JPH0940662A - Tricyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a tricyclic compound having antagonisms to substance P and bradykinin, and useful for curing and prevention of allergy, asthma, inflammation, pain relief, autoimmune disease, shock, etc. SOLUTION: This compound is expressed by formula I W is CH2 O, CH2 CH2 , etc.; (k) is 0-2; Y is OR<1> [R<1> is (CH2 )m R<2> , etc. (R<2> is a (substituted) aryl, etc.; (m) is 0-6), etc.]; one of V<1> and V<2> is H and another is S(CH2 )n ((n) is 2-4), etc.; L is NR<3> , etc. (R<3> is H or a lower alkyl); M is CO, CH(OH), etc.; (p) is 0-6; Q is a (substituted) aryl, etc.} and its salt, e.g. N-(2-morpholinoethyl)-11-[2-(4- benzylpiperidine)ethyl]thio-6,11-dihydrodibenze[b,e-]oxepin-2-carboxam ide. The compound is obtained by, e.g. converting a compound of formula II into a reactive derivative of carboxylic acid such as an acid halide or a mixed acid anhydride, etc., and condensing the derivative with a compound of the formula Y-H in the presence (or absence) of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has substance P antagonism and / or bradykinin antagonism, and is useful for treating and / or preventing various diseases such as allergy, asthma, inflammation, analgesia, autoimmune disease, shock and the like. It relates to a useful tricyclic compound or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Substance P is a neuropeptide belonging to the tachykinin family consisting of 11 amino acids,
It is known to be a neurotransmitter of noxious stimuli (pain or inflammatory information). In addition, in mast cells, release-inducing action of various chemical mediators such as histamine, vascular permeability enhancing action, vasodilatory action, immune cell (monocyte, lymphocyte, polynuclear leukocyte) activating action, sensory nerve stimulation It is known that the inflammation-expanding action and the like. On the other hand, bradykinin is a peptide consisting of 9 amino acids, and its production is known to be promoted in surgery, inflammation, allergic reaction, rheumatoid arthritis, bronchial asthma and the like. Therefore, antagonists to substance P and / or bradykinin are new types of antiallergic agents,
It is expected to be useful as an anti-asthma drug, anti-inflammatory drug, or analgesic drug.

On the other hand, the formula (B)

[0004]

Embedded image

[In the formula, the portion to which a dotted line is given represents a single bond or a double bond, and X ₁ -X ₂ is CH ₂ O or CH ₂ .
₂ S, CH ₂ CH ₂ or CH═CH, W ₀ is S
Or = CH, a represents an integer of 1 to 4, Y ₀ represents a single bond, CR ¹¹ R ¹² (CH ₂ ) _s or CR ¹³ = CR ¹⁴
(CH ₂ ) _t (wherein R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and represent hydrogen or lower alkyl, s
And t represents an integer of 0 to 4), and M ₀ is CO ₂
R ¹⁵ (in the formula, R ¹⁵ represents hydrogen or lower alkyl),
CONR ¹⁶ R ¹⁷ (in the formula, R ¹⁶ and R ¹⁷ are the same or different and represent hydrogen or lower alkyl) or tetrazolyl, Z ₀ is N—E ₀ -Q ₀ (wherein E ₀ is a single bond) , CO, CO ₂ or SO ₂ and Q ₀ represents a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aralkenyl, or an aromatic heterocyclic group) or C (L ₀ ). -E ₀ '-Q ₀ {In the formula, L ₀ represents hydrogen, hydroxyl or lower alkyl, E ₀ ' is a single bond, CO or CH (OR ¹⁸ ) (in the formula,
R ¹⁸ represents hydrogen or lower alkyl), Q ₀ has the same meaning as above}, and b represents an integer of 1 to 3].
It is disclosed that the tricyclic compound represented by the formula (3) has an antiallergic action or an antihistamine action by antagonizing thromboxane A ₂ (JP-A-1-308274).

[0006]

The object of the present invention is to have a substance P antagonism and / or a bradykinin antagonism and to treat various diseases such as allergy, asthma, inflammation, analgesia, autoimmune sickness and shock. And / or to provide a prophylactically useful tricyclic compound or a pharmaceutically acceptable salt thereof.

[0007]

The present invention relates to a compound of the formula (I)

[0008]

Embedded image

[Wherein W is CH₂O, CH₂S, CH₂
CH₂Or CH = CH, and k represents an integer of 0 to 2
And Y is OR¹[Wherein, R¹Is (CH₂)_mR²{formula
Medium, R²Is a substituted or unsubstituted aryl, substituted or
Is an unsubstituted heterocyclic group or NR^ThreeR^Four(Where R^ThreeAnd
And R^FourAre the same or different and are hydrogen or lower alkyl
Represents, and m represents an integer of 0 to 6]]
Is NR^FiveR⁶(Where R^FiveIs hydrogen or lower alkyl
Represent, R⁶Is R which has the same meaning as above¹Represents or R ^FiveWhen
R⁶Are substitutions formed together by sandwiching a nitrogen atom
Or an unsubstituted heterocyclic group), V¹and
V²One is hydrogen and the other is S (CH₂)_n(Where n is
Represents an integer of 2 to 4) or CH₂(CH₂)_q(formula
In which q represents an integer of 0 to 4) or together
Become-CH (CH₂)_{q '}(In the formula, q'is an integer of 0 to 4
Represents, and L is NR⁷(Where R⁷Is hydrogen or
Represents lower alkyl), or

[0010]

Embedded image

[In the formula, A is N, CH, C (OR ⁸ ) (in the formula, R ⁸ represents hydrogen or lower alkanoyl) or C (NHR ⁹ ) (in the formula, R ⁹ represents hydrogen or lower alkanoyl). Represents, and r represents an integer of 1 to 3}, M represents CO, CH (OH), CH-J (wherein J represents substituted or unsubstituted aryl or substituted or unsubstituted aralkyl). Or a single bond, p is 0 to 6
And Q represents a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl], or a pharmaceutically acceptable salt thereof.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound represented by the formula (I) is referred to as a compound (I), and the compounds represented by other formulas are also referred to in the same manner. In the definition of each group of the formula (1) and the substituents thereof, aryl represents C 6-10, for example, phenyl, naphthyl and the like. Aralkyl has 7 to 7 carbon atoms
13 represents, for example, benzyl, phenethyl, methylbenzyl, naphthylmethyl, benzhydryl and the like. The heterocyclic group or the heterocyclic group formed by sandwiching a nitrogen atom may be the same or different, for example, pyrrolidinyl, piperidino,
Piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,
Pyridyl, pyrimidinyl, indolinyl, indolyl,
It represents benzimidazolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl, quinazolinyl, quinuclidinyl and the like.

Lower alkyl represents a straight-chain or branched C1-C6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. . Lower alkanoyl has 1 to 6 carbon atoms which may be linear or branched, for example, formyl, acetyl, propionyl,
It represents butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl and the like.

The substituent of the aryl, aralkyl, heterocyclic group or heterocyclic group formed by sandwiching a nitrogen atom is the same or different and has 1 to 3 substituents, for example, halogen, lower alkyl, aralkyl, hydroxy, It represents lower alkoxy or trifluoromethyl and the like. In the substituent, the lower alkyl part of lower alkyl and lower alkoxy has the same meaning as the above lower alkyl, aralkyl has the same meaning as the above aralkyl, and halogen represents each atom of fluorine, chlorine, bromine or iodine.

Examples of the pharmacologically acceptable salt of compound (I) include inorganic acid salts such as hydrochloride, sulfate and phosphate, maleate, fumarate, oxalate and malate. Examples thereof include organic acid salts such as citrate and methanesulfonate, ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts and the like.

Next, a method for producing the compound (I) will be described.

Production Method 1 Compound (I) can be produced according to the following reaction steps.

[0018]

[Chemical 6]

(Wherein W, Y, V ¹ , V ² , L, M,
Q, k and p have the same meanings as described above.) Compound (I) can be obtained by condensing compound (II) described below with commercially available or known compound (III). As the condensation method, for example, a method of converting the compound (II) into a reactive derivative of a carboxylic acid such as an acid halide or a mixed acid anhydride, and then condensing with the compound (III) in the presence or absence of a base. (Step 1-1), or compound (II) and compound (III) using a condensing agent
And the like (step 1-2). Step 1-1 The acid halide of compound (II) can be obtained by reacting compound (II) with a halogenating reagent such as oxalyl chloride, thionyl chloride or phosphorus tribromide in the presence or absence of a base. . As a reaction solvent, methylene chloride,
Chloroform or the like is used. As the base, pyridine, triethylamine and the like are used. Compound (II)
On the other hand, the halogenating reagent is used in 1 to 5 equivalents and the base is used in 0 to 5 equivalents. The reaction is carried out at 0 ° C to the boiling point of the solvent used for 1
~ 24 hours.

Next, the compound (I) can be obtained by reacting the obtained acid halide with the compound (III) in the presence or absence of a base. As the reaction solvent, methylene chloride, chloroform and the like are used. As the base, pyridine, triethylamine and the like are used. The compound (III) is used in an amount of 1 to 5 equivalents and the base is used in an amount of 0 to 5 equivalents based on the acid halide. The reaction is 0
C. to the boiling point of the solvent used for 1 to 24 hours. Step 1-2 Compound (I) can be obtained by reacting compound (II) with compound (III) in the presence of a condensing agent. As the condensing agent, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, and iodinated 2-chloro-1
-Methylpyridinium, N, N-bis (2-oxo-3
-Oxazolinidyl) phosphinic acid chloride or the like is used. As the reaction solvent, tetrahydrofuran, ethyl ether, dioxane, methylene chloride, chloroform or the like is used. In contrast to compound (II), compound (II
I) is used in 1 to 2 equivalents, and the condensing agent is used in 1 to 2 equivalents. The reaction is carried out at 0 ° C to the boiling point of the solvent used for 1 to 24 hours.

Production Method 2 In compound (I), compound (Ib) in which M is CH (OH) can also be produced by the following reaction step.

[0022]

[Chemical 7]

(Wherein W, Y, V ¹ , V ² , L, Q, k
And p are as defined above) Step 2 Compound (Ia) wherein M is CO in compound (I)
Compound (Ib) can be obtained by reacting with a reducing agent such as sodium borohydride in a solvent such as methanol or ethanol. For compound (Ia),
The reducing agent is used in an amount of 1 to 20 equivalents. The reaction is carried out at 0 ° C. to room temperature for 0.1 to 12 hours.

Next, compounds used as raw materials
The manufacturing method of (II) will be described. To compound (II)
In addition, V¹And V²One is hydrogen and the other is S (CH
₂) _n(Wherein n is as defined above) or together
Become ━ CH (CH₂)_{q '}(In the formula, q'is as defined above.
The compound represented by (1) is described in JP-A-1-308274.
Manufactured according to the method listed or listed
be able to.

In the compound (II), V¹And V²
One is hydrogen and the other is CH₂(CH ₂)_q(In the formula, q is
Compounds having the same meaning as above are described below.
It can be manufactured by the method (manufacturing methods 3 to 6).

Production Method 3 Compound (II) wherein q is 2 (II
a) can be produced according to the following reaction steps.

[0027]

Embedded image

(Wherein W, L, M, Q, k and p are as defined above) Step 3-1 Compound (VI) is prepared from compound (IV) as described in JP-A-5-20.
The compound (V) obtained by the method described in 2021 can be obtained by a hydroboration reaction and then a reaction with a peroxide. For example, compound (V) is reacted with a borane reagent such as borane-tetrahydrofuran solution in an organic solvent such as tetrahydrofuran. Compound (V)
On the other hand, the borane reagent is used in an amount of 1 to 20 equivalents. The reaction is carried out at 0 ° C. to room temperature for 1 to 12 hours. The product is then reacted under basic conditions with an excess of peroxide such as 30% aqueous hydrogen peroxide. The reaction is carried out at 0 ° C to room temperature for 1 to
It will be held for 6 hours. Step 3-2 Compound (VIII) is a compound (VI) having a hydroxyl group of methanesulfonyloxy, p-toluenesulfonyloxy,
It can be obtained by reacting a compound (referred to as compound (C)) converted to a leaving group such as halogen with compound (VII). The conversion of the hydroxyl group of compound (VI) into a leaving group is carried out by reacting compound (VI) with 1 to 2 equivalents of methanesulfonyl chloride, p-toluenesulfonyl chloride, or a halogenating reagent such as phosphorus tribromide in pyridine. It is carried out by The reaction is performed at 0 ° C to room temperature at 0.5.
〜6 hours.

