JPH069609A - Dibenz(b, e)oxepin derivative - Google Patents

Abstract

PURPOSE:To obtain a new dibenz[b, e]oxepin derivative having antiallergic and/or anti-inflammatory action. CONSTITUTION:The compound of formula I {A is hydroxymethyl, alkoxymethyl, alkanoyl, carboxyl, alkoxycarbonyl, CONR1R2 (R1 and R2 are H or alkyl), 4,4-dimethyl-2-oxazolin-2-yl, etc.; Y is (CH2)m (m is 1-4) or CHR3-(CH2)p (R3 is alkyl; p is 0-4) substituted at the 2- or 3-position in the parent nucleus; X1-X2 is C=N, C=CH or CH-CH2; n is 0-4; Z is 4-methylpiperazino, 4- methylhomopiperazino, piperidino, pyrrolidino, (thio)morpholino or NR6R4 (R6 and R4 are H or alkyl)}, e.g. methyl cis-11-(3-dimethylaminopropylidene)-6,11- dihydrodibenz[b, e]oxepin-2-acetate. This compound is produced from a compound of formula II or formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel dibenz [b, e].
It relates to oxepin derivatives.

[0002]

2. Description of the Related Art Conventionally, it has been known to use 11-unsubstituted, 11-hydroxy or 11-oxodibenz [b, e] oxepin derivatives as an anti-inflammatory agent [J. Med.
Chem., 21 , 633-639 (1978)]. It is also known to use dibenz [b, e] oxepin derivatives having the substituents R _a and R _{b at} the 11-position having the following definitions for treating or treating allergic symptoms (US Pat. No. 4,282,365).
No.): R _a : H, OH, lower alkoxy, lower alkylthio,
Lower alkylsulfinyl, lower alkylsulfonyl,
Arylthio, NH ₂ , NHCHO or imidazolyl; R _b : H or lower alkyl; and R _a R _b together are ═O, ═CH—R _c (wherein R _c is H or aryl). Furthermore, 11- (4-methylpiperazino) dibenz [b, e] oxepin derivatives having an anti-asthma action are known (Japanese Patent Laid-Open No. 56-150082). Further, a dibenz [b, e] oxepin derivative having an anti-asthma action and the following structure is known (Japanese Patent Laid-Open No. 58-12688).
3):

[0003]

[Chemical 2]

Where R _d and R _e are lower alkyl and R _f is lower alkyl or halogen. In addition, dibenz having the following structure having an antiallergic effect [b,
e] Oxepin derivatives are known (JP-A-59-2).
27879):

[0005]

[Chemical 3]

(Wherein R _g and R _h are alkyl,
r is 2 or 3 and R _i is alkyl or halogen). Further, a dibenz [b, e] oxepin derivative having the following structure having an antiallergic action is known (Japanese Patent Laid-Open No. 60-28972).

[0007]

[Chemical 4]

[Wherein R _j is 4-alkylpiperazino,
3-quinuclidine Gilles amino or _{-X a - (CH 2) s} -NR
_l R _m (wherein X _a is —NH—, —S— or —O—, s is 2 or 3, R ₁ and R _m are alkyl), R _k is CN, 5- Tetrazolyl, CONH ₂ or CO ₂ R _n , where R _n is H, alkyl or 1- (ethoxycarbonyloxy) ethyl.

Furthermore, doxepin having an antidepressant action and the following structure is known [Drugs, 1
3 , 161 (1977)]:

[0010]

[Chemical 5]

Also, dothiepin having an antidepressant action and having the following structure is known [Arz.-Forsc
h., 13 , 1039 (1963); ibid, 14 , 100 (1964)]:

[0012]

[Chemical 6]

So-called anti-inflammatory steroids are known as compounds having both an anti-allergic action and an anti-inflammatory action.

[0014]

There is a constant need for new and useful compounds having antiallergic or antiinflammatory activity.

[0015]

The present invention provides a compound of formula (I)

[0016]

[Chemical 7]

[Wherein A is a hydroxymethyl group, a lower alkoxymethyl group, a triphenylmethyloxymethyl group, a lower alkanoyloxymethyl group, a lower alkanoyl group, a carboxyl group, a lower alkoxycarbonyl group,
Triphenylmethyloxycarbonyl group, -CONR ₁
R ₂ (in the formula, R ₁ and R ₂ are the same or different and represent a hydrogen atom or a lower alkyl group), 4,4-dimethyl-2-
Represents an oxazolin-2-yl group or -CONHOH,
Y is substituted at the 2-position or 3-position of the mother nucleus - (CH _{2) m} - (wherein, m represents 1, 2, 3 or 4), or -CHR ₃ -
(CH _{2) p} - (wherein, R ₃ represents a lower alkyl group, p
Represents 0, 1, 2, 3 or 4. It is assumed that the left side of each of the above formulas is bound to the mother nucleus. ), And X ₁ -X
₂ represents C = N, C = CH or CH-CH2, n represents 0, 1, ₂ , 3 or 4, Z is 4-methylpiperazino group, 4-methylhomopiperazino group, piperidino group, Pyrrolidino group, thiomorpholino group, morpholino group or -N
R ₆ R ₇ (in the formula, R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a lower alkyl group), and a dibenz [b, e] oxepin derivative [hereinafter referred to as compound (I)] . The same applies to compounds of other formula numbers] or a pharmaceutically acceptable salt thereof.

The lower alkyl group in the definition of each group of the formula (I) is a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. Include. In the definition of the group A, the lower alkyl part of the lower alkoxy part in the lower alkoxymethyl group and the lower alkoxycarbonyl group has the same meaning as the above lower alkyl group. Examples of the lower alkoxymethyl group include methoxymethyl, ethoxymethyl, n-propoxymethyl and isopropoxymethyl, and examples of the lower alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl. In the definition of group A, the lower alkanoyl group and the lower alkyl moiety of the lower alkanoyl moiety in the lower alkanoyloxymethyl group have the same meanings as the above lower alkyl group. Formyl as a lower alkanoyl group,
Acetyl and the like are exemplified by lower alkanoyloxymethyl groups such as formyloxymethyl and acetyloxymethyl.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The pharmacologically acceptable acid addition salt of compound (I) includes a hydrochloride salt,
Inorganic acid salts such as sulfates and phosphates, organic acid salts such as acetates, maleates, fumarates, tartrates and citrates are mentioned, and pharmacologically acceptable metal salts are sodium salts, Alkali metal salts such as potassium salts, magnesium salts,
In addition to alkaline earth metal salts such as calcium salts, aluminum salts and zinc salts are also included. As pharmacologically acceptable organic amine addition salts, addition salts such as morpholine and piperidine,
Examples of pharmaceutically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.

The compound (I) has the formula (II)

[0021]

[Chemical 8]

A compound represented by the formula (wherein Y and A are as defined above) or the formula (III)

[0023]

[Chemical 9]

It is produced from a compound represented by the formula (wherein Y and A are as defined above). Compound (II) is J. M
ed. Chem., 19 , 941 (1976), 20 , 20 , 1499 (1977) and JP-A-58-21679. Also,
Although the compound (III) is not described in the literature, it is disclosed in JP-A-58-
It can be synthesized according to the method described in 21679.

The production method of the compound (I) will be described below according to the type of the groups X ₁ -X ₂ .

Method 1 [Synthesis of Compound (I) wherein X ₁ -X ₂ is C = CH (Part 1)] First, the carboxyl group of the following compound (IIa) is protected according to the following reaction step.

[0027]

[Chemical 10]

[In the formula, Y has the same meaning as described above. IIa is II
Compound (II also applies to other numbers)]
a) and 1 to 5 equivalents of thionyl chloride and 1 to 5 equivalents of 2-amino-2-methyl-1-propanol relative to compound (IIa) in an inert solvent such as methylene chloride, if necessary, of a base such as triethylamine. In the presence of 0 ℃ ~ room temperature 1
Compound (IV) is obtained by reacting for 24 hours. In this reaction, the compound (IIa) may be first reacted with thionyl chloride, and then 2-amino-2-methyl-1-propanol may be reacted.

The compound (IV) is treated with 1 to 5 equivalents of thionyl chloride in an inert solvent such as methylene chloride, toluene and benzene at 0 ° C. to room temperature for 1 to 24 hours to obtain the compound (V). Next, compounds (Ia) and (Ib) are produced from compound (V) according to the following reaction steps.

