JPH03176487A - Dibenzoxepin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1>, R<2a> and R<2b> are H or lower alkyl; X is formula II, III, etc.; (n) is 0 or 1; (m) is 0-4; (l) is 0-2) or salt thereof. EXAMPLE:(E,E)-4-(6,11-Dihydrobenzo[b,e]oxepin-11-ylidene)-N-[3-(3-pyri dyl) propyl]-2-butenamide. USE:A inhibitor against blood platelet activating factor useful as a preventive and treating agent for a wide range of diseases such as ischemic disease, cerebrovascular diseases, inflammations or immunological diseases. PREPARATION:A compound expressed by formula IV (formula V is formula VI) is initially made to react with a ylide expressed by the formula (C6H5)3P= CH2 and the resultant product is then subjected to the Vilsmeier reaction. The obtained product is subsequently subjected to a reaction with a Horner-Emmons reagent and the formed alpha,beta-unsaturated ester substance is hydrolyzed to afford a compound expressed by formula VII, which is finally subjected to dehydrating condensation with an amine expressed by formula VIII.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to platelet activating factor (platelet act
The present invention relates to a novel dibenzoxepine derivative that strongly suppresses the physiological effects of PAF by having a receptor antagonistic effect on ivating factor (hereinafter abbreviated as PAF).

BACKGROUND OF THE INVENTION Conventionally, PAP is known to be a potent aggregating agent of platelets, and PAF is known to be a potent aggregator of platelets, and PAF is associated with airway hyperresponsiveness, shock, cardiac and systemic anaphylaxis/-1 gastrointestinal/I! It has been reported to be involved in cancer, psoriasis, immune and renal diseases, ischemic diseases and other inflammations [Trends in Pharcological Sciences].
Macological 5 Sciences) Volume 1O, page 23, 1989]. Therefore, PAF is thought to be involved in a wide range of diseases, examples of which include the following [Pharmacological Reviews (Pharmac.

Rev.) Volume 39, page 97, ■987].

(1) Ischemic diseases such as myocardial infarction, angina pectoris, thrombosis, brain contusion, and spinal cord injury (2) Cerebrovascular diseases such as transient cerebral ischemia, migraine, cerebral hemorrhage, and cerebral infarction (3) Peripheral vascular disease and diseases due to lipid imbalance, such as atherosclerosis, capillary spasm, peripheral ring insufficiency, hypertension, pulmonary embolism (4) Inflammation and allergic acute inflammation, such as bronchitis, pneumonia, nephritis, hepatitis, Rheumatoid arthritis, dermatitis, rhinitis (5) Asthma and systemic anaphylaxis - e.g. bronchial asthma, childhood asthma, airway hyperresponsiveness, anaphylactic shock (6) Tissue transplant rejection e.g. rejection after tissue transplant surgery (7) Cardiac anaphylaxis - e.g. hexagenic shock (8) Endotoxin and IgG-induced shock e.g. bacterial shock, allergic shock (9) Renal diseases and immune diseases e.g. renal immune injury, drug shock, membranous nephritis, glomerulonephritis 00 Gastrointestinal ulcers e.g. peptic ulcer, gastritis 01) Allergic skin diseases e.g. dry snoring, hives 00 Eye diseases e.g. retinitis, keratitis 00 Central diseases e.g. antidepression, panic disorder 00 Immune diseases e.g. , disease caused by abnormal immune response, systemic lupus erythematosus (S, L, E) Q! i1 Cancer and chemotherapy, e.g. cancer metastasis suppression α0 Cirrhosis e.g. liver cirrhosis O″0 Shock e.g. disseminated intravascular coagulation (DIC) other than the above
Neurotic shock, hemorrhagic shock, scald shock, traumatic shock Therefore, compounds that suppress the action of PAF have the effect of preventing or treating the above-mentioned diseases or other diseases that can be prevented by suppressing the action of PAF. It is expected that the

In addition, among drugs used for conventional medical purposes,
If its use is limited due to the occurrence of PAF-mediated or presumed PAF-mediated side effects or a decrease in the efficacy of the main drug, concomitant use of a PAF antagonist is expected to reduce side effects and increase the efficacy of the main drug. .

Pharmacological Reviews (Pharmacol
.

Rev. ), Vol. 39, p. 97 (1987), and Journal on Medicinal Chemistry (J.

Med, Chem, Vol. 31, p. 466 (1988) exemplifies PAF antagonists having a different structure from the compounds of the present invention.

JP-A-64-31766 discloses that a compound represented by the following formula has a PAF antagonistic effect.

In addition, dibenzoxepine derivatives have methine (・
A compound represented by the following formula having a carbamoyl group substituted via CH-) and having a blood sugar-lowering or blood lipid-lowering effect is disclosed in US Pat. No. 4,136,197.

l1 with dibenzoxepine derivatives like the compounds of the present invention.
No compound having a substituted carbamoyl group via a conjugated diene in this position is known.

Problems to be solved by the invention A novel and useful PAF inhibitor can be used to treat a wide range of diseases.
It is expected and sought after to have preventive and therapeutic effects.

The object of the present invention is to provide a novel dibenzoxepine derivative that suppresses the physiological effects of PΔF through PAF antagonism.