Then, the obtained compound (C) is reacted with compound (VII) in the presence or absence of a base to give compound (VIII). Methylene chloride, chloroform, ethyl acetate, toluene, etc. are used as the solvent, and pyridine, triethylamine, etc. are used as the base. For compound (B),
The base is used in 0 to 2 equivalents, and the compound (VII) is used in 1 to 2 equivalents. The reaction is carried out at 0 ° C. to the boiling point of the solvent used for 1 to 6 hours. Step 3-3 Compound (IIa) can be obtained by alkaline hydrolysis of compound (VIII). As the solvent, methanol or ethanol containing water is used, and as the alkali, 1 equivalent to excess amount of sodium hydroxide, potassium hydroxide, lithium hydroxide or the like is used. The reaction is
It is carried out at room temperature to the boiling point of the solvent used for 1 to 6 hours.

Production Method 4 In the compound (II), the compound (II
b) can be produced according to the following reaction steps.

[0031]

Embedded image

(In the formula, W, L, M, Q, k and p have the same meanings as described above) Step 4-1 Compound (IX) is prepared by mixing compound (V) in a mixed solvent of ether, tetrahydrofuran and water. , A catalytic amount of osmium tetroxide and 1 to 10 equivalents of sodium periodate. The reaction is carried out at 0 ° C to the boiling point of the solvent used for 1 to 24 hours. Step 4-2 Compound (X) is obtained by reacting Compound (IX) with Compound (VII) in a solvent such as methanol (neutral to weakly acidic) in the presence of a reducing agent such as sodium cyanoborohydride. Obtainable. The compound (VII) is used in the amount of 1 to 10 equivalents, and the reducing agent is used in the amount of 1 to 20 equivalents, relative to compound (IX). The reaction is carried out at 0 ° C. to room temperature for 1 to 12 hours. Step 4-3 Compound (IIb) can be produced by the same method as in Step 3-3.
It can be obtained from the compound (X).

Production Method 5 Compound (II) wherein q is 0 (II
c) can be produced according to the following reaction steps.

[0034]

Embedded image

(Wherein W, L, M, Q, k and p are as defined above) Compound (XII) is obtained from compound (XI) by the method disclosed in JP-A-5-132477. To be Compound (IIc) can be obtained from compound (XII) by the same method as in step 4-2 and step 4-3.

[0036]Manufacturing method 6 In compound (II), V¹And V²One side is hydrogen
And the other is CH₂(CH ₂)_q(In the formula, q has the same meaning as above.
A compound that represents) is produced by the following method.
Can be.

[0037]

Embedded image

(Where W, L, M, Q, k, p and q
Is the same as the above) Compound (XVI) can be obtained from compound (XV) by the same method as in the above step 3-2, or from compound (XIV) by the same method as in the above step 4-2. it can. Compound (IId) can be obtained from compound (XVI) by the same method as in step 3-3 above.

The intermediate and target compound in the above-mentioned production method can be isolated and purified by a purification method commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. . Also,
The intermediate may be subjected to the next reaction without particular purification. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is. When it is obtained in a free form, it may be dissolved or suspended in an appropriate solvent to remove the acid or acid. It may be formed by adding a base.

The compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. The compound (I) obtained by the above production method also includes all possible stereoisomers and mixtures thereof. Specific examples of compound (I) obtained by various production methods are shown in Table 1. In the table, Me, Et, and Ac represent methyl, ethyl, and acetyl, respectively.

[0041]

[Table 1]

[0042]

[Table 2]

[0043]

[Table 3]

[0044]

[Table 4]

The compound (I) has a substance P antagonism and / or a bradykinin antagonism, and is more effective for preventing and / or treating various diseases such as allergy, asthma, inflammation, analgesia, autoimmune sickness and shock. Asthma in detail,
Cough, bronchitis, rhinitis, rhinorrhea, obstructive pulmonary disease [eg emphysema, etc.], sputum, pneumonia, systemic infrastructure
Response Syndrome [systemic inflammatory re
spons syndrome (SIRS)], septic shock, irritable shock, endotoxin shock, adult respiratory distress syndrome, disseminated intravascular coagulation, arthritis, rheumatism, osteoarthritis, low back pain, inflammation-induced bone resorption, conjunctivitis, spring catarrh , Uveitis, iritis, iridocyclitis, headache, migraine, toothache, backache, superficial pain, cancer pain, postoperative pain, tendon pain,
Trauma [eg wound, burn (burn) etc.], rash (skin), redness (erythema), eczema or dermatitis [eg contact dermatitis,
Atobitic dermatitis, etc.], urticaria, herpes hives, pruritus, psoriasis, lichen, inflammatory bowel disease [eg ulcerative colitis, Crohn's disease, etc.], diarrhea, hepatitis, pancreatitis, gastritis, esophagitis, Food allergies, ulcers, irritable bowel syndrome, nephritis, angina, periodontitis, edema, hereditary vascular edema, cerebral edema, hypotension, thrombosis, myocardial infarction, cerebral vasoconstriction, congestion, blood clots , Gout, central nervous system disorder, premature birth, arteriosclerosis, dumping syndrome after gastrectomy, carcinoid syndrome, fluctuation of sperm motility, diabetic neuropathy, neuralgia, rejection at the time of transplantation and / or prevention. Furthermore, substance P and / or bradykinin may be, for example, prostaglandins,
Since it is known to be involved in the release of mediators such as leukotriene, histamine, thromboxane, etc., Compound (I) is useful for treating and / or preventing diseases induced by those mediators.

Next, the pharmacological action of compound (I) will be described in more detail with reference to test examples.

Test Example 1 Substance P Receptor Binding Experiment The method of Quirion et al. [J. Neurosc
i. , 6, 2187 (1986)]. Tissue Preparation Male rat cerebrum was placed in Tissue Preparation Buffer-1 (50 mM
Tris / HCl, pH 7.4, 120 mM NaC
1, 5 mM KCl) and then centrifuged.
(49000 g, 10 minutes). Precipitate the tissue preparation buffer-2 (50 mM Tris / HCl, pH 7.4,
The mixture was homogenized with 300 mM KCl, 10 mM EDTA · 2Na), cooled with ice for 30 minutes, and then subjected to the same centrifugation operation. 50 mM Tris-HCl buffer (pH 7.4) for precipitation
Then, the same centrifugation operation is performed, and this washing operation is further repeated.
Repeated times. The finally obtained precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.4) to give a tissue solution (about 1.2 mg protein / ml). Receptor binding experiment 12 mM MnCl ₂ , 0.08% BSA, 160 μg
/ Ml bacitracin, 8 μg / ml chy
mostatin, 16 μg / ml leupepti
A 50 mM Tris-hydrochloric acid buffer solution (pH 7.4) containing n, 16 μg / ml phosporamidon was prepared as a reaction buffer solution. In each reaction tube, add this buffer and 40 PM of [ ¹²⁵ I] -Bolt as a ligand.
on Hunterlabeled-Substance P,
Tissue homogenate from above and test compound added 2
Incubated at 5 ° C for 20 minutes. After that, 0.
It was suction filtered on a glass filter treated with 3% polyethyleneimine. The filter was washed three times with ice-cold 50 mM Tris-HCl buffer (pH 7.4), and its radioactivity was measured with a gamma counter for 1 minute. The amount of non-specific binding was measured in the presence of 1 μM unlabeled substance P.

The specific binding amount was determined by subtracting the non-specific binding amount from the total binding amount. The results of representative compounds are shown in Table 2.

[0049]

[Table 5]

Test Example 2 Substance P-Induced Airway Edema Inhibition Test in Guinea Pigs The inhibitory effect of the compounds on airway edema in vivo was determined by M. Murai et al. (M. Murai et a
l. , J. et al. Pharmacol. Exp. Ther. ,
262, 403, 1992) and the method described in the literature was partially modified for evaluation. That is, anesthetized Ha
Using rtley male guinea pigs, substance P (
A dye Evans blue (10 mg / ml; Tokyo Chemical Industry Co., Ltd.) solution containing 2.6 μg / ml; Ten minutes after the injection of substance P, the abdominal aorta was cut and the chest was opened. After injecting 50 ml of physiological saline from the pulmonary artery to wash away the blood in the lung, the airway system was removed. The lungs remove the parenchyma, leaving only the bronchioles, trachea,
Immerse in 1 ml of 1N KOH together with the bronchus, 37
It was completely dissolved at 24 ° C. for 24 hours. The mixture was neutralized and extracted with 9 ml of a 0.6N phosphoric acid-acetone mixed solution (5:13 v / v). The insoluble matter was precipitated by centrifugation (3,000 rpm, 10 minutes), and the absorbance in the supernatant (wavelength 620 n
m) was measured, and the amount of dye was determined from the calibration curve prepared in advance. The amount of pigment is the amount per sample (μg / mg),
The leakage dye amount of the group to which only the dye without the substance P was administered was subtracted. The test compound is substance P
It was dissolved in dimethylsulfoxide 10 minutes before the administration and administered intravenously. In this test, compound 14 (dose 1
mg / kg) showed an inhibitory effect of 48%.

Test Example 3 Bradykinin Receptor Binding Inhibition Experiment S. G. FIG. The method of Farmer et al. [J. Pharmaco
l. Exp. Ther. 248, 677 (198
9)] was followed. Tissue preparation The ileum of a Hartley male guinea pig was removed and buffered (25 mM trimethylaminoethanesulfonic acid (TES), 1 mM
1,10-phenanthroline, 1 μM pepstatin A, 1 μM
Leupeptin, 100 μM PMSF, 0.014% bacitracin (pH
6.8)), and then resuspending the precipitate by centrifugation at 50,000 xg for 10 minutes. After repeating centrifugation and washing twice, a buffer solution (25 mM TES, 1 mM 1,10-phenanthroline, 0.1 mM) was added to the final precipitate.
014% bacitracin, pH 6.8) was added and suspended to obtain a tissue homogenate used for binding experiments. Receptor binding experiment reaction was carried out by adding 50 μL of [ ³ H] bradykinin at a final concentration of 0.3 nM, and adding 400 μL of the above tissue homogenate to 50 μL of the test compound.
The reaction was carried out at 5 ° C for 90 minutes. After the reaction was completed, [ ³ H] bradykinin bound to the tissue was separated from unbound bradykinin by rapid filtration under reduced pressure. Radioactivity on the filters was measured with a liquid scintillation counter. A buffer solution was used instead of the drug solution for the calculation of the total binding amount, and 1 μM unlabeled bradykinin was used for the calculation of the nonspecific binding amount.

The specific binding amount was determined by subtracting the non-specific binding amount from the total binding amount. The results of representative compounds are shown in Table 3.

[0053]

[Table 6]

Test Example 4 Acute toxicity test A test compound was intraperitoneally administered to a male ddy mouse having a body weight of 20 ± 1 g. The mortality situation 7 days after administration was observed to determine the minimum mortality (MLD). Compound 14 is 1
No deaths were observed at the dose of 00 mg / kg. Although compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, it is usually preferable to use it as various pharmaceutical preparations.

The administration route is preferably the most effective route for treatment, and may be oral or parenteral such as rectal, buccal, subcutaneous, intramuscular and intravenous. Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like.

Liquid preparations such as emulsions and syrups suitable for oral administration include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil,
It can be produced by using oils such as soybean oil, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint and the like. Further, capsules, tablets, powders, granules, etc. include excipients such as lactose, glucose, sucrose, mannitol, etc., starch, disintegrating agents such as sodium alginate, lubricants such as magnesium stearate, talc, polyvinyl, etc. It can be produced using a binder such as alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin, and the like.

Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound isotonic with the blood of the recipient. For example, as an injection, a solution for injection is prepared by using a carrier such as a salt solution, a glucose solution or a mixture of salt water and a glucose solution. Topical formulations contain 1 active compound
It is prepared by dissolving or suspending in one or more media, such as mineral oil, polyhydric alcohols or other bases used in topical pharmaceutical formulations.

Formulations for enteral administration may be presented as suppositories with conventional carriers such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids. Further, also in these parenteral agents, diluents, fragrances, preservatives (including antioxidants), excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers, etc. exemplified for oral agents It is also possible to add one or more auxiliary components selected from

The effective dose of the compound (I) or a pharmaceutically acceptable salt thereof and the number of administrations will vary depending on the administration form, the age of the patient, the body weight, the nature or severity of the condition to be treated. Dosage is 1 to 1000m per day
The dose is g / person, and the administration frequency is preferably once a day or divided into several times for administration. Examples, reference examples and formulation examples are shown below.

