JPH06116273A - Tricyclic compound - Google Patents

Abstract

PURPOSE:To obtain a new compound having excellent antihistaminic action and antiallergic action and useful for allergic diseases and bronchial asthma, etc. CONSTITUTION:A compound of formula I [R<1> is lower alkyl or lower alkoxy; R<2> is H or lower alkyl; Y is (lower alkyl-substituted)1-5C alkylene] and its pharmacologically permissible salt, e.g. [4(5,1 l-dihydro-8- methylbenz[b]oxepino[4,3-b]pyridin-11-ylidene)piperidino]acetic acid ethyl ester. This compound of formula I is obtained by reacting, e.g. a compound of formula II with a compound of the formula Z-Y-CO2R<3> (R<3> is lower alkyl; Z is halogen) without or in an organic solvent or in the presence or absence of chlorine as a dehydrohalogenation agent to carry out N-alkylation of the compound of formula II and, as necessary, hydrolyzing the resultant product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a novel tricyclic compound having antihistamine action and antiallergic action and useful as a therapeutic agent for bronchial asthma, allergic rhinitis, skin diseases, urticaria and the like. It relates to a pharmacologically acceptable salt.

[0002]

BACKGROUND ART Several antihistamine agents or antiallergic agents having a tricyclic skeleton are known so far,
For example, as a tricyclic compound having a pyridine ring, azatadine (The Merck Index
x), 11th edition, 917] and loratadine [The Merck Index, 11th edition, 5455] and the like, which are used clinically.

Further, in JP-A-3-504012, a compound having a mother nucleus similar to that of the compound of the present invention and having a substituent such as an acetyl group introduced at the 1-position of the piperidine ring is a therapeutic agent for allergic diseases. However, no compound such as the compound of the present invention having a carboxyalkyl group introduced therein has been known so far.

[0004]

A number of antihistamines have been developed so far and used for the treatment of allergic skin diseases and rhinitis, but unfavorable pharmacological actions (central depressant action, anticholinergic action, etc.) Therefore, it is not always satisfactory in terms of safety such as causing side effects such as drowsiness, sedation, dry mouth, and mydriasis, and there are still problems. Under these circumstances, development of new antihistamines and antiallergic agents in which these problems are ameliorated is desired in the clinical field.

[0005]

Means for Solving the Problems As a result of intensive studies in view of the above circumstances, the present inventors have found that the novel tricyclic compound according to the present invention has a strong antihistamine action and an antiallergic action, and They have found that they are useful as antihistamines and antiallergic agents with few side effects such as central inhibitory action, and completed the present invention.

That is, the present invention has the following general formula (I):

[Chemical 2] (In the formula, R ¹ represents a lower alkyl group or a lower alkoxy group, R ² represents a hydrogen atom or a lower alkyl group, and Y represents a C ₁ -C ₅ alkylene group which may be substituted with a lower alkyl group.) The present invention relates to a novel tricyclic compound represented by and a pharmacologically acceptable salt thereof.

In the general formula (I) of the present invention, R ¹ and R
^The lower alkyl group represented by ² and the lower alkyl group which may be substituted on the alkylene group represented by Y include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group. , Sec-butyl group, tert
Examples of the lower alkoxy group represented by R ¹ such as butyl group include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group and the like. .

The compound of the present invention represented by the general formula (I) can be converted into a pharmacologically acceptable salt, if desired, or a base or an acid can be liberated from the produced salt. it can. Examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) of the present invention include acid addition salts and alkali addition salts. Examples of the acid addition salts include hydrochloric acid and hydrobromic acid. , Mineral acid such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, p- Organic acid salts such as toluene sulfonic acid and 10-camphor sulfonic acid
Examples of alkali addition salts include inorganic alkali salts such as sodium, potassium, calcium, ammonium, ethylenediamine, ethanolamine,
Examples thereof include salts of organic bases such as N, N-dialkylethanolamine and triethanolamine.