Means for Solving the Problems The present invention provides a compound of the formula (1) %formula% (wherein R', R'' and R2b are the same or different and represent hydrogen or lower alkyl, X is 0, m is 0
represents an integer of ~4, l represents an integer of 0 ~ 2) [hereinafter referred to as compound (
1). The same applies to compounds of other formula numbers] or a pharmacologically acceptable salt thereof.

Lower alkyl in the definition of each layer in formula (1) is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert- Includes butyl, pentyl, hexyl, etc.

The pharmacologically acceptable salts of compound (1) include pharmacologically acceptable acid addition salts, ammonium salts, amino acid addition salts, and the like. Pharmaceutically acceptable acid addition salts of compound (1) include inorganic acid salts such as hydrochloride, sulfate, and phosphate; acetate;
Examples include organic acid salts such as maleate, fumarate, tartrate, and citrate. Examples of pharmacologically acceptable amino acid addition salts include salts with addition of amino acids such as lysine, glycine, and phenylalanine.

Next, a method for producing compound (1) will be explained.

In addition, in the following description, in order to simplify the reaction formula,
A bicyclic moiety that does not directly participate in the reaction (in the formula, l has the same meaning as above) Compound (1) is combined with a reactive derivative of a carboxylic acid represented by formula ([1)] by formula (III) according to the following reaction process. The amines shown can be obtained by dehydration condensation.

(1) (In the formula, R1, 2a, R2b, m and X have the same meanings as above) Here, the reactive active form of carboxylic acid (II) includes active esters such as nitrophenyl ester and xysuccinimide ester, Examples include acid halides such as acid chloride and acid bromide, and mixed acid anhydrides such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester.

Example In the case of p-nitrophenyl ester of Eva compound (It), compound (n) is mixed with 1 to 5 equivalents of p-nitrophenol in the presence of a suitable condensing agent, preferably 1 to 10 equivalents of dicyclohexylcarbodiimide. It can be obtained by reaction in an active solvent such as dichloromethane, diethyl ether or dimethylformamide at 80 to 50°C for 0.1 to 24 hours. The obtained p-nitrophenyl ester was mixed with 1 to 10 equivalents of the compound ([) in an inert solvent, such as tetrahydrofuran or diethyl ether, at a temperature of -80°C to the boiling point of the solvent used, at a temperature of 1 to 24°C.
Compound (1) can be obtained by reacting for a period of time.

The acid halide of compound (II) is 1 to 1 with compound (II).
10 equivalents of a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, etc. without a solvent or in an inert solvent such as dichloromethane or toluene at -80 to 50°C. It is obtained by reacting for 0.1 to 24 hours. The obtained halide is mixed with 1 to 10 equivalents of 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, to -80 to 5
The compound (
1) can be obtained.

Furthermore, the mixed acid anhydride of compound (II) can be prepared using 1 to 10 equivalents of a suitable lower alkyl chloroformate, such as isobutyl chloroformate, in the presence of an equivalent to a large excess of an amine, such as triethylamine, and an inorganic acid such as dichloromethane. It is obtained by reacting in an active solvent at -80 to 50°C for 0.1 to 24 hours. Compound (N) can also be obtained by reacting the obtained mixed acid anhydride with compound ([II) in the same manner as for acid halide.

Starting compound (II) is produced using compound (IV) as a starting material in the following manner.

Noken (1'V) ↓ No (XI) Shin (XI) ([1) Ro is the same or different lower alkyl, or may be taken together to form a saturated nitrogen-containing heterocycle ,
R5 represents alkyl] Here, lower alkyl has the same meaning as the definition of lower alkyl in formula (1), and nitrogen-containing heterocycles include pyrrolidine, piperidine, N-methylpiperazine, morpholine, thiomorpholine, N-methylhomo Examples include piperazine.

The compound (rV) serving as the starting material is available from “Heterocyclic Compounds” published by Interscience.
ounds) Vol. 26 (1972), Chemical Abstracts Vol. 71, 81226.
U and 1o1591q, Volume 79, 136902j, etc.

Compound (IV) is mixed with a methyltriphenylphosphonium halide salt such as methyltriphenylphosphonium bromide and a suitable base such as n-butyllithium, potassium tert-butoxide, sodium hydride in an inert solvent such as tetrahydrofuran or diethyl ether. 1 to IO equivalent of ylide (V) produced by
Compound (VT) is obtained by reacting for 0.5 to 24 hours at the boiling point of the solvent used.

Compound (XI) can be produced by subjecting compound (VT) to the Vilsmeier reaction shown below. That is, in an inert solvent such as dichloroethane, tetrachloroethane, 1 to 10
An equivalent amount of phosphorus oxychloride and 1 to 10 equivalents of a formamide such as N,N-dimethylformamide or N-methylformamide are reacted at 0 to 100°C for 0.5 to 24 hours. To the reaction solution containing the generated Vilsmeier reagent,
Compound (XI) is obtained by adding compound (Vl) and reacting at 0 to 100°C for 0.5 to 24 hours.

Compound (XI) can also be converted to compound (V
It can be obtained from [). That is, compound (VT)
with 1 to 5 equivalents of a secondary amine (■) and an equivalent to a large excess of formaldehyde or its equivalent paraformaldehyde in a suitable solvent such as dichloroethane;
Compound (■) is obtained by reacting for 1 to 48 hours at room temperature to the boiling point of the solvent used in the presence of an equivalent to a large excess of an acid such as trifluoroacetic acid or trichloroacetic acid.