[0060]

【Example】

Example 1 N- (2-morpholinoethyl) -11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (compound 1) 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-
0.35 of triethylamine was added to a mixture of 1.00 g of sodium salt of 2-carboxylic acid and 150 ml of dichloromethane.
ml and oxalyl chloride 0.44 ml were added, and the mixture was stirred at room temperature for 5 hours. After distilling off the solvent and excess oxalyl chloride, the residue was dissolved in 100 ml of dichloromethane and 0.83 ml of 4- (2-aminoethyl) morpholine was added.
Was added and the mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the reaction solution and the mixture was extracted with dichloromethane. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent, chloroform / methanol = 5/2) to obtain 1.10 g of compound 1. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-1.9
(m, 2H), 2.3-2.7 (m, 8H), 2.51 (d, 2H, J = 6.6 Hz),
2.59 (t, 2H, J = 6.1 Hz), 3.5-3.6 (m, 2H), 3.7-3.8
(m, 4H), 4.88 and 6.41 (ABq, 2H, J = 12.9 Hz), 5.04
(s, 1H), 6.67 (brs, 1H), 6.86 (d, 1H, J = 8.6 Hz),
7.1-7.3 (m, 9H), 7.46 (dd, 1H, J = 2.3 Hz, 8.6 Hz),
7.79 (d, 1H, J = 2.3 Hz). 0.11 g of fumaric acid was added to 50 ml of acetone solution of 1.10 g of compound 1, the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were collected by filtration to give compound 1 0.5 fumarate
0.92 g of 0.4 hydrate was obtained. Melting point: 179-180 ° C IR (KBr tablet; cm ^-1 ): 2484, 1654, 1639, 1495, 131
6, 1252, 1119, 1011, 725, 701, 667.

Example 2 N- [2- (2-pyridyl) ethyl] -11- [2-
(4-Benzylpiperidino) ethyl] thio-6,11-
Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 2) According to the method of Example 1, 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b. , E] 0.50 g of the sodium salt of oxepin-2-carboxylic acid and 2- (2-aminoethyl) pyridine.
Using 36 ml, 0.40 g of compound 2 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-2.0
(m, 2H), 2.3-2.7 (m, 4H), 2.50 (d, 2H, J = 6.9 Hz),
2.7-2.9 (m, 2H), 3.08 (t, 2H, J = 6.1 Hz), 3.8-3.9
(m, 2H), 4.87 and 6.40 (ABq, 2H, J = 12.7 Hz), 5.04
(s, 1H), 6.83 (d, 1H, J = 8.6 Hz), 6.85 (brs, 1H),
7.1-7.4 (m, 10H), 7.4-7.5 (m, 2H), 7.6-7.7 (m, 1
H), 7.63 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.78 (d, 1H,
J = 2.3 Hz), 8.57 (d, 1H, J = 4.0 Hz). According to the method of Example 1, 0.39 g of compound 2 was used, and 0.5 fumarate of compound 2 and 0.6 water were used. Japanese food
32 g was obtained. Melting point: 175-177 ° C IR (KBr tablets; cm ^-1 ): 1701, 1638, 1606, 1571, 149
2, 1319, 1254, 1004, 749, 700.

Example 3 2-Morpholinoethyl 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylate (Compound 3) Example According to the method of 1, 1- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid sodium salt 0.75 g and 4- 0.35 g of Compound 3 was obtained using 0.37 ml of (2-hydroxyethyl) morpholine. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.3-2.0 (m, 7H), 2.3-2.8
(m, 14H), 3.72 (t, 4H, J = 4.7 Hz), 4.42 (t, 2H, J =
5.9 Hz), 4.89 and 6.45 (ABq, 2H, J = 12.9 Hz), 5.06
(s, 1H), 6.85 (d, 1H, J = 8.4 Hz), 7.1-7.3 (m, 9H),
7.77 (dd, 1H, J = 2.2 Hz, 8.4 Hz), 7.97 (d, 1H, J =
2.2 Hz). Compound 3, 0.33 g, was added with 5.4 M hydrochloric acid-ethanol solution 3 ml and stirred at room temperature. The solvent and excess hydrochloric acid were distilled off under reduced pressure, and the residue was triturated with ethyl acetate-isopropyl ether to obtain 0.27 g of the dihydrochloride salt of compound 3, 1.1 hydrate. Melting point: 190 ℃ (decomposition) IR (KBr tablets; cm ^-1 ): 2920, 1702, 1611, 1496, 145
0, 1277, 1241, 1129, 1115.

Example 4 N- (2-piperidinoethyl) -11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 4 ) According to the method of Example 1, 0.75 g of sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid. And 0.43 ml of 1- (2-aminoethyl) piperidine were used to obtain 0.33 g of compound 4. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.1-2.0 (m, 13H), 2.4-2.
8 (m, 14H), 3.52-3.53 (m, 2H), 4.88 and 6.41 (ABq,
2H, J = 12.9 Hz), 5.04 (s, 1H), 6.86 (d, 1H, J = 8.4 H
z), 7.0 (brs, 1H), 7.1-7.3 (m, 9H), 7.50 (dd, 1H,
J = 2.5 Hz, 8.4 Hz), 7.80 (d, 1H, J = 2.5 Hz). According to the method of Example 3, 0.31 g of compound 4 was used and the dihydrochloride dihydrate of compound 4 was used. 0.26 g was obtained. Melting point: 210 ℃ (decomposition) IR (KBr tablet; cm ^-1 ): 2920, 1655, 1490, 1445, 124
5, 1231.

Example 5 2-Dimethylaminoethyl 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylate (Compound 5) Implementation According to the method of Example 1, 0.50 g of sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid and 2 -Dimethylaminoethanol 0.30
Using ml, 0.62 g of compound 5 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 7H), 2.3-2.8
(m, 10H), 2.33 (s, 6H), 4.3-4.5 (m, 2H), 4.89 and 6.45 (ABq, 2H, J = 12.9 Hz), 5.06 (s, 1H), 7.1-7.3
(m, 9H), 7.79 (dd, 1H, J = 2.2 Hz, 8.7 Hz), 7.98
(d, 1H, J = 2.5 Hz). According to the method of Example 3, 0.65 g of compound 5 was used to obtain 0.25 g of dihydrochloride / 0.4 hydrate of compound 5. Melting point: 209 ℃ (decomposition) IR (KBr tablet; cm ^-1 ): 2896, 1717, 1609, 1496, 145
7, 1279, 1248, 1201.

Example 6 N- (3-phenylpropyl) -11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (compound 6) According to the method of Example 1, sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid. 50 g and 3-phenylpropylamine 0.43 m
0.49 g of compound 6 was obtained using 1. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.6 (m, 5H), 1.8-2.0
(m, 4H), 2.3-2.8 (m, 10H), 3.4-3.5 (m, 2H), 4.86
And 6.41 (ABq, 2H, J = 12.7 Hz), 5.01 (s, 1H), 6.11
(brs, 1H), 6.81 (d, 1H, J = 8.6 Hz), 7.1-7.3 (m, 14
H), 7.36 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.68 (d, 1H,
J = 2.3 Hz). According to the method of Example 3, 0.49 g of the compound 6 was used to obtain 0.34 g of the hydrochloride salt of the compound 6, 0.6 hydrate. Melting point: 116-118 ℃ IR (KBr tablet; cm ^-1 ): 2924, 1648, 1496, 1454, 125
7, 1236.

Example 7 N-benzyl-11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b,
e] Oxepin-2-carboxamide (Compound 7) According to the method of Example 1, 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin- Using 2.00 g of sodium salt of 2-carboxylic acid and 0.96 ml of benzylamine,
1.93 g of compound 7 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-1.9
(m, 2H), 2.3-2.7 (m, 4H), 2.50 (d, 2H, J = 6.6 Hz),
2.7-2.8 (m, 2H), 4.60 (brs, 2H), 4.87 and 6.41
(ABq, 2H, J = 12.7 Hz), 5.02 (s, 1H), 6.40 (brs, 1
H), 6.84 (d, 1H, J = 8.6 Hz), 7.1-7.4 (m, 14H), 7.52
(dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.77 (d, 1H, J = 2.3 H
z). Compound 7, 1.92 g of isopropanol-ethanol mixed solution was added with oxalic acid 0.31 g, stirred at room temperature, and the precipitated crystals were collected by filtration to give 0.5 oxalate salt of compound 7. 1.66 g of dihydrate / 0.5 isopropanol adduct was obtained. Melting point: 159-160 ℃ IR (KBr tablet; cm ^-1 ): 2922, 1604, 1495, 1315, 123
5, 1220, 701.

Example 8 N-[(2-methoxyphenyl) methyl] -11- [2
-(4-Benzylpiperidino) ethyl] thio-6,11
-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 8) According to the method of Example 1, 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [compound]. b, e] 2.00 g of the sodium salt of oxepin-2-carboxylic acid and 2-methoxyphenylmethylamine 1.
Using 15 ml, 2.00 g of compound 8 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-1.9
(m, 2H), 2.3-2.7 (m, 4H), 2.50 (d, 2H, J = 6.6 Hz),
2.7-2.9 (m, 2H), 3.88 (s, 3H), 4.62 (d, 2H, J = 5.5 H
z), 4.87 and 6.41 (ABq, 2H, J = 12.7 Hz), 5.02 (s,
1H), 6.56 (t, 1H, J = 5.5 Hz), 6.83 (d, 1H, J = 8.6 H
z), 6.9-7.0 (m, 2H), 7.1-7.4 (m, 11H), 7.46 (dd, 1
H, J = 2.1 Hz, 8.6 Hz), 7.77 (d, 1H, J = 2.1 Hz). According to the method of Example 1, 0.88 g of compound 8 was used and 0.5 fumarate of compound 8 was used. Was obtained. Melting point: 189-190 ℃ IR (KBr tablet; cm ^-1 ): 2918, 1638, 1605, 1493, 124
4, 1114, 701.

Example 9 N-[(2-pyridyl) methyl] -11- [2- (4-
Benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 9) According to the method of Example 1, 11- [2- (4-benzylpiperidino) was used. ) Ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid sodium salt 2.01 g and 2-aminomethylpyridine 0.84 ml
Was used to obtain 1.44 g of Compound 9. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.2 (m, 7H), 2.3-2.9
(m, 8H), 4.74 (d, 2H, J = 5.0 Hz), 4.88 and 6.42
(ABq, 2H, J = 12.9 Hz), 5.05 (s, 1H), 6.87 (d, 1H, J =
8.4 Hz), 7.1-7.7 (m, 14H), 7.84 (d, 1H, J = 2.5 Hz),
8.56 (d, 1H, J = 4.0 Hz). According to the method of Example 1, 1.34 g of Compound 9 was used to prepare 0.5 fumarate / 0.5 hydrate of Compound 9.
12 g were obtained. Melting point: 191-193 ° C IR (KBr tablet; cm ^-1 ): 2920, 2360, 1634, 1602, 154
1, 1493, 1239.

Example 10 N- [2- (indol-3-yl) ethyl] -11-
[2- (4-benzylpiperidino) ethyl] thio-6
11-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 10) According to the method of Example 1, 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo. 0.63 g of compound 10 was obtained using 0.89 g of the sodium salt of [b, e] oxepin-2-carboxylic acid and 0.58 g of tryptamine. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.8 (m, 5H), 1.8-2.0
(m, 2H), 2.3-2.7 (m, 4H), 2.50 (d, 2H, J = 6.6 Hz),
2.7-2.9 (m, 2H), 3.09 (t, 2H, J = 6.4 Hz), 3.7-3.8
(m, 2H), 4.85 and 6.31 (ABq, 2H, J = 12.9 Hz), 4.90
(s, 1H), 6.14 (t, 1H, J = 5.6 Hz), 6.80 (d, 1H, J =
8.6 Hz), 7.0-7.4 (m, 14H), 7.50 (d, 1H, J = 2.0 Hz),
7.66 (d, 1H, J = 7.9 Hz), 8.76 (brs, 1H). According to the method of Example 3, 0.62 g of the compound 10 was used to give a hydrochloride / ethyl acetate adduct of the compound 10. 54
g was obtained. Melting point: 158-160 ° C IR (KBr tablet; cm ^-1 ): 2908, 1633, 1607, 1561, 149
3, 1252, 703.

Example 11 1- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] -1,2,3 , 4-Tetrahydroisoquinoline (Compound 11) According to the method of Example 1, 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2- Using 2.01 g of sodium salt of carboxylic acid and 1.02 ml of 1,2,3,4-tetrahydroisoquinoline, 1.49 g of compound 11 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 8H), 2.3-3.0
(m, 9H), 3.6-4.1 (m, 2H), 4.6-5.0 (m, 2H), 4.88
And 6.38 (ABq, 2H, J = 12.9 Hz), 4.99 (s, 1H), 6.86
(d, 1H, J = 8.4 Hz), 7.1-7.3 (m, 14H), 7.44 (d, 1H,
J = 2.0 Hz). According to the method of Example 3, 1.01 g of compound 11 was used to obtain 1.01 g of hydrochloride / 1.5 hydrate of compound 11. Melting point: 137-140 ℃ IR (KBr tablet; cm ^-1 ): 2924, 2366, 1618, 1498, 143
1, 1237.

