WO1994008964A1 - N-phenethylazepine derivative and use thereof - Google Patents

Abstract

A compound represented by general formula (I) or a nontoxic salt thereof, and a remedy for diseases wherein sigma receptor participates containing the same as the active ingredient, wherein the nitrogenous ring B represents 3,3,5,5-tetramethylhexahydro-1H-azepin-1-yl, 3,3,5-trimethylhexahydro-1H-azepin-1-yl, 4,4-dimethylhexahydro-1H-azepin-1-yl, 1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl, 9-azabicyclo[3.3.2]decan-9-cyl or 3-azabicyclo[3.2.2]nonan-3-yl; R represents hydrogen, halogen, hydroxy, nitro or amino; and A represents C2-C3 saturated or unsaturated alkylene. The compound and nontoxic salt thereof have a high specific affinity for sigma receptor and scarcely any affinity for other receptors, thus being utilizable for treating diseases wherein sigma receptor participates, such as schizophrenia.

Description

 Specification

 N-phenethylazepine derivatives and their uses

 The present invention relates to a novel azepine derivative having an activity of specifically binding to a sigma receptor (σ receptor) and a pharmaceutical use thereof. Conventional technology

 It is known that dopamine nervous system function in the brain is overactive in schizophrenic patients. Therefore, conventional anti-schizophrenia drugs have been developed to block dopamine receptors, and typical examples include haloperidol and chlorpromazine. However, these conventional anti-schizophrenia drugs frequently cause extrapyramidal side effects such as Parkinson's symptoms, akathisia, and acute dystonia, and also cause refractory late-onset dyskinesia by chronic administration. It has been known. In addition, there are many cases in which these conventional anti-schizophrenia drugs do not improve.

 Recently, Rimukabul (Japanese Patent Application Laid-Open No. 55-64585) and Β Μ Υ-1482 (UK Patent No. 2 155 9 225) have been recently developed as anti-schizophrenic drugs having few side effects. Developments have been advanced, and all of these have been found to have affinity for the receptor. However, the affinity and specificity of these compounds for Recebu Yuichi were not sufficient. Problems to be solved by the invention

There is a need for the development of a new type of anti-schizophrenic drug that does not have extrapyramidal side effects and has a specific affinity for the receptor via the sigma receptor. Means for solving the problem

 The present inventors have synthesized various compounds, and have searched extensively for their pharmacological actions. The azepine derivative represented by the following general formula (1) has a high affinity to all receptors, It has been found that it shows almost no affinity for this receptor.

 The present invention has been completed based on the above findings. That is, the present invention provides a compound represented by the general formula (1):

R

(Wherein the nitrogen-containing ring B is 3,3,5,5-tetramethylhexahydro-1H-azepine-11-yl, 3,3,5-trimethylhexahydro-1H-azepine-11-yl) , 4,4-Dimethylhexahydro-1H-azepine-11-yl or 1,3,3-trimethyl-6-azabicyclo [3.2.1] octane-16-yl, 9-azabicyclo [3.3.2] decane One 9-yl or 3-azabicyclo [3.2.2] nonane-3-yl group; R represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group or an amino group, and A has 2 carbon atoms ~ 3 saturated or unsaturated alkylene groups) or a non-toxic salt thereof.

 The present invention also provides a therapeutic agent for a disease associated with σ-receptor, which comprises the formula (1) or a non-toxic salt thereof as an active ingredient.

Furthermore, the present invention provides a therapeutic agent for schizophrenia, which comprises the general formula (1) or a non-toxic salt thereof as an active ingredient. The compound (1) of the present invention has, for example, the general formula (2)

(Wherein the nitrogen-containing ring B has the same meaning as described above) and a general formula (3)

(3)

(In the formula, represents a hydrogen atom, a halogen atom, a nitro group or a protected amino group, A represents a saturated or unsaturated alkylene group having 2 to 3 carbon atoms, X represents a reactive organic sulfonyloxy group or a halogen atom. The reactive derivative of the formula (3) is reacted in an inert organic solvent in the presence of a base. When R, in the general formula (3) is a protected amino group, It can be obtained by removing a protecting group.

Among the above starting materials, the compound represented by the general formula (2) is a known compound and represented by the following formulas (21) to (26). 3,3,5,5-tetramethylhexahydro-1H-azepine (21) and 4,4-dimethylhexahydro-1H-azepine (22) are available from Tetrahedr 0 n, 37,107 1 9 8 1) According to the method described, 9-azabicyclo [3.3.2] decane (25) can be synthesized from bicyclo [3.3.1] nonane-oneone in two steps. . 3,3,5-trimethylhexahydro-1H-azepine (23), 1,3,3-trimethyl-1-azabicyclo [3.2.1] octane (24) and 3-azabicyclo [3.2.2] Nonane (26) is a commercially available compound. And easily available,

(21) (22)

(23) (24)

 (25) (26) Of the above reactive derivatives (3), the sulfonyl derivative has the general formula (4)

(Wherein and A have the same meaning as described above), in a dry inert reaction solvent such as methylene chloride, methanesulfonyl chloride, The halogenated derivative of the reactive derivative (3) obtained by sulfonylation with p-toluenesulfonyl chloride or the like can be obtained by converting the alcohol (4) into a dry inert reaction solvent such as methylene chloride in thionyl chloride. It is obtained by halogenation with a halogenating agent such as.

