JP2899028B2 - Dibenzoxepin derivative - Google Patents

Description

The present invention relates to a platelet activating factor.
ctor; hereinafter abbreviated as PAF) and a novel dibenzooxepin derivative that strongly inhibits the physiological action of PAF by having a receptor antagonistic action.

Conventionally, PAF is conventionally known as a potent aggregating agent for platelets, and PAF is also known as airway hypersensitivity, shock, cardiac and systemic anaphylaxis, gastrointestinal ulcers, psoriasis, immune and renal diseases,
It has been reported to be involved in ischemic diseases and other inflammations [Trens in Pharmacological
Sciences (Trends in Pharmacological Sciences)
10, 23, 1989]. Therefore, PAF is considered to be involved in a wide range of diseases, and examples thereof include the following [Pharmacol. Rev. 39:97, 1987].
Year〕.

(1) Ischemic disease, for example, myocardial infarction, angina, thrombosis, cerebral contusion, spinal cord injury (2) Cerebrovascular disease, for example, transient cerebral ischemia, migraine, cerebral hemorrhage, cerebral infarction (3) Peripheral vascular disease and disorders due to lipid imbalance, for example, atherosclerosis, capillary spasm,
Peripheral circulatory failure, hypertension, pulmonary embolism (4) Inflammation and allergic acute inflammation For example, bronchitis, pneumonia, nephritis, hepatitis, rheumatoid arthritis, dermatitis, rhinitis (5) Asthma and systemic anaphylaxis For example, bronchial asthma, children Asthma, airway hypersensitivity, anaphylactic shock (6) tissue transplant rejection, eg, rejection after tissue transplant surgery (7) cardiac anaphylaxis, eg, cardiogenic shock (8) endotoxin and IgG-induced shock, eg, bacterial shock, allergy Sexual shock (9) Kidney disease and immune disease For example, renal immune injury, drug shock, membranous nephritis, glomerulonephritis (10) Gastrointestinal ulcer, for example, peptic ulcer, gastritis (11) Allergic skin disease, for example, psoriasis, Urticaria (12) eye disease eg retinitis, keratitis (13) central disease eg antidepressant (14) Immune diseases, eg, diseases due to abnormal immune response, systemic lupus erythematosus (SLE) (15) Cancer and chemotherapy, eg, cancer metastasis suppression (16) Cirrhosis, eg, cirrhosis (17) Shock, eg, other than the above Generalized intravascular coagulation (DIC) in children
Nervous shock, hemorrhagic shock, burn shock, traumatic shock Accordingly, compounds that suppress the action of PAF prevent or treat the above diseases or other diseases that can be prevented by suppressing the action of PAF. It is expected to have.

In addition, in the case of drugs that have been used for conventional medical purposes, if the use is limited due to the occurrence of side effects that are presumed to be PAF-mediated or the reduction in the efficacy of the main drug, the use of PAF antagonists As a result, reduction of side effects and increase in the efficacy of the main drug are expected.

Pharmacolological Reviews (Pharmacol.Rev.)
Vol. 39, p. 97 (1987) and Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 31, p. 466 (1988) illustrate PAF antagonists having structures different from those of the compounds of the present invention. I have.

JP-A-64-31766 discloses a compound represented by the following formula:
It is disclosed that it has an AF antagonism.

In addition, methine (=
A compound represented by the following formula having a substituted carbamoyl group via CH-) and having a hypoglycemic or hypolipidemic effect is disclosed in U.S. Pat. No. 4,136,197.

As the compound of the present invention, a dibenzoxepin derivative
There is no known compound having a substituted carbamoyl group at a conjugated diene position.

Problems to be Solved by the Invention A new and useful PAF inhibitor is used for a wide range of diseases.
It is expected and expected to have prophylactic and therapeutic effects.

An object of the present invention is to provide a novel dibenzoxepin derivative that suppresses the physiological action of PAF by PAF antagonistic action.

Means for Solving the Problems The present invention provides a compound of the formula (I) Wherein R ¹ , R ^2a and R ^2b are the same or different and represent hydrogen or lower alkyl, and X is Wherein n represents 0 or 1, m represents an integer of 0 to 4, and l represents an integer of 0 to 2 A dibenzooxepin derivative [hereinafter, referred to as compound (I)]. The same applies to compounds of other formula numbers] or a pharmacologically acceptable salt thereof.

The lower alkyl in the definition of each group of the formula (I) is a linear or branched alkyl group having 1 to 6 carbon atoms,
Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, ammonium salts, amino acid addition salts and the like. The pharmacologically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate and phosphate, acetate, maleate, fumarate, tartrate, citrate and the like. Organic acid salts are exemplified, and pharmacologically acceptable amino acid addition salts include salts to which amino acids such as lysine, glycine, phenylalanine and the like are added.

Next, the production method of compound (I) will be described. In the following description, in order to simplify the reaction formula, a tricyclic moiety not directly involved in the reaction is used. (Where l is as defined above) May be abbreviated.

Compound (I) can be obtained by subjecting a reactive derivative of a carboxylic acid represented by the formula (II) and an amine represented by the formula (III) to dehydration condensation according to the following reaction steps.