[0030]

[Chemical 11]

(Wherein Y, Z, and n have the same meanings as described above,
R ₈ is a hydrogen atom or a lower alkyl group, R ₈ ′ is a lower alkyl group, and Hal is a halogen atom. Here, the definition of the lower alkyl group is the same as the definition of the lower alkyl group of each group of formula (I). . Also, the halogen atom is chlorine,
Includes bromine and iodine atoms. Compound (V) and 1-5
Compound (VII) is obtained by reacting an equivalent amount of compound (VI) in an inert gas atmosphere such as nitrogen or argon in an inert solvent such as tetrahydrofuran or diethyl ether. The reaction is carried out at 0 ° C to room temperature and is usually completed in 1 to 24 hours.

Next, the compound (VII) is treated with 1 to 5 equivalents of thionyl chloride or phosphorus oxychloride in the presence of a base such as pyridine in an inert solvent such as methylene chloride to obtain the compound (Ia). The reaction is carried out at 0 ° C to room temperature and is usually completed in 1 to 24 hours. Next, the compound (Ia) is kept at room temperature to the boiling point of the solvent in the presence of a suitable acid catalyst such as paratoluenesulfonic acid in a water-containing alcohol such as an aqueous methanol solution to obtain a compound of R ₈ = H in the compound (Ib). . The reaction is usually completed in 1 to 24 hours.

Alternatively, the compound (VII) may be maintained at room temperature to the boiling point of the solvent in the presence of a suitable acid catalyst such as paratoluenesulfonic acid in an alcohol of the formula R ₈ 'OH.
b) a compound in which R ₈ = lower alkyl is obtained. The reaction is usually completed in 1 to 24 hours.

Method 2 [Synthesis of Compound (I) in which X ₁ -X ₂ is C = CH (Part 2)] The carboxyl group of the compound of the following formula (IIa) is converted into a lower alkoxymethyl group or trityl according to the following reaction steps. It can be converted to an oxymethyl group.

[0035]

[Chemical 12]

(In the formula, Y is as defined above, R ₉ is a lower alkyl group, and R ₉ 'is a trityl group or a lower alkyl group.) The lower alkyl group is defined as each group of the formula (I). Is the same as the definition of the lower alkyl group of. First, compound (IIa) is reduced with 1 to 5 equivalents of lithium aluminum hydride in tetrahydrofuran at 0 ° C. to room temperature for usually 1 to 24 hours to obtain compound (VIII).

Then, the compound (VIII) is reacted with 1 to 5 equivalents of trityl chloride in pyridine at room temperature to 100 ° C. for 1 to 24 hours to obtain the compound (IX). Compound (IX) is oxidized with 1 to 5 equivalents of a suitable oxidizing agent such as potassium permanganate or pyridinium-chlorochromate reagent in an inert solvent such as methylene chloride or acetone to obtain R in compound (XI).
₉ ′ = trityl compound is obtained. The reaction is carried out at 0 ° C to the boiling point of the solvent and is usually completed in 1 to 24 hours.

On the other hand, the compound (VIII) is kept at room temperature to the boiling point of the solvent in the alcohol of the formula R ₉ OH in the presence of a suitable acid catalyst such as sulfuric acid to obtain the compound (X). The reaction is usually completed in 1 to 24 hours. Then, the compound (X) is oxidized with 1 to 5 equivalents of a suitable oxidizing agent such as Jones reagent in an inert solvent such as acetone to obtain a compound of R ₉ '= lower alkyl in the compound (XI). The reaction is carried out at 0 ° C to the boiling point of the solvent and is usually completed in 1 to 24 hours.

From compound (XI) according to the following reaction steps,
The compounds represented by the formulas (Ic) and (Id) and, if desired, the compound represented by the formula (Ie) can be synthesized.

[0040]

[Chemical 13]

(Wherein Y, Z, R ₉ ', n and Hal have the same meanings as described above) Compound (XI) and Compound (VI) which is a Grignard reagent are used in Method 1 (Compound (V) → Compound ( Compound (XII) is obtained by reacting in the same manner as the reaction of (VII). Then, the compound (XII) is replaced with the compound (VII) of the method 1 → the compound (I
By reacting in the same manner as the reaction of a), the compound (I
c) is obtained.

Next, the compound (Ic) is kept at room temperature to the boiling point of the solvent in a water-containing solvent, for example, water-containing dioxane in the presence of a suitable acid catalyst such as paratoluenesulfonic acid to obtain the compound (Id). The reaction is usually completed in 1 to 24 hours. The compound (Id) can also be obtained in one step by maintaining the compound (XII) at room temperature to the boiling point of the solvent in the presence of a suitable acid catalyst such as sulfuric acid in a water-containing solvent such as water-containing dioxane. The reaction is usually completed in 1 to 24 hours.

If desired, compound (Ie) can also be prepared by oxidizing compound (Id) with 1 to 5 equivalents of a suitable oxidizing agent such as Jones reagent in an inert solvent such as acetone. The reaction is carried out at 0 ° C to the boiling point of the solvent and is usually completed in 1 to 24 hours.

Method 3 [Synthesis of Compound (I) wherein X ₁ -X ₂ is C = CH (Part 3)]

[0045]

[Chemical 14]

(Wherein Y, Z, and n have the same meanings as described above,
A'represents a group excluding a lower alkanoyl group in the definition of group A) Compound (IIb) and 1 to 5 equivalents of compound (XIII) are mixed with an inert gas such as nitrogen or argon under an inert gas such as tetrahydrofuran. Compound (If) is obtained by reacting in an active solvent at 0 ° C to room temperature for usually 1 to 24 hours.

The compound (XIII), which is an ylide, is C.I.
It can be prepared as follows according to the method described in A., 63 , 16366a (1965).

[0048]

[Chemical 15]

(In the formula, Hal, n and Z have the same meanings as described above, and q is 1 or 2.) First, the compound (XIV) and an equivalent amount of triphenylphosphine are mixed in toluene in a solvent under reflux at 1 to 24. Compound (XV) is obtained by reacting for a time. Next, 1 to 5 equivalents of H with compound (XV)
After reacting with Z under reflux of a solvent in ethanol for usually 1 to 24 hours, excess HZ is distilled off under reduced pressure, and then the compound (X
1 to 5 equivalents of HHal are added to V) and the mixture is kept at 0 ° C to the boiling point of the solvent for 1 to 24 hours to obtain a compound (XVI) which is a Wittig reagent. Next, add the compound (XVI) to nitrogen,
1 to 2 equivalents of a suitable base, such as n-, in an inert solvent such as tetrahydrofuran under an inert gas atmosphere such as argon.
Treatment with butyllithium produces the ylide (XIII). The reaction is carried out at -78 ° C to room temperature and is usually completed in 1 to 24 hours.

Method 4 [Synthesis of Compound (I) wherein X ₁ -X ₂ is C = CH (Part 4)]

[0051]

[Chemical 16]

(Wherein Y, Z and A have the same meanings as above) This method is known as the Prince reaction [New Experimental Chemistry Lecture (Maruzen) Vol. 14, Synthesis and Reaction of Organic Compounds III.
, 1375 (1977)]. The compound (III), 1 to 5 equivalents of formaldehyde and 1 to 5 equivalents of HZ are reacted in the presence of an acid in an inert solvent such as tetrachloroethane in an atmosphere of an inert gas such as nitrogen or argon, or the acid itself. Is used as a solvent to produce the compound (Ig).

Formaldehyde or its multimers include formaldehyde paraformaldehyde, trioxane and the like. Acids include acetic acid, trichloroacetic acid, trifluoroacetic acid and the like. The reaction is carried out at room temperature to the boiling point of the solvent and is usually completed in 1 to 24 hours. Compound (II
I) can be produced according to the method disclosed in JP-A-58-21679, for example, as follows.

[0054]

[Chemical 17]

That is, 1 to 5 equivalents of methyltriphenylphosphonium bromide and 1 to 5 equivalents of n-butyllithium are reacted with compound (IIb) in an inert solvent at −78 ° C. to room temperature for usually 1 to 5 hours. The obtained Ylide (XVII) and 1
Compound (IIIa) is obtained by reacting an equivalent amount of compound (IIb) in an inert gas atmosphere in an inert solvent at -78 ° C to room temperature for usually 1 to 24 hours.

