CA1337603C - Dibenz[b,e]oxepin derivative and antiallergic and antiinflammatory agent - Google Patents

Abstract

A novel dibenz [b,e] oxepin derivative of formula I:

I

is prepared. This compound, especially in the cis form, can be employed in the treatment and control of allergic conditions such as asthma and also employed in the treatment of inflammation.

Description

~ITT-~ OF THE INV~NTION
DIBENZ [b,e] OXEPIN DERIVATIVE AS AN ANTIALLERGIC AND
ANTIINFLAMMATORY AGENT

This is a divisional application of copending application S.N. 531,043 filed March 3, 1987.

~ACRGROUND OF THE INVENTION
Heretofore, it has been known that 11-unsubstituted, ll-hydroxy or ll-oxodibenz [b,e] oxepin derivative is used for antiinflammatory agents [J. Med.
Che., 21, 633 - 639 (1978)]
Further, it is known that dibenz [b,e] oxepin derivative wherein substitutents R. and ~ at ll-position have the following definitions, is employed in the treatment and control of allergic conditions (USP
4,282,365).
R.: H, OH, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, arylthio, NH2, NHCHO or imidazolyl;
Rb : H or lower alkyl;
or R. and Rb taken together are = 0, z CH-RC wherein Rc is H or aryl.
Furthermore, it is known that 11-(4-methylpiperazino) diben~ [b,e] oxepin derivative has an antiasthmatic activity (USP 4,396,550, USP 4,465,835, EP-A-3856).

It is also known that dibenz [b,e]oxepin derivative having the following formula:

S~ NRdR~

~Rf wherein Rd and Re are lower alkyl and Rf is lower alkyl or halogen, has an antiasthmatic activity (EP-A-85870).
Dibenz ~b,e] oxepin derivative having an anti-allergic activity and having the following structural formula:
0'(~
~ ~Ri wherein R9 and Rh are alkyl, r is 2 or 3 and Rj is alkyl or halogen is known (JP-A-227879/84).
Dibenz tb,e] oxepin derivative having an anti-allergic activity and having the following structural formula:

[~R}

wherein R; is 4-alkylpiperazino, 3-quinuclidylamino or -Xa~(CH2) ,-NR~R~ wherein Xais -NH-, -S- or -0-, s is 2 or 3 and R~ and R~ are alkyl, and ~ is CN, 5-tetrazolyl, CONH2 or C02Rn wherein F~ i8 H, alkyl or 1- (ethoxycarbo-nyloxy) ethyl is known (EP-A-130555).
Doxepin having an antidepressant activity and having the following structural formula is known [Drugs, 13, 161 (1971)].

Dothiepin having an antidepressant activity and having the following structural formula is known ~Arz.-Forsch., 13 1039 (1963); ibid., 14 100 (1964)].
~,~CH~
[~1 As the compound having both an antiallergic activity and an antiinflammatory activity, steroids are known.
It is always desired that a novel compound having an antiallergic activity or an antiinflammatory activity be developed.

8UMMARY OF TR~ INVENTION

The present invention relates to a dibenz [b,e]
oxepin derivative represented by the formula (I):

~ N(C~
~ C~OOOH

and pharmaceutically acceptable salts thereof, and to its use for the treatment of allergic conditions and inflammation.
The present invention further pertains to a pharmaceutical composition containing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a carrier or an excipient.

DETAILED DE8CRIPTION OF TRE l..v~...lON

The pharmaceutically acceptable salt of Compound (I) includes pharmaceutically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt, amino acid addition salt, etc.
The pharmaceutically acceptable acid addition salt of Compound (I) includes inorganic acid salts such ` -~ 5 ~ 1 337603 as hydrochloride, sulfate, phosphate, etc., and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate, etc. The pharmaceutically acceptable metal salt includes alkalimetal salts such as sodium salt, potassium salt, etc., alkaline earch metal salts such as magnesium salt, calcium salt, etc., and aluminium salt, zinc salt, etc. The pharmaceutically acceptable organic amine addition salt includes addition salt or morpholine and piperidine and the pharmaceutically acceptable amino acid addition salt includes addition salt of lysine, glysine, phenylalanine, etc.
Compound (I) is prepared by using a compound represented by the formula (II):

o ~CH2COOH

or a compound represented by the formula (III):

~ C~OOOH
m Compound (II) is disclosed in J. Med. Chem., 19, 941 (1976), ibid., 20, 1499 (1977) and JP-A-21679/83.
Compound (III) can be prepared according to the method described in JP-A-21679/83 though it does not occur in the publication.

Process A

The carboxy group of Compound (II) is protected according to the following reaction scheme.