 The alcohol (4) is a known substance, for example, phenethyl alcohol, 0 (m or p) —fluorophenethyl alcohol, 0 (m or p) —chlorophenethyl alcohol, 0 (1Ώ) Or p) — bromophenethyl alcohol, 0 (m or p) — ditrophenethyl alcohol, 0 (m or p) — protected amino phenyl alcohol, 3-phenylpropyl alcohol, 3 — [0 (m or p) —Fluorophenyl] propyl alcohol, 3— [0 (m or p) —chlorophenyl] propyl alcohol, 3— [0 (m or p) —bromophenyl] propyl alcohol, (m or p) — 2-butane phenyl) propyl alcohol, 3 — [0 (m or p) — protected amino phenyl] pulp alcohol, cinnamyl alcohol, 0 (m or p) — fluorosin namyl alcohol And the like. Many of these are commercially available and readily available.

 Examples of the base used in the reaction of the amine (2) with the reactive derivative (3) include, for example, triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-methylmorpholine, pyridine, Examples include tertiary organic bases such as N, N-dimethylaminopyridine and inorganic bases such as carbonates, hydrogencarbonates, hydroxides and hydrides of alkali metal and alkaline earth metal. Examples of the inert organic solvent include acetonitrile, benzene, acetone, tetrahydrofuran and the like, with acetonitrile being particularly preferred.

The above reaction is usually performed appropriately at the reflux temperature of the reaction solvent used. The reaction time depends on the reaction temperature and the type of base. Since the progress of the reaction can be monitored by liquid chromatography or the like, the reaction may be appropriately terminated after the disappearance of compound (2). Although it cannot be generally specified, it is usually about 2 to 48 hours.

 In order to collect the target compound (1) from the above reaction mixture, insoluble substances are filtered off, the solvent is concentrated, and the residue is concentrated, for example, using a mixture of pore-form and acetone as an eluent. Separation and purification can be performed by a known purification method such as chromatography.

 Further, the compound (1) of the present invention is, for example, a compound of the formula (5) with the amine (2)

Wherein R ₂ represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group or a protected amino group, and Y represents a saturated or unsaturated alkylene group having 1 to 2 carbon atoms. The reaction is carried out in an active organic solvent in the presence of a reducing agent.

When R _{2 in} (5) is a protected amino group, it can be obtained by removing the protecting group of the amino group. '

The aldehyde compound (5) is a known substance, for example, phenylacetaldehyde, 0 (m or p) -fluorophenylacetaldehyde, 0 (m or p) -cloth phenylacetaldehyde, 0 (m or p) — bromophenylacetaldehyde, 0 (m or p) — hydroxyphenylacetaldehyde, 0 (m or p) — ditrophenylacetaldehyde, 0 (m or p) monoprotected amino 2-Diacetaldehyde, 3-phenylpropionaldehyde, 3- [0 (m or p) -fluorophenyl] propionaldehyde, 3- [0 (m or p) -clothphenyl] propionaldehyde, 3-Co (m or p) —bromophenyl] propionaldehyde, 3— [0 (m or p) —Hydroxyphenyl] propionaldehyde, 3— [0 (m or p) —Ditrophenyl] propionaldehyde, 3— [0 (m or p) —Protected aminophenyl] propionaldehyde, cinnamaldehyde, 0 (m or p) — Fluorosinnamaldehyde and the like. Many of these are commercially available and readily available.

 Examples of the reducing agent used in the reaction between the amine (2) and the aldehyde compound (5) include, for example, sodium borohydride, sodium cyanoborohydride, Pd—C, and the like. Examples of the inert organic solvent for the above reaction include alcohol-based organic solvents such as methanol.

 The above reaction usually proceeds sufficiently at room temperature, and the reaction time depends on the type of reducing agent and the type of aldehyde (5). Since the reaction can be traced, the reaction may be appropriately terminated after the disappearance of the compound (2). Although it cannot be generally specified, it is usually about 2 to 48 hours.

 In order to collect the target compound (1) from the reaction solution, separation and purification can be performed in the same manner as described above.

 Furthermore, the compound (1) of the present invention has the general formula (6)

(Wherein, R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected amino group, and the nitrogen-containing rings B and Y have the same meanings as described above). When R ₃ in the general formula (6) is a protected amino group, it can be obtained by removing the protecting group of the protected amino group. The compound (6) is obtained by reacting the amine (2) with a compound represented by the general formula (7)

(Wherein R ₃ and Y have the same meanings as described above) or a reactive derivative thereof.

 The carboxylic acid (7) is a known substance such as, for example, phenylacetic acid, 0 (m or p) -fluorophenylacetic acid, 0 (m or p) -clofen phenylic acid, 0 (m or p) —Bromophenylacetic acid, 0 (m or ρ) —Hydroxyphenylacetic acid, 0 (m or p) —Protected aminophenylacetic acid, 3-Phenylpropionic acid, 3— [0 (m or p) —Fluorophenyl] propionic acid, 3 —

[0 (m or p) — chlorophenyl] propionic acid, 3 — Co (m or p) monobromophenyl] propionic acid, 3 — [0 (ηιέ or p) — hydroxyphenyl] propionic acid, 3 — [ 0 (m or ρ) —protected aminophenyl) propionic acid, cinnamic acid, 0 (m or p) —fluorocinnamic acid, and the like. Many of these are commercially available and readily available.

The above acylation reaction can be performed according to a known acylation reaction. For example, when the carboxylic acid (7) is used in a free form, the reaction is carried out in the presence of a condensing agent. Examples of the condensing agent include N, N'-dicyclohexyl carbodiimide, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N '-(4-getyl Reagents such as carbodiimide compounds such as aminocyclohexyl) carposimid, diphenylphosphoryl azide, benzotriazolyl N-hydroxytris (dimethylamino) phosphonium hexafluorophosphoride, carbonyldiimidazole, N-methylformamide, N Amides such as N, N-dimethylformamide Reagents (so-called Vilsmeier reagents) formed by the reaction with halides such as phenyl, oxychloride, phosgene and the like. Other known condensing agents can also be used.