The compound represented by the general formula (I) of the present invention is an optical isomer based on asymmetry and, in some cases,
Although diastereomers may exist, the invention includes these isomers and mixtures thereof.

Preferred examples of the tricyclic compound of the present invention include the following compounds, but the present invention is not limited to these examples. (1) Ethyl 4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] acetate (2) [4- (5,11-Dihydro- 8-Methylbenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] acetic acid (3) 3- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-] b] pyridine-11-
(Ylidene) piperidino] ethyl propionate (4) 3- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] propionic acid (5) 4- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] butyric acid ethyl (6) 4- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] butyric acid (7) 5- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] ethyl valerate (8) 5- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] valeric acid (9) 6- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-
Ethyl (ylidene) piperidino] hexanoate (10) 6- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11
-Ylidene) piperidino] hexanoic acid (11) [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] ethyl acetate (12) [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] acetic acid (13) 3- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
Ethyl 1-ylidene) piperidino] propionate (14) 3- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
1-ylidene) piperidino] propionic acid (15) 4- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
Ethyl 1-ylidene) piperidino] butyrate (16) 4- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
1-ylidene) piperidino] butyric acid (17) 5- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
1-Ylidene) piperidino] valerate ethyl (18) 5- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
1-ylidene) piperidino] valeric acid (19) 6- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
Ethyl 1-ylidene) piperidino] hexanoate (20) 6- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-1
1-ylidene) piperidino] hexanoic acid

The novel tricyclic compound represented by the above general formula (I) of the present invention can be produced by the following method.

That is, the following general formula (II)

[Chemical 3] (Wherein R ¹ has the same meaning as described above) and the following general formula (III) Z—Y—CO ₂ R ³ or CH ₂ ═CHCO ₂
R ³ (III) (wherein Y represents the same meaning as described above, R ³ represents a lower alkyl group, and Z represents a halogen atom), and the compound is dehalogenated in a solvent-free or organic solvent. N- by reacting in the presence or absence of a base as a hydrogenating agent
After alkylation, it can be produced by hydrolysis if necessary.

Examples of the organic solvent used for N-alkylation in the present production method include alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and n-butanol, and aromatic solvents such as benzene, toluene and xylene. Hydrocarbon solvent, tetrahydrofuran,
Aprotic polar solvents such as 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, and dimethylsulfoxide are listed, and examples of the base used include sodium metal and hydrogen. And sodium alkoxide, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc., and the reaction range from under ice cooling to the reflux temperature of the solvent. Done in.

Hydrolysis is carried out using an acid or an alkali. Acids such as hydrochloric acid and sulfuric acid are used for acidic hydrolysis, and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like are used for alkaline hydrolysis. An alkali can be used, and these acids or alkalis can be used in the reaction as an aqueous solution, a solution of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, or the like in a water-containing organic solvent. The reaction is carried out in the range from ice-cooling to the reflux temperature of the solvent.

The compound represented by the general formula (II) used as a starting material in the present production method is a novel compound and can be produced as shown in the following scheme (Chemical formula 4). Described in the example.

[0016]

[Chemical 4] (In the formula, R ¹ represents the same meaning as described above, R ⁴ represents a lower alkyl group which may be substituted with a halogen atom, and Z ′ and Z ″ represent a halogen atom.)

The above-mentioned general formula (I) produced in this manner
The drug containing the novel tricyclic compound represented by the formula (1) and a pharmacologically acceptable salt thereof as an active ingredient is usually orally administered in tablets, capsules, powders, fine granules, granules, syrups, etc. It is administered as an agent, an injection, a suppository, an eye drop, an eye ointment, an ear drop, an external skin preparation, or the like. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral agents and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl) Pharmaceutical ingredients such as methylcellulose, polyvinylpyrrolidone, etc., lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), bases (polyethylene glycol, hard fat, etc.), For injections, eye drops, and ear drops, solubilizers or solubilizers (water for injection, physiological saline, propylene glycol, etc.) that can form a water-based or dissolution-in-use dosage form, pH adjusters (inorganic) Or organic acid or base), isotonic Formulation components such as agents (salt, glucose, glycerin, etc.), stabilizers, etc. In the case of ophthalmic ointments and external skin preparations, formulation components suitable for ointments, creams, and patches (white petrolatum,
Macrogol, glycerin, cotton cloth, etc.) are used.