H~ X OH ~ CH,CO~ ~ CH, IV

~ CH, Compound (II) is reacted with 1 to 5 equivalents of thionyl chloride and 1 to 5 equivalents of 2-amino-2-methyl-1-propanol on the basis of Compound (II) in an inert solvent such as methylene chlooride, if necessary in the presence of a base such as triethylamine at a temperature of from 0C to room temperature for 1 -24 hours to form Compound (IV). Compound (IV) can alsobe obtained by reacting Compound (II) with thionyl chloride in advance and then with 2-amino-2-methyl-1-propanol.
Compound (IV) is reacted with 1 - 5 equivalents of thionyl chloride in an inert solvent such as methylene chloride, toluene and benzene at a temperature of from - _ 7 _ 1 337603 0C to room temperature for 1 - 24 hours to form Compound (V) .
Compounds (I) and (Ia) can be prepared from Compound (V) according to the following reaction scheme.

O H~Mg(CH~(CH~, HO (CH~N(CH~, o ,CH,~ ~ Vl ~ CH,~ ~
CH, ~ ~ ~ N-t-CH, V V~

H (CH~CH~ H (CH~N(C~
-H,O ~ C~ O ~ ,C~COOH

O ~ CH, ~ O
h S wherein Hal is halogen, and includes chlorine, bromine and iodine.
Compound (V) is reacted with 1 - 5 equivalents of Compound (VI) in an inert solvent such as tetrahydrofuran and diethyl ether under atmosphere of an inert gas such as nitrogen and argon to form Compound (VII). The reaction is carried out at a temperature of from 0C to room temperature and is usually completed in 1 - 24 hours.

Compound (VII) is reacted with 1 - 5 equivalents of thionyl chloride or phosphoryl chloride in an inert solvent such as methylene chloride in the presence of a base such as pyridine to form Compound (Ia). The reaction is carried out at a temperature of from 0C to room temperature and is completed in 1 - 24 hours.
Compound (Ia) is incubated in an alcohol containing water, such as aqueous methanol solution, in the presence of an appropriate acidic catalyst such as p-toluenesulfonic acid at a temperature of from room temperature to the boiling point of the solvent to form Compound (I). The reaction is completed in 1 - 24 hours.

Process B

The carboxy group of the compound represented by formula (II) can be converted to a lower alkoxymethyl group for a trityloxymethyl group according to the following reaction scheme.

C~COOH

L~UH, OH
~ CH,C~OH

C~ ~ vm ~ H

OH o~
~C~,OC~ ~ CH,CH,O~

IX X

O~id~ ~.~

~CH2CI~OR,' In the formulae, F~ is a lower alkyl group and R9' is a trityl group or a lower alkyl group.

- lo 1 337 6 03 Compound (II) is reduced with 1 -5 equivalents of lithium aluminium hydride in tetrahydrofuran at a temperature of from 0C to room temperature for 1 - 24 hours to form Compound (VIII).
Compound (VIII) is reacted with 1 - 5 equivalents of trityl chloride in pyridine at a temperature of from room temperature to 100C for 1 - 24 hours to form Compound (IX).
Compound (IX) is oxidized with 1 - 5 equivalents of an appropriate oxidizing agent such as potassium permanganate and pyridinium chlorochromate in an inert solvent such as methylene chloride and acetone to form Compound (XI) wherein F9' is trityl. The reaction is carried out at a temperature of from 0C to the boiling point of the solvent and is completed in 1 -24 hours.
Compound (VIII) is incubated in an alcohol of R9OH in the presence of an appropriate acidic catalyst such as sulfuric acid at a temperature of from room temperature to the boiling point of the solvent to form Compound (X). The reaction is usually completed in 1 -24 hours.
Compound (X) is oxidized with 1 - 5 equivalents of an appropriate oxidizing agent such as Jones reagent in an inert solvent such as acetone to form Compound (XI) wherein R9' is a lower alkyl. The reaction is carried out at a temperature of from 0C to the boiling point of the solvent and is usually completed in 1 - 24 hours.

The compound represented by the formulae (Ib) and (Ic) and the compound of formula (I) can be synthesized from Compound (XI) according to the following reaction scheme.

~CHCHOR,' H~CH~N(CH~

HO (CE~ N(CH,), H~
,C~O~ -H,O ~ CH,C~

X~ \ / Ib H
H (C~,),N(CH,)2 [~CH2CH,OH

O~on H (CH~)2N(CH~, ~CH,COOH

` - 12 - 1 33 76 03 In the formulae, ~', and Hal have the same meanings as previously defined.
Compound (XI) is reacted with Compound (VI) which is Grignard reagent according to the same manner as in the reaction step from Compound (V) to Compound (VII) in Process A to form Compound (XII).
Compound (XII) is subjected to reaction according to the same manner as in the reaction step from Compound (VII) to Compound (Ia) in Process A to form Compound (Ib).
Compound (Ib) is incubated in a solvent containing water such as aqueous dioxane in the presence of an appropriate acidic catalyst such as p-toluenesulfonic acid at a temperature of from room temperature to the boiling point of the solvent to form Compound (Ic). The reaction is usually completed in 1 -24 hours.
Compound (Ic) can also be obtained in one step by incubating Compound (XII) in a solvent containing water such as aqueous dioxane in the presence of an appropriate acidic catalyst such as sulfonic acid at a temperature of from room temperature to the boiling point of the solvent. The reaction is usually completed in 1 -24 hour~.
If desired, Compound (Ic) is oxidized with 1 -S equivalents of an appropriate oxidizing agent such as Jones reagent in an inert solvent such as acetone to form Compound (I). The reaction is carried out at a temperature of from 0C to the boiling point of the solvent and is usually completed in 1 - 24 hours.