 Examples of the reactive derivative of the carboxylic acid (7) include an acid halide, an acid anhydride, an acid azide, an active ester, and an active amide. Preferred examples thereof include an acid chloride, an acid bromide, and the like. Mixed acid anhydrides with acid halides, acetic acid, vivalic acid, isovaleric acid, trichloroacetic acid, monoalkyl carbonate, etc., p-ditrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenol Active esters such as enyl ester, pentachlorophenyl ester, 1-hydroxy-1H-pyridone, N-hydroxysuccinimide, N-hydroxysulfinimide ester, pyrazole, imidazole, dimethylvirazole, benzotriabul, etc. Active amide and the like.

 The reaction using an acid halide or acid anhydride among the reactive derivatives in the above acylation reaction is preferably performed in the presence of a deoxidizing agent. Examples of the deoxidizing agent include tertiary organic bases such as triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-methylmorpholine, pyridine, and N, N-dimethylaminopyridine, and known inorganic bases. Is used.

The above acylation reaction is carried out in an organic solvent that does not adversely affect the reaction. Examples of the organic solvent include chloroform, methylene chloride, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, acetone or a mixed solvent thereof is used. The reaction temperature is not particularly limited, but usually proceeds sufficiently at room temperature. The reaction time depends on the reaction temperature and the reaction solvent, and cannot be generally specified, but is usually about 2 to 30 hours. In order to collect the compound (6) obtained by the above acylation reaction from the reaction solution, when the reaction solvent is a non-hydrophilic organic solvent, the reaction solution is washed with an alkaline aqueous solution, an acidic aqueous solution, or a saturated saline solution. After that, the organic layer is concentrated and the reaction solvent is hydrophilic. When the solvent is an organic solvent, the compound (6) can be obtained by distilling off the solvent, dissolving the residue in a non-hydrophilic organic solvent, and treating in the same manner as described above. The compound (6) can be further purified by a known purification method such as silica gel column chromatography.

 The carbonyl group of the compound (6) thus obtained is reduced to obtain the compound (1) of the present invention. In the above reaction, the compound (6) is hydrogenated in an inert organic solvent. It is carried out by refluxing in the presence of a reducing agent such as lithium aluminum, sodium aluminum hydride, sodium bis (2-methoxetoxy) aluminum hydride or borohydride. Examples of the inert organic solvent include tetrahydrofuran, getyl ether, 1,4-dioxane, toluene, and pyridin. The reaction is carried out under heating, preferably at reflux. The reaction time depends on the reaction temperature and the type of reducing agent, but the progress of the reaction can be monitored by thin-layer chromatography, high-performance liquid chromatography, etc. The reaction may be terminated. Although it cannot be generally specified, it is usually about 15 minutes to 10 hours.

 In order to collect the target compound (1) from the above reaction solution, when the reaction solvent is a non-hydrophilic organic solvent, the reaction solution is washed with an alkaline aqueous solution, an acidic aqueous solution or a saturated saline solution, and then the organic layer is concentrated. When the reaction solvent is a hydrophilic organic solvent, the solvent is distilled off, the residue is dissolved in a non-hydrophilic organic solvent, and the mixture is treated in the same manner as above to obtain the desired compound (1). be able to.

 Furthermore, the compound (1) of the present invention has the general formula (8)

(Wherein, the nitrogen-containing rings B and A have the same meaning as described above) It can also be obtained by reduction.

 The above reduction reaction is carried out in a mixed solvent of an alcoholic solvent such as methanol and an acid.

It is carried out by hydrogenation in the presence of a catalyst such as Pd—C.

 The catalyst is filtered off from the above reaction solution, the filtrate is concentrated, and the residue is treated with an organic solvent such as getyl ether, whereby the compound (1) of the present invention is collected in the form of an acid addition salt. The acid addition salt may be used, if desired, by freeing the desired compound by a known method.

It can be converted to (1).

In the above three steps for obtaining the target compound (1), protection in the case where R _{2 in the} general formula (5) and R ₃ in the general formula (5) and R ₃ in the general formula (7) are a protected amino group The group is a known amino protecting group, and these protecting groups are eliminated after the reaction by a known method for eliminating an amino protecting group.

 If the target compound (1) thus obtained needs to be further purified, it can be purified by a known purification method such as silica gel column chromatography using a mixture of black form and acetone as eluent. can do.

 The obtained compound (1) of the present invention can be converted into a pharmaceutically acceptable non-toxic salt thereof, if necessary. Examples of such salts include salts of inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, malic acid, glutamic acid, aspartic acid, Examples thereof include acid addition salts with organic acids such as methanesulfonic acid, mandelic acid, ρ-toluenesulfonic acid, and maleic acid.

 Even if the compound of the present invention (1) or a nontoxic salt thereof was intravenously administered to rats at 3 Omg / kg, no deaths were observed. It can be called a safe compound.

In order to use the compound (1) of the present invention or a non-toxic salt thereof as a medicament, it is necessary to formulate the compound and administer it orally or parenterally, such as by injection including infusion, in a dosage form of Depends on the age, weight, and symptoms of the recipient However, in general, it is about 0.1 to 100 mg per day per adult.