Compound (■) is usually obtained as a mixture of geometrically abnormal substances, but it can be obtained as a single geometric isomer by itself or by converting it into a salt with an appropriate acid such as trifluoroacetic acid, hydrochloric acid, p-)luenesulfonic acid, etc. It is also possible to purify the body.

Compounds (■) are listed in Chemistry Letters (Chem.

1977, p. 1025, the chloride (I) was prepared while maintaining the geometric isomer ratio.
X), which can then lead to alcohol (X). That is, the chloride (IX) is obtained by reacting the compound (■) with 1 to 10 equivalents of ethyl chloroformate in an inert solvent such as dichloromethane at 0 to 50°C for 1 to 24 hours. This is treated in a suitable polar solvent such as acetonitrile with 1-10 equivalents of an acetate salt such as potassium acetate and, if necessary, in the presence of a suitable phase transfer catalyst such as crown ether, tetrabutylammonium bromide, etc. C. to the boiling point of the solvent used for 1 to 24 hours to obtain an acetoxy compound. This product is then hydrolyzed, preferably in the presence of potassium hydroxide or potassium carbonate, in methanol at 50-60°C.
Alcohol compound (X) can be obtained by reacting for 24 hours.

Compound (XI) can be obtained by oxidizing compound (X). As an oxidation method, for example, Swan (S
(wern) oxidation is preferred. That is, 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. , then 1 to IO equivalents of triethylamine and 7
Compound (XI) can be obtained by reacting at 8 to 50°C for 0.1 to 24 hours. Regarding this oxidation method, for example, Corey-Kim oxidation is similarly effective.

Compound (XI) is dissolved in an inert solvent such as tetrahydrofuran or diethyl ether in an amount of 1 to 10 equivalents of Horner-Emmons reagent (
In the presence of X [[ and 0.2 to 1 equivalent base relative to the reagent (X[l), such as lithium hydride or potassium tart-butoxide, at -80°C to the boiling point of the solvent used, 0.5
By reacting for ~24 hours, an α,β-unsaturated ester compound is obtained.

Compound (■) is subjected to hydrolysis conditions for esters that are commonly used, such as hydrolyzed methanol or dioxane for 1~
in the presence of 10 equivalents of a suitable base, e.g. sodium hydroxide, sodium carbonate, at 0°C to the boiling point of the solvent used.
Compound (n) can be obtained by reacting for ~48 hours.

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

Along with compound (■), compound (
III), Journal on Medicinal Chemistry (J, Med, Chem,) Volume 31, 46
6 (19813) and Japanese Unexamined Patent Publication No. 84-31766, or a method similar thereto.

The intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as ρ-filtration, extraction, drying, concentration, recrystallization, and various chromatography. .

Moreover, the intermediate can also be subjected to the next reaction without being particularly purified.

When you want to obtain the salt of compound (1), if compound (1) is obtained in the form of a salt, you can simply purify it as it is,
If it is obtained in a free form, a salt may be formed by a conventional method.

Compound (r) obtained by the above production method may have geometric isomers or optical isomers in terms of stereochemistry, but the present invention covers all possible stereoisomers of compound ([) and their Mixtures of are included.

In addition, compound (1) and its pharmacologically acceptable salts are:
It 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 compound (I) obtained by the above production method are shown below.

Test example Next, the pharmacological action of compound (1) will be explained.

Binding experiment using 3H-labeled PAF The binding inhibitory activity of the compounds of the present invention to the PAF receptor was investigated using rabbit platelet membranes. The experimental method is a biochemist! J-([liochemistry) Volume 22, 4
The method described on page 756 (1983) was followed with some modifications.

That is, 1rn rabbit platelet membrane (25J1g protein)
1 buffer (10n+M) Lis-Salt #I pH 7.0,
10mM MgCj! , and 0.25% bovine serum albumin) and 0.3 nM 1-0-
C hexadecyl-1', 2', 'H(N))
-hexadecyl-2-acetyl-9n-glyceryl-3
-Phosphorylcholine Chexadecyl-1',
2', 3ft (N)]-]Hexadecy-2
-acetylsn-glyceryl-3-phos
phorylcholin (manufactured by NUN, hereinafter referred to as 'H
-C,6PAF)! 6 and various concentrations of drug were added. After incubating at 25℃ for 45 minutes, glass fiber filter paper GF/C
(manufactured by Whatman) and washed with the above buffer solution.The glass fiber filter paper was transferred to a vial, scintisol EX-H (manufactured by Wako Tsumugi Kogyo Co., Ltd.) was added, and the radioactivity was measured with a liquid scintillation counter. did.

The inhibition rate of 'll-Cl8PAF binding by the drug was calculated using equation (1).

Formula (1) Total binding is the amount of 'It-C,6PAF binding radioactivity in the absence of drug.

Non-specific binding is defined as 'in the presence of lμM C25PAF'
) I-C, PAF-bound radioactivity.

The results are shown in Table 1.

O in the compound numbers in Table 1 represents a salt or solvent adduct of the corresponding compound. The same applies to the table below.