(Wherein R ¹ , R ^2a , R ^2b , n, m and X have the same meanings as described above).
Active esters such as nitrophenyl ester and N-oxysuccinimide ester; acid halides such as acid chloride and acid bromide; and mixed acid anhydrides such as monoethyl carbonate and monoisobutyl carbonate.

For example, in the case of the p-nitrophenyl ester of the compound (II), the compound (II) can be obtained by adding 1 to 5 equivalents of paranitrophenol and a suitable condensing agent, preferably 1 to 10 equivalents of dicyclohexylcarbodiimide in an inert solvent, For example, it can be obtained by reacting in dichloromethane, diethyl ether or dimethylformamide at −80 to 50 ° C. for 0.1 to 24 hours. The obtained p-nitrophenyl ester is reacted with 1 to 10 equivalents of the compound (III) in an inert solvent, for example, tetrahydrofuran or diethyl ether, at -80 ° C to the boiling point of the used solvent for 1 to 24 hours. Compound (I) can be obtained.

The acid halide of the compound (II) is 1 to 10
An equivalent amount of a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide or the like is used in a solvent-free or inert solvent such as dichloromethane or toluene at -80 to 50 ° C for 0.1 to 0.1. It is obtained by reacting for ~ 24 hours. The obtained halide is reacted with 1 to 10 equivalents of the compound (III) in an inert solvent such as dichloromethane, if necessary, in the presence of an equivalent to a large excess of a base such as triethylamine or pyridine at -80 to 50 ° C. ~twenty four
Compound (I) can be obtained by reacting for an hour.

Further, the mixed acid anhydride of the compound (II) is prepared by using 1 to 10 equivalents of a suitable lower alkyl chloroformate, for example, isobutyl chloroformate, in the presence of an equivalent to a large excess of an amine, for example, triethylamine. It is obtained by reacting in an active solvent at -80 to 50 ° C for 0.1 to 24 hours. The obtained mixed acid anhydride can be reacted with the compound (III) in the same manner as in the acid halide to obtain the compound (I).

Starting compound (II) is produced as follows using compound (IV) as a starting material.

(In the formula, ^Represents the same meaning as described above, and R ^4a and R ^4b may be the same or different and are lower alkyl, or may together form a saturated nitrogen-containing heterocyclic ring, and R ⁵ represents alkyl.) Lower alkyl has the same meaning as the definition of lower alkyl in formula (I), and examples of the nitrogen-containing heterocycle include pyrrolidine, piperidine, N-methylpiperazine, morpholine, thiomorpholine, and N-methylhomopiperazine.

Compound (IV) as a starting material is described in “Heterocyclic Compounds, Vol. 26 (1972)” published by Interscience, as well as Chemical Abstracts Vol. 71, No. 8122.
6u and 101159q, Vol. 79, 136902j.

Compound (IV) is reacted with a methyltriphenylphosphonium halide salt such as methyltriphenylphosphonium bromide and an appropriate base such as n-butyllithium, potassium tert-butoxide, sodium hydride and the like in an inert solvent such as tetrahydrofuran and diethyl ether. Is reacted with 1 to 10 equivalents of ylide (V) produced at a temperature of −80 ° C. to the boiling point of the solvent used for 0.5 to 24 hours to give a compound (V
I get.

Compound (XI) can be produced by subjecting compound (VI) to a Vilsmeier reaction shown below. That is, in an inert solvent such as dichloroethane and tetrachloroethane, 1 to 10 equivalents of phosphorus oxychloride and 1 to 10 equivalents of N, N-dimethylformamide,
Formamides such as N-methylformamide are
Incubate at 0.5 ° C for 0.5-24 hours. Compound (VI) was added to the resulting reaction solvent containing the Vilsmeier reagent,
By reacting at -100 ° C for 0.5-24 hours, the compound (X
I get.

Compound (XI) can be prepared by the following method.
Can be obtained from I). That is, compound (VI) is reacted with 1 to 5 equivalents of secondary amine (VII) and an equivalent to a large excess of formaldehyde or its equivalent paraformaldehyde in a suitable solvent such as dichloroethane;
The compound (VIII) is obtained by reacting in the presence of an equivalent to a large excess of an acid such as trifluoroacetic acid or trichloroacetic acid at room temperature to the boiling point of the solvent used for 1 to 48 hours.

Compound (VIII) is usually obtained as a mixture of geometrically abnormal forms, but can be converted into a single geometric isomer by itself or by forming a salt with a suitable acid such as trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid and the like. Purification is also possible.

Compound (VIII) was obtained from Chemistry Letters (Chem.L
ett.), 1977, p. 1025, it is possible to lead to the chloro form (IX) and then the alcohol form (X) while maintaining the geometric isomer ratio. That is, compound (VIII) is treated with 1 to 10 equivalents of ethyl chloroformate in an inert solvent such as dichloromethane at 0 to 50 ° C for 1 to 1 equivalent.
The chlorinated product (IX) is obtained by reacting for 24 hours. This is dissolved in a suitable polar solvent such as acetonitrile,
The reaction is carried out with 0 to 10 equivalents of an acetate such as potassium acetate, if necessary, in the presence of a suitable phase transfer catalyst such as crown ether, tetrabutylammonium bromide or the like at 0 ° C. to the boiling point of the solvent used for 1 to 24 hours. Thereby, an acetoxy compound is obtained. Then, the product is hydrolyzed, preferably reacted in methanol at −50 to 60 ° C. for 1 to 24 hours in the presence of potassium hydroxide or potassium carbonate to obtain the alcohol (X).