 Examples of the dosage form for the formulation include tablets, pills, powders, granules, capsules, and injections. For the production thereof, various carriers corresponding to these formulations, for example, Oral preparations such as tablets, granules, and capsules include starch, lactose, sucrose, mannite, carboquin methylcellulose, corn starch, inorganic salts, and other excipients, starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, and methylcellulose. Binders such as sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, starch, hydroxypropyl starch, carboxypropylcellulose, sodium carboxymethylcellulose, hydrid Disintegrators such as roxypropylcellulose, sodium lauryl sulfate, soy lecithin, sucrose fatty acid esters, surfactants such as polysorbate 80, talc, wax, hydrogenated vegetable oil, sucrose fatty acid esters, magnesium stearate, magnesium stearate, Lubricants such as calcium stearate, fluidity promoters, flavoring agents, coloring agents, fragrances and the like can be used.

 The compound (1) of the present invention or a nontoxic salt thereof can also be used as a suspending agent, emulsion, syrup, and elixir.

 As the parenteral preparation, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, and the like can be generally used as a diluent. If necessary, a bactericide, a preservative, a stabilizer, a tonicity agent, a soothing agent and the like may be added. The invention's effect

Next, the compound (1) of the present invention or a non-toxic salt thereof (hereinafter, may be simply referred to as the “compound of the present invention”) will be described in terms of its ability to bind to a nobiose receptor. (A) Measurement method

 USA, vol. 83, 8784-1 8788 (1 986), E. Webereta 1 to bind the compound of the present invention to a sigma receptor according to the method described in Proc. Natl. The binding capacity was measured.

 After decapitation of a spray rat (Sprague—Dawley) male rat (7-week-old, sulliver), the brain was immediately removed, and the whole brain excluding the cerebellum was subjected to 5 Om TrisZHC1 buffer. (PH 8.0, TH buffer), followed by centrifugation at 7003 for 10 minutes. The supernatant was centrifuged at 48000 × g for 15 minutes, and the obtained precipitate was resuspended in TH buffer and incubated at 37 for 20 minutes. This was centrifuged at 48000 xg for 15 minutes, and the obtained sediment was suspended in TH buffer to obtain a membrane sample.

The membrane preparation (approximately 600 g protein content) and ^[3 H] 1, 3-di (2-Tris) grayed Anijin (DTG, manufactured by New Eng l and Nu cu lear Co.) (final concentration 3 nM) 25 ° The reaction was stopped for 60 minutes by suction filtration of the reaction mixture with a Kettman GFZC filter, and the reaction was measured with a radioactive scintillation counter adsorbed on the filter. The obtained value was regarded as the total binding amount. The amount of non-specific binding (NB) was determined by adding 10 uM haloperidol and measuring in the same manner. In order to measure the binding amount of the sample, an appropriate concentration of the sample was added instead of haloperidol, and the measurement was performed in the same manner to obtain a measured value (DTB) in the sample.

 (B) Ki value (affinity of drug for receptor) Calculation method

 The binding inhibition rate of the sample at a certain concentration was calculated by the following calculation method.

Binding inhibition rate (%) = {1-(DTB-NB) ÷ (TB-NB)} x 100 Determine the binding inhibition rate at an appropriate concentration (from high to low concentration) for each sample, and plot the horizontal axis. logarithm of the concentration and the vertical axis the binding inhibition rate was plotted to draw curve at non-linear least squares method, IC _5. The value was determined. ' The Ki value was calculated by the following formula.

Ki = IC ₅₀ ÷ [1 + (L) / Kd]

Where (L) is the concentration of the radioligand used in the experiment (3 nM), Kd is the concentration (10.6 nM) indicating the affinity of the radioligand for the receptor, and IC ₅₀ is the receptor and radioligand Is the drug concentration that inhibits the binding to 50%.

 (C) Measurement results

 Table 1 shows the results of measuring the binding ability of the compound of the present invention to the receptor.

Table 1 Compounds of Example No. (hydrochloride) Sigma (: ³ H) DTG

2 2. 1 5

 3 3. 3 4

 4 4 • 8 1

 8 7.0.6

 1 8 2. 2 6

 190.74 As is clear from the above measurement results, the compound of the present invention has a high affinity for the receptor, shows almost no affinity for other receptors, and is particularly characteristic of receptors. Since it has a different affinity, it is effective for the treatment of diseases associated with σ receptor, such as schizophrenia. Example

Next, the present invention will be described in more detail with reference to Reference Examples and Examples. Ming is not limited to this. Tables 2 and 3 show the physical properties of the target compound obtained in each of Examples and Reference Examples by mass spectrometry (MS) or nuclear magnetic resonance spectrum (H-NMR). Example 1

 1-Phenethyl-4,4-dimethylhexahydro-1H-azepine

 Dissolve 5 Omg of 4,4-dimethylhexahydro-1H-azepine and 0.065 ml of phenethylpromide in 2 Om1 of acetonitrile, add 0.081 g of lithium carbonate, and heat for 15 hours Refluxed. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ヮ Kogel, C200, chloroform: methanol = 250: 1) to obtain the title compound. Yield 37.4 mg (Yield 4 1%)

 To the obtained title compound, 2 molar equivalents of a methanol solution of hydrogen chloride was added, concentrated, and crystallized from getyl ether to obtain a hydrochloride. Example 2