The inert gas includes nitrogen, argon and the like, and the inert solvent includes tetrahydrofuran and the like. Here, the conversion of the group A ′ of the compound (IIIa) into a lower alkanoyl group can be easily carried out as described in Method 9 below, so that the compound (III) can be finally prepared.

Method 5 [Synthesis of Compound (I) wherein X ₁ -X ₂ is C = N]

[0058]

[Chemical 18]

Compound (IIb) and 1 to 10 equivalents of compound (XVIII) are mixed in an inert gas atmosphere such as nitrogen or argon in the presence of an inert solvent such as 1 to 10 equivalents of titanium tetrachloride in benzene. Compound (Ih) is obtained by reacting at 0 ° C to the boiling point of the solvent for 1 to 48 hours.

Method 6 [Synthesis of Compound (I) wherein X ₁ -X ₂ is CH-CH ₂ (Part 1)]

[0061]

[Chemical 19]

(Wherein Y, Z, n, R ₈ and Hal have the same meanings as described above) Compound (V) is added to 1 to 5 equivalents of lithium aluminum hydride in an inert solvent such as tetrahydrofuran or methanol.
It is usually 1 to 24 at 0 ° C to room temperature with sodium borohydride or the like.
The compound (XIX) is obtained by reduction over time. Then, compound (XIX) is reacted with 1 to 5 equivalents of thionyl chloride or phosphorus oxychloride in a suitable base such as pyridine at 0 ° C to room temperature to obtain compound (XX).

Then, the compound (XX) and 1 to 5 equivalents of the compound (VI) are reacted in the same manner as in the reaction of the compound (V) → the compound (VII) in the method 1 to obtain the compound (Ii). Compound (Ii) can be converted into compound (Ij) by subjecting it to a reaction similar to the reaction of compound (VII) → (Ib) or compound (Ia) → (Ib) in Method 1.

Method 7 [Synthesis of Compound (I) wherein X ₁ -X ₂ is CH-CH ₂ (Part 2)]

[0065]

[Chemical 20]

First, the compound (XXI) is chlorinated in the same manner as in Method 6 to obtain the compound (XXII), and then the compound (XXII) and the compound (VI) are reacted in the same manner as in Method 6 to obtain the compound (I
k) is obtained. Compound (Ik) can be treated in the same manner as in Method 2 to give compound (Il) and further compound (Im). Here, the starting material (XXI) includes the compound (IX) in its definition, and the compound (XI) is treated with 1 to 5 equivalents of lithium aluminum hydride or sodium borohydride in an inert solvent such as tetrahydrofuran or methanol. It can be obtained by reducing normally at 0 ° C. to room temperature for 1 to 24 hours.

Method 8 [Synthesis of Compound (I) in which X ₁ -X ₂ is CH-CH ₂ (3)] Compounds (Ia) to (Ig) obtained by the production methods shown in Methods 1 to 4 are used. Compound (I) can be synthesized by an appropriate reduction method, for example, a hydrogenation reaction using palladium carbon or the like as a catalyst and reduction.

Method 9 When a compound having a group defined as A is not directly provided in the production method shown in Methods 1 to 8, the products obtained by the respective production methods are used in a method commonly used in synthetic organic chemistry, for example, Such compounds can be easily synthesized by subjecting them to oxidation, reduction and hydrolysis. For example, in order to obtain the compound (I) in which A is a formyl group, the oxidation reaction may be carried out after applying the method 3 to the starting material (IIb) having the corresponding hydroxymethyl group.

The intermediates and target compounds in each of the above production methods are purified by a method commonly used in synthetic organic chemistry, for example, filtration, extraction with an organic solvent such as ethyl acetate or methylene chloride, drying, concentration, recrystallization, column chromatography. It can be isolated and purified by subjecting it to chromatography or the like. The compounds (Ia) to (Ih) obtained by each of the above-mentioned production methods are related to stereochemistry at the 11-position of dibenz [b, e] oxepin (Ia), (Ib), (Ic), (Id),
In (Ig) and (Ih), the trans form tends to occur, and in (If), the cis form tends to occur more.

When the compounds (I) other than the compounds (Ii) to (Im) are obtained in a cis-trans mixture, their isolation and purification are carried out by a method commonly used in synthetic organic chemistry, for example, column chromatography. It is possible by means of chromatography, recrystallization, etc. It is possible to isomerize the cis form to the trans form if desired, and the method is as follows:
In the presence of a suitable acid catalyst such as paratoluene sulfonic acid,
Treatment for 1 to 24 hours is included.

Regarding compound (I), the cis form (or syn form) and trans form (or anti form) are represented by a compound in which the side chain of the double bond is on the same side as oxygen of oxepin (or cis form). Syn form), and the opposite is the trans form (or anti form). If this is named according to the EZ notation method, the cis form (or syn form) can be displayed as the Z form and the trans form (or anti form) can be displayed as the E form. For example, the compounds below are in cis form (or syn form or Z form).

[0072]

[Chemical 21]

When it is desired to obtain a salt of compound (I), when compound (I) can be obtained in the form of a salt, it can be purified as it is. When it is obtained in a free form, a usual method can be used. The salt may be formed by. Specific examples of compound (I) or a pharmaceutically acceptable salt thereof obtained by each production method are shown in Table 1 and their structures are shown in Table 2. The characteristic signals in NMR and the retention time in HPLC, which are especially important as their physicochemical properties, are
The results are shown in Table 4 and Table 4.

[0074]

[Table 1]

[0075]

[Table 2]

[0076]

[Table 3]

[0077]

[Table 4]

[0078]

[Table 5]

[0079]

[Table 6]

[0080]

[Table 7]

[0081]

[Table 8]

[0082]

[Table 9]

[0083]

[Table 10]

[0084]

[Table 11]

[0085]

[Table 12]

[0086]

[Table 13]

Measuring instrument: SHIMAZU LC-3A Measuring condition: Column Yamamura Science YMC A-312 Eluent Ion pair system 3 types B 0.01 M PIC B-8 in 61.3% MeOH * PIC: Waters PIC reagent pressure 85 to 95 kg / cm ² temperature room temperature The compound (I) thus produced has an anti-allergic action and / or an anti-inflammatory action. Among them, the compound represented by the following formula (I ′) is Particularly, the compound represented by the following formula (I ″) has an excellent anti-allergic action, and the anti-inflammatory action is particularly excellent.

[0088]

[Chemical formula 22]

[In the formula, X ₁ -X ₂ , n and Z have the same meanings as described above. -Y'-A '' is X ₁ -X ₂ is C = CH or C
-Y-A (wherein, Y and A has the same meaning as defined above) when a H-CH ₂ represent, when X ₁ -X ₂ is a C = N is attached to the 2-position of the mother nucleus In the case, -YA (in the formula, Y and A have the same meanings as described above). ]

[0090]

[Chemical formula 23]

[In the formula, n and Z have the same meanings as described above.
Y ″ is —CH ₂ — or — substituted at the 2- or 3-position of the mother nucleus.
CHR ₃ — (in the formula, R ₃ represents a lower alkyl group), A ′ ″ represents a hydroxymethyl group, a lower alkoxymethyl group, a triphenylmethyloxymethyl group, a lower alkanoyloxymethyl group, a formyl group, a carboxyl group. Basis,
Lower alkoxycarbonyl group, triphenylmethyloxycarbonyl group, -CONR ₁ R ₂ (wherein R ₁ and R ₂ are the same or different and represent a hydrogen atom or a lower alkyl group), 4,4-dimethyl-2-oxazoline It represents a 2-yl group or -CONHOH. ]

Next, the antiallergic action and antiinflammatory action of compound (I) will be explained. Antiallergic activity test Antiallergic activity was observed in rat homologous PCA (p
It was examined according to the associative cutaneous anaphl axis) test.
As an experimental animal, a body weight of 180-
220 g of male Wistar rats weigh 1 for PCA test
Wistar male rats weighing 20 to 140 g were used.