Example 12 4-Methyl-1- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] piperazine ( Compound 12) According to the method of Example 1, sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 0 Using 0.50 ml of 0.50 ml of 1-methylpiperazine, 0.46 g of compound 12 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 7H), 2.3-2.8
(m, 12H), 2.32 (s, 3H), 3.5-3.8 (m, 4H), 4.87 and 6.36 (ABq, 2H, J = 12.9 Hz), 4.99 (s, 1H), 6.83
(d, 1H, J = 8.3 Hz), 7.1-7.4 (m, 10H), 7.38 (d, 1H,
J = 2.3 Hz). According to the method of Example 3, 0.44 g of compound 12 was used to obtain 0.30 g of dihydrochloride / hydrate of compound 12. Melting point: 200 ℃ (decomposition) IR (KBr tablet; cm ^-1 ): 2910, 1642, 1451, 1420, 125
3.

Example 13 4-benzyl-1- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] piperazine ( Compound 13) According to the method of Example 1, sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 0 0.38 g of compound 13 was obtained by using 0.50 ml of 0.50 ml of 1-benzylpiperazine. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 5H), 2.3-2.8
(m, 14H), 3.5-3.8 (m, 6H), 4.86 and 6.35 (ABq, 2
H, J = 12.9Hz), 4.98 (s, 1H), 6.82 (d, 1H, J = 8.3 H
z), 7.1-7.3 (m, 15H), 7.38 (d, 1H, J = 2.3 Hz). According to the method of Example 3, 0.37 g of compound 13 was used, and dihydrochloride. 0.38 g of 5 hydrate
Obtained. Melting point: 185-288 ° C IR (KBr tablet; cm ^-1 ): 2920, 1620, 1435, 1250, 123
5, 745.

Example 14 4- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] morpholine (Compound 1
4) 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-
2-carboxylic acid 2.11 g, morpholine 0.42 ml,
1-Ethyl-3 in a mixture of 50 ml of tetrahydrofuran
0.92 g of-(3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent, chloroform / methanol = 25/1) to obtain 2.23 g of compound 14. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.4-1.8 (m, 4H), 2.0-2.3
(m, 1H), 2.4-3.2 (m, 8H), 3.4-3.9 (m, 10H), 4.88
And 6.30 (ABq, 2H, J = 12.9 Hz), 5.05 (s, 1H), 6.85
(d, 1H, J = 8.6 Hz), 7.1-7.4 (m, 10H), 7.41 (d, 1H,
J = 1.4 Hz). According to the method of Example 3, 2.23 g of the compound 14 was used to obtain 1.32 g of the hydrochloride / 1.5 hydrate of the compound 14. Melting point: 139-141 ° C IR (KBr tablet; cm ^-1 ): 2936, 2850, 2368, 1605, 145
7, 1430, 1249, 1233, 1116.

Example 15 1- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] piperidine (Compound 1
5) According to the method of Example 1, sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 2. Using 00 g and 0.87 ml of piperidine, 1.99 g of compound 15 was obtained.

¹ HNMR (δ, ppm, CDCl ₃ ): 1.1-1.7 (m,
5H), 1.8-1.9 (m, 2H), 2.3-2.7 (m, 4H), 2.51 (d, 2
H, J = 6.9 Hz), 2.7-2.9 (m, 2H), 3.3-3.8 (brs, 4H),
4.86 and 6.35 (ABq, 2H, J = 12.9 Hz), 4.99 (s, 1H),
6.82 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 10H), 7.36 (d,
1H, J = 2.3 Hz). According to the method of Example 3, 1.95 g of the compound 15 was used to convert the hydrochloride of the compound 15, 0.8 hydrate, and 0.8 isopyrupyl ether adduct. 11 g were obtained. Melting point: 132-134 ℃ IR (KBr tablet; cm ^-1 ): 2932, 1611, 1497, 1437, 125
4, 1234, 1125, 1009, 701.

Example 16 4- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] thiomorpholine (Compound 16) According to the method of Example 1, 2.00 g of sodium salt of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid was added. Using 0.89 ml of thiomorpholine,
2.06 g of compound 16 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.8 (m, 5H), 1.8-1.9
(m, 2H), 2.3-2.7 (m, 8H), 2.51 (d, 2H, J = 6.9 Hz),
2.7-2.9 (m, 2H), 3.7-4.0 (brs, 4H), 4.87 and 6.36
(ABq, 2H, J = 12.9 Hz), 4.99 (s, 1H), 6.84 (d, 1H,
J = 8.6 Hz), 7.0-7.3 (m, 10H), 7.35 (d, 1H, J = 2.3 H
z). According to the method of Example 7, 0.82 g of Compound 16 was used to obtain 0.62 g of oxalate trihydrate of Compound 16. Melting point: 127 ° C (decomposition) IR (KBr tablet; cm ^-1 ): 2923, 1630, 1405, 1230, 104
6, 720.

Example 17 4- [11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-3-ylcarbonyl] morpholine (Compound 1
7) According to the method of Example 14, 1.04 g of 11- [2- (4-benzylpiperidino) ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-3-carboxylic acid.
And 0.22 ml of morpholine were used to prepare compound 17.
95 g was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-2.0
(m, 2H), 2.3-2.7 (m, 4H), 2.52 (d, 2H, J = 6.6 Hz),
2.7-2.9 (m, 2H), 3.3-3.8 (brs, 8H), 4.87 and 6.33
(ABq, 2H, J = 12.9 Hz), 5.01 (s, 1H), 6.87 (d, 1H,
J = 1.7 Hz), 6.93 (dd, 1H, J = 1.7 Hz, 7.7 Hz), 7.1-7.3
(m, 10H). According to the method of Example 1, 0.71 g of the compound 17 was used and 0.46 of the fumarate.
g was obtained. Melting point: 108-111 ° C IR (KBr tablet; cm ^-1 ): 2346, 1693, 1557, 1430, 128
0, 1115, 1013, 701.

Example 18 N- (2-morpholinoethyl) -11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 18 ) According to the method of Example 14, 11-obtained in Reference Example 4
[2- (4-benzylpiperidino) ethyl] -6,11
Using 0.41 g of dihydrodibenzo [b, e] oxepin-2-carboxylic acid (compound d) and 0.20 ml of 4- (2-aminoethyl) morpholine, 0.45 g of compound 18 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-2.0
(m, 2H), 2.2-2.7 (m, 10H), 2.53 (d, 1H, J = 6.4 Hz),
2.8-3.0 (m, 2H), 3.5-3.6 (m, 2H), 3.6-3.8 (m, 4H),
4.04 (brs, 1H), 4.97 and 5.60 (ABq, 2H, J = 14.1 H
z), 6.69 (brs, 1H), 6.95 (d, 1H, J = 8.4 Hz), 7.1-7.3
(m, 9H), 7.48 (dd, 1H, J = 2.3 Hz, 8.4 Hz), 7.72
(d, 1H, J = 2.3 Hz). According to the method of Example 3, 0.47 g of Compound 18 was used to obtain 0.37 g of hydrochloride of Compound 18. Melting point: 228 ℃ (decomposition) IR (KBr tablet; cm ^-1 ): 3294, 2858, 2534, 1656, 164
0, 1494, 1450, 1104, 700.

Example 19 N- (2-Piperidinoethyl) -11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 19) According to the method of Example 1, compound d obtained in Reference Example 4
0.50 g and 0.24 ml of 1- (2-aminoethyl) piperidine were used to obtain 0.47 g of Compound 19. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.6 (m, 9H), 1.8-1.9
(m, 2H), 2.1-2.6 (m, 14H), 2.84 (d, 2H, J = 11.2 H
z), 3.5-3.6 (m, 2H), 4.0-4.1 (m, 1H), 4.96 and 5.
60 (ABq, 2H, J = 14.0 Hz), 6.9 (brs, 1H), 6.94 (d, 1
H, J = 8.6 Hz), 7.1-7.3 (m, 9H), 7.50 (dd, 1H, J = 2.3
Hz, 8.6 Hz), 7.72 (d, 1H, J = 2.3 Hz). According to the method of Example 3, 0.46 g of the compound 19 was used to prepare the dihydrochloride / hydrate of the compound 19. 0.20g
Obtained. Melting point: 261-263 ° C (decomposition) IR (KBr tablet; cm ^-1 ): 3280, 2948, 1652, 1531, 149
4, 1454.

Example 20 N- [2- (1-Pyrrolidyl) ethyl] -11- [2-
(4-Benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 20) Compound d obtained in Reference Example 4 according to the method of Example 1.
0.50 g and 0.21 ml of 1- (2-aminoethyl) pyrrolidine were used to obtain 0.48 g of Compound 20. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.4 (m, 2H), 1.5-1.6
(m, 3H), 1.8-1.9 (m, 5H), 2.2-2.4 (m, 5H), 2.53
(d, 2H, J = 6.9 Hz), 2.6-2.7 (m, 4H), 2.72 (t, 2H, J =
5.9 Hz), 2.8-2.9 (m, 2H), 3.5-3.6 (m, 2H), 4.0-4.1
(m, 1H), 4.95 and 5.59 (ABq, 2H, J = 14.2 Hz), 6.93
(d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 9H), 7.51 (dd, 1H,
J = 2.3 Hz, 8.3 Hz), 7.72 (d, 1H, J = 2.3 Hz). According to the method of Example 3, 0.47 g of the compound 20 was used, and the dihydrochloride / 1.5 water of the compound 20 was used. 0.22g of Japanese food
Obtained. Melting point: 153-155 ° C IR (KBr tablet; cm ^-1 ): 1652, 1606, 1494, 1456, 131
5, 1240, 1008.

Example 21 N- [2- (4-thiomorpholino) ethyl] -11-
[2- (4-benzylpiperidino) ethyl] -6,11
-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 21) Compound d obtained in Reference Example 4 according to the method of Example 1.
Was used and 0.52 g of 4- (2-aminoethyl) thiomorpholine to obtain 0.85 g of Compound 21. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 9H), 2.1-2.9
(m, 16H), 3.5-3.6 (m, 2H), 4.0-4.1 (m, 1H), 4.96
And 5.61 (ABq, 2H, J = 13.9 Hz), 6.6 (brs, 1H), 6.9
4 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 9H), 7.45 (dd, 1
H, J = 2.3 Hz, 8.3 Hz), 7.71 (d, 1H, J = 2.3 Hz). According to the method of Example 7, 0.44 g of compound 21 was used and the dioxalate / water of compound 21 was used. 0.42 g of a Japanese product was obtained. Melting point: 161-162 ℃ IR (KBr tablet; cm ^-1 ): 1640, 1567, 1541, 1492, 140
2, 1233, 1201.

Example 22 N- [2- (1-hexamethyleneimino) ethyl] -1
1- [2- (4-benzylpiperidino) ethyl] -6, -6
11-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 22) Compound d obtained in Reference Example 4 according to the method of Example 1.
Of ## STR10 ## and 1- (2-aminoethyl) cyclohexamethyleneimine 0.82 g.
96 g were obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 15H), 2.2-2.
4 (m, 4H), 2.52 (d, 2H, J = 6.9 Hz), 2.6-2.9 (m, 8
H), 3.4-3.5 (m, 2H), 4.0-4.1 (m, 1H), 4.96 and
5.61 (ABq, 2H, J = 13.9 Hz), 6.9 (brs, 1H), 6.94 (d,
1H, J = 8.3 Hz), 7.1-7.3 (m, 9H), 7.48 (dd, 1H, J =
2.1 Hz, 8.3 Hz), 7.71 (d, 1H, J = 2.1 Hz). According to the method of Example 3, 0.82 g of compound 22 was used to obtain 0.46 g of dihydrochloride of compound 22. Melting point: 217 ℃ (decomposition) IR (KBr tablet; cm ^-1 ): 2937, 1657, 1538, 1492, 128
6, 1239.

Example 23 N- (1-ethylpyrrolidin-2-ylmethyl) -11
-[2- (4-Benzylpiperidino) ethyl] -6,1
1-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 23) Compound d obtained in Reference Example 4 according to the method of Example 1.
Was used and 0.84 ml of 2-aminomethyl-1-ethylpyrrolidine to obtain 0.96 g of Compound 23. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.12 (t, 3H, J = 7.3 Hz),
1.2-2.0 (m, 9H), 2.1-3.0 (m, 12H), 2.52 (d, 2H, J =
6.9 Hz), 3.1-3.4 (m, 2H), 3.6-3.8 (m, 1H), 4.0-4.1
(m, 1H), 4.9-5.0 (m, 1H), 5.6-5.7 (m, 1H), 6.8 (b
rs, 1H), 6.93 (d, 1H, J = 8.3 Hz), 7.1-7.4 (m, 9H),
7.5-7.6 (m, 1H), 7.71 (d, 1H, J = 2.0 Hz). According to the method of Example 1, using 0.70 g of compound 23, 1.5 fumarate salt of compound 23-2. 0.65 g of .5 hydrate was obtained. Melting point: 148-150 ℃ IR (KBr tablet; cm ^-1 ): 1701, 1640, 1567, 1492, 138
0, 1245.