Effect of PAF on mouse lethality British Journal on Pharma ml (Or, J
, Pharmacol, ) vol. 79, p. 595 (198
The test compound (100μ/k
g) and its vehicle (control group) were orally administered 1 hour before PAF administration, and then 40 μg/kg of PAF was administered intravenously. The poisoning symptoms were observed and the mortality rate was determined after 3 hours.

The results are shown in Table 2. In addition, Fisher's exact probability method [Fisher''5exa
ct probability jest) was used.

Table 2 a) Main chapter: ρ<0.01゜p<0.001 (represents a significant difference from the control group) Effect on foot edema caused by PAF Agents and Actions
nd Actions) vol. 18, p. 359 (1986
Weight 155-175 according to the method shown in
PAF was subcutaneously administered to Wistar rats in the following manner to induce a paw edema reaction. Pre-thysometer (ple-thysometer, Type
TK 101. After measuring a constant volume using a Unicon Corporation), the test compound (100 μ/kg) and the solvent were orally administered. One hour later, PAF (0.5 g) was subcutaneously injected into the foot, and 45 minutes later, the constant volume was measured again, and the edema rate was calculated from the comparison with the value before PAF administration.

The results are shown in Table 3. In addition, Student's t-test (Student's t-test) was used to test for significant differences with the control group.
test) was used.

Table 3 a) Standard error above the mean b) *Book: p<0.01 (represents a significant difference with respect to the control group) Thus, the compounds according to the present invention
vitr.

It also shows an inhibitory effect on PAF in an in vivo experimental system.

Compound (1) or a pharmacologically acceptable salt thereof can be administered alone as is, but it is usually preferable to provide it as various pharmaceutical preparations.

Additionally, these pharmaceutical preparations are for use in animals and humans.

The pharmaceutical formulation according to the present invention contains a compound (
1) or a pharmacologically acceptable salt thereof may be contained alone or optionally in a mixture with any other therapeutically active ingredient.

In addition, these pharmaceutical preparations contain a pharmacologically acceptable amount of the active ingredient.
The compound is mixed with one or more carriers and prepared by any method well known in the pharmaceutical art.

Here, other therapeutic active ingredients contained together with compound (I) or a pharmacologically acceptable salt thereof include, for example, steroids, non-steroidal anti-inflammatory drugs, peripheral analgesics, leuco-IJ antagonists, etc. agent, leukotriene biosynthesis inhibitor, H2 receptor antagonist, antihistamine, histamine a release inhibitor, bronchodilator, angiotensin converting enzyme inhibitor, thromboxane A2 biosynthesis inhibitor, thromboxane A, antagonist, H”- +＾TPase inhibitor, coronary vasodilator, calcium channel blocker, potassium channel agonist, diuretic, xanthine oxidase inhibitor, cerebral palsy ring improving agent, cerebral metabolism activator, cerebral protective agent, hepatoprotective agent, anti-inflammatory agent Platelet agent, thrombolytic agent, adrenergic alpha receptor antagonist, adrenergic beta receptor agonist, adrenergic beta receptor antagonist, serotonin antagonist, PAF biosynthesis inhibitor, phospholipase A inhibitor, adenosine receptor agonist, Examples include adenosine receptor antagonists, antihyperlipidemic agents, cholesterol biosynthesis inhibitors, immunostimulants, immunosuppressants, anticancer agents, and the like.

In addition, it is preferable to use the most effective route of administration for treatment, such as oral, rectal, topical, intranasal, intraocular, and parenteral administration such as intraoral, subcutaneous, intramuscular, and intravenous. can be mentioned.

Dosage forms include capsules, tablets, granules, powders,
There are syrups, emulsions, preparations, ointments, eye drops, nasal drops, troches, aerosols, injections, etc.

Liquid preparations, such as emulsions and syrups, suitable for oral administration may be made of water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, etc. It can be manufactured using preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint, etc. Also capsules,
Tablets, powders, granules, etc. contain excipients such as lactose, glucose, sucrose, and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, and hydroxypropyl. It can be manufactured using binders such as cellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin.

Formulations suitable for parenteral administration preferably consist of sterile aqueous preparations containing the active compound that are isotonic with the blood of the recipient. For example, for injections, a solution for injection is prepared using a carrier such as a salt solution, a glucose solution, or a mixture of salt water and glucose solution.

Nasal purifiers consist of purified aqueous solutions of active compounds with preservatives and tonicity agents. Such formulations are adjusted to a pH and isotonic state that is compatible with the nasal mucosa.

Ophthalmic-type formulations are manufactured in a similar manner to nasal sprays, 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, such as mineral oil, petroleum, polyhydric alcohols, or other bases used in topical pharmaceutical formulations.

Formulations for enteral administration are presented with the usual carriers such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

In addition, these parenteral preparations also include diluents, fragrances, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc., as exemplified for oral preparations. It is also possible to add one or more auxiliary ingredients selected from:

The effective dose and frequency of administration of Compound (1) or a pharmacologically acceptable salt thereof will vary depending on the dosage form, age and weight of the patient, and the nature or severity of the symptoms to be treated, but the usual dosage is: 0. The dose is 01 to 1000 mg/person, and the administration frequency is preferably once a day or in divided doses.