The dose of this drug to a patient to be treated depends on the symptoms of the patient, but in the case of an oral administration, which is usually an adult, the daily dose is 1 to 50.
It is about 0 mg.

[0019]

The present invention will be described below with reference to reference examples and examples, but the present invention is not limited to the specific details of these examples.

Reference Example 1 2-Cyano-3- (3-methylphenoxymethyl) pyridine 2-Cyano-3-methylpyridine 50.0 g, N-bromosuccinimide 83.0 g, benzoyl peroxide 0.5
A mixture of g and 1 L of 1,2-dichloroethane was heated under reflux for 2.5 hours. After cooling, the reaction solution was washed successively with an aqueous potassium carbonate solution and water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 110 g of a yellowish brown liquid. Metallic sodium 6.9
A solution of sodium ethoxide prepared from 0 g and 120 ml of absolute ethanol was added to m-cresol 3 under stirring with ice cooling.
1.4 ml was added dropwise. After stirring at room temperature for 1 hour, 110 g of the yellowish brown liquid obtained above was added dropwise under stirring with ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was mixed with water 20
0 ml was added and extracted with 400 ml of isopropyl ether. The organic layer is 10% sodium hydroxide aqueous solution and 10%
It was washed with hydrochloric acid three times each, and subsequently with 10% aqueous potassium carbonate solution and water. After drying on sodium sulfate, the solvent was distilled off under reduced pressure to obtain 90.0 g of yellowish brown crystals. This is purified by column chromatography (silica gel, benzene),
51.0 g of a slightly yellow viscous liquid was obtained. IR spectrum ν (liq) cm ⁻¹ : 2236 NMR spectrum δ (CDCl ₃ ) ppm: 2.35 (3H, s), 5.
29 (2H, s), 6.77-6.87 (3H, m), 7.21 (1H, t, J = 8Hz), 7.56 (1H,
dd, J = 8,5Hz), 8.07 (1H, dd, J = 8,2Hz), 8.67 (1H, dd, J = 5,2H
z) High resolution mass spectrum: C ₁₄ H ₁₂ N ₂ O theoretical value m / z: 224.0950 experimental value m / z: 224.0937

The compound of Reference Example 2 was obtained according to the method of Reference Example 1.

Reference Example 2 2-Cyano-3- (3-methoxyphenoxymethyl) pyridine Properties Colorless prismatic crystal (AcOEt) Melting point 76-77 ° C. Elemental analysis value C ₁₄ H ₁₂ N ₂ O ₂ theoretical value C, 69.99; H , 5.03; N, 11.66 Experimental value C, 70.10; H, 4.98; N, 11.80

Reference Example 3 5,11-Dihydro-8-methylbenz [b] oxepino [4,3-b] pyridin-11-one To 200 ml of trifluoromethanesulfonic acid, 2-cyano-3- (3 -Methylphenoxymethyl)
50.0 g of pyridine was added dropwise. After stirring at room temperature for 3 hours, the reaction solution was poured into 600 ml of ice water, 50 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 days. The precipitated crystals were collected by filtration, 1
It was made alkaline by adding a 0% sodium hydroxide aqueous solution. The crystals are collected by filtration, washed with isopropyl ether,
39.0 g of light brown crystals were obtained. Recrystallization from ethyl acetate gave slightly yellow prism crystals having a melting point of 135.5 to 136.5 ° C. Elemental analysis value C ₁₄ H ₁₁ NO ₂ theoretical value C, 74.65; H, 4.92; N, 6.22 experimental value C, 74.71; H, 5.00; N, 6.10

The compound of Reference Example 4 was obtained according to the method of Reference Example 3.