Example 24 N- [2- (1-methylpyrrol-2-yl) ethyl]
-11- [2- (4-benzylpiperidino) ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Carboxamide (Compound 24) Compound d obtained in Reference Example 4 according to the method of Example 1.
Was used and 0.73 ml of 2-aminoethyl-1-methylpyrrole to obtain 0.85 g of compound 24. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 5H), 2.1-2.4
(m, 4H), 2.53 (d, 2H, J = 6.9 Hz), 2.8-3.0 (m, 6H),
3.57 (s, 3H), 3.6-3.7 (m, 2H), 4.0-4.1 (m, 1H), 4.9
5 and 5.59 (ABq, 2H, J = 14.0 Hz), 5.9-6.0 (m, 1H),
6.08 (t, 1H, J = 3.1 Hz), 6.3 (brs, 1H), 6.58 (t, 1
H, J = 2.1 Hz), 6.91 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m,
9H), 7.43 (dd, 1H, J = 2.3 Hz, 8.3 Hz), 7.66 (d, 1H,
J = 2.3 Hz). According to the method of Example 7, 0.45 g of compound 24 was used to obtain 0.32 g of oxalate dihydrate of compound 24. Melting point: 143-145 ° C IR (KBr tablet; cm ^-1 ): 2937, 1718, 1652, 1635, 149
4, 1236, 1203.

Example 25 N- (3-morpholinopropyl) -11- [2- (4-
Benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 25) A mixture of 1.00 g of the compound d obtained in Reference Example 4 and 30 ml of dichloromethane was cooled with ice, A pyridine catalyst amount and thionyl chloride (0.33 ml) were added, and the mixture was stirred at room temperature for 8 hours.
The solvent and excess thionyl chloride were distilled off. A solution of the remaining 10 ml of dichloromethane was added to 0.99 ml of 4- (3-aminopropyl) morpholine in 20 ml of dichloromethane.
The solution was added dropwise under ice cooling. After completion of the reaction, water was added to the reaction solution and the mixture was extracted with dichloromethane. The extract was washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent, ethyl acetate / triethylamine = 10).
/ 1) to obtain 1.02 g of compound 25. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 11H), 2.1-2.
6 (m, 13H), 2.8-2.9 (m2H), 3.5-3.6 (m, 2H), 3.71
(t, 4H, J = 4.6 Hz), 4.0-4.1 (m, 1H), 4.95 and 5.6
1 (ABq, 2H, J = 14.0 Hz), 6.94 (d, 1H, J = 8.6 Hz), 7.
1-7.3 (m, 10H), 7.53 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.
73 (d, 1H, J = 2.3 Hz). According to the method of Example 7, using 0.97 g of the compound 25, 0.63 g of the dioxalate dihydrate of the compound 25.
Obtained. Melting point: 131-133 ℃ IR (KBr tablet; cm ^-1 ): 2877, 1717, 1632, 1487, 140
1, 1232, 718.

Example 26 N- (3-piperidinopropyl) -11- [2- (4-
Benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 26) According to the method of Example 25, 1.00 g of the compound d obtained in Reference Example 4 was used. Using 0.60 g of 1- (3-aminopropyl) piperidine, 0.92 g of compound 26 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 17H), 2.1-2.
6 (m, 10H), 2.7-2.9 (m, 2H), 3.4-3.7 (m, 2H), 4.0-
4.1 (m, 1H), 4.94 and 5.61 (ABq, 2H, J = 14.3Hz),
6.93 (d, 1H, J = 8.4 Hz), 7.1-7.4 (m, 9H), 7.58 (dd,
1H, J = 2.0 Hz, 8.4 Hz), 7.72 (d, 1H, J = 2.0 Hz), 8.
43 (brs, 1H). To a mixed solution of 0.52 g of compound 26 and 2 ml of isopropanol, 0.24 g of malic acid was added and stirred at room temperature. The solvent was distilled off under reduced pressure, and the residue was triturated with ether to obtain 0.52 g of the dimalate salt of compound 26 hydrate. IR (KBr tablet; cm ^-1 ): 2948, 1692, 1639, 1494, 132
0, 1240, 1094.

Example 27 N-piperidino-11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e]
Oxepin-2-carboxamide (Compound 27) Compound d obtained in Reference Example 4 according to the method of Example 1.
0.50 g and 0.18 ml of 1-aminopiperidine were used to obtain 0.34 g of compound 27. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 13H), 2.1-2.
4 (m, 4H), 2.53 (d, 2H, J = 6.9 Hz), 2.7-2.9 (m, 6
H), 4.0-4.1 (m, 1H), 4.94 and 5.60 (ABq, 2H, J = 13.
9 Hz), 6.7 (brs, 1H), 6.92 (d, 1H, J = 8.2 Hz), 7.1-
7.3 (m, 9H), 7.48 (d, 1H, J = 7.9 Hz), 7.6 (brs, 1H). According to the method of Example 3, 0.32 g of compound 27 was used to dihydrochloride of compound 27. -0.24 g of hydrate was obtained. Melting point: 177-179 ° C IR (KBr tablet; cm ^-1 ): 2685, 1677, 1606, 1565, 149
4, 1453, 1239, 750.

Example 28 4-Hydroxy-1- [11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] piperidine (Compound 28) Compound d obtained in Reference Example 4 according to the method of Example 1.
Was used and 0.57 g of 4-hydroxypiperidine to obtain 0.83 g of Compound 28. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 12H), 2.1-2.
4 (m, 4H), 2.52 (d, 2H, J = 6.9 Hz), 2.8-3.0 (m, 2
H), 3.2-3.4 (m, 2H), 3.7-4.1 (m, 4H), 4.95 and
5.57 (ABq, 2H, J = 14.2 Hz), 6.94 (d, 1H, J = 7.9 Hz),
7.1-7.4 (m, 11H). According to the method of Example 1, 0.63 g of compound 28 was used and 0.59 of fumarate hemihydrate of compound 28 was used.
g was obtained. Melting point: 197-199 ° C IR (KBr tablet; cm ^-1 ): 2853, 1703, 1615, 1498, 144
5, 1236, 1199.

Example 29 3-Hydroxy-1- [11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-ylcarbonyl] piperidine (Compound 29) Compound d obtained in Reference Example 4 according to the method of Example 1.
Was used and 0.78 g of 3-hydroxypiperidine to obtain 0.87 g of Compound 29. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 11H), 2.2-2.
4 (m, 4H), 2.53 (d, 2H, J = 6.9 Hz), 2.8-2.9 (m, 2
H), 3.2-3.9 (m, 6H), 3.9-4.1 (m, 1H), 4.96 and
5.55 (ABq, 2H, J = 14.0 Hz), 6.94 (d, 1H, J = 8.3 Hz),
7.1-7.4 (m, 11H). According to the method of Example 1, 0.79 g of compound 29 was used to obtain 0.72 g of 0.5 fumarate salt / 2.5 hydrate of compound 29. Melting point: 146-148 ^o C IR (KBr tablet; cm ^-1 ): 3382, 2942, 1702, 1615, 149
8, 1445, 1373, 1279, 1252.

Example 30 N- (quinuclidin-3-yl) -11- [2- (4-
Benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 30) According to the method of Example 25, the compound d obtained in Reference Example 4 was 1.00 g. 0.26 g of compound 30 was obtained using 0.92 g of 3-aminoquinuclidine. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.1-3.2 (m, 25H), 3.4-3.
5 (m, 1H), 4.0-4.1 (m, 1H), 4.1-4.2 (m, 1H), 4.96
And 5.59 (ABq, 2H, J = 13.9 Hz), 6.5-6.6 (m, 1H), 6.
95 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 9H), 7.5-7.6 (m,
1H), 7.7-7.8 (m, 1H). According to the method of Example 1, 0.22 g of compound 30 was used to obtain 0.17 g of fumarate dihydrate of compound 30. IR (KBr tablet; cm ^-1 ): 2932, 1714, 1640, 1492, 124
8, 980, 642.

Example 31 N- (2-morpholinoethyl) -11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-ylacetamide (compound 31) According to the method of Example 1, 1.00 g of 11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid and 4- ( Two
-Aminoethyl) morpholine 0.86 ml was used to obtain 0.47 g of compound 31. Melting point: 107-109 ° C IR (KBr tablet; cm ^-1 ): 3328, 2921, 1639, 1536, 150
^{0, 1222, 1116, 752. 1} HNMR (δ, ppm, CDCl 3): 1.2-1.9 (m, 7H), 2.2-2.9
(m, 10H), 2.53 (d, 2H, J = 6.9 Hz), 3.2-3.5 (m, 4
H), 3.39 (t, 4H, J = 4.4 Hz), 3.50 (s, 2H), 3.9-4.0
(m, 1H), 5.48 and 5.58 (ABq, 2H, J = 16.8 Hz), 6.0
(brs, 1H), 6.9-7.4 (m, 12H).

Example 32 N- (2-morpholinoethyl) -11- [2- (4-benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-3-carboxamide (Compound 32 ) 11- [2- (4-Benzylpiperidino) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-3-carboxylic acid 1.02 g and 4 according to the method of Example 25.
Using 1.03 ml of-(2-aminoethyl) morpholine, 1.07 g of compound 32 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-2.0 (m, 7H), 2.1-2.4
(m, 4H), 2.4-2.7 (m, 8H), 3.5-3.6 (m, 2H), 3.72
(t, 4H, J = 4.6 Hz), 4.0-4.1 (m, 1H), 5.51 and 5.56
(ABq, 2H, J = 5.8 Hz), 6.69 (brs, 1H), 7.0-7.5 (m, 1
2H). According to the method of Example 7, using 0.99 g of the compound 32, 1.07 g of the oxalate salt of the compound 32 was obtained. Melting point: 197-198 ° C IR (KBr tablet; cm ^-1 ): 1719, 1702, 1623, 1616, 155
8, 1540, 1508, 1388, 1313, 1203.

Example 33 N- [2- (2-pyridyl) ethyl] -11- [2-
[4-[(2-Methoxyphenyl) methyl] piperidino] ethyl] thio-6,11-dihydrodibenzo [b,
e] Oxepin-2-carboxamide (Compound 33) 11- [2- [4-[(2-methoxyphenyl) methyl] piperidino] ethyl obtained from Compound i (Reference Example 9) in the same manner as in Reference Example 4. Thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 1.22 g and 2- (2-aminoethyl) pyridine 0.5
Compound 3 was prepared according to the method of Example 14 using 8 ml.
0.72 g of 3 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.7 (m, 5H), 1.8-2.0
(m, 2H), 2.3-2.7 (m, 6H), 2.52 (d, 2H, J = 6.4 Hz),
2.7-2.9 (m, 2H), 3.09 (t, 2H, J = 6.2 Hz), 3.80 (s,
3H), 3.8-3.9 (m, 2H), 4.87 and 6.40 (ABq, 2H, J =
12.9 Hz), 4.97 (s, 1H), 6.84 (d, 1H, J = 8.6 Hz), 6.
8-6.9 (m, 2H), 7.05 (dd, 1H, J = 1.7 Hz, 7.2 Hz), 7.1
-7.3 (m, 6H), 7.4-7.5 (m, 1H), 7.49 (dd, 1H, J = 2.1
Hz, 8.6Hz), 7.6-7.7 (m, 1H), 7.78 (d, 1H, J = 2.1 H
z), 8.57 (d, 1H, J = 4.0 Hz). According to the method of Example 1, 0.63 g of the compound 33 was used to obtain 0.42 g of 0.5 fumarate of the compound 33. Melting point: 151-152 ° C IR (KBr tablet; cm ^-1 ): 1633, 1599, 1570, 1493, 132
0, 1243, 759, 666.

Example 34 N- (2-morpholinoethyl) -11- [2- (4-benzyl-1-piperazinyl) ethyl] thio-6,11-
Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 34) According to the method of Example 1, 11- [2- (4-benzyl-1-piperazinyl) ethyl] thio-6,11-dihydrodibenzo [compound]. b, e] Oxepin-2-carboxylic acid 0.
47 g and 4- (2-aminoethyl) morpholine 0.26
0.19 g of compound 34 was obtained using ml. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.7-1.9 (brs, 2H), 2.3-
2.7 (m, 16H), 3.5-3.6 (m, 2H), 3.49 (s, 2H), 3.7-
3.8 (m, 4H), 4.88 and 6.42 (ABq, 2H, J = 12.5 Hz),
5.05 (s, 1H), 6.67 (brs, 1H), 6.86 (d, 1H, J = 8.6 H
z), 7.1-7.3 (m, 9H), 7.46 (dd, 1H, J = 2.3 Hz, 8.6 H
z), 7.79 (d, 1H, J = 2.3 Hz). According to the method of Example 1, 0.13 g of the compound 34 was used, and the trifumarate. 1
1 g was obtained. Melting point: 145-148 ° C IR (KBr tablets; cm ^-1 ): 2364, 1703, 1657, 1650, 160
7, 1494, 1237, 983, 700.