Process C

H (CH~N(CH~
Il P~CH(CH~N(CH~ ~
~C~COOH xm ~ CH,COOH

I[ ~ I

Compound (II) is reacted with 1 - 5 equivalents of Compound (XIII) in an inert solvent such as tetrahydrofuran under atmosphere of an inert gas such as nitrogen and argon at a temperature of from 0C to room temperature for 1 - 24 hours to form Compound (I).
Compound (XIII) which is ylide, can be prepared according to the method described in C.A. 63 16366a (1965).

+ H~(CH~H~ ~ P~p(CH~,H~-H~ ~ P~P (CH~N(CH~-H~HH~) q 2)HH~
~V XV XVI

In the formulae, Hal has the same meaning as previously defined and q is 1 or 2.
Compound (XIV) is reacted with an equivalent of triphenylphosphine in toluene at reflux of the solvent for 1 - 24 hours to form Compound (XV).

-Compound (XV) is reacted with 1 - 5 equivalents of HZ in ethanol at reflux of the solvent for 1 - 24 hours and excess HZ is distilled away under reduced pressure. After the addition of 1 - 5 equivalents of HHal on the basis of Compound (XV), the mixture is incubated at a temperature of from 0C to the boiling point of the solvent for 1 - 24 hours to form Compound (XVI) which is Wittig reagent.
Compound (XVI) is treated with 1 - 2 equivalents of an appropriate base such as n-butyl lithium in an inert solvent such as tetrahydrofuran under atmosphere of an inert gas such as nitrogen and argon to form ylide (XIII). The reaction is carried out at -78C
- room temperature and is usually completed in 1 - 24 hours.
The intermediates and the desired compounds in each of the processes described above can be purified and isolated by a purification method which is usually used in the field of organic chemical synthesis, such as filtration, extraction with organic solvent such as ethyl acetate and methylene chloride, drying, concentration, recrystallization, column chromatography, etc.
When Compound (I) is produced as a cis-trans mixture, it is separated and purified by an appropriate method which is usually used in the field of organic chemical synthesis, such as column chromatography, recrystallization, etc.
If desired, ciæ form can be converted to trans form. For example, cis form is added to an acetic acid -` - 15 - 1 33 76 03 and the mixture is heated at reflux in the presence of an appropriate catalyst such as p-toluenesulfonic acid for 1 - 24 hours to form trans form.
With regard to the denotation of cis form (or cin form) and trans form (or anti form) of Compound (I), Compound (I) wherein the substituent bound to the double bond is on the same side as oxygen of oxepin, is cis form (or cin form) and Compound (I) wherein the substituent is on the opposite side is trans form (or anti form).
Further, if cis form or trans form is denoted according to E - Z expression, cis form (or cin form) is Z form and trans form (or anti form) is E form.
For example, the compound represented by the following formula is cis form (or cin form or Z form) H (CH~N(CH~
~,CH,COOH