Compound (XI) can be obtained by oxidizing compound (X). As an oxidation method, for example, swan (Sw
ern) Oxidation is preferred. That is, the compound (X) is reacted with 1 to 10 equivalents of oxalyl chloride in an inert solvent such as dichloromethane in the presence of 1 to 10 equivalents of dimethyl sulfoxide at -78 to 0 ° C for 0.5 to 24 hours, and then 0.1 to 2 at 1 to 10 equivalents of triethylamine and -78 to 50 ° C.
By reacting for 4 hours, compound (XI) can be obtained. Regarding this oxidation method, for example, Corey-Kim oxidation is also effective.

Compound (XI) is reacted in an inert solvent such as tetrahydrofuran or diethyl ether with 1-10 equivalents of Horner-Emmons reagent (XII) and reagent (XII)
Is reacted at −80 ° C. to the boiling point of the used solvent for 0.5 to 24 hours in the presence of 0.2 to 1 equivalent of a base, for example, lithium hydride and potassium tert-butoxide.
The β-unsaturated ester (XIII) is obtained.

The compound (VIII) is usually used for hydrolysis of esters, for example, 1 to 10 equivalents of a suitable base such as sodium hydroxide in hydrated methanol or hydrated dioxane.
0 ° C. in the presence of sodium carbonate to 0.5
By reacting for up to 48 hours, compound (II) can be obtained.

In the process for producing compound (II) described above, a mixture of all the geometric isomers (four types) usually present in compound (II) is obtained.

Compound (III), which is the starting material of compound (I) together with compound (II), is described in Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 31, p. 466 (1988), and JP-A-64-31766. It can be produced by the method disclosed in the gazette or a method analogous thereto.

The intermediate and the target compound in each of the above production methods can be isolated and purified by a purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, drying, concentration, recrystallization, various chromatography and the like. In addition, the intermediate can be subjected to the next reaction without purification.

When a salt of compound (I) is to be obtained, compound (I)
When is obtained in the form of a salt, it may be purified as it is, and when it is obtained in the free form, the salt may be formed by an ordinary method.

The compound (I) obtained by the above-mentioned production method may have a geometrical isomer or an optical isomer with respect to stereochemistry, but the present invention relates to all possible stereoisomers of the compound (I) and their Are included.

The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Specific examples of the compound (I) obtained by the above-mentioned production method are shown.

Test Example Next, the pharmacological action of compound (I) will be described. Binding Experiment Using ³ H-Labeled PAF The binding inhibitory activity of the compound according to the present invention on the PAF receptor was examined using rabbit platelet membrane. The experimental method was carried out with a slight modification to the method described in Biochemistry, Vol. 22, p. 4756 (1983).

That is, rabbit platelet membrane (25 μg protein) was added to 1 ml of buffer (10 mM Tris-HCl pH 7.0, 10 mM MgCl ₂ and 0.25
% Bovine serum albumin), 0.3 nM 1-0
- [hexadecyl ^{-1 ', 2', 3 H} (N) ] - hexadecyl-2-acetyl -sn- glyceryl-3-phosphorylase choline [hexadecyl-1 ', 2', 3 H (N) ] - hexadecyl
-2-acetyl-sn-glyceryl-3-phosphorylcholin
(NEN Corp., hereinafter, ^{3 is} referred to as H-C ₁₆ PAF) was added and various concentrations of the drug. After keeping at 25 ° C for 45 minutes, glass fiber filter paper
The solution was subjected to suction filtration on GF / C (manufactured by Whatman), and washed with the buffer. The glass fiber filter was transferred to a vial bin, scintizol EX-H (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the radioactivity was measured with a liquid scintillation counter.

Calculation of the inhibition rate against ³ H-C ₁₆ PAF binding by drug was determined by the equation (1).

Total binding is the ³ H-C ₁₆ PAF bound radioactivity in the absence of drug.

³ H-C in the presence of C ₁₆ PAF of 1μM and nonspecific binding
₁₆ PAF bound radioactivity.

 Table 1 shows the results.

Effect of PAF on lethality in mice According to the method of British Journal of Pharmacol. (Br. J. Pharmacol.) Vol. 79, p. 595 (1983), test compound (100 mg / kg) and its solvent (control group) After oral administration 1 hour before PAF administration, PAF
40 μg / kg was administered intravenously. The toxic symptoms were observed and the mortality was determined 3 hours later.

Table 2 shows the results. The significant difference test with the control group was performed by Fisher's exact
ability test).