A) Preparation of anti-EWA rat serum Stotland and Share method [Canad. J. Physiol. Pharm
acol., 52 , 1114 (1974)], anti-ovalbumin (EWA) rat serum was prepared. Ie 1 mg E
WA was mixed with 20 mg of aluminum hydroxide gel and 0.5 ml of pertussis diphtheria tetanus mixed vaccine, and the mixture was subcutaneously administered to the rat footpad in four divided doses. After 14 days, blood was collected from the carotid artery, serum was separated, and frozen and stored at -80 ° C.
The titer of 48-hour homologous PCA of this antiserum is 1:32.
Met.

B) 48-hour homologous PCA test of rats Using 3 rats per group, 0.05 ml of anti-EWA rat serum diluted 2-fold with physiological saline at two intradermal sites on the shaved back skin
Each was injected and passively sensitized. After 47 hours, the compound of the present invention or a solution thereof (physiological saline solution or CMC solution) was orally administered, and 1 hour later, 0.5 ml / 100 g of 1% Evans blue physiological saline solution containing 2 mg of the antigen EWA was administered by tail vein administration.

After 30 minutes, the animals were killed by exsanguination, the skin was peeled off, and the amount of leaked pigment in the blue-dyed part was determined by the method of Katayama et al. [Micr
obiol. Immunol., 22 , 89 (1978)].
That is, the blue-dyed part was cut with scissors, placed in a test tube containing 1 ml of 1N KOH, and incubated at 37 ° C. for 24 hours. Add 9 ml of a mixture of 0.6N phosphoric acid and acetone (5:13), shake, and then centrifuge at 2500 rpm for 10 minutes.
The absorbance at 620 μm was measured, and the amount of leaked dye was quantified from a calibration curve prepared in advance. 1 with an average value of 2 places
The inhibition rate of each individual was calculated from the following formula, using the value of the individual.

[0096]

[Equation 1]

PCA is used when the suppression rate is 50% or more.
The minimum effective dose (MED) with the minimum dose that is positive for the suppressive action and positive for at least one of the three individuals
And The results are shown in Table 5. Acute toxicity test A compound of the present invention was orally (po: 300 mg / kg) or intraperitoneally (ip: 100 mg / kg) using 3 dd male mice each weighing 20 ± 1 g. The mortality status 7 days after administration was observed and the MLD (minimum mortality) value was calculated. The results are shown in Table 5.

[0098]

[Table 14]

[0099]

[Table 15]

Anti-Inflammatory Action Test The anti-inflammatory action was determined by the rat carrageenin paw edema method [J. Patho
l., 104 , 15-29 (1971)]. Weight 15
0 g of Wistar male rats was used as one group consisting of 3 rats. The test compound was suspended in a 0.3% CMC aqueous solution and orally administered to the animal, and 60 minutes later, carrageenin paw edema was prepared by subcutaneously injecting 1% carrageenin into the footpad of the right hind leg at 0.1 ml / rat.

Immediately before and 3 hours after the administration of carrageenin, the paw volume was immersed in water just above the epiphysis of the fibula and measured using a plethysmometer. The ratio of the paw volume immediately before carrageenin administration and 3 hours after the administration was obtained, and then each ratio was compared with the ratio of the control group (0.3% CMC administration group) to calculate the edema suppression rate. The sixth result
Shown in the table.

[0102]

[Table 16]

As illustrated in Tables 5 and 6, Compound (I) and its pharmacologically acceptable salts have a PCA inhibitory action and / or a carrageenin paw edema inhibitory action. PCA
The inhibitory effect is considered to be based on the inhibitory effect on the release of chemical mediators such as histamine from skin mast cells. Therefore, the compound (I) and its pharmacologically acceptable salt are produced by the tracheal contraction effect of chemical mediators such as histamine. It is considered to be effective in treating allergic diseases such as bronchial asthma. On the other hand, the carrageenin paw edema inhibitory action is considered to be mainly based on the prostaglandin synthesis inhibitory action. Therefore, compound (I) and its pharmacologically acceptable salt are considered to be effective in treating acute inflammation and rheumatic diseases caused by excess prostaglandins. Compound (I) also includes compounds having both of the above actions, and these compounds are considered to be useful for treating allergic diseases accompanied by inflammation.

Compound (I) and its pharmacologically acceptable salt can be used in various pharmaceutical forms for the purpose of administration in view of its pharmacological action. The pharmaceutical composition of the present invention can be produced by uniformly mixing, as an active ingredient, an effective amount of a free form of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dose form suitable for oral or injection administration.

In preparing the composition in the oral dosage form, any useful pharmacologically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, alkyls. It can be manufactured by using preservatives such as para-hydroxybenzoate and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets are lactose, glucose,
Excipients such as sucrose and mannitol, starch, disintegrators such as sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surface active agents such as fatty acid esters. It can be manufactured using a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because they are easy to administer. When manufacturing tablets and capsules, individual pharmaceutical carriers are used. Injectable solutions can also be prepared using carriers that consist of salt solutions, glucose solutions or mixtures of saline and glucose solutions. The effective dose of compound (I) is 1 to 20 mg / kg / day, and the administration frequency is 1
3-4 times a day is preferred.

Reference examples and examples will be shown below. Reference Example 1 (Raw material 1) 11-oxo-6,11-dihydrodibenz [b,
e] Methyl oxepin-2-carboxylate Sodium salt of methyl p-hydroxybenzoate (348.
9 g), phthalide (402.4 g) and sodium chloride (200 g) are stirred at 150 ° C. for 6 hours. After the reaction was completed, after cooling to room temperature, 4 L of 10% acetic acid aqueous solution was added,
Leave at room temperature overnight. After stirring for 3 hours at room temperature, the crystals are filtered off. Water (6 L) is added to the crystals, the mixture is stirred at room temperature for 30 minutes, and the crystals are separated by filtration. 3 L of toluene was added to the crystals, the mixture was stirred at room temperature for 1 hour, and the crystals were filtered off and dried under reduced pressure to give 2- (4-methoxycarbonylphenoxy) methylbenzoic acid (393.9 g). IR (KBr tablets): 3400, 1700, 1610, 1260, 1235cm
^-1

2- (4-Methoxycarbonylphenoxy) methylbenzoic acid thus obtained (392.7 g)
Was suspended in 5.0 L of methylene chloride, 266.0 g of trifluoroacetic anhydride was added, and the mixture was stirred at room temperature for 1 hour, and then boron trifluoride ethyl ether complex 19.4 g was added and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and after separation, the organic layer was washed with a dilute aqueous solution of caustic soda and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 11-oxodibenz [b, e] oxepin-2-carboxylic acid. Methyl acid (335.3
g) is obtained as white crystals.

The melting point and elemental analysis are shown in Table 7. IR (KBr tablets): 1710, 1650, 1610, 1250, 1010
cm ^-1 NMR (CDCl ₃ , δ, ppm): 3.84 (s, 3H), 5.14
(s, 2H), 6.87-8.93 (m, 7H)

Reference Examples 2 to 5 (Raw material 2) 11-oxo-6,11-dihydrodibenz [b,
e] Oxepin-2-acetic acid (Raw material 3) 11-oxo-6,11-dihydrodibenz [b,
e] Oxepin-3-acetic acid (raw material 4) 2- (11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-yl) -propionic acid (raw material 5) 3- (11-oxo- 6,11-Dihydrodibenz [b, e] oxepin-2-yl) -propionic acid

Raw materials 2 to 5 were prepared by converting methyl p-hydroxybenzoate of Reference Example 1 into p-hydroxyphenylacetic acid, m-hydroxyphenylacetic acid, 2- (p-hydroxyphenyl) -propionic acid and 3- (p- It can be similarly produced by changing to (hydroxyphenyl) -propionic acid.

The melting point and elemental analysis are shown in Table 7. Reference Example 6 (Raw material 6) Methyl 11-methylene-6,11-dihydrodibenz [b, e] oxepin-2-carboxylate Methyl triphenylphosphonium bromide (25 g) was suspended in tetrahydrofuran (100 ml), and nitrogen was added thereto. Under atmosphere cooling with ice, n-butyllithium hexane solution (1.6 N, 40 ml) is added dropwise. After stirring for 30 minutes under ice cooling
A solution of methyl 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-carboxylate (15 g) in tetrahydrofuran (250 ml) was added dropwise, and the mixture was further stirred at room temperature for 2 hours and then depressurized. The lower solvent is distilled off. The obtained residue is subjected to column chromatography (silica gel,
Purification with an elution solvent hexane: ethyl acetate = 3: 1) gives the desired product (3.7 g).

