JP2017100953A - Tetrahydro benzo-furo azepine derivatives and pharmaceutical application thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent or preventive of stress urinary incontinence having 5-HT2C receptor actuation activity.SOLUTION: Tetrahydro benzo-furo azepine derivatives represented as follows or acid addition salts permitted pharmacologically are provided.SELECTED DRAWING: None

Description

  The present invention relates to a tetrahydrobenzoflozepine derivative and a pharmaceutical use thereof.

  Stress urinary incontinence means that urine leaks when transient abdominal pressure rises in daily life, such as when sneezing or coughing, laughing, running or lifting a heavy object It is a disease characterized by symptoms. The cause is thought to be due to trauma, ischemia or denervation of the pelvic floor muscle group or external urethral sphincter, which is a urethral closure tissue, due to childbirth, menopause or aging, etc. Many have been reported (Non-Patent Document 1).

  Treatment of stress urinary incontinence includes exercise therapy, surgery, or drug therapy. Pelvic floor muscle training, which is exercise therapy, can be effective after several weeks to several months by performing it continuously every day (Non-patent Document 2). No (non-patent document 3). Surgical surgery has been shown to have a certain effect, but since it depends on the severity and the will of the patient, there are currently few patients who actually undergo surgery (Non-patent Document 4).

  Regarding drug therapy, only duloxetine and clenbuterol are clinically used as therapeutic agents for the indication of stress urinary incontinence. Duloxetine has a therapeutic effect by constricting the urethra by inhibiting the reuptake of nerve terminals serotonin and noradrenaline. Clenbuterol has a therapeutic effect by stimulating the adrenergic β2 receptor of the external urethral sphincter and contracting the urethra. However, the treatment rate and the treatment continuation rate with these drugs are low (Non-patent Document 5), and the development of a new therapeutic agent or preventive agent for stress urinary incontinence is eagerly desired.

［式中、Ｒ^１は、Ｈ又はＣ１〜８アルキルであり、Ｒ^２は、Ｃ１〜４アルキル、−ＣＨ_２−Ｏ−（Ｃ１〜４アルキル）、−ＣＨ_２−Ｏ−（Ｃ１〜４ハロアルキル）又は−ＣＨ_２ＯＨであり、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６はそれぞれ独立して、Ｈ、Ｃ１〜４アルキル、アミノ、シアノ、ハロゲン、Ｃ１〜４ハロアルキル、ニトロ又はＯＨである、
ただしＲ^２がＣ１〜４アルキル、−ＣＨ_２−Ｏ−（Ｃ１〜４アルキル）及び−ＣＨ_２ＯＨの場合は、Ｒ^３及びＲ^６はどちらも水素ではない。］ Serotonin (hereinafter, 5-HT) 2C receptor is one of the receptors for the neurotransmitter serotonin and is mainly distributed in the central nervous system (Non-patent Document 6). For example, as an action of 5-HT2C receptor operation, an antifeedant action is known (Non-patent Document 7), and a benzazepine derivative represented by the following general formula (A) is a therapeutic or preventive agent for obesity and related disorders. It has been reported that it can be used as an agent (Patent Document 1).

[In the formula, ^{R 1} is H or C1~8 alkyl, ^{R 2} is C1 -4 _alkyl, -CH 2 -O- (C1 -4 _alkyl), - CH 2 -O- (C1~4 haloalkyl ) or a _-CH 2 ^OH, independently R ^3, R 4, ^{R 5} and ^{R 6} are each, H, a C1 -4 alkyl, amino, cyano, halogen, C1 -4 haloalkyl, nitro or OH,
However, if ^{R 2} is a C1 -4 _alkyl, -CH 2 -O- (C1~4 alkyl) and _-CH 2 OH, ^{R 3} and ^{R 6} are not both hydrogen. ]

  In recent years, it has been proposed that there is a urinary forbidden reflex mechanism that promotes urethral contraction when transient abdominal pressure rises (Non-patent Document 8), and 5-HT2C receptor agonists promote the urinary forbidden reflex mechanism. It has been reported that it can be expected as a therapeutic or preventive agent for stress urinary incontinence (Patent Documents 2 to 4 and Non-Patent Document 9).

  On the other hand, a compound having a tetrahydrobenzofuropyridine structure (Patent Document 5) has been reported as a 5-HT receptor ligand having a benzofuran structure.

International Publication No. 2005/003096 JP 2012-107032 A International Publication No. 2011-111817 International Publication No. 2008/117169 Special table 2005-522407

Irwin et al., British Journal of Urology International, 2011, 108, 7, p. 1132-1139 Sampselle et al., Journal of Obstetric, Gynecologic, and Neonatal Nursing, 1997, Vol. 26, No. 4, p. 375-385 Bishop et al., Journal of Obstetric, Gynecologic, and Neonatal Nursing, 1992, Vol. 21, No. 5, p. 401-406 Waetjen et al., OBSTETRICS & GYNECOLOGY, 2003, 101, No. 4, p. 671-676 Vella et al., International Urology Journal and Pelic Floor Dysfunction, 2008, Vol. 19, No. 7, p. 961-964 Helton et al., NeuroReport, 1994, Volume 5, p. 2617-2620 Smith et al., Obesity, 2008, 17, p. 494-503 Yoshimura et al., Japanese Pharmacology Journal, 2003, Vol. 121, No. 5, p. 290-298 Miyazaki et al., American Journal of Physiology: Renal physology, 2009, Vol. 297, No. 4, p. F1024-1031

  However, Patent Documents 1 to 4 and Non-Patent Document 9 do not describe that the tetrahydrobenzoflozepine derivative of the present application has 5-HT2C receptor agonist activity, nor does it even suggest the possibility. Patent Document 5 describes a 5-HT2C receptor, but does not disclose any specific structure of the tetrahydrobenzoflozepine derivative of the present application, and is useful for stress urinary incontinence, There is no specific medicinal data on urinary incontinence.