The characteristic NMR signal of the proton H~
in the compound of formula I

Ha~(CH,)2N(C~)2 ~CH,COOH

-has been measured. The chemical shift of H, is 5.66 ppm for the cis form, and 6.00 ppm for the trans form. These chemical shifts were measured in DMSO-d6.
The retention time in HPLC for the cis and trans derivatives of the compound of formula I is 9.93 minutes and 7.46 minutes respectively. The conditions for the HPLC experiment were as follows:
Instrument: SHIMAZU LC-3A
Column : Yamamurakagaku YMC A-312 Elvent : 0.01M PIC B-8 in 61.3% MeOH
* PIC: Pic reagent (produced by Water Ass ) Pressure : 85-95 kg/cm2 Temperature: room temperature The antiallergic activity and antiinflammatory activity of Compound (I) are described below:
Test for antiallergic activity:
Antiallergic activity was investigated by a homologous PCA (passive cutaneous anaphlaxis) of rats for 48 hours, where Wistar male rats having body weights of 180 to 220 g were used for sampling of antiserum and Wistar male rats having body weights of 120 to 140 g were used for the PCA test.
A) Preparation of anti EWA rat serum Anti-egg white albumin (EWA) rat serum was prepared according to Stotland and Share's method [Canad.
J. Physiol. Pharmacol. 52, 1114 (1974)]. That is, 1 mg of EWA was mixed with 20 mg of aluminium hydroxide gel and 0.5 ml of mixed vaccine of pertussis, diphtheria and tetanus, and the mixture was subcutaneously administered in four portions into rat's footpad. After 14 days, blood was sampled from the carotid artery, and the serum was separated from the sampled blood, and preserved under freezing at -80C. The potency of the antiserum in the homologous PCA for 48 hours was 1:32.
B) Homologous PCA test of rats for 48 hours Groups each consisting of 3 rats were used, and 0.05 ml of anti-EWA rat serum diluted with a physiological saline solution to 8 times as much was incutaneously injected each at two positions of depilated back to make the animals passively sensitised. After 47 hours, the compound of the present invention, or its solution (physiological saline solution or CMC solution) was orally administered. One hour thereafter, 0.5 ml/100 g of 1% Evan's blue physiological saline solution containing 2 mg of the antigen EWA was administered into the tail vein, and 30 minutes thereafter, the animals were sacrificed by exsanguination. Then, the skins were stripped and the amount of leaked pigment at the blue-dyed parts was measured according to the Xatayama et al method tMicrobiol. Immunol. 22, 89 (1978)]. That is, the blue-dyed parts were cut out by scissors, and placed in test tubes containing 1 ml of lN KOH and incubated at 37C for 24 hours. Then, 9 ml of a mixture of 0.6N
phosphoric acid and acetone (5:13) was added thereto, and the mixture was shaked and centrifuged at 2,500 rpm for 10 minutes. Absorbancy of the supernatant at 620 ~m was measured, and the amount of leaked pigment was quantitatively determined by the calibration curve prepared in advance. An average of measurements at the two position was made a value for one zooid, and inhibition rate for the individual zooid was calculated by the following formula:
Inhibition rate (%) =

Average leaked amount Te~ke~ amount of of solvent-admini- - test compound-stered group administered group x 100 Average leaked amount of solvent-administered group Cases where, the inhibition rate is So~ or higher, were regarded as positive PCA inhibition activity, and the minimum administered dosage, where a positive case was observed in at least one of three zooids was regarded as minimum effective dosage (MED).
The results are shown in Table 5.
Acute toxic test:
Groups each consisting of 3 dd, male mice having body weights of 20 + 1 g were used, and the compound of the present invention was administered orally (po: 300 mg/kg) or intraperitoneally (ip: 100 mg/kg).
Mortality 7 days after the administration was observed to obtain MLD (minimum lethal dosage). The results are shown in Table 1.

Table 1 Acute Antiallergic Activity toxicity Number of positive zooids Compound (MLD) in one group of 3 zooids M E D
mg/kg Dosage mg/kg mg/kg po ip 100 10 1 O. 1 O. 01 O. 001 (trans) >300 ~100 2/3 2/3 3/3 3/3 0/3 0/3 0.1 (cisJ >300 ~100 3/3 3/3 3/3 3/3 1/3 0/3 0.01 Antiinflammatory activity test:
Antiinflammatory activity was examined according to Rat carageenin paw edema [J. Pathol. 104, 15-29 (1971)], Groups each consisting of three Wistar S male rats weighing 150 g were used. The test compound was suspended in 0.3% aqueous CMC solution and the suspension was given orally. Sixty minutes later, 0.1 ml of 0.1% carageenin was subcutaneously injected in a hind paw to form carageenin paw edema.
The volume of paw was measured before the administration and 3 hours after the administration of carageenin with plethysmometer.
The ratio of the volume 3 hours after the administration to that before the administration of carageenin was calculated and each ratio is compared with the ratio of control group (0.3% CMC was administered) to give the edema inhibiting percentage.
PCA inhibiting activity is believed to be on the basis of an activity inhibiting liberation of chemical mediator such as histamine from fat skin cell.
Therefore, Compound (I) and pharmaceutically acceptable salts thereof are believed to be useful for treating an allergic disease such as bronchus asthma which is caused by trachea contractile activity of chemical mediator such as histamine.
On the other hand, carageenin paw edema inhibiting activity is believed to be on the basis of prostaglandin biosynthesis inhibiting activity. Thus, Compound (I) and pharmaceutically acceptable salts thereof are believed to be useful for treating an acute inflammation and rheumatism which are ascribed to excessive prostaglandin.
Compound (I) has both antiallergic and antiinflammatory activities described above which is useful for the treatment of allergic diseases accompanied by inflammation.
In view of the pharmacological activity of Compound (I), Compound (I) can be used in various medicament forms for the administration purposes.
The present medicament composition can be prepared by uniformly mixing an effective amount of a free Compound (I) or a pharmaceutically acceptable salt thereof as the active component with a pharmaceutically acceptable carrier or excipient. The carrier can take a wide range of forms in accordance with a desirable medicament form for the administration. These medicament compositions are desirably in a unit dosage form suitable for the oral administration or injection administration.
In the preparation of a composition in the oral dosage form, any useful, pharmaceutically acceptable carrier can be used. For example, an oral liquid preparation such as a suspended medicament or syrup medicament can be prepared using water; sugars such as sucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol, propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil, etc.; antiseptics such as alkyl parahydroxybenzoate, etc.; and flavors such as strawberry flavor, peppermint, etc. Powder, pills, capsules and tablets can be prepared using an excipient such as lactose, glucose, sucrose, mannitol, etc.; a disintegrator such as starch, sodium alginate, etc.; a lubricant such as magnesium stearate, talc, etc.; a bindersuch as polyvinyl alcohol, hydroxypropylcellulose, gelatin, etc.; a surfactant such as fatty acid esters;
and a plasticizer such as glycerine, etc. Tablets and capsules are the most useful, oral unit dosage forms because of easy administration. To prepare tablets and capsules, solid carriers for medicament are used.
Injection solution can be prepared using a carrier consisting of a salt solution, a glucose solution or a mixture of the salt solution and the glucose solution.
The effective dosage of Compound (I) is 1 to 20 mg/kg/day for a human being, and number of administration is 3 to 4 per day.

