compound 23) 2.1 g and 0 sodium hydroxide
．． 4g of 3-(112
1.5 g of -dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-yl]propionic acid (compound 26) are obtained.

The obtained 1.3 g of Compound 26 was converted into a hydrochloride in the same manner as in Example 8, and the monohydrochloride of Compound 26 (Compound 26'
) Obtain 1.4 g.

Example 27 By the same method as in Example 8, 3-(11-(4methylpiperazino)-6,11-dihydrodibenz(b,e
) Oxepin-2-yl] methyl propionate (Compound 24 > 2.7 g is hydroxylated) Hydrolysis is carried out using 0.6 g of IJium, and after neutralizing the reaction solution, the precipitated crystals are collected with P. , 3-C1 by heating and drying under reduced pressure
1.7 g of 1-(4-methylpiperazino)-6,11-dihydrodibenz(b,e)oxepin-2-yl]propionic acid (compound 27) are obtained.

271.7 g of the obtained compound was converted into a hydrochloride salt by the same method as in Example 8, and dihydrochloride of compound 27 (compound 27
'H, 75g is obtained.

Example 28 By the same method as in Example 8, methyl 4-(11-(2-dimethylaminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]butyrate (compound 25 1.7 g of 4-(11-(2- dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-yl]butyric acid (compound 28
Obtain H,Og.

281.0 g of the obtained compound is converted into a hydrochloride in the same manner as in Example 8 to obtain 1.1 g of compound 28 monohydrochloride 0.5 hydrate (compound 28').

Example 29゜By the same method as in Example 15, 3-(11-(2-
2.8 g of methyl dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-yl]propionate (compound 23) was reduced with 0.6 g of lithium aluminum hydride, and the resulting crude The product was purified by silica gel column chromatography (eluent: chloroform:methanol = 10:1), and 1l-(
2-dimethylaminoethyl)thio-2-(3-hydroxypropyl)-8,11-dihydrodibenz [b, e)
Oxepin (compound 29) L, Og is obtained.

1.0 g of the obtained Compound 29 is converted to a fumarate salt in the same manner as in Example 15 to obtain 0.7 g of a 1% fumarate hydrate of Compound 29 (Compound 29').

Example 30゜By the same method as in Example 15, 4-(11-(2-
dimethylaminoethyl)thio-6,11-dihydrodibenz(b,e)oxepin-2-yl]methyl butyrate2.
5 g was reduced with 0.5 g of lithium aluminum hydride, and the resulting crude product was subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 10:
1), and 1l-(2-dimethylaminoethyl)thio-2-(4-hydroxybutyl)-6,11-dihydrodibenz(b,e)oxepin (compound 30) 1
．． Obtain 6g.

301.6 g of the obtained compound was converted into fumarate salt by the same method as in Example 15, and 17 malate salt of compound 30 (
1.9 g of compound 30') is obtained.

Example 31゜By the same method as in Example 2, 11-hydroxy-6,
11-dihydrodibenz(b,e) oxepin-2-methyl acetate 3.0 g, thionyl chloride 0.9 ml and N
-Methylhomopiperazine 6.0g -(4-methylhomopiperazino)-6,11-dihydrodibenz(b
, e) Oxepin-2-methyl acetate (compound 31)
Obtain 2.7 g.

Example 32゜By the same method as in Example 8, 1l-(4-methylhomopiperazino)-6,11-dihydrodibenz (b, e)
Example 9 2.7 g of oxepin-2-methyl acetate was hydrolyzed using 0.4 g of sodium hydroxide, and the reaction solution was
1l-(4-
methyl homopiperazino)-6,11-dihydrodibenz (b, e) oxepin-2-acetic acid (compound 32) 2.3
get g.

322.2 g of the obtained compound is converted into a hydrochloride in the same manner as in Example 8 to obtain 1.6 g of dihydrochloride 0.5 hydrate of compound 32 (compound 32').

Reference Example 1 1.4 g of 60% sodium hydride, which had been previously washed with n-pentane, was suspended in 5 Qml of tetrahydrofuran, and 5.5 nl of ethyl diethylphosphonoacetate was added dropwise under ice cooling under a nitrogen atmosphere. After stirring at 0°C for 30 minutes, 11-oxo-6,11-dihydrodibenz [b,e
] A solution of 5.5 g of oxepin-2-carbaldehyde dissolved in 300 nl of tetrahydrofuran is added dropwise. 0℃
The mixture was stirred at room temperature for 1 hour and then at room temperature for 1 hour. Add 500 ml of ethyl acetate and 200 nl of water to the reaction solution, and after shaking,
Discard the aqueous layer. The organic layer is washed successively with 2N aqueous hydrochloric acid, saturated sodium chloride solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: hexane:ethyl acetate =
1:1), and the main fraction was concentrated to dryness under reduced pressure.

The obtained crude crystals were purified by recrystallization from ethyl ether to obtain ethyl 3-(11-oxo-6゜11-dihydrodibenz(b,e)oxepin-2-ylcoacrylate 3).
．． Obtain 3g.