Reference Example 4 5,11-Dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridin-11-one Properties slightly yellow crystal (AcOEt) Melting point 126-127 ° C. Elemental analysis value C ₁₄ H ₁₁ NO ₃ theoretical value C, 69.70; H, 4.60; N, 5.81 experimental value C, 69.78; H, 4.57; N, 5.53

Reference Example 5 5,11-Dihydro-8-methyl-11- (1-methyl-4-piperidinyl) benz [b] oxepino [4,3]
-B] Pyridin-11-ol 4-chloro-1-methylpiperidine 44.9 g, scraped magnesium 8.17 g and anhydrous tetrahydrofuran 29
To a Grignard reagent solution prepared from 0 ml, while stirring under ice cooling, 5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridin-11-one 37.9 g was added.
Was added in small portions. After stirring for 2 hours under ice cooling, 354 g of a 15% -ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography [silica gel, dichloromethane: methanol (30:
1)] to obtain 22.6 g of light brown crystals. Recrystallization from ethyl acetate gave pale brown prism crystals having a melting point of 137 to 139 ° C. Elemental analysis value C ₂₀ H ₂₄ N ₂ O ₂ theoretical value C, 74.05; H, 7.46; N, 8.63 experimental value C, 73.97; H, 7.36; N, 8.63

According to the method of Reference Example 5, the compound of Reference Example 6 was obtained.

Reference Example 6 5,11-Dihydro-8-methoxy-11- (1-methyl-4-piperidinyl) benz [b] oxepino [4,4]
3-b] Pyridin-11-ol Properties Colorless prismatic crystal (AcOEt) Melting point 136-139 ° C Elemental analysis value C ₂₀ H ₂₄ N ₂ O ₃ theoretical value C, 70.43; H, 7.09; N, 8.23 Experimental value C, 70.57 H, 7.11; N, 8.23

Reference Example 7 5,11-Dihydro-8-methyl-11- (1-methylpiperidin-4-ylidene) benz [b] oxepino [4,3-b] pyridine hydrochloride trifluoromethanesulfonic acid 60. A small amount of 22.1 g of 2,11-dihydro-8-methyl-11- (1-methyl-4-piperidinyl) benz [b] oxepino [4,3-b] pyridin-11-ol was added to 2 ml of the mixture at room temperature with stirring. Added one by one. After stirring at room temperature for 1 hour, the reaction solution was poured into ice water. After adding potassium carbonate to adjust the pH to 10 to 11, the mixture was extracted with dichloromethane. The dichloromethane layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, dichloromethane: methanol (30: 1 → 10: 1)],
18.7 g of a light brown amorphous solid was obtained. According to a conventional method, a hydrochloride is obtained and then recrystallized from isopropanol to give a melting point of 2
Colorless needle crystals of 38 to 241 ° C. (decomposition) were obtained. Elemental analysis _{C 20 H 22 N 2 O ·} HCl · H 2 O Theoretical value C, 66.56; H, 6.98; N, 7.76 Found C, 66.71; H, 6.82; N, 7.68

The compound of Reference Example 8 was obtained according to the method of Reference Example 7.