Colorless oil NMR (CDCl ₃ , δ, ppm) 3.83 (s, 3H), 5.15 (s,
2H), 5.29 (s, 1H), 5.74 (s, 1H), 6.69-8.22 (m, 7H) Melting point and elemental analysis are shown in Table 7.

Reference Example 7 (Raw material 7) 11-Methylene-6,11-dihydrodibenz [b, e] oxepin-2-methylacetate 11-oxo-6,11-dihydrodibenz [b, e in Reference Example 6] e] Methyl oxepin-2-carboxylate is converted into 11-oxo-6,11-dihydrodibenz [b, e] oxepin-
The same production can be performed by changing to 2-acetic acid.

Colorless oil NMR (CDCl ₃ , δ, ppm) 3.48 (s, 2H), 3.61 (s,
3H), 5.05 (s, 2H), 5.20 (s, 1H), 5.62 (s, 1H), 6.59-
7.43 (m, 7H) IR (liquid film, cm ⁻¹ ) 2950, 1740, 1615, 1490, 1010 Melting point, Elemental analysis is shown in Table 7.

Reference Example 8 (Raw material 8) 11-methylene-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid 11-methylene-6,11-dihydrodibenz [b, e] oxepin-2 -Methyl acetate (raw material 7, reference example 7) (2.9
g) is heated under reflux for 2 hours in a mixed solvent of methanol (200 ml) and 2N aqueous sodium hydroxide solution (50 ml). After allowing to cool, the mixture is concentrated under reduced pressure and then adjusted to pH 1.0 by adding 4N hydrochloric acid aqueous solution. Extract with ethyl acetate (500 ml), wash with 1N aqueous hydrochloric acid solution and saturated brine successively,
After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure.

The obtained crude product is crystallized from hexane to obtain the desired product (2.7 g). White solid NMR (DMSO-d ₆ + D ₂ O, δ, ppm) 3.45 (s, 2
H), 5.02 (s, 2H), 5.16 (s, 1H), 5.60 (s, 1H), 6.45-7.
The melting point and elemental analysis of 44 (m, 7H) are shown in Table 7.

[0117]

[Table 17]

[0118]

[Table 18]

Reference Example 9 (Raw material 9) 11-methylene-6,11-dihydrodibenz [b, e] oxepin-3-methylacetate 11-oxo-6,11-dihydrodibenz [b, e in Reference Example 6] e] Methyl oxepin-2-carboxylate is converted to 11-oxo-6,11-dihydrodibenz [b, e] oxepin-
It can be similarly produced by changing to 3-acetic acid.

Reference Example 10 (Raw material 10) 11-methylene-6,11-dihydrodibenz [b, e] oxepin-3-acetic acid 11-methylene-6,11-dihydrodibenz [b, e] in Reference Example 8 ] Methyl oxepin-2-acetate was used as 11-methylene-6,11-dihydrodibenz [be] oxepin-3
-Similarly synthesized by changing to methyl acetate.

Reference Example 11 (Reagent 1) (3-Dimethylaminopropyl) -triphenylphosphonium bromide hydrobromide Triphenylphosphine (350.0 g) and dibumopropane (270.0 g) were suspended in toluene (700 ml). It is heated to reflux for 25 hours. After cooling, the product was collected by filtration and washed with toluene (2 L) to obtain (3-bromopropyl) -triphenylphosphonium bromide hydrobromide (550.0 g). Melting point 233-234 ° C

Next, this (3-bromopropyl) -triphenylphosphonium bromide hydrobromide (100.0 g) was added.
Was suspended in ethanol (500 ml), dimethylamine aqueous solution (50%) (300 ml) was added thereto, and the mixture was heated under reflux for 10 minutes and then left to cool. By distilling off the solvent under reduced pressure and recrystallizing the obtained crude product from ethanol,
The expected product (64.0 g) is obtained. The physical properties are shown in Table 8.

Reference Examples 12 to 14 Reagent 2 (3-Diethylaminopropyl) -triphenylphosphonium bromide hydrobromide 1/3 hydrate Reagent 3 (4-Dimethylaminobutyl) -triphenylphosphonium bromide hydrobromide Salt Reagent 4 (3-Pyrrolidinopropyl) -triphenylphosphonium bromide hydrobromide hemihydrate is prepared in the same manner as in Reference Example 11.

Table 8 shows the physical properties.

[0125]

[Table 19]

Reference Example 15 11- [2- (4-Methylpiperazino) ethylidene] -6,
Methyl 11-dihydrodibenz [b, e] oxepin-2-carboxylate (Compound a) 4-Methylpiperazine (1.5 ml) and paraformaldehyde (0.37 g) were dissolved in tetrachloroethane (100 ml). Trifluoroacetic acid (5 ml) is added dropwise to.
After stirring at 60 ° C for 2 hours, 11-methylene-6,11-
A solution of methyl dihydrodibenz [b, e] oxepin-2-carboxylate (1.8 g) in tetrachloroethane (30 ml) was added dropwise, and the mixture was further stirred at 90 ° C. for 3 hours. The mixture is concentrated to dryness under reduced pressure, 4N aqueous hydrochloric acid solution is added to the residue to adjust to pH 1, and the mixture is washed with diethyl ether. Then 1
The pH is adjusted to 13 by adding 0N aqueous sodium hydroxide solution. It is extracted with methylene chloride (200 ml), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (silica gel, elution solvent hexane: ethyl acetate: triethylamine = 5: 5: 1) to give the desired product (2.
2 g) are obtained.

Colorless oily cis NMR (CDCl ₃ , δ, ppm) 2.24 (s, 3H),
2.45 (s, 8H), 2.94-3.32 (m, 2H), 3.84 (s, 3H), 5.22
(bs, 2H), 5.85 (t, 1H, J = 6.8Hz), 6.66-8.07 (m, 7H) mass spectrum (m / z) 378 (M ⁺ ) trans isomer NMR (CDCl ₃ , δ, ppm) 2.24 (s,
3H), 2.45 (s, 8H), 2.94-3.32 (m, 2H), 3.84 (s, 3H),
5.22 (bs, 2H), 6.22 (t, 1H, J = 6.8Hz) Mass spectrum (m / z) 378 (M ⁺ )

Reference Example 16 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz- [b, e] oxepin-2-carboxylic acid (Compound b) 11- (3-Dimethylaminopropylidene) Methyl-6,11-dihydrodibenz [b, e] oxepin-2-carboxylate (26.1 g) was added to methanol (500 ml) and water (3
Dissolved in a mixed solvent of 0 ml) and sodium hydroxide (6.2
g) is added and the mixture is heated under reflux for 2 hours. After cooling, 4N hydrochloric acid aqueous solution was added to adjust the pH to 7 and concentrated under reduced pressure. This was purified by high-porous polymer (HP-20) column chromatography (elution solvent water: methanol = 1: 2) to obtain the desired product ( 25.0 g) are obtained.

White crystals of cis body Melting point 162-164 ° C NMR (DMSO-d ₆ , δ, ppm) 2.28 (s, 6H), 2.40
-2.70 (m, 4H), 5.20-5.40 (broad, 2H), 5.72 (t, 1H, J =
7.0Hz), 6.85-7.90 (m, 7H) IR (KBr tablet, cm ^-1 ) 3400, 1610, 1370, 1220, 1
005

White crystal of trans form Melting point 242-244 ° C NMR (DMSO-d ₆ , δ, ppm) 2.25 (s, 6H), 2.40
-2.70 (m, 4H), 5.20-5.40 (broad, 2H), 6.09 (t, 1H, J =
7.0Hz), 6.78-7.90 (m, 7H) IR (KBr tablet, cm ^-1 ) 3400, 1610, 1380, 1222, 1
010

Reference Example 17 1/2 Fumarate of Compound b, 1/5 Hydrate (Compound b ′) 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] Oxepin-2-carboxylic acid (compound b) (3.95 g) was dissolved in acetone (100 ml), fumaric acid (1.42 g) was added thereto, and the mixture was stirred at room temperature. The precipitated crystals are filtered and the resulting crude crystals are recrystallized from isopropanol to give the desired product (4.15).
g) is obtained.