  Then, an object of this invention is to provide the therapeutic agent or preventive agent of stress urinary incontinence which has 5-HT2C receptor operation activity.

  As a result of intensive studies to achieve the above object, the present inventors have found a novel tetrahydrobenzoflozepine derivative having potent 5-HT2C receptor agonist activity, and have completed the present invention.

［式中、Ｒ^１〜Ｒ^３は、いずれか一つのみがメトキシ基又はメチルチオ基を、その他が水素原子を表し、Ｒ^３がメトキシ基を表す場合、Ｒ^４は、水素原子、メチル基又はエチル基を表し、Ｒ^３が水素原子又はメチルチオ基を表す場合、Ｒ^４は、水素原子を表す。］ That is, the present invention provides a tetrahydrobenzoflozepine derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[In the formula, any one of R ^{1 to} R ³ represents a methoxy group or a methylthio group, the other represents a hydrogen atom, and when R ³ represents a methoxy group, R ⁴ represents a hydrogen atom, a methyl group, or When it represents an ethyl group and R ³ represents a hydrogen atom or a methylthio group, R ⁴ represents a hydrogen atom. ]

In the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, ^one of R ¹ and R ³ is a methoxy group or a methylthio group, and the other is a hydrogen atom, R ² is a hydrogen atom, and when R ³ represents a methoxy group, R ⁴ is preferably a hydrogen atom or a methyl group, R ¹ and R ² are a hydrogen atom, and R ³ is a methoxy group. And R ⁴ is more preferably a methyl group.

  In this case, high 5-HT2C receptor agonist activity can be expected.

  The present invention also provides a pharmaceutical and a 5-HT2C receptor agonist, which contains, as an active ingredient, the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof. To do.

  The medicament is preferably a therapeutic or prophylactic agent for stress urinary incontinence.

  The tetrahydrobenzoflozepine derivative of the present invention or a pharmacologically acceptable acid addition salt thereof has a potent 5-HT2C receptor agonistic activity and has an excellent therapeutic effect or preventive effect on stress urinary incontinence. Can demonstrate.

It is a figure which shows the effect | action of the compound of Example 7 with respect to the pressure at the time of rat leak under anesthesia.

［式中、Ｒ^１〜Ｒ^３は、いずれか一つのみがメトキシ基又はメチルチオ基を、その他が水素原子を表し、Ｒ^３がメトキシ基を表す場合、Ｒ^４は、水素原子、メチル基又はエチル基を表し、Ｒ^３が水素原子又はメチルチオ基を表す場合、Ｒ^４は、水素原子を表す。］ The tetrahydrobenzoflozepine derivative of the present invention is characterized by being represented by the following general formula (I).

[In the formula, any one of R ^{1 to} R ³ represents a methoxy group or a methylthio group, the other represents a hydrogen atom, and when R ³ represents a methoxy group, R ⁴ represents a hydrogen atom, a methyl group, or When it represents an ethyl group and R ³ represents a hydrogen atom or a methylthio group, R ⁴ represents a hydrogen atom. ]

  Of the tetrahydrobenzoflozepine derivatives represented by the above general formula (I) or pharmacologically acceptable acid addition salts thereof, preferred specific examples are shown in Table 1, but the present invention is not limited thereto. .

  The compounds described in Table 1 also include pharmacologically acceptable acid addition salts thereof.

  Examples of the “pharmacologically acceptable acid addition salt” of the tetrahydrobenzoflozepine derivative represented by the general formula (I) include, for example, hydrochloride, sulfate, nitrate, hydrobromide, hydroiodic acid Inorganic acid salts such as salt or phosphate, acetate, trifluoroacetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, malein Organic carboxylates such as acid salts, benzoates or phthalates, or organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or camphorsulfonate Among them, hydrochloride, hydrobromide, trifluoroacetate, tartrate or methanesulfonate is preferable, and hydrochloride or trifluoroacetate is more preferable.

  The tetrahydrobenzoflozepine derivative (I) represented by the above general formula (I) or a pharmacologically acceptable salt thereof may be an anhydride or form a solvate such as a hydrate. It doesn't matter. Here, the solvate is preferably a pharmacologically acceptable solvate. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferable. Examples of the solvent constituting the solvate include alcohol solvents such as methanol, ethanol, and n-propanol, N, N-dimethylformamide, dimethyl sulfoxide, and water.

  The tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof can be produced by an appropriate method based on characteristics derived from the type of the substituent. The starting materials and reagents used for the production of these compounds can be generally purchased or can be produced by known methods.

  The tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, and intermediates and starting materials used for the production thereof can be isolated and purified by known means. . Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

［式中、Ｒ^４は、上記定義に同じである。］ Among the tetrahydrobenzoflozepine derivatives represented by the above general formula (I) or pharmacologically acceptable salts thereof, any one of R ^{1 to} R ³ is a methoxy group (Ia) or (Ib) The represented compound can be obtained, for example, by the method described in Production Method 1.

[Wherein R ⁴ is the same as defined above. ]

Process 1
Compound (III) can be obtained by reaction of bromophenol derivative (II) with hydroxy-O-sulfonic acid.

  The equivalent of the bromophenol derivative (II) is preferably 1 to 20 equivalents, more preferably 1 to 5 equivalents, based on hydroxy-O-sulfonic acid.

  Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, and propanol, halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether, and tetrahydrofuran (hereinafter, THF); A mixed solvent thereof can be used.

  Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and calcium hydroxide.

  The reaction temperature is preferably 0 ° C to 100 ° C, more preferably 20 ° C to 90 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-24 hours are preferable, and 30 minutes-5 hours are more preferable.