Examples and Reference Examples are given below:

Reference example ~
(Raw material 1) Methyl ll-oxo-6,11-dihydrodibenz [b,e]
oxepin-2-carboxylate In this example, 348.9 g of sodium salt of methyl p-hydroxybenzoate, 402,4 g of phthalide and 200 g of sodium chloride are mixed with one another and stirred at 150C for 6 hours. After completion of the reaction, the mixture is cooled until the temperature is brought back to room temperature, 4 ~ of aqueous 10% acetic acid solution is added thereto and the mixture is allowed to stand at room temperature overnight. After stirring the mixture at room temperature for 3 hours, deposited crystals are separated by filtration, and 6 e of water is added thereto. After stirring the mixture at room temperature for 30 minutes, the deposited crystals are separated by filtration. After the addition of 3 e of toluene to the crystals, the mixture is stirred at room temperature for one hour. The crystals are separated by filtration and dried over heating under reduced pressure to yield 393.9 g of 2-(4-methoxycarbonylphenoxy) methyl benzoic acid.

-IR (KBr disk):3400, 1700, 1610, 1260, 1235 cm~
The thus obtained 2-(4-methoxycarbonylphenoxy) methyl benzoic acid (392.7 g) i8 suspended in 5.0 ~ of methylene chloride and 266.0 g of trifluoroacetic anhydride is added thereto. After stirring the mixture at room temperature for one hour, 19.4 g of boron trifluoride-ethylether complex is added thereto and the mixture is stirred at room temperature for two hours. The reaction solution is poured into ice water. After an organic solvent layer is separated from the mixture, the organic layer is washed with diluted aqueous sodium hydroxyde solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 335.3 g of methyl 11-oxodibenz[b,e]oxepin-2-carboxylate as a white crystal. Melting point and elemental analysis are shown in Table 2.
IR(KBr disk): 1710, 1650, 1610, 1250, 1010 cm1 NMR (CDC13, ~, ppm): 3.84 (s, 3H), 5.14 (s, 2H), 6.87-8.93 (m, 7H) Reference ex~mpl~ 2 (Raw material 2) 11-Oxo-6,11-dihydrodibenz[b,e~ oxepin -2- acetic acid Raw-materials 2 is produced by substituting p-hydroxyphenyl acetic acid, for methyl p-hydroxybenzoate in Reference example 1.

Melting point and elemental analysis thereof is shown in Table 2.

Table 2 Raw Melting point Elemental analysis t%) material (C) 1 128 -129 as C16H1204 C H
(Isopropyl Calculated 71.63 4.51 ether) Found 71.55 4.48 2 130 -132 as C16H1204 C H
(Ethyl Calculated 71.63 4.51 acetate) Found 71.86 4.55 -` - 25 - l 33 7 6 03 R~ference Ex~mpl~ 3 (Reagent 1) (3-Dimethylaminopropyl) -triphenylphos-phonium bromide hydrobromide In this Example, 350.0 g of triphenylphosphine and 270.0 g of dibromopropane are suspended in 700 ml of toluene and the suspension is heated at reflux for 25 hours. After allowing the suspension to stand for cooling, the formed product is separated by filtration and washed with 2 e of toluene to obtain 550.0 g of (3-bromopropyl)-triphenylphosphonium bromide hydrobromide having m.p. 233-234C.

Then, 100.0 g of (3-bromopropyl) -triphenyl-phosphonium bromide hydrobromide is suspended in 500 ml of ethanol and 300 ml of 50 % aqueous dimethylamine solution is added thereto. After heating the mixture at reflux for 10 minutes, the mixture is allowed to stand for cooling. The solvent is distilled away under reduced pressure and the resultant crude product is recrystallized from ethanol to obtain 64.0 g of the desired product having the physicochemical properties as identified in Table 3.