Effects of PAF on foot edema Agents and A
According to the method described in Vol. 18, p. 359 (1986), PAF was subcutaneously administered to the footpad to induce paw edema reaction using Wistar rats weighing 155 to 175 g as follows. Pre-isomer (ple-thysometer, Type TK
After measuring the paw volume with a test compound (100, manufactured by Unicon), the test compound (100 mg / kg) and a solvent were orally administered. One hour later, PAF (0.5 μg) was injected subcutaneously into the footpad, and 45 minutes later,
The paw volume was measured again, and the edema rate was calculated from the comparison with the value before PAF administration.

Table 3 shows the results. Note that a Student's t test (Student's test) was used for a significant difference test with the control group.

As described above, the compounds according to the present invention exhibit an inhibitory effect on PAF in in vitro and in vivo experimental systems.

Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.

The pharmaceutical preparations according to the present invention can contain compound (I) or a pharmaceutically acceptable salt thereof alone or optionally as a mixture with any other active ingredient for treatment as an active ingredient. In addition, these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers and by any method well known in the pharmacy art.

Here, the active ingredient for the other treatment contained together with the compound (I) or a pharmacologically acceptable salt thereof includes, for example, steroids, non-steroidal anti-inflammatory drugs, peripheral analgesics, leukotriene antagonists, leukotrienes biosynthesis inhibitors, H ₂ receptor antagonists, antihistamines, histamine release inhibitors, bronchodilators, angiotensin converting enzyme inhibitors, thromboxane A ₂ biosynthesis inhibitor, thromboxane A ₂ antagonists, H ⁺ -K ⁺ ATP Ase inhibitor, coronary vasodilator, calcium antagonist, potassium channel agonist, diuretic, xanthine oxidase inhibitor, cerebral circulation improving agent,
Brain metabolism activator, brain protectant, hepatoprotectant, antiplatelet agent, thrombolytic agent, adrenergic α receptor antagonist, adrenaline β
Receptor agonist, adrenergic β receptor antagonist, serotonin antagonist, PAF biosynthesis inhibitors, phospholipase A ₂ inhibitors, adenosine receptor agonists, adenosine receptor antagonists, hypolipidemic agents, cholesterol biosynthesis Examples include inhibitors, immunostimulants, immunosuppressants, anticancer agents and the like.

In addition, the administration route is preferably the one that is most effective for treatment, and is orally or, for example, rectally,
Parenteral, such as topical, intranasal, ocular, buccal, subcutaneous, intramuscular, and intravenous, may be mentioned.

Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, ointments, eye drops, nasal drops, troches, aerosols, injections and the like.

Liquid preparations suitable for oral administration, for example, emulsions and syrups, include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil. , And preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Capsules, tablets, powders, granules and the like include excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, polyvinyl alcohol And a binder such as hydroxypropylcellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.

Formulations suitable for parenteral administration comprise sterile aqueous preparations containing the active compound which are preferably isotonic with the blood of the recipient.
For example, as an injection, a solution for injection is prepared using a carrier composed of a salt solution, a glucose solution or a mixture of saline and a glucose solution.

Nasal spray formulations consist of a purified aqueous solution of the active compound with preservatives and isotonic agents. Such formulations are adjusted to a pH and isotonic state compatible with the nasal mucosa.

Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are adjusted to match that of the eye.

Topical formulations are prepared by dissolving or suspending the active compound in one or more vehicles, for example, mineral oils, petroleum, polyalcohols, or other bases used in topical pharmaceutical formulations.

Formulations for enteral administration are provided as suppositories with conventional carriers, such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

Also in these parenteral preparations, diluents, fragrances, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for the oral preparations One or more auxiliary components selected from the following may also be added.

The effective amount and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof are determined according to the administration form, age, body weight,
Depending on the nature or severity of the condition to be treated,
Usually, the dose is 0.01 to 1000 mg / person per day, and the administration frequency is preferably once a day or divided.

 Examples, reference examples and preparation examples are shown below.

In the description in the following examples, Q in the compound number means a salt or a solvent adduct of the corresponding compound as described above.

Example 1. (E, E) -4- (6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) -N- [3- (3-pyridyl) propyl] -2-butenamide (Compound 1 The compound g0.31 g obtained in Reference Example 7 was diluted with dichloromethane 30
Then, 0.15 ml of triethylamine and 0.19 ml of oxalyl chloride were added dropwise thereto under ice cooling, and the mixture was further stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 50 ml of dichloromethane. This was added dropwise to 80 ml of a dichloromethane solution containing 0.45 g of 3- (3-pyridyl) propylamine, and the mixture was further stirred at room temperature overnight. Dichloromethane 20
Extracted with 0 ml, washed sequentially with saturated aqueous sodium bicarbonate and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: triethylamine = 10: 1), and the resulting crude product was recrystallized from ethyl acetate to give 10.23 g of a white crystalline compound. Obtained.