 1 [2— (4-Fluorophenyl) ethyl] 1,4,4-dimethylhexahydro 1 H-azepine

Dissolve 63 ml of 2- (4-fluorophenyl) ethyl alcohol in 2 ml of methylene chloride, cool to 0 ° C, and add 0.47 ml of methanesulfonyl chloride, followed by 1.05 ml of triethylamine. Then, the mixture was gradually returned to room temperature and stirred for 23 hours. The reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. To this were added 0.82 g of 4,4-dimethylhexahydro-1H-azepine hydrochloride and 2.08 g of potassium carbonate, and the mixture was heated and refluxed for 9 hours as a solution of acetonitrile in 2 Oml. The insoluble material was separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ヮ co-gel, C200, chromate form: acetone = 20: 1 to 1: 1). Purification by 5: 1) afforded the title compound. Yield: 80 g (64% yield) The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 3

 1- [2- (4-Hydroxyphenyl) ethyl] 1,4-dimethylhexahydro-1H-azepine

 Dissolve 0.82 g of 4,4-dimethylhexahydro 1 H-azepine hydrochloride and 0.92 g of 4-hydroxyphenylacetic acid in 20 ml of methylene chloride, add 0.84 ml of triethylamine, and add 0 ° Stirred at C for 30 minutes. This is followed by 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (WSC) 1.

35 g was added, and the mixture was gradually returned to room temperature and stirred for 24 hours. The reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure. Without isolation, the solution was added to a solution of 0.339 g of lithium aluminum hydride in 30 ml of THF, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled, water was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography-(co-gel, C200, chloroform: methanol = 10: 1 to 5: 1) to obtain the title compound. Yield 0.79 (Yield 64)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 4

 1- [2— (4-12-trophenyl) ethyl] 1,4-dimethylhexahydro 1 H-azepine

 4,64-dimethylhexahydro-1H-azepine hydrochloride 1.64 g and 2- (

(4-12 trophenyl) ethyl bromide 2.78 g was dissolved in acetonitrile 30 ml, potassium carbonate 4.16 g was added, and the mixture was heated under reflux for 12 hours. The insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography. Purification by chromatography (ヮ Kogel, C200, black form: acetone = 40: 1 to 10: 1) gave the title compound. Yield 2.16 g (78% yield) The same treatment as in Example 1 was carried out to obtain a hydrochloride.

, Example 5

 1- [2— (4-aminophenyl) ethyl] 1,4-dimethylhexahydro 1 H-azepine hydrochloride

 1 [2-(4-12 trophenyl) ethyl] 1,4,4-dimethylhexahydro 1 H-azepine 1. 70 g of methanol 15 ml and 10% in a mixed solution of 1.5 ml of 12N hydrochloric acid 10% 34 g of Pd—CO was added, and the mixture was catalytically reduced at room temperature and normal pressure for 3 hours under a hydrogen stream. The catalyst in the reaction solution was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from ether, which was filtered to give the title compound. Yield 1.76 g (90% yield) Example 6,

 1-Phenethyl-3,3,5,5-tetramethylhexahydro-1H-azepine

 Dissolve 0.13 g of 3,3,5,5-tetramethylhexahydro-1H-azepine and 0.10 g of phenethyl bromide in 10 ml of benzene, add 0.1 ml of triethylamine, and add 0.1 ml of triethylamine. The mixture was heated under reflux for 15 hours. Ether was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Picogel, C200, black form) to obtain the title compound. Yield 0.15 g (90% yield)

The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 7

 1- [2- (4-Fluorophenyl) ethyl] 1,3,3,5,5-tetramethylhexahydro-1H-azepine

 Dissolve 0.63 ml of 2- (4-fluorophenyl) ethyl alcohol and 1.05 ml of triethylamine in 20 ml of methylene chloride, cool to 0, and add 0.47 ml of methanesulfonyl chloride. The mixture was gradually returned to room temperature and stirred for 8 hours. The reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. To this was added 0.78 g of 3,3,5,5-tetramethylhexahydro 1H-azepine and 1.04 g of potassium carbonate to obtain a solution of acetonitrile in 20 ml, and the mixture was refluxed for 14 hours. Insolubles were filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Picogel, C200, chloroform) to obtain the title compound. Yield 0.46 g (33% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 8

 1 [2— (4-hydroxyphenyl) ethyl] 1 3,3,5,5-tetramethylhexahydro-1H-azepine

0.78 g of 3,3,5,5-tetramethylhexahydro-1H-azepine and 0.77 g of 4-hydroxyphenylacetic acid were dissolved in 20 ml of methylene chloride, and 0.70 ml of triethylamine was added. The mixture was stirred at 0 ° C for 30 minutes. To this, 1.35 g of WSC was added, and the mixture was gradually returned to room temperature and stirred for 14 hours. The reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain an amide form. Without isolation, the solution was added to a solution of lithium aluminum hydride (0.39 g) in THF (30 ml) and heated under reflux for 1 hour. The reaction solution was cooled, water was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ヮ co-gel, C200, black form: acetone) Purification from 10: 1 to 5: 1) gave the title compound. Yield 0.59 g (Yield 4 3

%)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 9

 1- [2— (4,2-trophenyl) ethyl] 1,3,3,5,5-tetramethylhexahydro-1H-azepine

1.56 g of 3,3,5,5-tetramethylhexahydro-1H-azepine and 2.78 g of 2- (412-trophenyl) ethyl bromide were dissolved in 30 ml of acetonitrile, and potassium carbonate was added. 0.08 g was added, and the insoluble material was filtered off from the reaction mixture _c which was heated and refluxed for 13 hours, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Picogel, C200, black form) to give the title compound. Yield 1.25 g (41% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 10

 1 [2— (4-Aminophenyl) ethyl] 1,3,3,5,5-tetramethylhexahydro-1H-azepine hydrochloride