Examples, reference examples, and formulation examples are shown below.

In addition, in the description in the following examples, Q in the compound number
As mentioned above, means the salt or solvent adduct of the corresponding compound.

Example 1゜(E,E)-4-(6,11-dihydrodibenzo[b
, e]oxepin-11-ylidene)-N-[:3
- (3-pyridyl)propyl]-2-butenamide (
Compound l) 0.31 g of the compound obtained in Reference Example 7 was dissolved in 30% of dichloromethane, and 0.0% of triethylamine was added to the solution under water cooling.
15- and oxalyl chloride 0.19- were added dropwise, and the mixture was further stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 50 ml of dichloromethane.
The mixture was added dropwise to 80 g of a dichloromethane solution containing 0.45 g of -(3-pyridyl)propylamine, and further stirred overnight at room temperature.

Extract with dichloromethane 200rn11, saturated sodium bicarbonate solution,
After washing successively with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate: triethylamine = 10 + 1), and the obtained crude product was further recrystallized from ethyl acetate to obtain 10.23 g of a white crystal compound. .

Melting point 137-138℃ NMR (DMSO-d, δ, ppm) 1.65-1
．． 79(m, 2)1), 2.59(t, J=7.
7Hz, 2H).

3.08-3.16 (+n, 21(), 4.8-5.
5 (wide, 21(), 6.27(d, J=14
．． 8flz, 1tl), 6.78(dd, J=1
．． 1 and 8.11(z, It(), 6.86
(d, j211.7t(z, IH), 6
．． 926.99 (m, LH), 7.04 (dd,
J=11.7 and 14.8tlz.

LH), 7.17-7.55 (m, 7H), 7.
62 (d, J=7.9Hz, Ift).

8.13 (t, J=5.7Hz, IH), 8.4
3(bs, 2H)IR (KBr tablet, cm-') 1662, 1616.1479.1328. 1275
．． 1205.1141°99 JJASS (m/z) 396 (M”) Elemental analysis (%
) CHN as Ca-H24N-02 Measured value 78.88 6.19 6.90 Calculated value 78.76 6.10 7.06 Example 2° Step 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 the compound obtained in Reference Example 11 and (± )-2-
Using 0.96 g of amino-5-(3-pyridyl)pentane, 1.92 g of Compound 2 as a slightly yellow oil was obtained in the same manner as in Example 1.

NMR (CDCj! 3, δ, ppm) 1, 13 (d,
J=6.6Hz, 3tl), 1.30-1.70
(m, 4N).

2.45-2.70 (m, 2H), 3.73 (s,
3N), 3.80-4.22(m, III),
5.09 (bs, 2H), 5.42 (d, J=8
．． 0IIz, ltl>.

5.95 (d, J=14.7Hz, III), 6
．． 35 (cl, J=2.4tlz, l1l).

6.50 (dd, J=2.4Hz and 9.0Hz,
IH), 6.62 (d.

J=11.9Hz, LH>, 7.0-7.5(m,
8)1), 8.41(bs, 2tOIR(CHC
j! , ,. □-1) 1645, 1596. +497. 1322.127
1. 1228.1212°1162, 1040.
984 MASS (n+/z) 454 (M”) Step B.

(±)-(E,E)-4-(3-methoxy-6゜11-
DihydrodibenzoCb,e]oxepin-11-ylidene)-N-[:1-methyl-4-(3-pyridyl)butyl-2-butenamide 1.57 malic acid (compound 2Q
) 1.85 g of compound 2 obtained in step A and 0.7 g of 7-malic acid.
48g of isoproper tool 100ml! and stirred at room temperature for 1 hour. Acetonitrile was gradually added and the precipitated solid was collected by filtration. By recrystallizing the obtained crude product from acetonitrile, compound 2Q was obtained as white crystals.
1.57g was obtained.

Melting point 176-177℃ NMR (DMSO-d, , δ, ppm > 1.03 (d
, J=6.711z, 3)1), IJO-1,6
5(m, 41().

2.50-2.65 (m, 2N), 3.71 (s,
3N), 3.75-3.95(m, LH), 4
．． 9-5.4 (very wide), 6.19 (d, J
=15.0Hz, 1tl), 6J4(d, J=2
．． 7Hz, IH), 6.57 (dd.

J=2.7 and 8.7Hz, 1tl), 6.6
3(s, 3H, fumanoleic acid), 6.73(d,
J=11.911z, LH), 7.08(dd,
J=11.9 and 15. otlz, IH), 7.
19-7.60 (m, 7H), 785 (d, J
=8.2Hz, IH), 8.39 (bs,
21()IR (KBr tablet, am-') 1715, 1702. 1558. 1270. 1
231. 1171. 980 elemental analysis (%) C2
,H,oN,O,・1.5C,H,0, as IIN Actual value 66.93 5.76 4.30 Calculated value 66.87 5.77 4.46 Example 3
゜(E, E)-4-(3-methoxy-6, ■1-dihydrodibenzo(b, e]oxepin-11-ylidene)
-N-C3-(5-Azabenzimidazolyl>propyl-2-butenamide (compound 3)) Example I A crudely purified target product was obtained in the same manner as above, and by recrystallizing it from ethyl acetate, compound 30 0.7 of white crystals was obtained.
7g was obtained.