Mp _{137~138 ℃ NMR (DMSO-d 6} , δ, ppm) 1.65-1.79 (m, 2H), 2.59 (t, J = 7.7Hz, 2H), 3.08-
3.16 (m, 2H), 4.8-5.5 (wide, 2H), 6.27 (d, J = 14.8H
z, 1H), 6.78 (dd, J = 1.1 and 8.1 Hz, 1H), 6.86 (d, J =
11.7Hz, 1H), 6.92-6.99 (m, 1H), 7.04 (dd, J = 11.7 and 14.8Hz, 1H), 7.17-7.55 (m, 7H), 7.62 (d, J = 7.9H
z, 1H), 8.13 (t, J = 5.7Hz, 1H), 8.43 (bs, 2H) IR (KBr tablet, cm- ¹ ) 1662,1616,1479,1328,1275,1205,1141,999 MASS (m / z) 396 (M ⁺ ) Elemental analysis (%) as C ₂₆ H ₂₄ N ₂ O ₂ CH N Found 78.88 6.19 6.90 Calculated 78.76 6.10 7.06 Example 2. Process A. (±) − (E, E ) -4- (3-Methoxy-6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) -N-
[1-Methyl-4- (3-pyridyl) butyl] -2-butenamide (Compound 2) 1.5 g of compound k obtained in Reference Example 11 and 0.96 of (±) -2-amino-5- (3-pyridyl) pentane g of compound 21 as a slightly yellow oil by the same method as in Example 1 using g.
92 g were obtained.

NMR (CDCl ₃ , δ, ppm) 1.13 (d, J = 6.6 Hz, 3H), 1.30-1.70 (m, 4H), 2.45 −
2.70 (m, 2H), 3.73 (s, 3H), 3.80-4.22 (m, 1H), 5.09
(Bs, 2H), 5.42 (d, J = 8.0Hz, 1H), 5.95 (d, J = 14.7Hz,
1H), 6.35 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 2.4 Hz and
9.0Hz, 1H), 6.62 (d, J = 11.9Hz, 1H), 7.0-7.5 (m, 8
H), 8.41 (bs, 2H) IR (CHCl ₃ , cm ⁻¹ ) 1645,1596,1497,1322,1271,1228,1212,1162,1040,984 MASS (m / z) 454 (M ⁺ ) Step B (±)-(E, E) -4- (3-methoxy-6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) -N-
[1-Methyl-4- (3-pyridyl) butyl] -2-butenamide 1.5 fumaric acid (compound 2Q) 1.85 g of compound 2 obtained in Step A and 0.48 g of fumaric acid are dissolved in 100 ml of isopropanol, and dissolved at room temperature. Stirred for hours. Acetonitrile was gradually added, and the precipitated solid was collected by filtration. By recrystallizing the obtained crude product from acetonitrile, 1.57 g of compound 2Q as white crystals was obtained.

Mp _{176-177 ℃ NMR (DMSO-d 6} , δ, ppm) 1.03 (d, J = 6.7Hz, 3H), 1.30-1.65 (m, 4H), 2.50-
2.65 (m, 2H), 3.71 (s, 3H), 3.75-3.95 (m, 1H), 4.9-
5.4 (very wide), 6.19 (d, J = 15.0 Hz, 1H), 6.34 (d, J
= 2.7Hz, 1H), 6.57 (dd, J = 2.7 and 8.7Hz, 1H), 6.63
(S, 3H, fumaric acid), 6.73 (d, J = 11.9Hz, 1H), 7.08 (dd,
J = 11.9 and 15.0Hz, 1H), 7.19-7.60 (m, 7H), 7.85
(D, J = 8.2Hz, 1H ), 8.39 (bs, 2H) IR (KBr tablet, cm ^-1) 1715,1702,1558,1270,1231,1171,980 Elemental analysis _{(%) C 29 H 30 N} 2 O ₃ · 1.5C ₄ H ₄ as O ₄ C H N Found 66.93 5.76 4.30 calculated 66.87 5.77 4.46 example 3. (E, E) -4- ( 3- methoxy-6,11-dihydro-dibenzo [b, e] oxepin-11-ylidene) -N- [3-
(5-azabenzimidazolyl) propyl] -2-butenamide (Compound 3) A compound k of 1.0 g obtained in Reference Example 11 and 0.7 g of 3- (5-azabenzimidazolyl) propylamine were used in the same manner as in Example 1. A crude product was obtained and recrystallized from ethyl acetate to give a white crystalline compound.
0.77 g of 3Q was obtained.

Melting point 177-179.5 ° C MASS (m / z) 466 (M ⁺ ) Elemental analysis (%) CH ₂₈ N as C ₂₈ H ₂₆ N ₄ O ₆ Actual measured value 71.85 5.68 11.94 Calculated value 72.08 5.62 12.01 Example 4.4- ( 3-methoxy-6,11-dihydrodibenzo [b, e]
Oxepin-11-ylidene) -N- [3- (6-azabenzimidazolyl) propyl] -2-butenamide (Compound 4) 1.0 g of compound k obtained in Reference Example 11 and 0.7 of 3- (6-azabenzimidazolyl) propylamine g, a crude product was obtained in the same manner as in Example 1, and this was recrystallized from acetonitrile to give a white crystalline compound.
0.38 g of 4Q was obtained.