1 [2- (4-Ditrophenyl) ethyl] 1,3,3,5,5-tetramethylhexahydro 1H-azepine 0.76 g of methanol 10 ml and 12 N hydrochloric acid 1 ml 1 15% Pd—CO.15 was added to the mixed solution of the above, and the mixture was subjected to catalytic reduction under a hydrogen stream at normal temperature and normal pressure for 5 hours. The catalyst in the reaction solution was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ether and filtered to give the title compound. 0.64 s (74% yield) Example 1 1

 1 1- (2-phenylethyl) 1,3,3,5-trimethylhexahydro-1H-azepine

 3,3,5-Trimethylhexahydro-1H-azepine 1.65 ml and phenethyl chloride 1.68 g are dissolved in benzene 2 Om 1, and triethylamine 2.1 Om 1 is added thereto for 3 hours and a half. Heated to reflux. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant is filtered off, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (ヮ -gel, C 200, chloroform: methanol = 200: 1). To give the title compound. Yield 73 g (Yield 71%)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 1 2

 6- (2-phenylethyl) 1-1,3,3-trimethyl-6-azabicyclo [3.2.1] octane

 1,3,3-Trimethyl-1-azabicyclo [3.2.1] Octane 1.7 Oml and phenethyl chloride 1.69 g are dissolved in benzene 2 Om1 and triethylamine is added. 2. 1 Om 1 was added and the mixture was heated under reflux for 3 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ヮ -gel, C 200, chromatographic form: methanol = 300: 1). The title product was obtained. Yield 2.18 g (86% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 13

6— [2 -— (4-nitrophenyl) ethyl] —1,3,3-trimethyl-6 —Azabicyclo [3.2.1] octane

 1,3,3-Trimethyl-6-azabicyclo [3.2.1] octane 0.67 ml and 0.92 g of 2- (412-trophenyl) ethyl bromide were dissolved in 10 ml of benzene, and 0.67 ml of triethylamine was added, and the mixture was heated under reflux for 8 hours. Ether was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (Peco-gel, C200, chloroform) to obtain the title compound. Yield 0.7 1 g (61% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 14

 1-cinnamyl-3,3,5-trimethylhexahydro-1H-azepine 3,3,5-trimethylhexahydro-1H-azepine 1.65m1 and thinner milk mouth light 1.67m1 to benzene 20m1 And triethylamine 2.10 ml was added thereto, and the mixture was heated under reflux for 3 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant is filtered off, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (ヮ co-gel, C200, chloroform: methanol = 200: 1). And the title compound was obtained. Yield 1.932 (Yield 72%)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 15

 1 Cinnamyl-3,3,5,5-tetramethylhexahydro-1H-azepine

Dissolve 0.15 g of 3,3,5,5-tetramethylhexahydro-1H-azepine and 0.2 Om1 of cinnamaldehyde in 1 Om1 of methanol and cool to 0 ° C Then, 0.061 g of sodium cyanopolohydride was added thereto. The mixture was gradually returned to room temperature and stirred for 24 hours. The reaction solution was poured into water and extracted with ether, and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (Pecogel, C200, chloroform) to obtain the title compound. Yield 0.20 g (71% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 16

 1-[(3-phenyl) -1 1-propyl] 1,3,3,5,5-tetramethylhexahydro Draw 1 H-azepine

 (1) Single cinnamyl-3,3,5,5-tetramethylhexahydrol 20 g of 1H-azepine is dissolved in 5 ml of ethanol, 10% Pd—C2Omg is added, and the mixture is hydrogen-flowed and 5 atm. It was catalytically reduced at room temperature for 5 hours. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (Picogel, C200, Glo-mouth form) to give the title compound. Yield 4 Omg (Yield 20

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 17

 6-cinnamyl-1,3,3-trimethyl-6-azabicyclo [3.2.1] octane

1,3,3-Trimethyl-6-azabicyclo [3.2.1] octane 1.7 Om 1 and cinnamyl bromide 2.36 g are dissolved in benzene 2 Om 1 and triethylamine 2.1 Om 1 is added. The mixture was refluxed for 3 and a half hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. The drying agent is filtered off, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography. The product was purified by chromatography (Pecogel, C200, chloroform: methanol = 250: 1) to give the title compound. Yield 2.3 93 (84% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Reference example 1

 9-azabicyclo [3.3.2] Decane 1—one

 Vincro [3.3.1] 1.0 g of nonane-1-one and 1.23 g of hydroxylamine-10-sulfonic acid were heated under reflux in 15 ml of acetic acid for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with saturated aqueous sodium bicarbonate as a chloroform solution, and dried over anhydrous sodium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (Pecogel, C200, chloroform: acetone = 5: 1) to give the title compound. I got something. Yield 84 g (Yield 76%) Reference Example 2

 9-azabicyclo [3.3.2] decane hydrochloride

 To a solution of lithium aluminum hydride (0.11 g) in THF (3 ml) was added a solution of 9-azabicyclo [3.3.2] decane-8-one (0.21 g) in THF (3 ml). The reaction solution was cooled, water was added, and the insolubles were removed by filtration, and only THF in the filtrate was concentrated under reduced pressure. 12 N hydrochloric acid was added to the obtained residue, followed by drying under reduced pressure. The obtained residue was collected by filtration with ether to give the title compound. Yield 0.19 g (78% yield Example 18

9- [2- (4-Fluorophenyl) ethyl] -1-9-azabicyclo [3.3.2] decane Dissolve 36 ml of 2- (4-fluorophenyl) ethyl alcohol in 10 ml of methylene chloride, cool to 0 ° C, and add 0.43 ml of methanesulfonyl chloride followed by 0.98 ml of triethylamine. Then, the mixture was gradually returned to room temperature and stirred for 22 hours. The reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. This is 9-azabicyclo

 [3.3.2] 0.19 g of decane hydrochloride and 0.82 g of potassium carbonate were added, and the mixture was heated and refluxed for 18 hours as a 10 ml solution of acetonitrile. The insolubles were filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ヮ co-gel, C200, black form to black form: acetone = 5).