Reference Example 8 5,11-Dihydro-8-methoxy-11- (1-methyl-4-piperidinyl) benz [b] oxepino [4,4]
3-b] Pyridine / hydrochloride Properties Colorless needle crystals (iso-PrOH) Melting point 248 to 250 ° C Elemental analysis value C ₂₀ H ₂₂ N ₂ O ₂ · HCl 5 / 2H ₂ O theoretical value C, 59.51; H, 6.99; N, 6.94 experimental value C, 59.14; H, 6.62; N, 6.83

Reference Example 9 Ethyl 4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidinocarboxylate 114 ml of ethyl chlorocarbonate and 1,2- To a mixture of 50 ml of dichloroethane, under stirring at room temperature, 5,11-dihydro-
A solution of 17.82 g of 8-methyl-11- (1-methylpiperidine-4-ylidene) benz [b] oxepino [4,3-b] pyridine in 80 ml of 1,2-dichloroethane was added dropwise. Subsequently, 25 ml of triethylamine was added dropwise, and the reaction solution was heated under reflux for 7 hours. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography [silica gel, dichloromethane → dichloromethane: methanol (50:
1)] to obtain 18.1 g of a light brown amorphous solid. IR spectrum ν (liq) cm ⁻¹ : 1694 NMR spectrum δ (CDCl ₃ ) ppm: 1.26 (3H, t, J = 7
Hz), 2.24 (3H, s), 2.18-2.24 (1H, m), 2.46-2.69 (3H, m), 3.0
6-3.29 (2H, m), 3.72-3.92 (2H, m), 4.15 (2H, q, J = 7Hz), 4.82
(1H, d, J = 12.5Hz), 5.59 (1H, d, J = 12.5Hz), 6.63 (1H, s), 6.7
0 (1H, d, J = 8Hz), 6.98 (1H, d, J = 8Hz), 7.22 (1H, dd, J = 7.5,5H
z), 7.67 (1H, dd, J = 7.5,1.5Hz), 8.53 (1H, dd, J = 5,1.5Hz) High resolution mass spectrum: C ₂₂ H ₂₄ N ₂ O ₃ theoretical value m / z: 364.1783 Experimental value m / z: 364.1787

The compound of Reference Example 10 was obtained according to the method of Reference Example 9.

Reference Example 10 4- (5,11-dihydro-8-methoxybenz [b]]
Oxepino [4,3-b] pyridine-11-ylidene)
Ethyl piperidinocarboxylate Properties Light brown amorphous solid IR spectrum ν (KBr) cm ^-1 : 1696 NMR spectrum δ (CDCl ₃ ) ppm: 1.26 (3H, t, J = 7
Hz), 2.25-2.33 (1H, m), 2.48-2.69 (3H, m), 3.05-3.13 (1H,
m), 3.22-3.30 (1H, m), 3.73 (3H, s), 3.75-3.90 (2H, m), 4.15
(2H, q, J = 7Hz), 4.84 (1H, d, J = 12Hz), 5.60 (1H, d, J = 12Hz),
6.35 (1H, d, J = 2.5Hz), 6.48 (1H, dd, J = 8.5,2.5Hz), 7.00 (1
H, d, J = 8.5Hz), 7.22-7.30 (1H, m), 7.68-7.74 (1H, m), 8.55
(1H, dd, J = 5,2Hz) High resolution mass spectrum: C ₂₂ H ₂₄ N ₂ O ₄ Theoretical value m / z: 380.1736 Experimental value m / z: 380.1733

Reference Example 11 5,11-Dihydro-8-methyl-11- (4-piperidylidene) benz [b] oxepino [4,3-b] pyridine hydrochloride 5,11-dihydro-8-methyl-11 -(1-Methylpiperidine-4-ylidene) benz [b] oxepino [4,3-b] pyridine 18.0 g, potassium hydroxide 2
A mixture of 7.7 g and 110 ml isopropanol was heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 14.6 g of a light brown oily substance. After converting to hydrochloride by a conventional method, it is recrystallized from ethanol and has a melting point of 290 to
Light pink crystals at 294 ° C (decomposition) were obtained. Elemental analysis value C ₁₉ H ₂₀ N ₂ O · HCl theoretical value C, 69.40; H, 6.44; N, 8.52 experimental value C, 69.10; H, 6.43; N, 8.49

According to the method of Reference Example 11, Reference Example 12
Was obtained.