Melting point 111-114 ° C MASS (m / z) 466 (M ⁺ ) Elemental analysis (%) C ₂₈ H ₂₆ N ₄ O ₃ .1.4 H ₂ O CH N Actual value 68.43 6.30 11.29 Calculated value 68.39 5.90 11.39 Reference example 1 .11-Methyl-6,11-dihydrodibenzo [b, e] oxepin (compound a) 80.4 g of methyltriphenylphosphonium bromide was suspended in 500 ml of tetrahydrofuran, and 7.5 g of sodium hydride (oily, 60%) was added thereto under ice-cooling in an argon atmosphere, followed by heating under reflux for 1.5 hours. After cooling, 11-oxo-6,11
-Dihydrodibenzo [b, e] oxepin (31.5 g) was added, and the mixture was stirred at room temperature for 3 hours. Ice water was added, the mixture was extracted with 1000 ml of ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent
Hexane: ethyl acetate = 10: 1), and the resulting crude product was solidified with hexane to give 17 g of compound a.
I got

77-79 ° C NMR (CDCl ₃ , δ, ppm) 5.12 (s, 2H), 5.22 and 5.65 (s, 2H respectively), 6.70
−7.55 (m, 8H) IR (KBr tablet, cm ⁻¹ ) 1438,1297,1249,1220,1046,1003 MASS (m / z) 208 (M ⁺ ) Elemental analysis (%) As C ₁₅ H ₁₂ O C H Observed 86.55 5.96 Calculated 86.51 5.81 Reference Example 2. (E) / (Z) -11-[(4-methyl-1-piperazinyl) ethylidene] -6,11-dihydrodibenzo [b, e] oxepin-2 Trifluoroacetic acid salt (compound b) 18 ml of 1-methylpiperazine and 4.8 g of paraformaldehyde were dissolved in 180 ml of dichloroethane, and 62 ml of trifluoroacetic acid and 20 ml of acetic acid were added dropwise. After stirring at 60 ° C. for 1 hour, a solution prepared by dissolving 17 g of the compound a obtained in Reference Example 1 in 50 ml of dichloroethane was added dropwise, and the mixture was further heated under reflux for 1 hour. The mixture was concentrated to dryness under reduced pressure, extracted with 500 ml of methylene chloride, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue containing the trifluoroacetate salt was recrystallized from isopropanol to obtain 20.2 g of a compound b as white crystals.

Melting point 166-166.5 ° C NMR (CDCl ₃ , δ, ppm) 2.5-3.8 (m, 10H), 4.8-5.5 (very wide, 2H), 6.03
(T, J = 7.0 Hz, 1H, E form), 6.6-7.6 (m, 8H) IR (KBr tablet, cm ^-1 ) 1663,1480,1404,1128,1015 Reference Example 3. (E) / (Z ) -11- (2-Chloroethylidene) -6,11
-Dihydrodibenzo [b, e] oxepin (compound c) 20.2 g of the compound b obtained in Reference Example 2 was shaken in an aqueous solution of sodium hydrogen carbonate and dichloromethane, and the organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to give the free base.
13.6 g was obtained. This was dissolved in dichloroethane (300 ml), sodium acetate (17.4 g) was added and suspended, and then ethyl chloroformate (20 ml) was added dropwise. After stirring at room temperature for 3 hours, the mixture was extracted with 300 ml of methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 15.9 g of a colorless oily compound c.

NMR (CDCl ₃ , δ, ppm) 4.15 (d, J = 7.0 Hz, 2H), 4.5-5.5 (wide, 2H), 6.22
(T, J = 7.0 Hz), 6.6-7.5 (m, 8H) IR (CHCl ₃ , cm ⁻¹ ) 1687,1481,1108,1007 MASS (m / z) 256 (M ⁺ ) Reference Example 4. (E ) / (Z) -11- (2-hydroxyethylidene)-
6,11-dihydrodibenzo [b, e] oxepin (compound d) Compound c obtained in Reference Example 3 was mixed with acetonitrile 200 ml
And 7.0 g of potassium acetate and Tris [2-
(2-Methoxyethoxy) ethyl] amine (TDA-1)
Three drops were added and stirred at 60 ° C. for 3 hours. 300 ml of ethyl acetate
, Washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1) to give (E) / (Z) as a colorless oil.
1.25 g of -11- (2-acetoxyethylidene) -6,11-dihydrodibenzo [b, e] oxepin was obtained.

NMR (CDCl ₃ , δ, ppm) 2.06 (s, 3H), 4.65 (d, J = 7.0 Hz, E-form) and 4.90
(D, J = 6.8 Hz, Z body), 5.21 (bs, 2H), 5.82 (t, J = 6.8 Hz,
Z-form) and 6.15 (t, J = 7.0 Hz, E-form), 6.6-7.4 (m, 8H) IR (liquid film, cm ^-1 ) 1741,1604,1481,1442,1226,1111,1009 MASS (m / z) 280 (M ⁺ ) Dissolve 1.25 g of the above acetoxy derivative in 100 ml of methanol, add 10 ml of a 5% potassium hydroxide-methanol solution,
Stirred overnight at room temperature. After neutralization with dilute aqueous acetic acid, the solvent was distilled off under reduced pressure, and the obtained residue was extracted with 300 ml of ethyl acetate. This was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.2 g of a colorless oily compound d.