  The concentration at the start of the reaction is preferably 0.1 mM to 3M.

  The bromophenol derivative (II) and hydroxy-O-sulfonic acid can be purchased or can be produced by a known method or a method analogous thereto.

Process 2
Compound (IV) can be obtained by a Fischer indole reaction between compound (III) and azepan-4-one hydrochloride.

  1-20 equivalent is preferable with respect to compound (III), and, as for the equivalent of azepan-4-one hydrochloride, 1-5 equivalent is more preferable.

  Examples of the reaction solvent include alcohol solvents such as methanol, ethanol or propanol, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether or THF, benzene, toluene or xylene. A hydrocarbon solvent such as the above or a mixed solvent thereof can be used.

  Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, and phosphoric acid, and hydrochloric acid, sulfuric acid, and phosphoric acid are preferable.

  The reaction temperature is preferably 0 ° C to 130 ° C, more preferably 20 ° C to 110 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-48 hours are preferable, and 30 minutes-24 hours are more preferable.

  The concentration at the start of the reaction is preferably 0.1 mM to 2M.

Process 3
Compound (V) can be obtained by a palladium-catalyzed coupling reaction between compound (IV) and bispinacol diborane and a subsequent oxidation reaction.

  1-20 equivalent is preferable with respect to compound (IV), and, as for the equivalent of bispinacol diborane, 1-5 equivalent is more preferable.

  Examples of the palladium catalyst include tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, or 1,1′-bis (diphenylphosphino) ferrocene-palladium ( II) Dichloride-dichloromethane complex and the like.

  The equivalent of the palladium catalyst is preferably 0.01 to 1 equivalent with respect to the compound (IV).

  Examples of the base include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium acetate or potassium acetate.

  The equivalent of the base is preferably 1 to 5 equivalents.

  Examples of the reaction solvent include halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether or THF, hydrocarbon solvents such as benzene, toluene or xylene, N, N- An aprotic polar solvent such as dimethylformamide or dimethyl sulfoxide or a mixed solvent thereof can be used.

  The reaction temperature is preferably 0 ° C to 120 ° C, more preferably 20 ° C to 100 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-48 hours are preferable, and 30 minutes-5 hours are more preferable.

  The concentration at the start of the reaction is preferably 0.1 mM to 1M.

  Bispinacol diborane can be purchased, or can be produced by a known method or a method analogous thereto.

Process 4
Compound (VI) can be obtained by reacting compound (V) with iodomethane.

  The equivalent of iodomethane is preferably 1 to 20 equivalents, more preferably 1 to 5 equivalents, relative to compound (V).

  Examples of the reaction solvent include halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether or THF, and aprotic polar solvents such as N, N-dimethylformamide or dimethyl sulfoxide. Alternatively, a mixed solvent thereof can be used.

  As the base, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like are preferable.

  The reaction temperature is preferably 0 ° C to 80 ° C, more preferably 0 ° C to 40 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-24 hours are preferable and 5 minutes-12 hours are more preferable.

  The concentration at the start of the reaction is preferably 0.1 mM to 1M.

Process 5
Compound (Ia) can be obtained by de-Boc reaction of compound (VI).

  Examples of the reaction solvent include alcohol solvents such as methanol, ethanol or propanol, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether or THF, hexane or ethyl acetate, etc. Or a mixed solvent thereof can be used.

  Examples of the acid to be added include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid, and hydrochloric acid and trifluoroacetic acid are more preferable.

  The reaction temperature is preferably 0 ° C to 60 ° C, more preferably 0 ° C to 40 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-72 hours are preferable and 5 minutes-24 hours are more preferable.

Step 6
Compound (Ib) can be obtained by reductive amination reaction of compound (Ia) with an aldehyde derivative or a ketone derivative.

  1-20 equivalent is preferable with respect to compound (Ia), and, as for the equivalent of an aldehyde derivative or a ketone derivative, 1-10 equivalent is more preferable.

  Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.

  Examples of the reaction solvent include alcohol solvents such as methanol, ethanol or propanol, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether or THF, or a mixed solvent thereof. Can be used.

  The reaction temperature is preferably 0 ° C to 100 ° C, more preferably 0 ° C to 80 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-48 hours are preferable, and 5 minutes-24 hours are more preferable.

  The aldehyde derivative or ketone derivative can be purchased, or can be produced by a known method or a method analogous thereto.

Of the tetrahydrobenzoflozepine derivatives represented by the above general formula (I) or pharmacologically acceptable salts thereof, a compound represented by (Ic) wherein any one of R ^{1 to} R ³ is a methylthio group Can be obtained, for example, by the method described in Production Method 2.

Process 1
Compound (VII) can be obtained by a palladium-catalyzed coupling reaction between compound (IV) and methyl mercaptan sodium.

  1-20 equivalent is preferable with respect to compound (IV), and, as for the equivalent of methyl mercaptan sodium, 1-10 equivalent is more preferable.

  Examples of the palladium catalyst include tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium acetate, or 1,1′-bis (diphenylphosphino) ferrocene-palladium ( II) Dichloride-dichloromethane complex and the like.

  The equivalent of the palladium catalyst is preferably 0.01 to 1 equivalent with respect to the compound (IV).

  Examples of the reaction solvent include halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane, diethyl ether or THF, hydrocarbon solvents such as benzene, toluene or xylene, or N, N- Examples include aprotic polar solvents such as dimethylformamide or dimethyl sulfoxide.

  The reaction temperature is preferably 0 ° C to 180 ° C, more preferably 30 ° C to 160 ° C.

  Although reaction time changes with substrates or reaction conditions, 1 to 48 hours are preferable and 1 to 24 hours are more preferable.

  The concentration at the start of the reaction is preferably 0.1 mM to 1M.