Reference Example 12 5,11-Dihydro-8-methoxy-11- (4-piperidylidene) benz [b] oxepino [4,3-b] pyridine Properties Light brown crystals (AcOEt) Melting point 168-170 ° C Elemental analysis Value C ₁₉ H ₂₀ N ₂ O ₂ 1 / 2H ₂ O Theoretical value C, 71.90; H, 6.67; N, 8.83 Experimental value C, 72.16; H, 6.48; N, 8.83

Example 1 Ethyl 3- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] propionate 5,11-dihydro-8 A mixture of -methyl-11- (4-piperidylidene) benz [b] oxepino [4,3-b] pyridine 2.50 g, ethyl acrylate 1.85 ml and ethanol 20 ml was heated under reflux for 8.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography [silica gel, dichloromethane-methanol (50: 1 → 1.
0: 1)] to obtain 2.31 g of a light brown oily substance. IR spectrum ν (liq) cm ⁻¹ : 1734 NMR spectrum δ (CDCl ₃ ) ppm: 1.25 (3H, t, J = 7
Hz), 2.03-2.88 (12H, m), 2.23 (3H, s), 4.13 (2H, q, J = 7Hz),
4.81 (1H, d, J = 12.5Hz), 5.61 (1H, d, J = 12.5Hz), 6.61 (1H,
s), 6.68 (1H, d, J = 8Hz), 6.98 (1H, d, J = 8Hz), 7.19 (1H, dd, J =
7.5,5Hz), 7.66 (1H, dd, J = 7.5,1.5Hz), 8.52 (1H, dd, J = 5,1.
5Hz) High resolution mass spectrum: C ₂₄ H ₂₈ N ₂ O ₃ theoretical value m / z: 392.2100 experimental value m / z: 392.2094

According to the method of Example 1, the compound of Example 2 was obtained.

Example 2 Ethyl 3- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] propionate Properties Brown oil IR spectrum ν (liq) cm ⁻¹ : 1734 NMR spectrum δ (CDCl ₃ ) ppm: 1.25 (3H, t, J =
7.5Hz), 2.00-2.89 (12H, m), 3.72 (3H, s), 4.14 (2H, q, J = 7.5
Hz), 4.81 (1H, d, J = 12.5Hz), 5.61 (1H, d, J = 12.5Hz), 6.34 (1
H, d, J = 2.5Hz), 6.46 (1H, dd, J = 8.5,2.5Hz), 7.00 (1H, d, J =
8.5Hz), 7.20 (1H, d, J = 7.5,5Hz), 7.66 (1H, dd, J = 7.5,2Hz),
8.53 (1H, d, J = 5,2Hz) High resolution mass spectrum: C ₂₄ H ₂₈ N ₂ O ₄ theoretical value m / z: 408.2049 experimental value m / z: 408.2038

Example 3 Ethyl 4- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] butyrate 5,11-dihydro-8- Methyl-11- (4-piperidylidene) benz [b] oxepino [4,3-b] pyridine 2.50 g, ethyl bromobutyrate 2.50 g, potassium carbonate 1.77 g and N, N-dimethylformamide 2
0 ml of the mixture was stirred at 70 ° C. for 4 hours. Water 6 in the reaction solution
0 ml was added and extracted with ether. The extract was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, dichloromethane: methanol (50: 1 → 10: 1)] to obtain 2.41 g of a light brown oily substance. IR spectrum ν (liq) cm ⁻¹ : 1732 NMR spectrum δ (CDCl ₃ ) ppm: 1.25 (3H, t, J = 7
Hz), 2.23 (3H, s), 1.75-2.89 (14H, m), 4.12 (2H, q, J = 7Hz),
4.80 (1H, d, J = 12.5Hz), 5.61 (1H, d, J = 12.5Hz), 6.61 (1H,
s), 6.68 (1H, d, J = 8Hz), 6.69 (1H, d, J = 8Hz), 7.19 (1H, dd, J =
7.5,5Hz), 7.65 (1H, dd, J = 7.5,1.5Hz), 8.52 (1H, dd, J = 5,1.
5Hz) High resolution mass spectrum: C ₂₅ H ₃₀ N ₂ O ₃ theoretical value m / z: 406.2256 experimental value m / z: 406.2264