NMR (CDCl ₃ , δ, ppm) 4.24 (d, J = 7.0 Hz, E-form), 4.49 (d, J = 6.6 Hz, Z-form), 5.
21 (bs, 2H), 5.89 (t, J = 6.6 Hz, Z form), 6.23 (t, J = 7.0 H
z, E form), 6.6-7.5 (m, 8H) IR (liquid film, cm ^-1 ) 3306,1602,1477,1437,1277,1107,1004 MASS (m / z) 238 (M ⁺ ) Reference example 5 (E) / (Z) -2- (6,11-dihydrodibenzo [b,
e] oxepin-11-ylidene) ethanal (compound e) 0.65 ml of oxalyl chloride was dissolved in 20 ml of dichloromethane and cooled to -60 ° C. To this, 10 ml of a dichloromethane solution of 0.6 ml of dimethyl sulfoxide was added dropwise, and further −6.
Stirred at 0 ° C. for 30 minutes. Compound d obtained in Reference Example 4
10 ml of a 1.2 g dichloromethane solution was added dropwise, and the temperature was further reduced to -60 ° C.
For 2 hours. After dropwise addition of 2 ml of triethylamine, the temperature was gradually returned to room temperature. The mixture was extracted with 300 ml of dichloromethane, washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1) to obtain 0.9 g of compound e as a yellow oil.

NMR (CDCl ₃ , δ, ppm) Regarding protons of aldehyde E-form 9.62 (d, J = 8.1 Hz) Z-form 9.90 (d, J = 7.7 Hz) MASS (m / z) 236 (M ⁺ ) Reference Example 6. Ethyl (E, E) -4- (6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) -2-butenoate (compound f) 1.67 g of ethyl diethylphosphonoacetate was dissolved in 20 ml of tetrahydrofuran, and 0.27 g of sodium hydride (oily, 60%) was added thereto under ice cooling, followed by stirring at room temperature for 30 minutes.
To this was added 15 ml of a tetrahydrofuran solution of 0.8 g of the compound e obtained in Reference Example 5, and the mixture was further stirred at room temperature for 1 hour. The mixture was extracted with 200 ml of ethyl acetate, washed sequentially with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 1), and the obtained crude product was recrystallized from diisopropyl ether to give 0.4 g of a compound f as white crystals. Obtained as a single isomer.

111-112 ° C NMR (DMSO-d ₆ , δ, ppm) 1.18 (t, J = 7.1 Hz, 3H), 4.10 (q, J = 7.1 Hz, 2H), 4.8
−5.5 (wide, 2H), 6.25 (d, J = 15.0Hz, 1H), 6.80 (d, J
= 8.2Hz, 1H), 6.94-7.58 (m, 9H) IR (KBr tablet, cm- ¹ ) 1715,1618,1291,1137,1002 MASS (m / z) 306 (M ⁺ ) Elemental analysis (%) C ₂₀ H ₁₈ O ₃ CH measured 78.59 5.94 calculated 78.41 5.92 Reference Example 7. (E, E) -4- (6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) -2-butene Acid (compound g) 0.4 g of the compound f obtained in Reference Example 6, 0.1 g of sodium hydroxide, 50 ml of methanol and 20 ml of water were mixed, heated under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. The mixture was diluted with water and adjusted to pH 2.0 using a 2N aqueous hydrochloric acid solution. The precipitated solid was collected by filtration to obtain 0.33 g of white solid compound g as 0.1 hydrate.

Mp _{236.5-237 ℃ NMR (DMSO-d 6} , δ, ppm) 4.8-5.5 ( broad, 2H), 6.17 (d, J = 14.9Hz, 1H), 6.80
(Dd, J = 1.1 and 8.2 Hz, 1H), 6.96 (d, J = 11.5 Hz, 1
H), 6.94-7.00 (m, 1H), 7.19 (dd, J = 11.5 and 14.9H
z, 1H), 7.20-7.57 (m, 6H), 12.2 (bs, 1H) IR (KBr tablet, cm ^-1 ) 1683,1610,1276,1203,1113 MASS (m / z) 278 (M ⁺ ) Element analysis _{(%) C 18 H 14 O} 3 · 0.1H 2 O as a C H Found 76.89 4.83 calculated 77.18 5.11 reference example 8. 11-methylene-3-methoxy-6,11-dihydro-dibenzo [b, e] oxepin (Compound h) 89.2 g of methyltriphenylphosphonium bromide, 11 g of sodium hydride (oil-based, 60%) and 11-oxo-
32.1 g of 3-methoxy-6,11-dihydrodibenzo [b, e] oxepin was used in the same manner as in Reference Example 1 to obtain 22.1 g of a compound h as a white solid.