: 3) to give the title compound. Yield 0.10 g (37% yield)

 The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 19

 3- [2- (4-Fluorophenyl) ethyl] -1-3-azabicyclo [3.2.2.

2] Nonan

 Dissolve 32 ml of 2- (4-fluorophenyl) ethyl alcohol in 15 ml of methylene chloride and set to 0. After cooling to C, 0.30 ml of methanesulfonyl chloride and 0.72 ml of triethylamine were added, and the mixture was gradually returned to room temperature and stirred for 8 hours. The reaction solution was concentrated under reduced pressure to obtain a crude mesyl compound. To this, 0.32 g of 3-azabicyclo [3.2.2] nonane and 0.71 g of potassium carbonate were added, and the mixture was heated and refluxed for 38 hours as a 15 ml solution of acetonitrile. Insolubles were separated from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ヮ co-gel, C 200, black form to black form: acetone = 5: 1) to obtain the title compound. Yield 0.3 68 (Yield 56%)

The product was treated in the same manner as in Example 1 to obtain a hydrochloride. Example 20

 Production of injections

 3- [2- (4-Monophenyl) ethyl] 1-3-azabicyclo [3.2.2] nonane hydrochloride (1.0 g) was dissolved in 1 L of distilled water for injection, and the solution was dissolved in 1 N aqueous sodium hydroxide solution. After the pH was adjusted to 6 to 7, the solution was sterilized, and the solution was filled into ampoules in 5 ml portions to obtain injections. Example 2 1

 Tablet manufacturing

 3- [2-((4-Fluorophenyl) ethyl] -1-3-azabicyclo [3.2] nonane hydrochloride

 5 0.Omg

 Corn starch 4 0. Omg

 Microcrystalline cellulose 8 0.Omg

 0.5 mg of magnesium stearate

 Talc 29.5 mg

A tablet of 20 Omg per tablet having the following composition was obtained by dry tableting.

Table 2 Example 'H-NMR (CDC 13 or CD ₃ OD [*]) MS δ δ (p pm)

1 0.87 (6H, s), 1.3 to 1.7 (6H, m) FAB

, 2.6 to 2.9 (8H, m) .7.7.4 232 (5H, m) (MH ⁺ ) (Continued in Table 2) 0.9 1 (6 H, s), 1.4 to 1.5 (2 H, m) FAB, 1.6 to 1.8 (6 H, m), 2.5 ~ 2.825 0

(8 H, m), 6.96 (2H, t), 7.14 (MH ⁺ )

(2H, d d)

0.92 (6H, s) .1.4-1.5 (2H, m) FAB, 1.6-7 (4H, m), 2.7-2.9 24 8

(8H, m), 6.73 (2H, d), 6.98 (MH +)

(2H, d)

0.91 (6H, s), 1.4 to 1.5 (2H, m) FAB, 1.5 to 1.6 (2H, m), 1.6 to 1.7277

(2H, m), 2.5 to 2.6 (2H, m), (MH ⁺ ) 2.6 to 2.7 (2H, m), 2.7 to 2.8

 (2H, m), 2.8 to 2.9 (2H, m),

7.35 (2H, d), 8.14 (2H, d)

*) 1.00 (3H, s), 1.10 (3H, s), FAB 1.5 to 1.9 (6H, m), 3.

(8 H, m), 7.40 (2H, d), 7.52 (MH ⁺ )

(2H, d)

0.93 (6H, s), 0.96 (6H, s), 1.FAB 30 (2H, s), 1.53 (2H, t), 2.4025 8 (2H , s), 2 64 (2H, t), 27-2. (Μ-1) 9 (4 H, m), 7.1-7.4 (5 H, m) (No. 2i continues)

0.91 (6H, s), 0.95 (6H, s),

 1.29 (2H, s), 1.52 (2H, t),

 2.38 (2H, s), 2.6 to 2.8 (6H, m)

, 6.95 (2H, dd), 7.15 (2H, dd)

0.93 (6H, s), 0.96 (6H, s),

 1.30 (2H, s), 1.54 (2H, t),

 2.40 (2H, s), 2.6 to 2.8 (6H, m)

, 6.74 (2H, d), 7.05 (2H, d)

0.89 (6H, s) .0.95 (6H, s),

 1.22 (2H, s), 1.52 (2H, t),

 2.38 (2 H, s), 2.62 (2 H, t),

 2.73 (2H, d d), 2.86 (2H, d d), c ^

7.37 (2H, d), 8.1 (2H, d) ^{+ + + +} do DO C DOndn en oo

*) 1. 1 & (1 2H, s), 1.68 (1 H, d)

, 1.77 (1H, d), 1.90 (1H, dd),

2.18 (1H, dd), 3.2 to 3.7 (8H,

m), 7.50 (2H, d), 7.63 (2H, d)

0.86 (3H, d), 0.92 (6H, s), FAB 1.2 to 2.0 (5H, m), 2.Ball 2.9 246 (8H, m), 7.23 (5 H, s) (MH ⁺ ) (Continued in Table 2)