Melting point 177-179.5℃ MASS (m/z) 466 (Ma elemental analysis <%
) C2eLJ40- as HN Actual value 71.85 5,68 11.94 Calculated value 72,08 5,62 12.01 Example 4゜4-(3-methoxy-6,11-dihydrodibenzo[b
,eloxepin-11-ylidene)~NC3-(6-
Azabenzimidazolyl> Propyl-2-butenamide (Compound 4) Compound k1 obtained in Reference Example 11. A crudely purified target product was obtained in the same manner as in Example 1 using 0.7 g of 3-(6-azabenzimidazolyl)propylamine and recrystallized from acetonitrile to obtain 0.38 g of compound 4Q as white crystals. I got it.

Melting point 111-114℃ MASS (m/z) 466 (M”) Elemental analysis (%)
C2,Il,,N,0.・1.4H,0C)IN Actual value 68.43 6.30 11.29 Calculated value 68.39 5.90 11J9 Reference Example 1°11~Methyl-6,11-dihydrodibenzo[b.

e] Oxepin (compound a) Methyltriphenylphosphonium bromide 80.4 g
is suspended in tetrahydrofuran 500- and hydrogenated under ice-cooling in an argon atmosphere) IJum (oil-based, 60
%) was added thereto, and the mixture was heated under reflux for 1.5 hours. After cooling,
11-oxo-6,11-dihydrodibenzo[b,
e:] 31.5 g of oxepin was added, and the mixture was stirred at room temperature for 3 hours. Add ice water and extract with ethyl acetate 10100O.
The mixture was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane:ethyl acetate = 10:1), and the obtained crude product was solidified with hexane to obtain compound a17.
I got g.

Melting point 77-79℃ NRIR (CDCI, , δ, ppm) 5.12 (s,
2) 1), 5.22 and 5.65 (s, respectively)
2ft) 6, 70-7.55 (m, 8) 1) IR
(KBr tablet, cll> 1438, 1297.1249. 1220. 10
46. 1003! JASS (m/z>208
(M”) Elemental analysis (%) C,,11,20 as C
H Actual value 8155 5.96 Calculated value 86.51 5.81 Reference example 2゜(E)/(Z)-11-[(4-methyl-1-piperazinyl)ethylidene)-6,11-dihydrodibenzo[
b, e) Oxepine 2-trifluoroacetate (compound b) l-Methylpiperazine 18- and 4.8 g of paraformaldehyde were dissolved in 180-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 of 17 g of Compound A obtained in Reference Example 1 dissolved in 50% 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 brine, dried over anhydrous sulfuric acid, and then the solvent was distilled off under reduced pressure.

Compound b was obtained by recrystallizing the residue containing the trifluoroacetate of the target compound with isopropanol.
20.2 g was obtained as white crystals.

Melting point 166-166.5°C NMR (COCj!3, δ, ppm)2.
5-3.8 (m, 10H), 4.8-5.5 (very wide, 211>.

6.03(t, J=7.Hz, if, [i
body), 6.6-7.6 (m, 811) IR (K
Br tablet, cll) 1663, 14B0. 1404. 1128. 1
015 Reference Example 3゜(E)/(Z)-11-(2-chloroethylidene)-
6,11-dihydrodibenzo[b,el oxepin (compound C) 20.2 g of compound b obtained in Reference Example 2 was shaken in an aqueous sodium bicarbonate solution and dichloromethane, and the organic layer was further washed with saturated brine. After drying this over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 13.6 g of free base. Add this to 300 ml of dichloroethane
-, 17.4 g of sodium acetate was added and suspended, and then 20 - of ethyl chloroformate was added dropwise. 3 at room temperature
After stirring for an hour, the mixture was extracted with 300 g of methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 15.9 g of compound c as a colorless oil.

NMlt (COCf, , δ, ppm)4.
15 (d, J=7.0Hz, 2N), 4゜5
-5.5 (wide, 2N).

6.22 (t, J=7.0Hz>, 6.6-7.5
(m, 8N)rR(CHC13, elm-') 1'687.1481.1108.1007MA10O
7/z) 256(M”) Reference Example 4°(E)/(Z)-11-(2-hydroxyethylidene)-6,11-dihydrodibenzo[b,e,'oxepin (compound d) Reference Example 3 Compound C obtained in acetonitrile 200-
7.0 g of potassium acetate and Tris (
2-(2-methoxyethoxy)ethyl]amine (TDA
-1) 3 drops were added and stirred at 60°C for 3 hours. The extract was extracted with 300 ml of ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent
1.25 g of (E)/(Z)-11-(2-acetoxyethylidene)-6,11-dihydrodibenzo(b,e)oxepin was purified with hexane:ethyl acetate = 10:1) as a colorless oil. I got it.