Process 2
Compound (Ic) can be obtained by de-Bocation reaction of compound (VII).

  Examples of the reaction solvent include alcohol solvents such as methanol, ethanol or propanol, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as dioxane or diethyl ether, carbonization such as hexane or ethyl acetate. A hydrogen-based solvent or a mixed solvent thereof can be used.

  Examples of the acid to be added include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid, and hydrochloric acid and trifluoroacetic acid are more preferable.

  The reaction temperature is preferably 0 ° C to 60 ° C, more preferably 0 ° C to 40 ° C.

  Although reaction time changes with substrates or reaction conditions, 5 minutes-72 hours are preferable and 5 minutes-24 hours are more preferable.

  The medicament of the present invention and a 5-HT2C receptor agonist contain the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient. Yes. The medicament is preferably a therapeutic or prophylactic agent for stress urinary incontinence.

  A “5-HT2C receptor agonist” is a drug that interacts with the 5-HT2C receptor and has an action of enhancing its signal transduction.

  The tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has 5-HT2C receptor agonist activity, for example, Jerman et al. (European Journal of Pharmacology, 2001, Vol. 414, p. 23-30) and can be confirmed in an in vitro experimental system using cells expressing human 5-HT2C receptor. Specifically, for example, human 5-HT2C receptor can be forcibly expressed in HEK-293 cells derived from human fetal kidney, and the increase in intracellular calcium concentration due to the agonistic activity of the compound can be measured.

  In addition, the fact that the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is effective for the treatment or prevention of stress urinary incontinence indicates that urethral resistance in the urine accumulation phase It can be confirmed by measuring the leakage time pressure indicating Leak Point Pressure.

  Leak Point Pressure is the intravesical pressure when urine leakage occurs in the absence of detrusor contraction, and indicates the maximum urethral resistance that can resist the increase in intravesical pressure. In an animal model, it has been shown that a drug having an effect of increasing the leakage pressure is effective for treating or preventing stress urinary incontinence.

  As a method for measuring the leakage time pressure, for example, Lee et al. (International Urology Journal, 2003, Vol. 14, No. 1, p. 31-37) or Miyazato et al. (American Journal of Physiology). : Renal physology, 2008, Vol. 295, No. 1, p.F264-271), and it is reported that duloxetine, a therapeutic agent for stress urinary incontinence, increases the pressure at the time of leakage (Miyazato et al., American Journal of Physiology: Renal physology, 2008, Vol. 295, No. 1, p. F264-271).

  The tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can be used in mammals (for example, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human). ), Especially when administered to humans, it can be used as a useful medicament (especially a therapeutic or preventive agent for stress urinary incontinence).

  When the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is used clinically as a pharmaceutical, the tetrahydrobenzoflozepine represented by the above general formula (I) Derivatives or pharmacologically acceptable acid addition salts thereof may be used as they are, such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents or isotonic agents. Additives may be mixed as appropriate. Moreover, the said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers suitably. Examples of the administration form of the medicine include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or ointments for topical administration. Agents, creams or patches. Further, it may be a known continuous preparation.

  The pharmaceutical preferably contains 0.00001 to 90% by weight of the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, and 0.01 to 70%. It is more preferable to contain by weight. The dose is appropriately selected according to the patient's symptom, age and weight, and administration method. As an amount of the active ingredient for an adult, 0.1 μg to 1 g per day for an injection, 1 μg to 10 g for an oral formulation, affixed In the case of an agent, 1 μg to 10 g is preferable, and can be administered once or several times.

  Examples of the pharmacologically acceptable carrier or diluent of the pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, Sorbitol or glycine) or a lubricant (magnesium stearate, polyethylene glycol, talc, silica, etc.).

  The above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic or preventive effect or reduce the dose.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example, a reference example, and a comparative example, this invention is not limited to these.

  In addition, the commercially available compound was used about the compound which is not described in the synthesis method by the compound used for the synthesis | combination of an Example compound. “Room temperature” in the following Examples, Reference Examples and Comparative Examples usually indicates about 10 ° C. to about 35 ° C. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), m (multiple line), and brs (respectively). Wide). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technology). As the silica gel, TLC Silica gel 60 F254 (Merck KGaA) was used. NH silica (Fuji Silysia Chemical) was used as the amino silica gel. All solvents were commercially available. YFLC W-prep2XY (Yamazensha) was used for flash chromatography.

２−ブロモフェノール（１０ｇ、５８ｍｍｏｌ）の２−プロパノール（８．５ｍＬ）／トルエン（１５ｍＬ）／水（１．５ｍＬ）溶液に、水酸化カリウム（３．２ｇ、５８ｍｍｏｌ）を加え、８０℃で４０分間撹拌した。反応混合物に、ヒドロキシルアミン−Ｏ−スルホン酸（１．６ｇ、１４ｍｍｏｌ）の水（８．５ｍＬ）溶液を５０分間かけて滴下し、８０℃で４０分間撹拌した。反応混合物を室温まで冷却後、１０重量％の水酸化ナトリウム水溶液を加え、ジエチルエーテルで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をアミノシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９０／１０）で精製し、表題化合物（０．９２ｇ、褐色油状物、収率３４％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.53 (1H, dd, J = 8.3, 1.5 Hz), 7.47 (1H, dd, J = 7.9, 1.6 Hz), 7.30-7.26 (1H, m), 6.84 (1H, td, J = 7.3, 1.5 Hz), 6.03 (2H, brs). Reference Example 1 Synthesis of O- (2-bromophenyl) hydroxylamine:

To a solution of 2-bromophenol (10 g, 58 mmol) in 2-propanol (8.5 mL) / toluene (15 mL) / water (1.5 mL), potassium hydroxide (3.2 g, 58 mmol) was added, and Stir for minutes. To the reaction mixture, a solution of hydroxylamine-O-sulfonic acid (1.6 g, 14 mmol) in water (8.5 mL) was added dropwise over 50 minutes, and the mixture was stirred at 80 ° C. for 40 minutes. The reaction mixture was cooled to room temperature, 10% by weight aqueous sodium hydroxide solution was added, and the mixture was extracted twice with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was subjected to amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 90/10). To give the title compound (0.92 g, brown oil, 34% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.53 (1H, dd, J = 8.3, 1.5 Hz), 7.47 (1H, dd, J = 7.9, 1.6 Hz), 7.30-7.26 (1H, m), 6.84 ( 1H, td, J = 7.3, 1.5 Hz), 6.03 (2H, brs).