Melting point 80-82.5 ° C NMR (CDCl ₃ , δ, ppm) 3.74 (s, 3H), 5.14 (s, 2H), 5.18 (d, J = 1.1 Hz, 1H),
5.59 (d, J = 1.1Hz, 1H), 6.37 (d, J = 2.5Hz, 1H), 6.51
(Dd, J = 2.5 and 8.6 Hz, 1H), 7.10-7.45 (m, 5H) IR (KBr tablet, cm ^-1 ) 1620,1599,1414,1318,1265,1030,907 MASS (m / z) 238 (M ⁺ ) Reference Example 9. (E) / (Z) -2- (3-methoxy-6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) ethanal (Compound i) A mixed solution of 10 ml of phosphorus oxychloride and 13 ml of dichloroethane was kept at 16 to 18 ° C, and N-methylformanilide 1 was added thereto.
3.6 ml was added dropwise. After stirring at 30 ° C. for 30 minutes, 19.7 g of the compound h obtained in Reference Example 8 was added. This is 50-70
The mixture was stirred for 1 hour while being kept at ° C. After 100 ml of diloroethane was added, 50 ml of water was added while cooling to 10-20 ° C. Extract with 800 ml of dichloromethane, wash twice with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1),
15.3 g of compound i were obtained.

NMR (CDCl ₃ , δ, ppm) Regarding proton of aldehyde E-form 9.60 (d, J-8.1 Hz) Z-form 9.88 (d, J = 7.9 Hz) MASS (m / z) 266 (M ⁺ ) Reference Example 10. Ethyl (E, E) -4- (3-methoxy-6,11-dihydrodibenzo [b, e] oxepin-11-ylidene) -2-butenoate (compound j) Using 25.6 g of ethyl diethylphosphonoacetate, 4.2 g of sodium hydride (oily, 60%) and 13.8 g of the compound i obtained in Reference Example 9, diisopropyl ether was used as a recrystallization solvent in the same manner as in Reference Example 6. This gave 5.5 g of compound j as a white crystalline single isomer.

145-146 ° C NMR (CDCl ₃ , δ, ppm) 1.26 (t, J = 7.1 Hz, 3H), 3.74 (s, 3H), 4.17 (q, J = 7.
1Hz, 2H), 5.12 (bs, 2H), 6.03 (d, J = 15.2Hz, 1H), 6.35
(D, J = 2.4Hz, 1H), 6.53 (dd, J = 2.5 and 8.7Hz, 1H),
6.68 (d, J = 11.9 Hz, 1H), 7.10-7.55 (m, 6H) IR (KBr tablet, cm ⁻¹ ) 1715,1609,1270,1231,1136,1039 MASS (m / z) 336 (M ⁺ ) Elemental analysis (%) as C ₂₁ H ₂₀ O ₄ CH measured 74.88 6.02 calculated 74.98 5.99 Reference Example 11. (E, E) -4- (3-methoxy-6,11-dihydrodibenzo [b, e Oxepin-11-ylidene) -2-butenoic acid (compound k) 4.9 g of a white solid compound k was obtained from 5.5 g of the compound j obtained in Reference Example 10 in the same manner as in Reference Example 7.

Mp _{251-252 ℃ NMR (DMSO-d 6} , δ, ppm) 3.74 (s, 3H), 6.00 (d, J = 14.9Hz, 1H), 6.32 (d, J =
2.4Hz, 1H), 6.52 (dd, J = 2.4 and 8.7Hz, 1H), 6.71
(D, J = 11.4 Hz, 1H), 7.19-7.50 (m, 6H) IR (KBr tablet, cm ^-1 ) 1695,1608,1288,1167,1143,1039 MASS (m / z) 308 (M ⁺ ) Elemental analysis (%) As C ₁₉ H ₁₆ O ₄ Actual value of CH 73.89 5.46 Calculated value 74.01 5.23 Formulation example 1. Tablet A tablet having the following composition is prepared by a conventional method.

 Compound 1 200 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Fine amount Formulation example 2. Powder A powder having the following composition is prepared by a conventional method.

Compound 2Q 200 mg Lactose 300 mg Formulation Example 3. Syrup A syrup having the following composition is prepared by a conventional method.

 Compound 1 200 mg Purified sucrose 30 g Ethyl p-hydroxybenzoate 40 mg P-hydroxyhydroxybenzoate 10 mg Strawberry flavor 0.1 cc Add water to this to make a total amount of 100 cc.

Formulation Example 4. Tablet A tablet having the following composition is prepared by a conventional method.

Compound 1 200 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar pigment Fine preparation Example 5. Syrup A syrup having the following composition is prepared by a conventional method.

 Compound 2Q 200 mg Purified sucrose 30 g Ethyl p-hydroxybenzoate 40 mg P-hydroxybenzoate propyl 10 mg Strawberry flavor 0.1 cc Add water to make a total volume of 100 cc.

Effects of the Invention According to the present invention, there is provided compound (I) which has PAF antagonistic activity and is expected to have a prophylactic and therapeutic effect on a wide range of diseases, and a pharmaceutically acceptable salt thereof.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 405/12 C07D 471/04 A61K 31/55

Claims (1)

(57) [Claims] (1) Expression Wherein R ¹ , R ^2a and R ^2b are the same or different and represent hydrogen or lower alkyl, and X is And n represents 0 or 1, m represents an integer of 0 to 4, and represents an integer of 0 to 2. A dibenzooxepin derivative represented by｝ or a pharmaceutically acceptable salt thereof.