Example 35 N- (2-morpholinoethyl) -11- [2- [4-
[(2-Methoxyphenyl) methyl] -1-piperazinyl] ethyl] thio-6,11-dihydrodibenzo [b,
e] Oxepin-2-carboxamide (Compound 35) According to the method of Example 14, 11- [2- [4-[(2
-Methoxyphenyl) methyl] -1-piperazinyl] ethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 1.50 g and 4- (2-aminoethyl) morpholine 0.78 ml were used. And compound 3
1.17 g of 5 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.7-1.9 (brs, 2H), 2.4-
2.7 (m, 16H), 3.5-3.6 (m, 2H), 3.56 (s, 2H), 3.7-
3.8 (m, 4H), 3.80 (s, 3H), 4.88 and 6.42 (ABq, 2
H, J = 12.9 Hz), 5.04 (s, 1H), 6.74 (brs, 1H), 6.86
(d, 1H, J = 8.5 Hz), 6.9-7.0 (m, 2H), 7.1-7.3 (m, 6
H), 7.47 (dd, 1H, J = 2.2 Hz, 8.5 Hz), 7.79 (d, 1H, J
= 2.2 Hz). According to the method of Example 7, 0.39 g of compound 35 and 0.39 g of trioxalate dihydrate of compound 35 are used.
Obtained. Melting point: 170 ℃ (decomposition) IR (KBr tablet; cm ^-1 ): 2364, 1702, 1606, 1492, 143
9, 1403, 1280, 1102, 1009, 761, 721, 707.

Example 36 N- [2- (2-pyridyl) ethyl] -11- (2-benzylaminoethyl) thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 36) According to the method of Example 14, 11- (2-benzylaminoethyl) thio-6,11-dihydrodibenzo [b,
e] 0.55 g of oxepin-2-carboxylic acid and 2- (2
Using 0.20 ml of -aminoethyl) pyridine, 0.23 g of compound 36 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.9-2.1 (brs, 2H), 2.5-
2.8 (m, 2H), 3.09 (t, 2H, J = 6.2 Hz), 3.76 (s, 2H),
3.8-3.9 (m, 2H), 4.86 and 6.38 (ABq, 2H, J = 12.9
Hz), 5.00 (s, 1H), 6.84 (d, 1H, J = 8.4 Hz), 7.1-7.4
(m, 11H), 7.49 (dd, 1H, J = 2.3 Hz, 8.4 Hz), 7.62
(dt, 1H, J = 1.8 Hz, 7.7 Hz), 7.78 (d, 1H, J = 2.3 Hz),
8.55 (d, 1H, J = 4.9 Hz). According to the method of Example 1, 0.15 g of compound 36 was used, and 0.12 g of 0.5 fumarate / 0.2 hydrate of compound 36 was used. Obtained. Melting point: 193 ° C (decomposition) IR (KBr tablet; cm ^-1 ): 2926, 1637, 1607, 1567, 154
1, 1492, 1254, 1008, 699.

Example 37 N- [2- (2-pyridyl) ethyl] -11- [2-
(2-Methoxyphenylmethyl) aminoethyl] thio-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Carboxamide (Compound 37) According to the method of Example 14, 11- [2- (2-methoxyphenylmethyl) aminoethyl] thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 1 0.89 g and 2- (2-aminoethyl) pyridine 0.6
Using 3 ml, 0.42 g of compound 37 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.8-2.0 (brs, 2H), 2.5-
2.8 (m, 2H), 3.09 (t, 2H, J = 6.2 Hz), 3.7-3.9 (m, 2
H), 3.82 (s, 2H), 3.82 (s, 3H), 4.85 and 6.38 (AB
q, 2H, J = 12.9 Hz), 4.99 (s, 1H), 6.84 (d, 1H, J = 8.
6 Hz), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 8H), 7.51 (dd,
1H, J = 2.1 Hz, 8.6 Hz), 7.62 (dt, 1H, J = 1.8 Hz, 7.
7 Hz), 7.77 (d, 1H, J = 2.1 Hz), 8.54 (d, 1H, J = 5.0
According to the method of Example 1, 0.41 g of the compound 37 was used to obtain 0.36 g of 0.5 fumarate · 0.2 hydrate of the compound 37. Melting point: 216 ° C (decomposition) IR (KBr tablet; cm ^-1 ): 1640, 1606, 1542, 1495, 125
4, 757, 724.

Example 38 N- (2-morpholinoethyl) -11- [3- (4-benzylpiperidino) propyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 38 ) 11- [3- (4-) obtained from compound a (Reference Example 1)
Benzylpiperidino) propyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 0.2
8g and 4- (2-aminoethyl) morpholine 0.08m
According to the method of Example 14, 0.21 g of compound 38 was obtained using 1. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.3-1.8 (m, 5H), 1.9-2.6
(m, 10H), 2.51 (d, 2H, J = 5.3 Hz), 2.61 (t, 2H, J =
6.1 Hz), 2.9-3.1 (m, 2H), 3.5-3.6 (m, 2H), 3.6-3.8
(m, 4H), 3.88 (t, 1H, J = 7.9 Hz), 4.97 and 5.56
(ABq, 2H, J = 14.2Hz), 6.97 (d, 1H, J = 8.5 Hz), 7.0-
7.3 (m, 9H), 7.53 (dd, 1H, J = 2.2 Hz, 8.5 Hz), 7.72
(d, 1H, J = 2.2 Hz). According to the method of Example 1, using 0.13 g of compound 38, 0.14 g of 1.5 fumarate salt / 1.2 hydrate of compound 38 was obtained. It was Melting point: 127-129 ° C IR (KBr tablet; cm ^-1 ): 2930, 1643, 1490, 1453, 122
8, 1116, 1011, 985, 703.

Example 39 N- (2-morpholinoethyl) -11- (4-benzylpiperidino) methyl-6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 3
9) 11- (4-benzylpiperidino) methyl-obtained from compound g (Reference Example 7) in the same manner as in Reference Example 4.
6,11-Dihydrodibenzo [b, e] oxepin-2
According to the method of Example 14, 0.47 g of compound 39 was obtained using 0.54 g of carboxylic acid and 0.20 ml of 4- (2-aminoethyl) morpholine. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.1-1.6 (m, 5H), 2.4-2.5
(m, 6H), 2.49 (d, 2H, J = 5.3 Hz), 2.60 (t, 2H, J = 6.
9 Hz), 2.7-2.9 (m, 2H), 2.9-3.1 (m, 2H), 3.5-3.6
(m, 2H), 3.7-3.8 (m, 4H), 4.12 (t, 1H, J = 6.9 Hz),
4.96 and 5.56 (ABq, 2H, J = 14.0 Hz), 6.70 (brs, 1
H), 6.96 (d, 1H, J = 8.6 Hz), 7.0-7.3 (m, 9H), 7.50
(dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.72 (d, 1H, J = 2.3 H
z). According to the method of Example 3, 0.45 g of compound 39 and 0.44 g of dihydrochloride / hemihydrate of compound 39 are used.
Obtained. Melting point: 222 ° C (decomposition) IR (KBr tablet; cm ^-1 ): 2856, 1650, 1496, 1452, 110
3, 703.

Example 40 N- (2-morpholinoethyl)-(E) -11- [2-
(4-Benzylpiperidino) ethylidene] -6,11-
Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 40) According to the method of Example 14, (E) -11- [2- (4
-Benzylpiperidino) ethylidene] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 1.54 g and 4- (2-aminoethyl) morpholine.
Using 38 ml, 1.17 g of compound 40 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.3-1.7 (m, 6H), 2.5-2.6
(m, 6H), 2.60 (t, 2H, J = 6.1 Hz), 2.9-3.4 (m, 6H),
3.4-3.5-3.6 (m, 2H), 3.73 (t, 4H, J = 4.6 Hz), 4.5-
5.8 (brs, 2H), 6.26 (t, 1H, J = 6.8 Hz), 6.7 (brs, 1
H), 6.79 (d, 1H, J = 8.6 Hz), 7.1-7.4 (m, 9H). According to the method of Example 3, 0.98 g of compound 40 was used, and dihydrochloride. 0.84 g of hydrate was obtained. Melting point: 190-193 ℃ IR (KBr tablet; cm ^-1 ): 2926, 2360, 1649, 1605, 148
7, 1454, 1249, 1230.

Example 41 N- (2-morpholinoethyl)-(E) -11- [2-
(4-Benzylpiperidino) ethylidene] -6,11-
Dihydrodibenzo [b, e] oxepin-2-ylacetamide (Compound 41) According to the method of Example 1, (E) -11- [2- (4-
Benzylpiperidino) ethylidene] -6,11-dihydrodibenzo [b, e] oxepin-2-acetic acid 0.54 g
And 0.20 ml of 4- (2-aminoethyl) morpholine were used to obtain 0.47 g of compound 41. Melting point: 156-159 ° C IR (KBr tablet; cm ^-1 ): 3300, 2918, 1641, 1544, 148
9, 1118, 1012, 758, 700. 1 HNMR (δ, ppm, CDCl 3): 1.2-1.7 (m, 5H), 2.2-2.4
(m, 6H), 2.51 (d, 2H, J = 6.9 Hz), 2.8-3.0 (m, 2H),
3.2-3.3 (m, 2H), 3.3-3.4 (m, 4H), 3.48 (s, 2H), 4.7
-4.9 (brs, 1H), 5.4-5.6 (brs, 1H), 5.99 (brs, 1H),
6.16 (t, 1H, J = 6.7 Hz), 6.75 (d, 1H, J = 8.4 Hz), 7.
01 (dd, 1H, J = 2.1 Hz, 8.4 Hz), 7.1-7.4 (m, 10H).

Example 42 N- (2-morpholinoethyl) -11- [2- (4-benzyl-1-piperazinyl) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 42) In accordance with the method of Example 25, 11- [2- (4-benzyl-1-piperazinyl) ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid 1.0
0g and 4- (2-aminoethyl) morpholine 0.89m
1.02 g of compound 42 was obtained using 1. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 7H), 2.2-2.9
(m, 10H), 2.53 (d, 2H, J = 6.9 Hz), 3.2-3.5 (m, 4
H), 3.39 (t, 4H, J = 4.4 Hz), 3.50 (s, 2H), 3.9-4.0
(m, 1H), 5.48 and 5.58 (ABq, 2H, J = 16.8 Hz), 6.0
(brs, 1H), 6.9-7.4 (m, 12H). According to the method of Example 7, 1.03 g of the compound 42 was used, and the dioxalate. 9
6 g were obtained. Melting point: 164-166 ° C IR (KBr tablets; cm ^-1 ): 1719, 1702, 1635, 1492, 140
3, 1232, 1110.

Example 43 N- (2-morpholinoethyl) -11- [2- [4-
(2-Methoxyphenyl) -1-piperazinyl] ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 43) According to the method of Example 25, 11- [2- [4 -(2-
Methoxyphenyl) -1-piperazinyl] ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Compound 43 was added 1.82 using carboxylic acid 2.00 g and 4- (2-aminoethyl) morpholine 1.72 ml.
g was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.3-2.7 (m, 14H), 3.0-3.
2 (m, 4H), 3.5-3.6 (m, 2H), 3.71 (t, 4H, J = 4.6 Hz),
3.85 (s, 3H), 4.1-4.2 (m, 1H), 4.98 and 5.62 (AB
q, 2H, J = 14.0 Hz), 6.7 (brs, 1H), 6.8-7.1 (m, 5H),
7.1-7.3 (m, 4H), 7.48 (dd, 1H, J = 2.3 Hz, 8.3 Hz),
7.76 (d, 1H, J = 2.3 Hz). According to the method of Example 7, 0.91 g of the compound 43 was used, and the dioxalate.
0 g was obtained. Melting point: 170-172 ° C IR (KBr tablets; cm ^-1 ): 1638, 1608, 1497, 1402, 127
8, 1242, 1115, 718.

Example 44 N- (2-morpholinoethyl) -11- [2- [4-
(3-Methoxyphenyl) -1-piperazinyl] ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 44) According to the method of Example 25, 11- [2- [4 -(3-
Methoxyphenyl) -1-piperazinyl] ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Compound 44 0.21 using carboxylic acid 1.00 g and 4- (2-aminoethyl) morpholine 0.86 ml.
g was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.2-2.7 (m, 14H), 3.2-3.
3 (m, 4H), 3.5-3.6 (m, 2H), 3.73 (t, 4H, J = 4.6 Hz),
3.79 (s, 3H), 4.1-4.2 (m, 1H), 4.99 and 5.62 (AB
q, 2H, J = 14.0 Hz), 6.41 (dd, 1H, J = 2.3 Hz, 7.9 H
z), 6.46 (t, 1H, J = 2.3 Hz), 6.54 (dd, 1H, J = 2.3 Hz,
8.3 Hz), 6.7 (brs, 1H), 6.97 (d, 1H, J = 8.3 Hz), 7.
1-7.3 (m, 5H), 7.50 (dd, 1H, J = 2.3 Hz, 8.3 Hz), 7.
76 (d, 1H, J = 2.3 Hz). According to the method of Example 7, 0.21 g of compound 44 was used and 0.2 oxalate / 0.5 hydrate of compound 44 was used.
3 g were obtained. Melting point: 173-174 ℃ IR (KBr tablet; cm ^-1 ): 1648, 1600, 1494, 1230, 121
8, 1201.