３−ブロモフェノール（１５ｇ、８７ｍｍｏｌ）の２−プロパノール（１３ｍＬ）／トルエン（２２ｍＬ）／水（２．２ｍＬ）溶液に、水酸化カリウム（４．７ｇ、８７ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応混合物に、ヒドロキシルアミン−Ｏ−スルホン酸（２．５ｇ、２２ｍｍｏｌ）の水（１３ｍＬ）溶液を３０分間かけて滴下し、８０℃で１時間撹拌した。反応混合物を室温まで冷却後、１０重量％の水酸化ナトリウム水溶液を加え、ジエチルエーテルで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をアミノシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９０／１０）で精製し、表題化合物（１．４ｇ、褐色油状物、収率３５％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.38 (1H, t, J = 2.2 Hz), 7.12 (1H, t, J = 7.9 Hz), 7.07 (1H, dt, J = 7.8, 1.6 Hz), 7.02 (1H, dq, J = 7.8, 1.2 Hz), 5.87 (2H, brs). Reference Example 2 Synthesis of O- (3-bromophenyl) hydroxylamine:

To a solution of 3-bromophenol (15 g, 87 mmol) in 2-propanol (13 mL) / toluene (22 mL) / water (2.2 mL) was added potassium hydroxide (4.7 g, 87 mmol), and the mixture was stirred at 80 ° C. for 1 hour. did. To the reaction mixture, a solution of hydroxylamine-O-sulfonic acid (2.5 g, 22 mmol) in water (13 mL) was added dropwise over 30 minutes, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 10% by weight aqueous sodium hydroxide solution was added, and the mixture was extracted twice with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was subjected to amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 90/10). To give the title compound (1.4 g, brown oil, 35% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.38 (1H, t, J = 2.2 Hz), 7.12 (1H, t, J = 7.9 Hz), 7.07 (1H, dt, J = 7.8, 1.6 Hz), 7.02 (1H, dq, J = 7.8, 1.2 Hz), 5.87 (2H, brs).

４−ブロモフェノール（１０ｇ、５８ｍｍｏｌ）の２−プロパノール（８．５ｍＬ）／トルエン（１５ｍＬ）／水（１．５ｍＬ）溶液に、水酸化カリウム（３．２ｇ、５８ｍｍｏｌ）を加え、８０℃で５０分間撹拌した。反応混合物に、ヒドロキシルアミン−Ｏ−スルホン酸（３．３ｇ、２９ｍｍｏｌ）の水（８．５ｍＬ）溶液を４０分間かけて滴下し、８０℃で２時間撹拌した。反応混合物を室温まで冷却後、１０重量％の水酸化ナトリウム水溶液を加え、ジエチルエーテルで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をアミノシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜８８／１２）で精製し、表題化合物（１．７ｇ、褐色油状物、収率３１％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.36 (2H, d, J = 6.2, 3.9 Hz), 7.03 (2H, t, J = 6.2, 3.9 Hz), 5.86 (2H, brs). Reference Example 3 Synthesis of O- (4-bromophenyl) hydroxylamine:

To a solution of 4-bromophenol (10 g, 58 mmol) in 2-propanol (8.5 mL) / toluene (15 mL) / water (1.5 mL) was added potassium hydroxide (3.2 g, 58 mmol), and 50 ° C. at 50 ° C. Stir for minutes. To the reaction mixture, a solution of hydroxylamine-O-sulfonic acid (3.3 g, 29 mmol) in water (8.5 mL) was added dropwise over 40 minutes and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, 10% by weight aqueous sodium hydroxide solution was added, and the mixture was extracted twice with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was subjected to amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 88/12). To give the title compound (1.7 g, brown oil, 31% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.36 (2H, d, J = 6.2, 3.9 Hz), 7.03 (2H, t, J = 6.2, 3.9 Hz), 5.86 (2H, brs).

Ｏ−（２−ブロモフェニル）ヒドロキシルアミン（２００ｍｇ、１．１ｍｍｏｌ）及びアゼパン−４−オン塩酸塩（２５０ｍｇ、１．２ｍｍｏｌ）の酢酸（１．３ｍＬ）溶液に、濃硫酸（０．１５ｍＬ）を加え、１００℃で２時間撹拌した。反応混合物を室温まで冷却後、濃縮した。得られた濃縮物にジクロロメタン及び水を加え、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、７−ブロモ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピンを得た。得られた７−ブロモ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピンをジクロロメタン（１０ｍＬ）に溶解し、ジ−ｔｅｒｔ−ブチルジカルボナート（４６４ｍｇ、２．１ｍｍｏｌ）を加え、室温で１２時間撹拌した。反応混合物を濃縮し、シリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜８４／１６）で精製し、表題化合物（３７ｍｇ、無色油状物、収率９．３％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.38 (1H, d, J = 7.8 Hz), 7.33 (1H, t, J = 7.0 Hz), 7.08 (1H, t, J = 7.8 Hz), 3.69 (4H, td, J = 11.8, 6.2 Hz), 3.17 (1H, t, J = 5.4 Hz), 3.13 (1H, t, J = 5.6 Hz), 2.86 (1H, t, J = 5.2 Hz), 2.81 (1H, t, J = 5.5 Hz), 1.49 (9H, s).
MS(ESI) : 310 (M-tBu+H)⁺. Reference Example 4 Synthesis of tert-butyl 7-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