White solid Melting point 253-254 ° C. Isomeric purity Trans type 99% (determined by HPLC)

Reference Example 18 Sodium salt monohydrate of compound c (compound c ') 11- (2-diethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-carboxylic acid (compound c) (1.00 g) is dissolved in methanol (100 ml), 28% sodium methoxide methanol solution (5.5 ml) is added thereto, and the mixture is stirred for 1 hour and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the residue to solidify it, and this is filtered to obtain the desired product (0.98 g).

White solid Unclear due to melting point and hygroscopicity Isomeric ratio Syn: anti = 1: 1

Example 1 11- (3-Dimethylaminopropylidene) -2- (2-
Triphenylmethyloxyethyl) -6,11-dihydrodibenz [b, e] oxepin (Compound 15) Step A: 11-hydroxy-2- (2-hydroxyethyl) -6,11-dihydrodibenz [b, e) Oxepin 11-oxo-6,11-dihydrodibenz [b, e] Methyl acetate (20 g) was dissolved in tetrahydrofuran (500 ml), lithium aluminum hydroxide (6.0 g) was added, and the mixture was stirred at room temperature. Stir for 1 hour. After adding water to decompose excess reagent, the inorganic reagent residue is filtered off.
The filtrate was concentrated to dryness under reduced pressure to give the desired product (17.7
g) is obtained.

White solid Melting point 132-136 ° C. NMR (CDCl ₃ + DMSO-d ₆ + D ₂ O, δ, ppm) 2.59 (t,
2H, J = 6.8Hz), 3.55 (t, 2H, J = 6.8Hz), 4.89 and 5.71
(ABq, 2H, J = 12.6Hz), 5.60 (s, 1H), 6.46-7.49 (m, 7H)

Step B: 11-hydroxy-2- (2-triphenylmethyloxyethyl) -6,11-dihydrodibenz [b, e] oxepin 11-hydroxy-2- (2-hydroxyethyl) -6, 11
-Dihydrodibenz [b, e] oxepin (17.2 g)
Is dissolved in pyridine (50 ml), triphenylchloromethane (30 g) is added thereto, and the mixture is stirred at 50 ° C. for 5 hours. After adding water and stirring for 2 hours, the solvent is distilled off under reduced pressure. Extract with ethyl acetate (1000 ml), wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The obtained residue is subjected to column chromatography (silica gel, elution solvent hexane: ethyl acetate =
Purification by 3: 1) gives the desired product (21.7 g).

Colorless amorphous NMR (CDCl ₃ + D ₂ O, δ, ppm) 2.47-2.95
(m, 2H), 2.96-3.45 (m, 2H), 4.87 and 5.71 (ABq, 2H,
J = 13.2Hz), 5.43 (s, 1H), 6.33-7.51 (m, 22H)

Step C: 11-oxo-2- (2-triphenylmethyloxyethyl) -6,11-dihydrodibenz [b, e] oxepin 11-hydroxy-2- (2-triphenylmethyloxyethyl) -6,11-Dihydrodibenz [b, e] oxepin (10 g) in acetone (800 ml), water (1000 ml),
It is dissolved in a solution of a saturated aqueous solution of magnesium sulfate (20 ml) and disodium phosphate (0.2 g), an aqueous solution of sodium permanganate (2.6 g) is added dropwise thereto, and the mixture is stirred at room temperature for 4.5 hours. Add methanol (100 ml) and heat to reflux for 3 hours. After cooling, the insoluble matter was filtered off,
Ethyl acetate (1000 ml) is added to the filtrate for extraction, and the extract is washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The desired product (8.0 g) is obtained by recrystallizing the obtained crude product from isopropanol.

White crystal Melting point 132-134 ° C. Elemental analysis (%) Calculated as C ₃₅ H ₂₈ O ₃ C 84.65 H 5.68 Measured value C 84.56 H 5.67 NMR (CDCl ₃ , δ, ppm) 2.61-3.04 (m, 2H ),
3.05-3.46 (m, 2H), 5.01 (s, 2H), 6.63-8.07 (m, 22H)

Step D: 11- (3-Dimethylaminopropyl) -11-hydroxy-2- (2-triphenylmethyloxyethyl) -6,11-dihydrodibenz [b, e] oxepin Tetrahydrofuran under nitrogen atmosphere In 10 ml, dibromoethane as a catalyst and magnesium (0.2 g) and 3
11-oxo-2- (2-triphenylmethyloxyethyl) -dissolved in tetrahydrofuran (10 ml) under ice cooling in a solution of 3-dimethylaminopropyl magnesium chloride prepared from dimethylaminopropyl chloride (1.0 g) 6,11-Dihydrodibenz [b, e] oxepin (2.0 g) was added dropwise, and the mixture was further stirred at room temperature for 1 day.
Aqueous ammonium chloride solution is added, 4N aqueous hydrochloric acid solution is further added to adjust the pH to 7.0, and the solvent is distilled off under reduced pressure. Extract with methylene chloride (200 ml), wash with saturated aqueous sodium hydrogen carbonate and saturated brine successively, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The obtained residue is purified by column chromatography (silica gel, elution solvent hexane: ethyl acetate: triethylamine = 10: 10: 1) to obtain the desired product (1.2 g).

Colorless amorphous NMR (CDCl ₃ , δ, ppm) 0.85-1.83 (m, 4H),
2.08 (s, 6H), 2.67-3.44 (m, 6H), 4.94 and 5.36 (ABq, 2
H, J = 15.8Hz), 6.63-8.13 (m, 22H) Mass spectrum (m / z) 583 (M ⁺ )

Step E: 11- (3-Dimethylaminopropylidene) -2- (2-triphenylmethyloxyethyl) -6,11-dihydrodibenz [b, e] oxepin 11- (3-dimethylaminopropyl) ) -11-Hydroxy-2- (2-triphenylmethyloxyethyl) -6,11
Dihydrodibenz [b, e] oxepin (1.2 g) was dissolved in pyridine (50 ml), and phosphorus oxychloride (0.8 g) was added dropwise thereto under a nitrogen atmosphere and ice cooling. After stirring at room temperature for 1 hour, the solvent is distilled off under reduced pressure. It is extracted with methylene chloride (100 ml), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (silica gel, elution solvent hexane: ethyl acetate:
Purification with triethylamine = 10: 10: 1) gives the desired product (0.82 g).

Colorless oil Mass spectrum (m / z) 565 (M ⁺ ) NMR (CDCl ₃ , δ, ppm) 2.16 (s, 6H), 2.30
-2.40 (m, 4H), 2.79 (t, 2H, J = 6Hz), 3.24 (t, 2H, J = 6H
z), 5.97 (t, 1H, J = 7Hz), 6.60-7.40 (m, 22H) (However,
Transformer type)

Example 2 11- (3-Dimethylaminopropylidene) -2- (2-
Hydroxyethyl) -6,11-dihydrodibenz [b,
e] Oxepin (Compound 14) 11- (3-Dimethylaminopropylidene) -2- (2-
Triphenylmethyloxyethyl) -6,11-dihydrodibenz [b, e] oxepin (0.92 g) is dissolved in a mixed solvent of dioxane (20 ml) and water (20 ml). Add paratoluenesulfonic acid (60mg) to this and add 2
The mixture is heated under reflux for hours and the solvent is distilled off under reduced pressure. Ethyl acetate (2
(00 ml), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (silica gel, elution solvent ethyl acetate: triethylamine = 1)
Purification in 0: 1) gives the desired product (0.4 g).

Cis white solid, melting point 100-102 ° C
(Diethyl ether) NMR (CDCl ₃ , δ, ppm) 2.32 (s, 6H), 2.30-2.
70 (m, 4H), 2.76 (t, 2H, J = 6Hz), 3.78 (t, 2H, J = 6Hz),
5.66 (t, 1H, J = 7Hz), 6.80-7.40 (m, 7H) mass spectrum (m / z) 323 (M ⁺ ) trans white solid, melting point 96-97 ° C (diethyl ether) NMR (CDCl ₃ , δ) , Ppm) 2.21 (s, 6H), 2.30-2.
70 (m, 4H), 2.76 (t, 2H, J = 6Hz), 3.78 (t, 2H, J = 6Hz),
6.01 (t, 1H, J = 7Hz), 6.68-7.40 (m, 7H) Mass spectrum (m / z) 323 (M ⁺ )

Example 3 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 3) 11- (3-Dimethylaminopropylidene) -2 -(2-
Hydroxyethyl) -6,11-dihydrodibenz [b,
e] Oxepin (2.2 g) is dissolved in acetone (100 ml), Jones reagent is added thereto until the reaction solution becomes orange, and the mixture is further stirred at room temperature for 1 hour. Baking soda is added, the inorganic substances are filtered off, and the solvent of the filtrate is distilled off under reduced pressure to obtain the desired product. The physical properties of this product are in good agreement with those obtained in Example 17.