NMR (CDCf 3 , δ, ppm) 2.06 (s,
311), 4.65(d, J=7.0Hz, E
body> and 4.90 (d, J=6.8Hz, Z body)
, 5.21 (bs, 2H), 5.82 (t, J
=6.811z, Z body> and 6.15 (t, J near, 0Hz, 8 bodies), 6.6-7.4 (m, 8f
t) lit (liquid film, cm −' ) 1741, 1604.1481.1442.1226.
1111.1009MASS(m/z) 280(M
”) 1.25 g of the above acetoxy compound was added to 10 g of methanol.
The mixture was dissolved in 0ml, added with 10rrt1 of a 5% potassium hydroxide-methanol solution, and stirred overnight at room temperature. After neutralizing with dilute aqueous acetic acid, the solvent was distilled off under reduced pressure, and the resulting residue was extracted with 300 ml of ethyl acetate. This was washed successively with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to form a colorless oily compound d.
1.2g was obtained.

NMR (CDfJ, , δ, ppm) 4.24 (d,
J=7.0Hz, E body), 4.49(d, J
=6.6Hz, 2 bodies), 5.21 (bs, 2H)
, 5.89 (t, J=6.6flz, 1 body).

6.23 (t, J=7.0Hz, 0 bodies), 6
．． 6-7.5 (m, 8tl) IR (liquid film, am-'
) 3306, 1602.1477, 1437.1277,
1107.1004MA10O4/z) 238(
M'') Reference Example 5゜(E)/(Z)-2-(6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)ethanal (compound e) 0.65 mfl' of oxalyl chloride was dissolved in 20 ml of dichloromethane. and cooled to -60°C.To this was added a dichloromethane solution of 0.6-dimethyl sulfoxide and 10-
was added dropwise, and the mixture was further stirred at -60°C for 30 minutes. Dichloromethane solution 1 of 1.2 g of compound d obtained in Reference Example 4
0 m was added dropwise, and the mixture was further stirred at -60°C for 2 hours. After adding triethylamine 2- dropwise, the temperature was gradually returned to room temperature. The extract was extracted with 300 ml of dichloromethane, washed successively with (1) normal aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and then 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 9 g of a yellow oily compound eo.

NMR (CDCj) 3, δ, ppm) Regarding the proton of aldehyde, E form 9.62 (d, J=8.1Hz) Z form 9
．． 90 (d, J=7.7Hz) MASS (m/z
) 236 (M”) Reference Example 6゜(E,E)-4-(6,11-dihydrodibenzo[b,
e] Oxepin-11-ylidene>ethyl butenoate (compound f) CJ500C.

1.67 g of ethyl phosphonoacetate was dissolved in 20 ml of tetrahydrofuran, and 0.27 g of sodium hydride (oil-based, 60%) was added thereto under water cooling, followed by stirring at room temperature for 30 minutes. In addition, the compound eo obtained in Reference Example 5,
15 ml of a solution of 8 g in tetrahydrofuran was added, and the mixture was further stirred at room temperature for 1 hour.

The extract was extracted with 200% ethyl acetate, washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane:
By subjecting it to ethyl acetate-4,1) and further recrystallizing the obtained crude product from diisopropyl ether,
14 g of compound rO was obtained as a single isomer of white crystals.

Melting point 111-112℃ NMR (DMSO-d, , δ, ppm) 1.18 (t
, J=7.1flz, 3H), 4.10(q,
J=7.1)1z, 2H).

4, 8-5.5 (wide, 2H), 6.25 (d,
J=15.0Hz, LH).

6.80 (d, J=8,2tlz, 1)1),
6.94-7.58 (m, 9H) IR (KBr tablet, cm-') 1715, 1618. 1291. 1137. 1
100211Ass (/z) 306 (M”) Elemental analysis (%) C, oH,,0, CH Actual value 78.59 5.94 Calculated value 7
B, 41 5.92 Reference Example 7゜(E,E)-4-(6,11-dihydrodibenzo(b,
e, l oxepin-11-ylidene)-2-butenoic acid (compound g) 4 g of the compound fo obtained in Reference Example 6, 0.1 g of sodium hydroxide, 50 ml of methanol, and 20 ml of water were mixed and heated under reflux for 1 hour. Thereafter, the solvent was distilled off under reduced pressure. It was diluted with water and adjusted to pH 2.0 using a 2N aqueous hydrochloric acid solution. By filtering the precipitated solid, 0.33 g of compound g as a white solid was obtained as 0.1 hydrate.

Melting point 236.5-237°C NMR (DMSO-d, , δ, ppm) 4, 8-5.
5 (wide, 211), 6.17 (d, J=
14.9Hz, LH).

6.80 (dd, J=1.I and 8.2Hz,
1) 1), 6.96 (d, J-11,5Hz, E
), 6.94-7.00 (m, IH), 7.19
(dd, J-11,5 and 14.9Hz, l1
l), 7.20-7.57 (m, 6H).

12.2 (bs, 1H) IR (KBr tablet, cm −' ) 16B3.1610.1276, 1203.1113M
ASS (m/z) 278 (M""> Elemental analysis (%)
C+sLJ*・0. CH actual value as ILO? 6.89 4.83 Calculated value 77.18 5.11 Reference example 8゜11-methylene-3-methoxy-6,l 1-dihydrodibenzo[b,e]oxepin (compound h) methyltriphenylphosphonium bromide 89 , 2 g, 11 g of sodium hydride (oil-based, 60%) and 11-oxo-
3-methoxy-6゜11-dihydrodibenzo [b,
e] Oxepin 30 and Og were used in the same manner as in Reference Example 1 to obtain 22.1 g of compound h as a white solid.