To a solution of O- (2-bromophenyl) hydroxylamine (200 mg, 1.1 mmol) and azepan-4-one hydrochloride (250 mg, 1.2 mmol) in acetic acid (1.3 mL) was added concentrated sulfuric acid (0.15 mL). In addition, the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. Dichloromethane and water were added to the resulting concentrate, neutralized with a saturated aqueous sodium carbonate solution, and extracted twice with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 7-bromo-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine. The obtained 7-bromo-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (464 mg, 2. 1 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 84/16) to give the title compound (37 mg, colorless oil, yield 9.3%). Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.38 (1H, d, J = 7.8 Hz), 7.33 (1H, t, J = 7.0 Hz), 7.08 (1H, t, J = 7.8 Hz), 3.69 (4H , td, J = 11.8, 6.2 Hz), 3.17 (1H, t, J = 5.4 Hz), 3.13 (1H, t, J = 5.6 Hz), 2.86 (1H, t, J = 5.2 Hz), 2.81 (1H , t, J = 5.5 Hz), 1.49 (9H, s).
MS (ESI): 310 (M-tBu + H) ⁺ .

Ｏ−（４−ブロモフェニル）ヒドロキシルアミン（１７６ｍｇ、０．９４ｍｍｏｌ）の２−プロパノール（１．６ｍＬ）溶液に、アゼパン−４−オン塩酸塩（１４０ｍｇ、０．９４ｍｍｏｌ）及び濃塩酸（０．４３ｍＬ）を加え、９０℃で１３時間撹拌した。反応混合物を室温まで冷却後、濃縮した。得られた濃縮物の２−プロパノール（２．３ｍＬ）／水（２．３ｍＬ）溶液に、炭酸カリウム（３８８ｍｇ、２．８ｍｍｏｌ）及びジ−ｔｅｒｔ−ブチルジカルボナート（６１９ｍｇ、２．８ｍｍｏｌ）を加え、室温で２時間撹拌した。反応混合物を濃縮し、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９１／９）で精製し、表題化合物（８０ｍｇ、無色油状物、収率２３％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.51 (1H, d, J = 2.3 Hz), 7.31 (1H, dd, J = 8.4, 2.3 Hz), 7.23 (1H, d, J = 8.6 Hz), 3.68 (4H, td, J = 11.3, 5.3 Hz), 3.11 (1H, t, J = 5.4 Hz), 3.05 (1H, t, J = 5.2 Hz), 2.82 (1H, t, J = 5.4 Hz), 2.78 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS(ESI) : 310 (M-tBu+H)⁺. Reference Example 5 Synthesis of tert-butyl 9-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

To a solution of O- (4-bromophenyl) hydroxylamine (176 mg, 0.94 mmol) in 2-propanol (1.6 mL) was added azepan-4-one hydrochloride (140 mg, 0.94 mmol) and concentrated hydrochloric acid (0.43 mL). ) And stirred at 90 ° C. for 13 hours. The reaction mixture was cooled to room temperature and concentrated. To a solution of the obtained concentrate in 2-propanol (2.3 mL) / water (2.3 mL), potassium carbonate (388 mg, 2.8 mmol) and di-tert-butyl dicarbonate (619 mg, 2.8 mmol) were added. The mixture was further stirred at room temperature for 2 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 91/9). Purification gave the title compound (80 mg, colorless oil, 23% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.51 (1H, d, J = 2.3 Hz), 7.31 (1H, dd, J = 8.4, 2.3 Hz), 7.23 (1H, d, J = 8.6 Hz), 3.68 (4H, td, J = 11.3, 5.3 Hz), 3.11 (1H, t, J = 5.4 Hz), 3.05 (1H, t, J = 5.2 Hz), 2.82 (1H, t, J = 5.4 Hz), 2.78 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS (ESI): 310 (M-tBu + H) ⁺ .

Ｏ−（３−ブロモフェニル）ヒドロキシルアミン（３００ｍｇ、１．６ｍｍｏｌ）の２−プロパノール（２．７ｍＬ）溶液に、アゼパン−４−オン塩酸塩（２３９ｍｇ、１．６ｍｍｏｌ）及び濃塩酸（０．３６ｍＬ）を加え、９０℃で５時間撹拌した。反応混合物を室温まで冷却後、濃縮した。得られた濃縮物に酢酸エチル及び水を加え、飽和炭酸ナトリウム水溶液で中和し、酢酸エチルで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、８−ブロモ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン及び１０−ブロモ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピンの混合物を得た。得られた混合物をジクロロメタン（１０ｍＬ）に溶解し、ジ−ｔｅｒｔ−ブチルジカルボナート（３１４ｍｇ、２．１ｍｍｏｌ）を加え、室温で１４時間撹拌した。反応混合物を濃縮し、シリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９６／４〜８５／１５）で精製し、ｔｅｒｔ−ブチル ８−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（９８ｍｇ、無色油状物、収率１７％）及びｔｅｒｔ−ブチル １０−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（５８ｍｇ、無色油状物、収率１０％）を得た。
ｔｅｒｔ−ブチル ８−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート：
¹H NMR (400MHz, CDCl₃) δ: 7.53 (1H, s), 7.32 (1H, dd, J = 8.3, 1.7 Hz), 7.24 (1H, d, J = 7.4 Hz), 3.68 (4H, td, J = 11.8, 5.9 Hz), 3.09 (1H, t, J = 5.2 Hz), 3.04 (1H, t, J = 5.2 Hz), 2.84 (1H, t, J = 5.1 Hz), 2.79 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS(ESI) : 310 (M-tBu+H)⁺.
ｔｅｒｔ−ブチル １０−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート：
¹H NMR (400MHz, CDCl₃) δ: 7.33 (1H, d, J = 7.6 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 8.0 Hz), 3.74-3.66 (4H, m), 3.34 (1H, t, J = 4.9 Hz), 3.29 (1H, t, J = 5.0 Hz), 3.10 (1H, t, J = 5.5 Hz), 3.06 (1H, t, J = 5.5 Hz), 1.50 (9H, s).
MS(ESI) : 310 (M-tBu+H)⁺. Reference Example 6 tert-butyl 8-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate and tert-butyl 10-bromo-4,5-dihydro Synthesis of -1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