Example 4 3- [4- (5,11-dihydro-8-methylbenzo [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] propionic acid 3- [4- (5 A solution of 2.12 g of ethyl 11-dihydro-8-methylbenzo [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] propionate in 20 ml of methanol was stirred at room temperature under stirring at room temperature, and 5.4 ml of 2N sodium hydroxide solution was added. Was added and the mixture was heated under reflux for 1 hour. The reaction solution was neutralized with 10% hydrochloric acid and then dried under reduced pressure. The residue was extracted with a mixed solution of ethanol and dichloromethane, and the extract was concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol to obtain pale pink prism crystals having a melting point of 125 to 127 ° C. IR spectrum ν (liq) cm ⁻¹ : 1616 NMR spectrum δ (DMSO-d ₆ ) ppm: 2.18 (3H, s),
2.09-2.23 (2H, m), 2.23-2.40 (2H, m), 2.37 (2H, t, J = 7Hz),
2.40-2.80 (4H, m), 2.60 (2H, t, J = 7Hz), 4.93 (1H, d, J = 12.5H
z), 5.49 (1H, d, J = 12.5Hz), 6.58 (1H, s), 6.68 (1H, dd, J = 7.
5,1.5Hz), 6.90 (1H, d, J = 7.5Hz), 7.31 (1H, dd, J = 7.5,5Hz),
7.86 (1H, dd, J = 7.5,1.5Hz), 8.49 (1H, dd, J = 5,1.5Hz) High resolution mass spectrum: C ₂₂ H ₂₄ N ₂ O ₃ theoretical value m / z: 364.1787 experimental value m / z: 364.1786

According to the method of Example 4, the compounds of Examples 5 and 6 were obtained.

Example 5 4- [4- (5,11-dihydro-8-methylbenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] butyric acid / hydrochloride Properties Pale yellow needle crystals (MeOH-Et ₂ O) Melting point 246 to 249 ° C. (decomposition) Elemental analysis value C ₂₃ H ₂₆ N ₂ O ₃ .HCl.1 / 4H ₂ O theoretical value C, 65.86; H, 6.61; N, 6.68 experimental value C , 66.07; H, 6.57; N, 6.66

Example 6 3- [4- (5,11-dihydro-8-methoxybenz [b] oxepino [4,3-b] pyridine-11-ylidene) piperidino] propionic acid Properties colorless needle crystals (EtOH ) mp 132 to 135 ° C. elemental analysis _{C 22 H 24 N 2 O 4} · 7 / 4H 2 O theoretical value C, 64.17; H, 6.73; N, 6.81 Found C, 64.33; H, 6.58; N, 6.97

[0045]

INDUSTRIAL APPLICABILITY The novel tricyclic compound represented by the above general formula (I) and the pharmaceutically acceptable salt thereof are
Has excellent antihistamine and antiallergic effects,
Moreover, since it does not show side effects such as central depressant action,
It is extremely useful as a therapeutic agent for various allergic diseases and bronchial asthma.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroyuki Nishino 23-14 Matsuda, Aratsu-cho, Katsuyama-shi, Fukui Prefecture (72) Inventor Makoto Takeshita 1-3-14, Tachikawa-cho, Katsuyama-shi, Fukui Prefecture

Claims (1)

[Claims] 1. The following general formula: (In the formula, R ¹ represents a lower alkyl group or a lower alkoxy group, R ² represents a hydrogen atom or a lower alkyl group, and Y represents a C ₁ -C ₅ alkylene group which may be substituted with a lower alkyl group.) And a pharmacologically acceptable salt thereof.