Melting point 115-116. t (Recrystallized from ethyl ether) IR (Niho tablet): 1700.1600.14
70.1380.1300cm”NMR(CDC1
3, δppm) 1.33 (t, 3H), 4.26
(q, 2H).

5.15 (s, 2H), 6.36 (d, IH), 6
．． 87-8.02 (m, 7tl).

8, 33 (d, 111) Elemental analysis value C+ s Hle O- as (%) CH Theoretical value ? 4.01 5.23 Actual value 7
4.09 5.14 Reference Example 2゜3.3g of the compound obtained in Reference Example 1 was added to ethanol 5Q+
Dissolve y+1 in 10 Qml of tetrahydrofuran, add 1 g of sodium borohydride, and stir at room temperature for 1 hour. Add water and IN-hydrochloric acid aqueous solution to neutralize the reaction solution,
Concentrate to dryness under reduced pressure. 200ml ethyl acetate and 10ml water
After adding Qml and shaking, the aqueous layer is discarded and the organic layer is dried over anhydrous sodium sulfate. By concentrating to dryness under reduced pressure and recrystallizing the obtained crude product from toluene, 3-(11-hydroxy-6,11-dihydrodibenz(b,e)oxybin-2-yl) was obtained. 2.6 g of ethyl acrylate is obtained.

Melting point 130-132℃ (recrystallized from toluene) I R
(KBr tablet'): 3400.2900.1?10
．． 1640.16101500cm” NMR (CDI 3.δppm) 1.23(t
, 3) 1), 4.15(q, 2H).

4, 15 (broad s, IH), 4.94 a
nd 5.82 (ABq, 2H).

5.62 (s, IH), 6.23 (d, IH), 6
．． 57-7.87 (m.

8H) Elemental analysis value C+sH5go2.1/6) As toluene (%) CH Theoretical value 74.29 5.92 Actual value
? 4.16 5.92 Reference example 3゜1l-(2-tetrahydropyranyl)oxy-6゜11
20.2 g of ethyl dihydrodibenzoxepine-2-carboxylate was reduced using 2.5 g of lithium aluminum hydride in the same manner as in Example 15 to obtain an oily 2-carboxylate.
17.0 g of -hydroxymethyl-11-(2-tetrahydropyranyl)oxy-6,11-dihydrodibenz(b,e)oxepin are obtained.

IR (liquid film) 3450.2900.1730.16
10.1500 cm-'NMR (CDCI 5.
δppm) 1.21-2.09 (m, 6H),
3.65-4.01 (m, 2H), 4.50 (s
, 2H), 4.79 and 4.83 (dx2.L
H), 4.72-4.90 (m, IJI), 5.4
1.5.45(sX2.1)I), 5.94.5.9
7 (dX2.LH>, 6.68-7.38 (m,
7H) Reference Example 4゜6.9 g of the compound obtained in Reference Example 3 was washed with n-pentane in advance and 1.8 g of oily 60% sodium hydride was added.
The mixture was refluxed in tetrahydrofuran for 1 hour under a nitrogen atmosphere. Add 4.3 g of epichlorohydrin and reflux for an additional hour and a half. After cooling, add 11 ethyl acetate and 50 Q
ml and shake, then discard the aqueous layer. The organic layer is washed successively with 1N-hydrochloric acid and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain oily 2-(2,
4.1 g of oxepin are obtained.

IRC liquid film) 2920.1?30.1620.15
00cm-'NMR(CDC1a, δppm)
1.23-1.96 (m, 6H), 2.44-4.2
4 (m, 7H), 4.56 (s, 2H), 4.95
．． 4.98 (dX2.IH), 4.87-5.04 (
m, LH), 5.66 and 5.70(s
．． LH), 6.12 and 6.16 (d X2
．． If) Reference Example 5゜4.1 g of the compound obtained in Reference Example 4 was added with 0 potassium hydroxide.
．． Reflux for 2 hours in ethanol with 5 g. After cooling, the reaction solution is neutralized by adding acetic acid and concentrated under reduced pressure. 50 Qml of ethyl acetate and 20 Qml of water
After shaking, the aqueous layer is discarded and the organic layer is dried over anhydrous sodium sulfate. By concentrating under reduced pressure, 2-(
3-ethoxy-2-hydroxybropyloxy)methyl-11-(2-tetrahydropyranyl)-oxy-6,
11-dihydrodibenz(b,e)oxepin 4.7g
get.

IR (liquid film) 3420.2900.1730.16
20.1500cm-'NMR(CDCA3.δ
ppm) 1.22 (t, 3H), 1.26-1
．． 96 (m, 5H), 3.19-4゜36 (m, 9f
l), 4.56 (s, 2) 1).

4.72-4.90 (m, LH), 4.97 and
5.00 (dx2.IH).

5.68 and 5.72 (sx2, 1tl),
6.13 and6, 17 (d X2. LH),
6.80-7.76 (m, 71 () Reference Example 6゜ 4.7 g of the compound obtained in Reference Example 5 was added to 10 ml of pyridine.
and acetic anhydride 2+111 at room temperature for 5 hours. Concentrate under reduced pressure, add 50 Qml of ethyl acetate and 20 Qml of water to the residue, and after shaking, discard the aqueous layer.