0.87 (3H, s), 1.02 (3H, s), EI 1.18 (3H, s), 0.8 to 1.8 (6H, m) 257, 2.16 ( 1H, d), 2.6-3.2 (6H, (M ⁺ ) m), 7.0-7.4 (5H, m)

0.85 (3H, s), 1.02 (3H, s), EI 1.07 (3H, s), 1.1 to 1.2 (2H, m) 302, 1.2 to 1.4 (2H, m), 1.4 to 1.6 (M ⁺ ) (2H, m), 2.11 (1H, dd), 2.6 to

 2.8 (3H, m), 2.8-3.0 (2H, m),

 3.0 to 3.1 (1H, m), 7.37 (2H, d)

, 8.1 2 (2H, d)

0.85 (3H, s), 0.93 (6H, s), EI 1.2 to 1.9 (5H, m), 2.0 to 2.7 259 (4H, m), 3 75 (2H, d), to 6.2 (M ⁺ ) 6.5 (1H, m), 6.54 (1H, d),

7.1 to 7.5 (5H, m)

0.93 (6H, s), 0 96 (6H, s),

 1.33 (2H, s), 154 (1H, d), FAB

1.56 (1H, d), 236 (2H, s), 270

2.59 (1 H, d), 26 1 (1 H, d), (M-l)-

3.26 (2H, d), 62-6.5 (1H, m)

6.62 (1H, d), 7.1 to 7.5 (Continued in Table 2)

(5H, m)

0.96 (1 2 H, s), 1.25 (2 H, s) FAB 1.57 (1 H, d), 1.59 (1 H, d), 274 1.80 (1 H, d) ), 1.83 (1H, d), (MH ⁺ ) 2.37 (2H, s), 2.52 (1H, d),

 2.54 (1 H, d), 2.6 to 2.7 (4 H, m)

, 7.1 to 7.3 (5H, m)

0.8 9 (3H, s), 1.02 (3H, s), E I

1.Table 1.3 (2H, m), 1.29 (3H, s) 257, 1.6 to 1.8 (5H, m), 2.15 (1H, (M ⁺ ) dd) 3.10 (1H, dd), 3.3.4

 (2H, m), 6.21 (1H, dt), 6.54

 (1 H, d), 7.1 to 7.4 (5H, m)

1.4 to 2.1 (12 H, m), 2.2 to 2.3 FAB (1 H, m), 2.7 to 3.0 (6H, m), 3.3 262 to 3, 4 (1H, m), 6.96 (2H, ddd). (MH ⁺ ) 7.19 (2H, dd)

1.5 to 1.9 (10 H, m), 2.5 to 2.8 FAB (8H, m), 6.95 (2H, t), 7.18 248 (2H, dd) (MH ⁺ ) Table 3 Reference Example ¹ H-NMR (CDC 13 or CD ₃ ODO)) MS

¾ "δ (ρ pm)

1 1.5 to 1.7 (6Η, m), 1.7 to 1.9

 (6Η, m), 2.8-2.9 (1Η, m),

 3.5 to 3.6 (1Η, m), 6.31 (1Η,

 b s)

2 *) 1.5 to 2.1 (1 3 Η, m),

2.2 to 2.3 (1 Η, m),

 3.05 (2Η, d),

 3.4 to 3.5 (1 Η, m)

 , +

⁺ CO

Claims

1. —General formula (1) Mi (1)  Body

(Wherein the nitrogen-containing ring 3, is 3,3,5,5-tetramethylhexahydro-1Η-azepine-11-yl, 3,3,5-trimethylhexahydro-1 ー -azepine-11- ィ yl , 4,4-Dimethylhexahydro-enclosed 1-azebine-11-yl, 1,3,3-trimethyl-6-azabicyclo [3.2.1] octane-6-yl, 9-azabicyclo [3. 3. 2] Decane 9-1yl or 3-azabicyclo [3.2.2] Nonyl-3-yl group, R represents hydrogen atom, halogen atom, hydroxyl group, nitro group or amino group, and Α represents saturated or unsaturated group having 2 to 3 carbon atoms. Or a non-toxic salt thereof. 2. —Crotch type (1)

(Wherein the nitrogen-containing ring B is 3,3,5,5-tetramethylhexahydro-1H-azepine-11-yl, 3,3,5-trimethylhexahydro-1H-azepine-11-yl) , 4,4-Dimethylhexahydro-1H-azepine-11-yl or 1,3,3-trimethyl-6-azabicyclo [3.2.1] octane-16-yl, 9-azavinclo [3.3.2] decane One 9-yl or 3-Azabi Chlo [3.2.2.2] represents a nonane-3-yl group, R represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group or an amino group, and A represents a saturated or unsaturated group having 2 to 3 carbon atoms. Or a non-toxic salt thereof represented by the formula (1) or a non-toxic salt thereof as an active ingredient. 3. General formula (1)

(Wherein the nitrogen-containing ring B is 3,3,5,5-tetramethylhexahydro-1H-azepine-11-yl, 3,3,5-trimethylhexahydro-1H-azepine-11-yl) , 4,4-Dimethylhexahydro-1H-azepine-11-yl or 1,3,3-trimethyl-6-azabicyclo [3.2.1] octane-16-yl, 9-azabicyclo [3.3.2] decane 1-9-yl or 3-azabicyclo [3.2.2] nonane-3-yl group, R represents hydrogen atom, halogen atom, hydroxyl group, nitro group or amino group, and A has 2-3 carbon atoms Or a non-toxic salt thereof as an active ingredient.