Example 45 N- (2-morpholinoethyl) -11- [2- [4-
(4-Methoxyphenyl) -1-piperazinyl] ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 45) According to the method of Example 25, 11- [2- [4 -(4-
Methoxyphenyl) -1-piperazinyl] ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Compound 45 was added to 1.00 using carboxylic acid 1.00 g and 4- (2-aminoethyl) morpholine 0.86 ml.
g was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.3-2.6 (m, 14H), 3.11
(t, 4H, J = 4.9 Hz), 3.5-3.6 (m 2H), 3.71 (t, 4H, J =
4.6 Hz), 3.77 (s, 3H), 4.1-4.2 (m, 1H), 4.98 and
5.62 (ABq, 2H, J = 14.0 Hz), 6.7 (brs, 1H), 6.8-6.9
(m, 4H), 6.97 (d, 1H, J = 8.6 Hz), 7.2-7.3 (m, 4H),
7.48 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.75 (d, 1H, J = 2.3
Hz). According to the method of Example 7, 0.95 g of compound 45 was used and 0.9% of the dioxalate / 0.8 hydrate of compound 45 was added.
0 g was obtained. Melting point: 138-139 ° C IR (KBr tablet; cm ^-1 ): 1635, 1610, 1513, 1492, 140
3, 1245.

Example 46 N- (2-morpholinoethyl) -11- [2- [4-
(4-Chlorophenyl) -1-piperazinyl] ethyl]
-6,11-Dihydrodibenzo [b, e] oxepin-
2-Carboxamide (Compound 46) According to the method of Example 25, 11- [2- [4- (4-
Chlorophenyl) -1-piperazinyl] ethyl] -6,
0.96 g of compound 46 was obtained by using 1.00 g of 11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid and 0.85 ml of 4- (2-aminoethyl) morpholine. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.2-2.6 (m, 14H), 3.17
(t, 4H, J = 4.9 Hz), 3.5-3.6 (m, 2H), 3.71 (t, 4H, J
= 4.9 Hz), 4.0-4.1 (m, 1H), 4.98 and 5.62 (ABq, 2
H, J = 14.0 Hz), 3.7 (brs, 1H), 6.8-6.9 (m, 2H), 6.9
7 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 6H), 7.47 (dd, 1
H, J = 2.3 Hz, 8.3 Hz), 7.76 (d, 1H, J = 2.3 Hz). According to the method of Example 7, 0.87 g of the compound 46 was used and the dioxalate. .5 hydrate to 0.9
4 g were obtained. Melting point: 163-164 ° C IR (KBr tablets; cm ^-1 ): 1641, 1496, 1403, 1241, 123
2.

Example 47 N- (2-morpholinoethyl) -11- [2- [4-hydroxy-4- (3-trifluoromethylphenyl) piperidino] ethyl] -6,11-dihydrodibenzo [b, e ] Oxepin-2-carboxamide (Compound 4
7) According to the method of Example 25, 11- [2- [4-hydroxy-4- (3-trifluoromethylphenyl) piperidino] ethyl] -6,11-dihydrodibenzo [b,
e] 1.76 g of oxepin-2-carboxylic acid and 4- (2
Using 1.35 ml of -aminoethyl) morpholine, 1.04 g of compound 47 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.1-2.8 (m, 14H), 3.5-3.
6 (m, 2H), 3.71 (t, 4H, J = 4.6 Hz), 4.0-4.1 (m, 1
H), 4.99 and 5.62 (ABq, 2H, J = 13.9 Hz), 6.7 (brs,
1H), 6.97 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 4H), 7.4
-7.5 (m, 3H), 7.70 (d, 1H, J = 7.6 Hz), 7.77 (d, 1H,
J = 2.3 Hz), 7.8 (brs, 1H). According to the method of Example 1, 1.03 g of compound 47 was used and trituration was performed with ether to give the difumarate salt of compound 47.0.5. 1.02 g of a hydrate / ether adduct was obtained. Melting point: 124-125 ° C IR (KBr tablet; cm ^-1 ): 1637, 1573, 1494, 1330, 124
7, 1118, 983.

Example 48 N- (2-morpholinoethyl) -11- [2- [4-
(4-Fluorophenylcarbonyl) piperidino] ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 48) According to the method of Example 25, 11- [2- [4- ( 4-
Fluorophenylcarbonyl) piperidino] ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
Compound 1.48 was added 2.01 using 1.90 g of carboxylic acid and 1.58 ml of 4- (2-aminoethyl) morpholine.
g was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.8-2.6 (m, 16H), 2.8-3.
0 (m, 2H), 3.1-3.2 (m, 1H), 3.5-3.6 (m, 2H), 3.7-3.
8 (m, 4H), 4.0-4.1 (m, 1H), 4.98 and 5.61 (ABq, 2
H, J = 14.0 Hz), 6.7 (brs, 1H), 6.96 (d, 1H, J = 8.3 H
z), 7.1-7.2 (m, 6H), 7.50 (dd, 1H, J = 2.3 Hz, 8.6 H
z), 7.72 (d, 1H, J = 2.3 Hz), 7.9-8.0 (m, 2H). According to the method of Example 7, 0.33 g of the compound 48 was used to give 1.5 oxalic acid of the compound 48. 0.3 salt / dihydrate
1 g was obtained. Melting point: 121-123 ° C IR (KBr tablets; cm ^-1 ): 1635, 1598, 1494, 1228.

Example 49 N- (2-morpholinoethyl) -11- [2- [4-
[1- (4-Fluorophenyl) -1-hydroxymethyl] piperidino] ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 49) Compound 48, 1.01 g of methanol 20 ml solution Under ice cooling, 0.14 g of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent, ethyl acetate / triethylamine / methanol = 10/1/1) to give compound 49
73 g were obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.3-3.0 (m, 20H), 3.5-3.
6 (m, 2H), 3.72 (t, 4H, J = 4.1 Hz), 4.0-4.1 (m, 1
H), 4.3-4.4 (m, 1H), 4.96 and 5.59 (ABq, 2H, J = 14.
0 Hz), 6.7 (brs, 1H), 6.9-7.3 (m, 9H), 7.4-7.5 (m,
1H), 7.73 (d, 1H, J = 2.0 Hz). According to the method of Example 1, 0.64 g of the compound 49 was used to give the difumarate. 5
6 g were obtained. IR (KBr tablet; cm ^-1 ): 1704, 1640, 1603, 1492, 125
0, 1104.

Example 50 N- (2-morpholinoethyl) -11- [2- (4-acetamido-4-phenylpiperidino) ethyl] -6, -6
11-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 50) According to the method of Example 25, 11- [2- (4-acetamido-4-phenylpiperidino) ethyl] -6,11.
0.52 g of compound 50 was obtained by using 0.83 g of dihydrodibenzo [b, e] oxepin-2-carboxylic acid and 0.27 ml of 4- (2-aminoethyl) morpholine. Melting point: 189-191 ° C IR (KBr tablet; cm ^-1 ): 2930, 2815, 1650, 1639, 154
8, 1494, 1238, 1116, 759. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.8-2.0 (m, 2H), 1.85
(s, 3H), 2.07 (t, 4H, J = 4.0 Hz), 2.1-2.7 (m, 10H),
3.2-3.5 (m, 8H), 4.1-4.2 (m, 1H), 4.5 (brs, 1H),
5.00 and 5.61 (ABq, 2H, J = 13.9 Hz), 6.90 (d, 1H,
J = 8.2 Hz), 7.1-7.4 (m, 8H), 7.60 (dd, 1H, J = 2.1 H
z, 8.4 Hz), 7.7-7.8 (m, 2H), 8.2-8.3 (m, 1H).

Example 51 N- (2-morpholinoethyl) -11- [2- (4-diphenylmethyl-1-piperazinyl) ethyl] -6,1
1-Dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 51) According to the method of Example 25, 11- [2- (4-diphenylmethyl-1-piperazinyl) ethyl] -6,11-.
1.13 g of compound 51 was obtained by using 1.06 g of dihydrodibenzo [b, e] oxepin-2-carboxylic acid and 0.80 ml of 4- (2-aminoethyl) morpholine. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.2-2.6 (m, 18H), 3.5
(m, 2H), 3.71 (t, 4H, J = 4.6 Hz), 4.0-4.1 (m, 1H),
4.21 (s, 1H), 4.95 and 5.59 (ABq, 2H, J = 13.9 Hz),
6.6 (brs, 1H), 6.94 (d, 1H, J = 8.6 Hz), 7.1-7.4 (m,
14H), 7.46 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.69 (d, 1
H, J = 2.3 Hz). According to the method of Example 7, 1.06 g of the compound 51 was used to obtain 1.06 g of the dioxalate salt of the compound 51. Melting point: 218-220 ℃ IR (KBr tablet; cm ^-1 ): 1716, 1700, 1652, 1646, 154
0, 1490, 1452, 1405, 1280, 1230, 1201, 1106, 721.

Example 52 N- (2-morpholinoethyl) -11- [2- [4-
[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 5
2) According to the method of Example 1, 11- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethyl] -6,11-dihydrodibenzo [b, e].
Compound 5 was prepared by using 1.00 g of oxepin-2-carboxylic acid and 0.71 ml of 4- (2-aminoethyl) morpholine.
0.68 g of 2 was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.2-2.6 (m, 18H), 3.5-3.
6 (m, 2H), 3.71 (t, 4H, J = 4.0 Hz), 4.0-4.1 (m, 1
H), 4.20 (s, 1H), 4.96 and 5.59 (ABq, 2H, J = 13.9 H
z), 6.7 (brs, 1H), 6.94 (d, 1H, J = 8.6 Hz), 7.1-7.4
(m, 13H), 7.46 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.7
(m, 1H). According to the method of Example 7, 0.43 g of the compound 52 was used to obtain 0.41 g of the dioxalate salt of the compound 52. Melting point: 205-206 ℃ IR (KBr tablet; cm ^-1 ): 1641, 1633, 1608, 1490, 140
5, 1230, 1201, 721.

Example 53 N- (2-morpholinoethyl) -11- [3- [4-
[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] propyl] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxamide (Compound 5
3) According to the method of Example 25, 11- [3- [4-[(4
-Chlorophenyl) phenylmethyl] -1-piperazinyl] propyl] -6,11-dihydrodibenzo [b,
e] oxepin-2-carboxylic acid 1.00 g and 4- (2
-Aminoethyl) morpholine 0.58 ml was used to obtain 1.07 g of compound 53. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.3-1.5 (m, 2H), 1.9-2.0
(m, 2H), 2.0-2.6 (m, 16H), 3.5-3.6 (m, 2H), 3.72
(t, 4H, J = 4.6 Hz), 3.89 (s, 1H), 4.17 (s, 1H), 4.9
6 and 5.58 (ABq, 2H, J = 14.0 Hz), 6.7 (brs, 1H), 6.
94 (d, 1H, J = 8.6Hz), 7.1-7.4 (m, 13H), 7.45 (dd, 1
H, J = 2.3 Hz, 8.6 Hz), 7.69 (d, 1H, J = 2.3 Hz). According to the method of Example 7, 0.99 g of the compound 53 was used and the dioxalate salt of the compound 53. Pentahydrate 1.01
g was obtained. Melting point: 141-144 ° C IR (KBr tablet; cm ^-1 ): 1642, 1638, 1486, 1458, 140
3, 1234, 1203, 1103, 721.

Reference Example 1 11- (3-Hydroxypropyl) -6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid methyl ester (Compound a) Obtained by the method described in JP-A-5-202021. 11-
To a solution of 3.24 g of allyl-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid methyl ester in 200 ml of tetrahydrofuran was added 110 ml of a 1.0 M borane / tetrahydrofuran solution under ice-cooling, and 2.5 Stir for hours. The reaction solution was poured into ice water and stirred for 1.5 hours, then, 10% aqueous solution of 30% hydrogen peroxide and 1
2 ml of 0N sodium hydroxide aqueous solution was added and stirred for 1 hour. The reaction solution was adjusted to pH 4 with 4N hydrochloric acid and extracted with ethyl acetate. The extract is saturated aqueous sodium hydrogen carbonate,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent, hexane / ethyl acetate = 2/1) to obtain 2.27 g of compound a. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.5-1.6 (m, 3H), 2.1-2.3
(m, 2H), 3.6-3.7 (m, 2H), 3.88 (s, 1H), 3.9-4.0
(m, 1H), 4.99 and 5.62 (ABq, 2H, J = 13.9 Hz), 6.93
(d, 1H, J = 7.5 Hz), 7.2-7.3 (m, 4H), 7.79 (dd, 1H,
J = 2.0 Hz, 7.5 Hz), 7.89 (d, 1H, J = 2.0 Hz).