Example 4 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-methyl acetate (Compound 1) Under nitrogen atmosphere (3-dimethylaminopropyl)- Triphenylphosphonium bromide hydrobromide (48 g) was suspended in tetrahydrofuran (200 ml) and cooled under ice cooling to 1.6
A normal n-butyllithium hexane solution (80 ml) is added. Stir for 1 hour under ice cooling.

A solution of 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (5.0 g) in tetrahydrofuran (120 ml) was added dropwise under ice cooling. After stirring at room temperature for 2 hours, the solvent was evaporated under reduced pressure, water (200 ml) was added, and diethyl ether (200 ml) was added.
ml). A 4N hydrochloric acid aqueous solution is added to adjust the pH to 1, and the mixture is washed with diethyl ether.

Next, 10N sodium hydroxide aqueous solution was added.
The pH is adjusted to 7 and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in methanol (400 ml), paratoluenesulfonic acid (5 g) is added thereto, the mixture is heated under reflux for 2 hours, and then the solvent is evaporated under reduced pressure. It is extracted with ethyl acetate (300 ml), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is subjected to column chromatography (silica gel, elution solvent hexane: ethyl acetate: triethylamine = 10: 1).
Purify at 0: 1) to obtain the desired product (4.0 g).

Colorless oily cis NMR (CDCl ₃ , δ, ppm) 2.06-2.67 (m, 4H), 2.
16 (s, 6H), 3.46 (s, 2H), 3.58 (s, 3H), 5.08 (bs, 2H),
5.69 (t, 1H, J = 7Hz), 6.53-7.30 (m, 7H) Trans NMR (CDCl ₃ , δ, ppm) 2.06-2.67 (m, 4H), 2.
16 (s, 6H), 3.46 (s, 2H), 3.58 (s, 3H), 5.08 (bs, 2H),
6.06 (t, 1H, J = 7Hz), 6.53-7.30 (m, 7H)

Example 5 Methyl 11- (4-dimethylaminobutylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetate (Compound 4) (3-Dimethylaminopropyl) in Example 4 -Triphenylphosphonium bromide hydrobromide (4-
The desired product is obtained by substituting dimethylaminobutyl) -triphenylphosphonium bromide hydrobromide.

Example 6 Methyl 11- (3-pyrrolidinopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-methyl acetate (Compound 6) (3-Dimethylaminopropyl) in Example 4 -Triphenylphosphonium bromide hydrobromide (3-
The desired product is obtained by substituting pyrrolidinopropyl) -triphenylphosphonium bromide hydrobromide hemihydrate.

Example 7 3- [11- (3-Dimethylaminopropylidene) -6,11
-Dihydrodibenz [b, e] oxepin-2-yl]
-Methyl propionate (Compound 10) 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid in Example 4 was converted to 3- (11-oxo-
The desired product is obtained by replacing 6,11-dihydrodibenz [b, e] oxepin-2-yl) -propionic acid.

Example 8 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-3-methylacetate (Compound 12) 11-oxo-6,11 in Example 4 Dihydrodibenz [b, e] oxepin-2-acetic acid as 11-oxo-6,11-
The desired product is obtained by changing to dihydrodibenz [b, e] oxepin-3-acetic acid.

Example 9 11- (2-Dimethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-methyl acetate (Compound 17) 11-oxo-6,11-dihydrodibenz [B, e] Methyl oxepin-2-acetate (22.0 g) and N, N-dimethylethylenediamine (68.7 g) were dried over benzene (700 m
l), and a solution of titanium tetrachloride (17.2 ml) in dry benzene (40 ml) was added dropwise thereto, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added, the insoluble material was filtered off, the filtrate was extracted with ethyl acetate (500 ml), washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distill off. The obtained residue is purified by column chromatography (silica gel, elution solvent ethyl acetate: triethylamine = 10: 1) to give the desired product (13.8
g) is obtained.

Colorless oil NMR (CDCl ₃ , δ, ppm) 2.14 (s, 6H), 2.63 (t,
2H, J = 6.9Hz), 3.51 (s, 2H), 3.58 (s, 3H), 3.38-3.80
(m, 2H), 5.04 (bs, 2H), 6.56-7.60 (m, 7H) IR (liquid film, cm ^-1 ) 2950, 1740, 1630, 1305, 1015 Mass spectrum (m / z) 352 (M ⁺ )

Example 10 Methyl 11- (2-diethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-acetate (Compound 19) The N, N-dimethylethylenediamine in Example 9 was replaced with N. , N-diethylethylenediamine is obtained to obtain the desired product. Mass spectrum (m / z) 380 (M) as colorless oily C ₂₃ H ₂₈ O ₃ N _2.
⁺ )

Example 11 Methyl 11- (3-dimethylaminopropyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-acetate (Compound 21) The N, N-dimethylethylenediamine in Example 9 was The target product is obtained by changing to N, N-dimethylpropylenediamine. Mass spectrum (m / z) 366 (M) as colorless oily C ₂₂ H ₂₆ O ₃ N _2.
⁺ )

Example 12 3- [11- (2-Dimethylaminoethyl) imino-6,11
-Dihydrodibenz [b, e] oxepin-2-yl]
-Methyl propionate (Compound 23) Methyl 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-acetate in Example 10 was replaced with 3- (11-oxo-6,11-dihydrodibenz [ b, e] -Oxepin-2-yl) -propionic acid gives the desired product. As a colorless oily C ₂₄ H ₃₀ O ₃ N ₂ , mass spectrum (m / z) 394 (M
⁺ )

Example 13 2- [11- (2-dimethylaminoethyl) imino-6,11
-Dihydrodibenz [b, e] oxepin-2-yl]
-Methyl propionate (Compound 25) Methyl 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-acetate in Example 9 was replaced with 2- (11-oxo-6,11-dihydrodibenz [ b, e] Oxepin-
The desired product is obtained by changing to 2-yl) -propionic acid. Mass spectrum (m / z) 366 (M) as colorless oily C ₂₂ H ₂₆ O ₃ N _2.
⁺ )

Example 14 11- (2-Dimethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-3-methylacetate (Compound 27) 11-oxo-6,11 in Example 9 -Methyl dihydrodibenz [b, e] oxepin-2-acetate with 11-oxo-
The desired product is obtained by substituting methyl 6,11-dihydrodibenz [b, e] oxepin-3-acetate. Mass spectrum (m / z) 352 (M as colorless oily C ₂₁ H ₂₄ O ₃ N ₂
⁺ )

Example 15 11- (3-Dimethylaminopropyl) imino-6,11-dihydrodibenz [b, e] oxepin-3-methylacetate (Compound 29) 11-oxo-6,11 in Example 11 -Methyl dihydrodibenz [b, e] oxepin-2-acetate with 11-oxo-
The desired product is obtained by substituting methyl 6,11-dihydrodibenz [b, e] oxepin-3-acetate. Mass spectrum (m / z) 366 (M) as colorless oily C ₂₂ H ₂₆ O ₃ N _2.
⁺ )

Example 16 11- [2- (4-Methylpiperazino) ethylidene] -6,
Methyl 11-dihydrodibenz [b, e] oxepin-2-acetate (Compound 8) 11-methylene-6,11-dihydrodibenz [b, e] -oxepin-2-carboxylate methyl in Reference Example 15
The desired product is obtained by substituting methyl-methylene-6,11-dihydrodibenz [b, e] oxepin-2-acetate.

Example 17 11- (3-Dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 3) Hydrolyzed in the same manner as in Reference Example 16 to give the desired product. Get things.