1 3376~13 Table 3 Reagent Melting point Elemental analysis (%) (C) 287 - 289 as C23H28NPBr2 (Ethanol) C H N
C~ ted 54.24 5.54 2.75 Found 54.12 5.63 2.93 Example 1 1 1-(3-Dimethylaminopropylidene)-2-(2-triphenylmethyloxymethyl) -6,11-dihydrodibenz[b,e] oxepin (Compound 3) Process A:
11-Hydroxy-2-(2-hydl o~ethyl)-6,11-dihydrodibenz [b,e] oxepin In this process, 20 g of methyl 11-oxo-6,11-dihydrodibenz [b,e] oxepin-2-acet~te is dissolved in 500 ml of tetrahydrofuran. To the solution is added 6.0 g of lithium ~lumini~
hydroxide and the mixture is stirred at room temperature for one hour. After decomposing an excess of the reagent by the addition of water to the solution, the mLxture is filtered to remove inorganic salts and the filtrate is concentrated to dryness under reduced pres~u-e to obtain 17.7 g of the desired product as a white solid.

Nelting point: 132 - 136C
NMR (CDCl3 + DMS0-d6 + D20, ~, 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, lH), 6.46-7.49(m, 7H) Process B:
ll-Hydroxy-2-(2-triphenylmethyloxyethyl)-6, 11-dihydrodibenztb,e] oxepin In this process, 17.2 g of 11-hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e] oxepin is dissolved in 50 ml of pyridine. To the solution is added 30 g of triphenylchloromethane and the mixture is stirred at 50C
15 for 5 hours. After adding water and stirring the mixture for 2 hours, the solvent is distilled away under reduced pressure. The mixture is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The 20 solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 3:1) to obtain 21.7 g of the desired product as a colorless amorphous.

NMR (CDCl3 + D20, ~, 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, lH), 6.33-7.51(m, 22H) Process C:
ll-Oxo-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin In this process, 10 g of 11-hydroxy-2-(2-tri-phenylmethyloxyethyl)-6lll-dihydrodibenz[b~e] oxepin is dissolved in a solution comprising 800 ml of acetone, 1000 ml of water, 20 ml of saturated aqueous magnesium sulfate solution and 0.2 g of disodium phosphate. To the solution is dropwise added 2.6 g of aqueous sodium permanganate solution and the mixture is stirred at room temperature for 4.5 hours. Then, 100 ml of methanol is added thereto and the mixture is heated at reflux for 3 hours. After allowing the mixture to stand for cooling, the mixture is filtered and the filtrate is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant crude product is recrystallized from isopropanol to obtain 8.0 g of the desired product having melting point of 132 - 134C as a white crystal.
Elemental analysis (%): as C3sH28O3 Calculated: C 84.65 H 5.68 Found: C 84.56 H 5.67 N~ (CDCl3, ~, ppm): 2.61-3.04(m, 2H), 3.05-3.46 (m, 2H), 5.01(s, 2H), 6.63-8.07(m, 22H) - 29 - l 33 76 03 Process D:
11-(3-Dimethylaminopropyl)-ll-hydroxy-2-(2-tripenylmethyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin To a solution of 3-dimethylaminopropyl magnesium chloride obtained by reacting 0.2 g of magnesium with 1.0 g of 3-dimethylaminopropyl chloride in 10 ml of tetrahydrofuran under a nitrogen atmosphere using dibromoethane as a catalyst, is dropwise added a solution obtained by dissolving 2.0 g of 11-oxo-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin in 10 ml of tetrahydrofuran under ice cooling and the mixture is stirred at room temperature for one day.
Aqueous ammonium chloride solution is added thereto and the pH of the mixture is adjusted to 7.0 with aqueous 4N-hydrochloric acid solution. The solvent is distilledaway under reduced pressure. The mixture is extracted with 200 ml of methylene chloride and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order.
After drying the extract over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: hexane: ethyl acetate: triethylamine = 10 : 10 : 1) to obtain 1.2 g of the desired product as a colorless amorphous.
NMR (CDCl3, ~, ppm): 0.85-1.83(m, 4H), 2.08(s, 6H), 2.67-3.44(m, 6H), 4.94 and 5.36(ABq, 2H, J=
15.8Hz), 6.63-8.13(m, 22H) Mass spectrum (m/z): 583 (M~) _ 30 _ 1 3 3 ~ 6 03 Process E:
11-(3-Dimethylaminopropylidene)-2-(2-triphenyl-methyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin In this process, 1.2 g of 11-(3-dimethylamino-S propyl)-ll-hydroxy-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz~b,e] oxepin is dissolved in 50 ml of pyridine. To the solution is dropwise added 0.8 g of phosphorusoxychloride under a nitrogen atmosphere and ice-cooling.
After stirring the mixture at room temperature for one hour, the solvent is distilled away under reduced pressure. The residue is extracted with 100 ml of methylene chloride, and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order. After drying the mixture over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent:
hexane: ethylacetate: triethylamine = 10 : 10 : 1) to obtain 0.82 g of the desired product as a colorless oily matter.
NMR (CDCl3, ~, ppm): 2.16(s, 6H), 2.30-2.40(m, 4H), 2.79(t, 2H, J=6Hz), 3.24(t, 2H, J=6Hz), 5.97 (t, lH, J=7Hz), 6.60-7.40(m, 22H), (trans form) Mass spectrum (m/z): 565 (M) ~xampl~ 2 11-(3-Dimethylaminopropylidene)-2-(2-hydroxy-ethyl)-6,11-dihydrodibenztb,e] oxepin (Compound 2) In this example, 0.92 g of 11-(3-dimethylamino-propylidene)-2-(2-triphenylmethyloxyethyl)-6,11-dihydro-dibenz[b,e] oxepin is dissolved in a mixed solvent of 20 ml of water and 20 ml of dioxane. To the solution is added 60 mg of p-toluene sulfonic acid and the mixture is heated at reflux for two hours. The solvent is distilled away under reduced pressure and the residue is extracted with 200 ml of ethylacetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium hydrochloride solution in order and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent:
ethylacetate: triethylamine = 10: 1) to obtain 0.4 g of the desired product.