Reference Example 2 11-Formylmethyl-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid methyl ester (Compound b) 11-allyl-6,11-dihydrodibenzo [b, e]
Oxepin-2-carboxylic acid methyl ester 2.30
0.16 g of osmium tetroxide and then 6.70 g of sodium periodate were added to a mixture of g, 100 ml of ether and 100 ml of water, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water was added to the reaction solution and the mixture was extracted with ethyl acetate.
The extract was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent, hexane / ethyl acetate = 2/1) to obtain 1.87 g of compound b. ¹ HNMR (δ, ppm, CDCl ₃ ): 3.3-3.4 (m, 2H), 3.89
(s, 1H), 4.69 (t, 1H, J = 7.2 Hz), 5.08 and 5.53 (A
Bq, 2H, J = 14.5 Hz), 7.00 (d, 1H, J = 8.4 Hz), 7.1-7.
3 (m, 4H), 7.85 (dd, 1H, J = 2.2Hz, 8.7 Hz), 7.96
(d, 1H, J = 2.2 Hz), 9.72 (t, 1H, J = 1.2 Hz).

Reference Example 3 11- [2- (4-benzylpiperidino) ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Carboxylic acid methyl ester (Compound c) 0.75 ml of 4-benzylpiperidine in a solution of 0.56 g of the compound b obtained in Reference Example 2 in 20 ml of methanol,
Next, 0.59 g of sodium cyanoborohydride was added, the reaction solution was kept weakly acidic with a hydrochloric acid-ethanol solution (indicator, bromcresol green), and the mixture was stirred at room temperature for 22 hours. The reaction solution was made alkaline and extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent, hexane / ethyl acetate / triethylamine = 20/10 /
Purified in 1), 0.76 g of compound c was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.2-1.9 (m, 7H), 2.0-2.3
(m, 4H), 2.54 (d, 2H, J = 6.6 Hz), 2.8-2.9 (m, 2H),
3.88 (s, 3H), 4.0-4.1 (m, 1H), 4.96 and 5.63 (AB
q 2H, J = 13.7 Hz), 6.91 (d, 1H, J = 8.6 Hz), 7.1-7.3
(m, 9H), 7.78 (dd, 1H, J = 2.1 Hz, 8.6 Hz), 7.92 (d,
1H, J = 2.1 Hz).

Reference Example 4 11- [2- (4-benzylpiperidino) ethyl]-
6,11-Dihydrodibenzo [b, e] oxepin-2
-Carboxylic acid (Compound d) To a solution of 14.5 g of the compound c obtained in Reference Example 3 in 320 ml of ethanol was added 63 ml of 1N sodium hydroxide solution, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the pH was adjusted to 5 with 4N hydrochloric acid. The precipitated crystals were collected by filtration, and heated and triturated with ethanol to obtain 10.3 g of compound d. ¹ HNMR (δ, ppm, DMSO-d ₆ ): 1.2-1.9 (m, 7H), 2.0-
2.3 (m, 4H), 2.4-2.5 (m, 2H), 2.7-2.9 (m, 2H), 4.1
-4.2 (m, 1H), 5.00 and 5.62 (ABq, 2H, J = 13.9Hz),
6.89 (d, 1H, J = 8.3 Hz), 7.1-7.3 (m, 9H), 7.67 (dd,
1H, J = 2.0 Hz, 8.3 Hz), 7.87 (d, 1H, J = 2.0 Hz).

Reference Example 5 2-Methoxycarbonyl-6,11-dihydrodibenzo [b, e] oxepin-11-spiro-2'-oxirane (Compound e) Sodium hydride (60% oiliness) 1.53 g, dimethyl sulfoxide 50 ml and tetrahydrofuran 50 m
7.83 g of trimethylsulfonium iodide was added to the mixture of 1 under ice cooling, and the mixture was stirred at that temperature for 1 hour. A mixed solution of 6.86 g of 11-oxo-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid methyl ester 6.86 g of dimethyl sulfoxide 50 ml-tetrahydrofuran 50 ml was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. . After completion of the reaction, water was added to the reaction solution under ice cooling, and the mixture was extracted with ether. The extract was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.04 g of compound e. ¹ HNMR (δ, ppm, CDCl ₃ ): 3.00 and 3.23 (ABq, 2
H, J = 6.4 Hz), 3.88 (s, 3H), 5.09 and 5.75 (ABq, 2
H, J = 12.9 Hz), 6.85 (d, 1H, J = 8.4 Hz), 7.3-7.5 (m,
4H), 7.84 (dd, 1H, J = 2.2 Hz, 8.4 Hz), 8.17 (d, 1
H, J = 2.2 Hz).

Reference Example 6 11-formyl-6,11-dihydrodibenzo [b,
e] Oxepin-2-carboxylic acid methyl ester (compound f) To a solution of the compound e obtained in Reference Example 5 (4.02 g) in dichloromethane (100 ml) was added boron trifluoride / ether complex (0.18 ml) at -18 ^° C. Stir at room temperature for 20 hours. After completion of the reaction, water was added to the reaction solution and the mixture was extracted with dichloromethane. The extract was washed successively with 0.5N sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with isopropyl ether to give compound f 3.1.
9 g were obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 3.90 (s, 3H), 4.65 (s, 1
H), 4.89 and 5.30 (ABq, 2H, J = 13.9 Hz), 7.00 (d,
1H, J = 8.4 Hz), 7.3-7.4 (m, 4H), 7.91 (dd, 1H, J =
2.0 Hz, 8.4 Hz), 7.96 (d, 1H, J = 2.0 Hz), 9.92 (s,
1H).

Reference Example 7 11- (4-benzylpiperidino) methyl-6,11-
Dihydrodibenzo [b, e] oxepin-2-carboxylic acid methyl ester (Compound g) According to the method of Reference Example 3, the compound f obtained in Reference Example 6, 2.00 g, and 4-benzylpiperidine 2.50 ml.
Was used to obtain 0.70 g of compound g. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.4-1.6 (m, 5H), 1.9-2.2
(m, 2H), 2.48 (d, 1H, J = 6.9 Hz), 2.7-2.8 (m, 2H),
2.9-3.0 (m, 2H), 3.89 (s, 3H), 4.0-4.1 (m, 1H), 4.9
5 and 5.59 (ABq, 2H, J = 14.4 Hz), 7.1-7.3 (m, 10
H), 7.79 (dd, 1H, J = 2.0 Hz, 8.4 Hz), 7.92 (d, 1H,
J = 2.0 Hz).

Reference Example 8 11- (2-Aminoethyl) thio-6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid methyl ester (Compound h) 11-Methoxy-6,11-dihydrodibenzo [ b,
e] Oxepin-2-carboxylic acid methyl ester 10.
To a solution of 0 g of dichloromethane in 200 ml, at room temperature were added 2.80 ml of 2-aminoethylmercaptan-hydrochloride and 2.20 ml of boron trifluoride-ether complex, and the mixture was allowed to stand at room temperature for 2 minutes.
Stir for 0 hours. After the reaction was completed, 1N sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ether. The extract was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent, ethyl acetate / triethylamine = 20/1) to obtain 9.05 g of compound h. ¹ HNMR (δ, ppm, CDCl ₃ ): 1.48 (brs, 2H), 2.5-2.8
(m, 4H), 3.89 (s, 3H), 4.91 and 6.46 (ABq, 2H, J = 1
2.9 Hz), 6.86 (d, 1H, J = 8.6 Hz), 7.2-7.3 (m, 4H),
7.80 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 7.96 (d, 1H, J = 2.
3 Hz).

Reference Example 9 11- [2-[(2-methoxyphenyl) methylamino] ethyl] thio-6,11-dihydrodibenzo [b,
e] Oxepin-2-carboxylic acid methyl ester (Compound i) According to the method of Reference Example 3, using the compound h (2.23 g) obtained in Reference Example 8 and 1.64 ml of 2-anisaldehyde, the compound i was obtained. 2.85 g was obtained. ¹ HNMR (δ, ppm, CDCl ₃ ): 2.5-2.7 (m, 4H), 3.75
(s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.87 and 6.4
5 (ABq, 2H, J = 12.9 Hz), 4.97 (s, 1H), 6.85 (d, 1H,
J = 8.7 Hz), 6.9-7.0 (m, 2H), 7.1-7.3 (m, 6H), 7.79
(dd, 1H, J = 2.2 Hz, 8.7 Hz), 7.95 (d, 1H, J = 2.2 H
z).

Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. Compound 14 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Trace amount

Formulation Example 2 Powder A powder having the following composition is prepared by a conventional method. Compound 14 150 mg Lactose 280 mg

Formulation Example 3 Syrup A syrup having the following composition is prepared by a conventional method. Compound 14 100 mg Purified sucrose 40 g Ethyl p-hydroxybenzoate 40 mg Propyl p-hydroxybenzoate 10 mg Strawberry flavor 0.1 ml Water is added to make a total volume of 100 ml.

[0127]

INDUSTRIAL APPLICABILITY The present invention has a substance P antagonism and / or a bradykinin antagonism and is useful for treating and / or preventing various diseases such as allergy, asthma, inflammation, analgesia, autoimmune sickness and shock. A tricyclic compound or a pharmaceutically acceptable salt thereof is provided.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 31/47 ACF A61K 31/47 ACF 31/495 ABN 31/495 ABN 31/535 ABL 31/535 ABL ABM ABM AED AED 31/54 AAH 31/54 AAH 31/55 ABE 31/55 ABE C07D 337/12 C07D 337/12 405/12 211 405/12 211 213 213 405/14 211 405/14 211 213 213 217 217 453 / 02 453/02 // (C07D 405/12 211: 10 313: 12) (C07D 405/14 211: 10 213: 16 313: 12) (C07D 405/14 209: 10 211: 10 313: 12) (C07D 405/14 207: 08 211: 10 313: 12) (C07D 405/14 207: 323 211: 10 313: 12) (72) Inventor Chihiro Nosaka 1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture (72) Inventor Hiroshi Kase 3-35-18 Maehara-cho, Koganei-shi, Tokyo (72) Inventor Toshihide Ikemura 4352-1, Wakamatsu-cho, Mishima-shi, Shizuoka Prefecture (72) Inventor Takemori Omori 2-Fuyodai, Mishima-shi, Shizuoka Prefecture 14-3

Claims (8)

[Claims] 1. A compound of the formula (I)[Where CH is CH₂O, CH₂S, CH₂CH₂Or
CH = CH, k is an integer of 0 to 2, Y is OR
¹[Wherein, R¹Is (CH₂)_mR²{In the formula, R²Is replaced
Or unsubstituted aryl, substituted or unsubstituted complex
Ring group or NR^ThreeR^Four(Where R^ThreeAnd R^FourIs the same
Or differently represents hydrogen or lower alkyl),
m represents an integer of 0 to 6] or NR^FiveR
⁶(Where R^FiveRepresents hydrogen or lower alkyl, R⁶
Is R which has the same meaning as above¹Represents or R ^FiveAnd R⁶Are together
Becomes a substitution or non-formation formed by sandwiching a nitrogen atom.
Represents a substituted heterocyclic group), V¹And V²On the other hand
Is hydrogen and the other is S (CH₂)_n(In the formula, n is an integer of 2 to 4
Represents a number) or CH₂(CH₂)_q(In the formula, q is 0 to
Represents an integer of 4) or together together-CH
(CH₂)_{q '}(In the formula, q ′ represents an integer of 0 to 4)
And L is NR⁷(Where R⁷Is hydrogen or lower alkyl
Represents) or{In the formula, A is N, CH, C (OR⁸) (Where R is⁸Is water
Represents elementary or lower alkanoyl) or C (NH
R⁹) (Where R is⁹Represents hydrogen or lower alkanoyl
, R is an integer of 1 to 3, and M is C
O, CH (OH), CH-J (wherein J is a substitution or
Unsubstituted aryl or substituted or unsubstituted aralkyl
Or represents a single bond, p represents an integer of 0 to 6
Q is a substituted or unsubstituted aryl or substituted
Represents an unsubstituted aralkyl]
Substance or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein W is CH ₂ O. 3. Y is NR ⁵ R ⁶ (wherein R ⁵ and R ⁶
Is the same as defined above). 4. ^One of V ¹ and V ² is hydrogen and the other is S.
(CH _{2) n} (wherein, n the same meanings as defined above) The compound according to any one of claims 1 to 3 is. 5. ^One of V ¹ and V ² is hydrogen and the other is C
The compound according to claim 1, which is H ₂ (CH ₂ ) _q (wherein q has the same meaning as defined above). 6. The compound according to claim 1, wherein p is an integer of 1 to 6. 7. The compound according to claim 4, wherein p is an integer of 1 to 6. 8. The compound according to claim 5, wherein p is an integer of 1 to 6.