White crystals of cis body Melting point 118-120 ° C. (isopropanol) NMR (DMSO-d ₆ , δ, ppm) 2.16 (s, 6H), 2.30-2.
60 (m, 4H), 4.04 (s, 2H), 5.15 (bs, 2H), 5.69 (t, 1H,
J = 7Hz), 6.73-7.40 (m, 7H) IR (KBr tablet, cm ^-1 ) 3400, 1580, 1225, 1005 Mass spectrum (m / z) 337 (M ⁺ )

White crystal of trans form Melting point 158-160 ° C. (acetonitrile) NMR (DMSO-d ₆ , δ, ppm) 2.05 (s, 6H), 2.30-
2.60 (m, 4H), 4.04 (s, 2H), 5.15 (bs, 2H), 6.06 (t, 1
H, J = 7Hz), 6.73-7.40 (m, 7H) IR (Liquid film, cm ^-1 ) 3380, 1575, 1220, 1005 Mass spectrum (m / z) 337 (M ⁺ )

Examples 18-21 11- (4-Dimethylaminobutylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 5) 11- (3-Pyrrolidinopropylidene) -6,11-Dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 7) 11- [2- (4-Methylpiperazino) ethylidene] -6,
11-Dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 9) 3- [11- (3-Dimethylaminopropylidene) -6,11
-Dihydrodibenz [b, e] oxepin-2-yl]
-Propionic acid (Compound 11) It is hydrolyzed in the same manner as in Example 17 to obtain the desired product. The physical property values are shown in Table 9 and the subsequent tables.

[0169]

[Table 20]

Compound 11 White crystals of cis body Melting point 136-138 ° C. (isopropyl ether) NMR (DMSO-d ₆ , δ, ppm) 2.32 (m, 2H), 2.38 (s,
6H), 2.44-2.56 (m, 2H), 2.73 (m, 4H), 5.15 (bs, 2H),
5.50 (m, 1H), 6.7-7.4 (m, 7H) IR (KBr tablet, cm ^-1 ) 3380, 1645 Mass spectrum (m / z) 351 (M ⁺ )

White crystal of trans form Melting point 148-149 ° C. (acetonitrile) NMR (DMSO-d ₆ , δ, ppm) 2.05 (s, 6H), 2.24 (m,
2H), 2.35 (m, 2H), 2.47 (t, 2H, J = 7.5Hz), 2.72 (t,
2H, J = 7.5Hz), 4.80-5.50 (broad, 2H), 5.99 (t, 1H, J =
7.1Hz), 6.6-7.5 (m, 7H) IR (KBr tablet, cm ^-1 ) 3380, 1700 Mass spectrum (m / z) 351 (M ⁺ )

Example 22 11- (2-Dimethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (compound
18) Hydrolyze in the same manner as in Reference Example 16 to obtain the desired product as a mixture of 8% syn and 92% anti. White crystal Melting point 174-176 ° C (as hemihydrate) NMR (DMSO-d ₆ , δ, ppm) 2.07 (s, 6H), 2.30-2.
80 (m, 4H), 3.47 (s, 2H), 4.90-5.30 (broad, 2H), 6.74
-7.62 (m, 7H) IR (KBr tablet, cm ^-1 ) 3350, 1575, 1370, 1010

Examples 23-28 11- (2-diethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (compound
20) 11- (3-Dimethylaminopropyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (compound 22) 3- [11- (2-diethylaminoethyl) imino-6,11
-Dihydrodibenz [b, e] oxepin-2-yl]
-Propionic acid (Compound 24) 2- [11- (2-Dimethylaminoethyl) imino-6,11
-Dihydrodibenz [b, e] oxepin-2-yl]
-Propionic acid (Compound 26) 11- (2-Dimethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-3-acetic acid (Compound
28) 11- (3-Dimethylaminopropyl) imino-6,11-dihydrodibenz [b, e] oxepin-3-acetic acid (Compound 30) Hydrolyze in the same manner as in Example 22 to obtain the desired product. .
The physical property values are shown in Table 10.

[0174]

[Table 21]

[0175]

[Table 22]

Examples 29 to 33 In the same manner as in Reference Example 17, the target compounds shown in Table 11 are obtained. Physical property values are shown in Table 12.

[0177]

[Table 23]

[0178]

[Table 24]

Examples 34 to 35 In the same manner as in Reference Example 18, the target compounds shown in Table 13 are obtained. Physical properties are shown in Table 14.

[0180]

[Table 25]

[0181]

[Table 26]

Example 36 Methyl 11- (3-Methylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetate (Compound 34) (3-Dimethylaminopropyl) in Example 4 -Triphenylphosphonium bromide hydrobromide (3-
Methylaminopropyl) -triphenylphosphonium-
The desired product is obtained by replacing the bromide hydrobromide salt. Mass spectrum (m / z) 337 (M ⁺ ) as colorless oily C ₂₁ H ₂₃ O ₃ N

Example 37 Methyl 11- (3-aminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetate (Compound 3
6) (3-Dimethylaminopropyl) -triphenylphosphonium bromide hydrobromide in Example 4 was added to (3-
The desired product is obtained by substituting aminopropyl) -triphenylphosphonium bromide hydrobromide. Mass spectrum (m / z) 323 (M ⁺ ) as colorless oily C ₂₀ H ₂₁ O ₃ N

Examples 38-39 11- (3-Methylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 3
5) 11- (3-Aminopropylidene) -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (Compound 37) Hydrolyze in the same manner as in Reference Example 16 to obtain the desired product.
The physical property values are shown in Table 15.

[0185]

[Table 27]

Formulation Example 1 Powder A powder having the following composition is prepared by a conventional method. Trans-11- (3-dimethylaminopropylidene)-
6,11-Dihydrobibenz [b, e] oxepin-2-acetic acid fumarate 3/2 hydrate (Compound 3 ') 30 mg Lactose 270 mg

Formulation Example 2 Syrup A syrup having the following composition is prepared by a conventional method. 11- (2-Dimethylaminoethyl) imino-6,11-dihydrodibenz [b, e] oxepin-2-acetic acid (compound
18) 300 mg Purified sucrose 40 g Methyl paraoxybenzoate 40 mg Propyl paraoxybenzoate 10 mg Strawberry flavor 0.1 cc Add water to make a total volume of 100 cc.

[0188]

INDUSTRIAL APPLICABILITY Compound (I) and its pharmacologically acceptable salt have an antiallergic action and / or an antiinflammatory action.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/495 9360-4C 31/535 9360-4C 31/54 9360-4C 31/645 9360-4C (72) Inventor Kenmori Omori 2-14-3 Fuyodai, Mishima City, Shizuoka Prefecture (72) Inventor Hidee Ishii 847-3 Minamie, Nirayama-cho, Takata-gun, Shizuoka (72) Haruhiko Sanbe Mayor, Hayato-gun, Shizuoka 1188 Shimochiri, Izumi-cho Seiwa Dormitory (72) Inventor Tadashi Tamura Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture 1188 Shimochi-ryo Dormitory (72) Inventor Shoichi Suto 410-1 Narimai, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture

Claims (1)

[Claims] 1. The formula: [In the formula, A is hydroxymethyl group, lower alkoxymethyl group, triphenylmethyloxymethyl group, lower alkanoyloxymethyl group, lower alkanoyl group, carboxyl group, lower alkoxycarbonyl group, triphenylmethyloxycarbonyl group, -CONR ₁ R ₂ (where R
₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group), 4,4-dimethyl-2-oxazoline-
2-yl represents a group or -CONHOH, Y is substituted at the 2-position or 3-position of the mother nucleus - (CH _{2) m} - (wherein, m is 1,
2, 3 or represents a 4) or _{-CHR 3 - (CH 2) p} -
(In the formula, R ₃ represents a lower alkyl group, and p is 0, 1,
Represents 2, 3, or 4. It is assumed that the left side of each of the above formulas is bound to the mother nucleus. ), And X ₁ -X ₂ is C =
N, represents C = CH or CH-CH _2, n is 0,
2, 3 or 4, Z is a 4-methylpiperazino group, 4
- methylhomopiperazine piperazino group, piperidino group, pyrrolidino group, thiomorpholino group, a morpholino group, or -NR ₆ R ₇
(Wherein R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a lower alkyl group), and a dibenz [b, e] oxepin derivative or a pharmaceutically acceptable salt thereof.