Melting point 80-82.5℃ NMR (COCjl!, , δ, ppm) 3
．． 74 (s, 3N), 5.14 (s, 2tl),
5.18 (d, J=1.1Hz.

il+), 5.59(d, J=1.1Hz,
LH>, 6.37 (d, J=2.5Hz.

IH), 6.51 (dd, J=2.5 and 8.6
Hz, LH).

7, 10-7.45 (m, 5B) IR (KBr tablet, am-') 1620, 1599. 1414. 1318. 1
265. 1030. 907MASS(o+/z)
23B(M”) Reference Example 9゜(E)/(Z)-2-(3-methoxy-6,11dihydrodibenzo[:b,e]oxepin-11ylidene>ethanal〈Compound 1) Phosphorous oxychloride 10ml A mixed solution of 13 ml of dichloroethane was maintained at 16 to 18°C, and 13.6 ml of N-methylformanilide was added dropwise thereto. After stirring at 30°C for 30 minutes, compound h obtained in Reference Example 8 was obtained.
g was added. This was stirred for 1 hour while maintaining the temperature at 50 to 70°C. After adding dichloroethane 10011112, water 50I1112 was added while cooling to 10-20°C. Extract with dichloromethane at 800mC, and extract with saturated saline for 2 hours.
After washing twice and 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:■) to obtain 15.3 g of compound i.

NMR (CDCj! s, δ, ppm) Regarding the proton of aldehyde, E form 9.60 (d, J-8,1Hz) 2 forms 9
．． 88(d, J=7.9Hz>MASS(m/z)
266 (M”) Reference Example 1O1 (E,E)-4-(3-methoxy-6,11-dihydrodibenzo(b,e]oxepin-11-ylidene)
Ethyl-2-butenoate (compound) ethyl diethylphosphonoacetate 25.6 g, hydrogenated) Urum (oil-based, 6
0%) 4.2g and Compound i obtained in Reference Example 9
Using 13.8 g, 5.5 g of compound j was obtained as a white crystal single isomer by the same method as in Reference Example 6 and using diisopropyl ether as the recrystallization solvent.

Melting point 145-146°C NMR (CDCj! 3, δ, ppm > 1.26 (t,
J=7. lHz, 311), 3.74(s, 3
H), 4.17 (q.

J=7.1Hz, 211), 5.12(bs, 2
ft), 6.03(d, J=15.211z.

Iff) 6.35(d, J=2.4Hz, I
ff), 6.53 (dd, J: 2.5 and 8.7
Hz, 1ll), 6.68(d, J=11.91
1z, LH) 7, 10-7.55 (m, 6H) IR (Br tablet, Cm-') 1715, 1609.127 (1,1231,1136
, 1039MASS (m/z) 336 (M”) Elemental analysis (%) CH as C2+1I2oO1 Actual value 74°88 6.02 Calculated value
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 was obtained from 5.5 g of the compound j obtained in Reference Example 10 in the same manner as in Reference Example 7.

Melting point 251-252℃ NMR (DMSOJs, δ, ppm) 3.74 (s,
3H), 6.00(d, J=14.9Hz,
1tl), 6J2(d, J=2.4Hz, 1tl
), 6.52 (dd, J=2.4 and 8.7Hz,
IH), 6.7Hd, J=11.4Hz, IH
), 7.19-7.50 (m.

611) IR (KBr tablet, cm-') 1695, 1608.1288.1167, 1143.
1039! , IAss (m/z) 308 (M ”)
Elemental analysis (%) CI actual value as C, 9H, 60, ? 3.89 5.46 Calculated value 7
4. QI 5.23 Preparation Example Tablets with the following composition are prepared using a conventional method.

Compound 1 200■Lactose
60ff1g potato starch 30mg polyvinyl alcohol 2mg magnesium stearate
l mg tar pigment fine Total formulation example 2. A powder having the following composition is prepared by a conventional powder method.

Compound 2Q 200mg milk
u 300mg formulation example 3. Syrup A syrup having the following composition is prepared by a conventional method.

Compound 1 200mg Purified White 8
30gp-hydroxybenzoic acid ethyl 40mgp-hydroxybenzoic acid buOvir 10■ Strawberry flavor 0. I
ceAdd water to this to make a total volume of 100cc.

Formulation example 4. Tablets Tablets having the following composition are prepared by a conventional method.

Compound 1 200mg milk 1
! 60■ Potato starch 30mg Polyvinyl alcohol 2mg Magnesium stearate
1. Example of a small amount of Tal dye preparation 5. Syrup A syrup having the following composition is prepared by a conventional method.

Compound 2Q 200■fi! r White sugar 30 g Ethyl p-hydroxybenzoate 40 ■ Propyl p-hydroxybenzoate 10 mg Strobe, Lee flavor 0
．． Add water to 1 cc to make a total of 1100 cc.

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

Claims (1)

[Claims] Formulas include mathematical formulas, chemical formulas, tables, etc. (In the formula, R^1, R^2^a and R^2^b are the same or different and represent hydrogen or lower alkyl, There are ▲mathematical formulas, chemical formulas, tables, etc.▼, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, n represents 0 or 1, m represents an integer from 0 to 4, and l represents an integer from 0 to 2). Pin derivatives or pharmacologically acceptable salts thereof.