The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
Oily 2-(2-acetoxy-3-ethoxy-propyloxy)methyl-11-(2-tetrahydropyranyl)
4.6 g of oxy-6,11-dihydrodibenz(b,e)oxepin are obtained.

IR (liquid film) 2900.1?40.1610.15
00cm-Kudzu NMR (CDCI5. δppm)
1.22 (t, 38), 1.35-1.95 (
m.

6H), 2.14(s, 3H), 3.30-4.0
8 (m, 88).

4.55 (s, 2H), 4.97 and 5.01
(dX2.IH), 4.85-5.41 (m, 2H
), 5.67 and 5.7HdX2.1)1),
6.13 and 6.17 (d X2. IH),
6.84-7.90 (m, 711) Reference Example 7゜ 4.6 g of the compound obtained in Reference Example 6 was mixed with dioxane 12
Qml, water 60IIllSp-React with 0.5g of toluenesulfonic acid l hydrate at 40°C for 3.5 hours. After cooling, saturated sodium chloride water is added to neutralize the mixture, and the mixture is concentrated under reduced pressure. Add 50 Qml of ethyl acetate to the residue.

After adding 30 Qml of water and shaking, the aqueous layer is discarded, and the organic layer is dried over anhydrous sodium sulfate. Concentration under reduced pressure yields 3.8 g of oily 2-(2-acetoxy-3-ethoxy-propyloxy)methyl-11-hydroxy-6°11-dihydrodibenz(b,e)oxepin.

IR (liquid film') 3400.2900.1730.1
610.1490°1370cr' NMR(C[lCJ,,δppm) 1.17
(t, 31(>, 2.09(s, 3H).

3.28-3.79 (m, 6H), 4.51 (s,
2tl), 5.06 and5.96(ABq, 2H
), 5.72 (s, IJI), 6.81-7.
72(m, 7H) Reference Example 8゜2-hydroxymethyl-11-(2-tetrahydropyranyl)oxy-6,11-dihydrodibenz(b,el
Oxepin (compound obtained in Reference Example 3) 7.6 g
was dissolved in methylene chloride 2001111, 5.5 g of methoxyethoxymethyl chloride and 15 ml of diisopropylethylamine were added, and the mixture was stirred at room temperature for 1 hour. After adding 30 Qml of methylene chloride and 10 Q++I of saturated soda water and shaking, the aqueous layer is discarded. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (elution solvent: hexane:ethyl acetate = 2:1), and the main fraction was concentrated to obtain 1l-(2-tetrahydropyranyl)oxy-2-( 6.8 g of 2-methoxyethoxy)methoxymethyl-6,11-dihydrodibenz(b,e)oxepin are obtained.

IR (liquid film) 2900.1610.1500cm-
'NMR(CD(J!,,899m) 1.2
2-1.96 (m, 6H), 3.41 (s, 3H),
3.38-4.16(m, 6B>, 4.58(s
, 2H).

4.81 (s, 2H), 4.73-4.99 (m, L
H), 4.94 and4.98 (dX2.1)1)
, 5.63 and 5.67 (sX2.LH).

6.09 and 6.13 (dX2.LH), 6
．． 74-7.59 (m, 7H) Reference Example 9゜By treating 6.8 g of the compound obtained in Reference Example 8 with p-)luenesulfonic acid in the same manner as in Reference Example 7, 11-hydroxy-2 -(2-methoxyethoxy)
Methoxymethyl-6,11-dihydrodibenz (b, e
) Obtain 5.2 g of oxepin.

IR (liquid film) 3400.2900.1610.14
90cm-'NMR(CDIJ3.δp9rn)
3J8 (s, 3H), 3.43-3.92 (m,
4H), 4.55(s, 2H), 4.77(s, 2
H), 5.01and 5.9(1(AElq, 2)
1), 5.65 (s, IH), 6.77-7, 58
(m, 7H) Effects of the Invention Compound (I)a and its pharmacologically acceptable 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 is (CH_2)mOR^3 (In the formula, R^
3 is a hydrogen atom, CH_2CH(OH)CH_2OCH_
2CH_3, CH_2CH (OAc) CH_2OCH_
2CH_3 or CH_2OCH_2CH_2OCH
_3, and m represents an integer from 1 to 4. ), CH (CH
_3) CH_2OR^3 (in the formula, R^3 represents the same meaning as above), CH=CHCOOR^4 (in the formula, R^4 represents a hydrogen atom or a lower alkyl group) (CH_2
)nCOOR^4 (in the formula, R^4 represents the same meaning as above, and n represents an integer from 1 to 3), or CH(CH_
3) COOR^4 (in the formula, R^4 represents the same meaning as above), R^2 is a 4-lower alkylpiperazino group,
4-lower alkyl homopiperazino group or Y-(CH
_2)_lNR^5R^6 (In the formula, Y represents NH, O or S, R^5 and R^6 represent the same or different lower alkyl groups, and l represents an integer of 2 to 5.)
represents. ] 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.