Cis form white solid, Meltin~ point: 100 -102C (diethylether) NMR (CDC13, ~, 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, lH, J=7Hz), 6.30-7.40(m, 7H) Mass spectrum: 323 (M ) Trans form white solid, Meltingpoint: 96 - 97C (diethylether) NMR (CDC13, ~, 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, lH, 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 1) In this FY~mple, 2.2 g of 11-(3-dimethylaminopropylidene)-2-(2-l-yd~ yethyl)-6, 11-dihydrodibenz[b,e] oxepin is dissolved in 100 ml of acetone. The Jones reagent is added to the solution until the reaction solution shows an orange color and the mixture is stirred at room temperature for one hour. Sodium bicarbonate is added thereto and an inorganic subst~nce is removed by filtration. The solvent of the filtrate is distilled away under reduced ple;,;,u.e to obtain the desired product. The physiocochemical properties of the product coincide with those of the product obtained in Example 6.

Example 4 Methyl 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate (Compound 6) In this Example, 45 g of (3-dimethylaminopropyl)-triphenylphosphonium bromide hyd~oblolllide is suspended in 200 ml of tetrahydrofuran under a nitrogen atmosphere and 82 ml of 1.6N-n-butyl lithium hexane solution is added thereto under ice-cooling. The mixture is stirred under ice-cooling for one hour. To the mixture is dropwise added under ice-cooling a solution obtained by dissolving 10 g of methyl 11-oxo-6,11-dihydrodibenz~b,e]oxepin-2-carboxylate in 200 ml of tetrahydrofuran. After stirring the mixture at room temperature for 2 hours, the mixture is extracted with 800 ml of ethyl acetate. After washing the extract with saturated aqueous sodium chloride solution and drying the extract over anhydrous magnesium sulfate, the solvent is distilled away under reduced pressure. The residue is purified by column chromatography on silica gel (eluent:
hexane:ethyl acetate:triethylamine = 10:10:1) to obtain 2.0 g of trans form and 5.6 g of cis form of the desired product.
Cis form NMR (CDCl3, ~, ppm): 2.23 (s, 6H), 2.17-2.81 (m, 4H), 5.28 (bs, 2H), 5.61 (t,lH), 6.80-8.10 (m, 7H).
trans form NMR (CDC13, ~, ppm): 2.15 (s, 6H), 2.17-2.81 (m, 4H), 5.00-5.50 (broad, 2H), 6.06 (t, lH), 6.70-8.10 (m, 7H).

Example 5 Methyl ll-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetate (Compound 4) In this Example, 48 g of (3-dimethylamino-propyl)-triphenylphosphonium bromide hydrobromide is suspended in 200 ml of tetrahydrofuran under a nitrogen atmosphere and 80 ml of 1.6N-n-butyl lithium hexane solution is added thereto under ice-cooling. The mixture is stirred under ice-cooling for one hour. A solution obtained by dissolving 5.0 g of 11-oxo-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid in 120 ml of tetrahydrofuran is dropwise added under ice-cooling.
After stirring the mixture at room temperature for two hours, the solvent is distilled away under reduced pressure. Then, 200 ml of water is added to the residue and the mixture is washed with 200 ml of diethyl ether.
The pH of the mixture is adjusted to 1 with aqueous 4N-hydrochloric acid solution and the mixture is washed with diethyl ether.
Then, aqueous lON-sodium hydroxide solution is added thereto to adjust the pH of the mixture to 7 and the solvent is distilled away under reduced pressure.
The resultant residue is dissolved in 400 ml of methanol and 5 g of p-toluene sulfonic acid is added thereto.
After heating the mixture at reflux for two hours, the solvent is distilled away under reduced pressure. The residue is extracted with 300 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order and dried over anhydrous sodium sulfate.

The solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane : ethyl acetate: triethylamine = 10 : 10 :1) to obtain 4.0 g of the desired product as a colorless oily matter.

Cis form NMR (CDCl3, ~, 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, lH, J=7Hz), 6.53-7.30(m, 7H) Trans form NMR (CDCl3, ~, 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, lH, J=7Hz), 6.53-7.30(m, 7H) Example 6 11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid (Compound 5) In this Example, 26.1 g of methyl 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-carboxylate is dissolved in a mixed solvent of 500 ml of methanol and 30 ml of water and 6.2 g of sodium hydroxide is added thereto. The mixture is heated at reflux for two hours. After allowing the mixture to stand for cooling, aqueous 4N-hydrochloric acid solution is added thereto to adjust the pH to 7 and the mixture is concentrated under reduced pressure. The concentrate is purified by column chromatography on high porous polymer (HP-20) eluent: water: methanol = 1 : 2) to obtain 25.0 g of the desired product.

Cis form white crystal Melting point: 162 - 164C
NMR (DMSO-d6, ~, ppm): 2.28(s, 6H), 2.40-2.70(m, 4H), 5.20-5.40(broad, 2H), 5.72(t, lH, J=7.0Hz), 6.85-7.90(m, 7H) IR (KBr disk, cm1): 3400, 1610, 1370, 1220, 1005 Elemental analysis (%): as C2oH21O3N l/3 H2O
C H N
Found: 73.00 6.67 4.14 Calculated: 72.93 6.63 4.25 Trans form white crystal Melting point: 242 - 244C
NMR (DMSO-d6, ~, ppm): 2.25(s, 6H), 2.40-2.70(m, 4H), 5.20-5.40(broad, 2 H), 6.09(t, lH, J=7.0Hz), 6.78-7.90(m, 7H) IR (KBr disk, cm1): 3400, 1610, 1380, 1222, 1010 Elemental analysis (%):
C H N
Found: 74.30 6.60 4.30 Calculated: 74.28 6.55 4.30 Exampl~ 7 11-(3-Dimethylaminopropylidene)-6,11-dihydro-dibenztb,e] oxepin-2-acetic acid (Compound 1) The product is obtained by hydrolysis as in the same manner as in Example 6.

Cis form white crystal Melting point: 118 - 120C (Isopropanol) NMR (DMSO-d6, ~, ppm): 2.16(s, 6H), 2.30-2.60(m, 4H), 4.04(s, 2H), 5.15(bs, 2H), 5.69(t, lH, J=7Hz), 6.73-7.40(m, 7H) IR (KBr disk, cm 1): 3400, 1580, 1225, 1005 Mass spectrum (m/z): 337 (M~) Elemental analysis (%): as C21H23O3N monohydrate C H N
Found: 70.77 7.36 3.74 Calculated: 70.96 7.09 3.94 Trans form white crystal Melting point: 158 - 160C (Acetonitrile) NMR (DMSO-d6, ~, ppm): 2.05(s, 6H), 2.30-2.60(m, 4H), 4.04(s, 2H), 5.15(bs, 2H), 6.06(t, lH, J=7Hz), 6.73-7.40(m, 7H) IR (neat, cm~1): 3380, 1575, 1220, 1005 Mass spectrum (m/z): 337 (M~) Elemental analysis (%): as C21H23O3N monohydrate C H N
Found: 71.06 6.66 3.92 Calculated: 70.96 7.09 3.94

Claims (6)

1. The 11-(3-dimethylamino propylidene)-6,11-dihydrodibenzo[b,e] oxepin-2-acetic acid.

2. The cis-11-(3-dimethylamino propylidene)-6,11-dihydrodibenzo[b,e] oxepin-2-acetic acid.

3. A pharmaceutical composition comprising the 11-(3-dimethylamlno propylidene)-6,11-dihydrodibenzo[b,e]
oxepin-2-acetic acid in association with a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising the cis-ll-(3-dimethylamino propylidene)-6, 11-dihydrodibenzo[b,e] oxepin-2-acetic acid in association with a pharmaceutically acceptable carrier.

5. The use of 11-(3-dimethylamino propylidene)-

6,11-dihydrodibenzo[b,e] oxepin-2-acetic acid for treating and controlling allergic conditions.

6 . The use of cis-11-(3-dimethylamino propylidene)-6,11-dihydrodibenzo[b,e] oxepin-2-acetic acid for treating and controlling allergic conditions.