To a solution of O- (3-bromophenyl) hydroxylamine (300 mg, 1.6 mmol) in 2-propanol (2.7 mL) was added azepan-4-one hydrochloride (239 mg, 1.6 mmol) and concentrated hydrochloric acid (0.36 mL). ) And stirred at 90 ° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated. Ethyl acetate and water were added to the resulting concentrate, neutralized with a saturated aqueous sodium carbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, then 8-bromo-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine and 10-bromo-2. , 3,4,5-Tetrahydro-1H-benzofuro [2,3-d] azepine was obtained. The obtained mixture was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (314 mg, 2.1 mmol) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated, purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 96/4 to 85/15), and tert-butyl 8-bromo-4,5-dihydro- 1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (98 mg, colorless oil, 17% yield) and tert-butyl 10-bromo-4,5-dihydro-1H-benzofuro [2 , 3-d] azepine-3 (2H) -carboxylate (58 mg, colorless oil, 10% yield).
tert-Butyl 8-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.53 (1H, s), 7.32 (1H, dd, J = 8.3, 1.7 Hz), 7.24 (1H, d, J = 7.4 Hz), 3.68 (4H, td, J = 11.8, 5.9 Hz), 3.09 (1H, t, J = 5.2 Hz), 3.04 (1H, t, J = 5.2 Hz), 2.84 (1H, t, J = 5.1 Hz), 2.79 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS (ESI): 310 (M-tBu + H) ⁺ .
tert-Butyl 10-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.33 (1H, d, J = 7.6 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 8.0 Hz), 3.74-3.66 (4H, m), 3.34 (1H, t, J = 4.9 Hz), 3.29 (1H, t, J = 5.0 Hz), 3.10 (1H, t, J = 5.5 Hz), 3.06 (1H, t, J = 5.5 Hz), 1.50 (9H, s).
MS (ESI): 310 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル ７−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（３５ｍｇ、０．０９６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）溶液に、ビスピナコールジボラン（４８ｍｇ、０．１９ｍｍｏｌ）、１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（１２ｍｇ、０．０１４ｍｍｏｌ）及び酢酸カリウム（２８ｍｇ、０．２９ｍｍｏｌ）を加え、８０℃で１２時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮した。得られた粗生成物をＴＨＦ（１．０ｍＬ）に溶解し、１Ｎ水酸化ナトリウム水溶液（０．１９ｍＬ）及び過酸化水素水（０．０５４ｍＬ）を０℃で加え、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和チオ硫酸ナトリウム及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝８８／１２〜６７／３３）で精製し、表題化合物（９．６ｍｇ、白色固体、収率３３％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.08 (1H, t, J = 7.8 Hz), 6.97 (1H, d, J = 6.3 Hz), 6.77 (1H, d, J = 7.8 Hz), 5.23 (1H, d, J = 14.9 Hz), 3.68 (4H, dt, J = 18.0, 6.2 Hz), 3.12 (1H, t, J = 5.5 Hz), 3.07 (1H, t, J = 5.5 Hz), 2.86 (1H, t, J = 5.2 Hz), 2.81 (1H, d, J = 5.2 Hz), 1.49 (9H, s).
MS(ESI) : 248 (M-tBu+H)⁺. Reference Example 7 Synthesis of tert-butyl 7-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 7-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (35 mg, 0.096 mmol) in N, N-dimethylformamide (1.0 mL ) Solution of bispinacol diborane (48 mg, 0.19 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (12 mg, 0.014 mmol) and potassium acetate (28 mg, 0 .29 mmol) was added and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was dissolved in THF (1.0 mL), 1N aqueous sodium hydroxide solution (0.19 mL) and hydrogen peroxide solution (0.054 mL) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate = 88 / 12- 67/33) to give the title compound (9.6 mg, white solid, yield 33%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.08 (1H, t, J = 7.8 Hz), 6.97 (1H, d, J = 6.3 Hz), 6.77 (1H, d, J = 7.8 Hz), 5.23 (1H , d, J = 14.9 Hz), 3.68 (4H, dt, J = 18.0, 6.2 Hz), 3.12 (1H, t, J = 5.5 Hz), 3.07 (1H, t, J = 5.5 Hz), 2.86 (1H , t, J = 5.2 Hz), 2.81 (1H, d, J = 5.2 Hz), 1.49 (9H, s).
MS (ESI): 248 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル ８−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（２５ｍｇ、０．０６８ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．６８ｍＬ）溶液に、ビスピナコールジボラン（３５ｍｇ、０．１４ｍｍｏｌ）、１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（８．４ｍｇ、０．０１０ｍｍｏｌ）及び酢酸カリウム（２０ｍｇ、０．２１ｍｍｏｌ）を加え、８０℃で１３時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮した。得られた粗生成物をＴＨＦ（０．６８ｍＬ）に溶解し、１Ｎ水酸化ナトリウム水溶液（０．１４ｍＬ）及び過酸化水素水（０．０３９ｍＬ）を０℃で加え、室温で２．５時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和チオ硫酸ナトリウム及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝８８／１２〜６７／３３）で精製し、表題化合物（１７ｍｇ、白色固体、収率８３％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.20 (1H, t, J = 8.3 Hz), 6.88 (1H, d, J = 2.2 Hz), 6.75 (1H, dd, J = 8.4, 2.6 Hz), 5.15 (1H, br s), 3.67 (4H, dt, J = 18.9, 6.6 Hz), 3.07 (1H, t, J = 5.5 Hz), 3.02 (1H, t, J = 5.2 Hz), 2.82 (1H, t, J = 5.4 Hz), 2.78 (1H, t, J = 5.1 Hz), 1.49 (9H, s).
MS(ESI) : 248 (M-tBu+H)⁺. Reference Example 8 Synthesis of tert-butyl 8-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 8-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (25 mg, 0.068 mmol) in N, N-dimethylformamide (0.68 mL ) Solution of bispinacol diborane (35 mg, 0.14 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (8.4 mg, 0.010 mmol) and potassium acetate (20 mg). 0.21 mmol), and the mixture was stirred at 80 ° C. for 13 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was dissolved in THF (0.68 mL), 1N aqueous sodium hydroxide solution (0.14 mL) and hydrogen peroxide solution (0.039 mL) were added at 0 ° C., and the mixture was stirred at room temperature for 2.5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate = 88 / 12- 67/33) to give the title compound (17 mg, white solid, 83% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.20 (1H, t, J = 8.3 Hz), 6.88 (1H, d, J = 2.2 Hz), 6.75 (1H, dd, J = 8.4, 2.6 Hz), 5.15 (1H, br s), 3.67 (4H, dt, J = 18.9, 6.6 Hz), 3.07 (1H, t, J = 5.5 Hz), 3.02 (1H, t, J = 5.2 Hz), 2.82 (1H, t , J = 5.4 Hz), 2.78 (1H, t, J = 5.1 Hz), 1.49 (9H, s).
MS (ESI): 248 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル ９−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（３０ｍｇ、０．０８２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．８２ｍＬ）溶液に、ビスピナコールジボラン（４２ｍｇ、０．１６ｍｍｏｌ）、１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（８．４ｍｇ、０．０１０ｍｍｏｌ）及び酢酸カリウム（１０ｍｇ、０．１２ｍｍｏｌ）を加え、８０℃で１３時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮した。得られた粗生成物をＴＨＦ（０．８２ｍＬ）に溶解し、１Ｎ水酸化ナトリウム水溶液（０．１６ｍＬ）及び過酸化水素水（０．０４６ｍＬ）を０℃で加え、室温で１．５時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和チオ硫酸ナトリウム及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝８４／１６〜６７／３３）で精製し、表題化合物（１７ｍｇ、白色固体、収率６９％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.21 (1H, d, J = 8.5 Hz), 6.82 (1H, d, J = 12.2 Hz), 6.72 (1H, brs), 3.71-3.65 (4H, m), 3.08 (1H, t, J = 5.2 Hz), 3.03 (1H, t, J = 5.5 Hz), 2.82 (1H, t, J = 5.5 Hz), 2.75 (1H, t, J = 5.5 Hz), 1.49 (9H, s).
MS(ESI) : 248 (M-tBu+H)⁺. Reference Example 9 Synthesis of tert-butyl 9-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 9-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (30 mg, 0.082 mmol) in N, N-dimethylformamide (0.82 mL ) Solution of bispinacol diborane (42 mg, 0.16 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (8.4 mg, 0.010 mmol) and potassium acetate (10 mg). 0.12 mmol), and the mixture was stirred at 80 ° C. for 13 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was dissolved in THF (0.82 mL), 1N aqueous sodium hydroxide solution (0.16 mL) and hydrogen peroxide solution (0.046 mL) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate = 84/16 to 67/33) to give the title compound (17 mg, white solid, 69% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.21 (1H, d, J = 8.5 Hz), 6.82 (1H, d, J = 12.2 Hz), 6.72 (1H, brs), 3.71-3.65 (4H, m) , 3.08 (1H, t, J = 5.2 Hz), 3.03 (1H, t, J = 5.5 Hz), 2.82 (1H, t, J = 5.5 Hz), 2.75 (1H, t, J = 5.5 Hz), 1.49 (9H, s).
MS (ESI): 248 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル １０−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（１６６ｍｇ、０．４５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（４．５ｍＬ）溶液に、ビスピナコールジボラン（２３０ｍｇ、０．９１ｍｍｏｌ）、１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（５６ｍｇ、０．０６８ｍｍｏｌ）及び酢酸カリウム（１３３ｍｇ、１．４ｍｍｏｌ）を加え、８０℃で１３時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮した。得られた粗生成物をＴＨＦ（４．５ｍＬ）に溶解し、１Ｎ水酸化ナトリウム水溶液（０．９０ｍＬ）及び過酸化水素水（０．２６ｍＬ）を０℃で加え、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和チオ硫酸ナトリウム及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝８９／１１〜６８／３２）で精製し、表題化合物（１０８ｍｇ、白色固体、収率７９％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.01 (1H, t, J = 7.9 Hz), 6.95 (1H, t, J = 9.9 Hz), 6.50 (1H, dd, J = 10.0, 7.8 Hz), 3.71-3.66 (4H, m), 3.26 (1H, t, J = 5.1 Hz), 3.16 (1H, t, J = 5.5 Hz), 3.07 (1H, t, J = 5.0 Hz), 3.02 (1H, t, J = 5.7 Hz), 1.49 (9H, s).
MS(ESI) : 248 (M-tBu+H)⁺. Reference Example 10 Synthesis of tert-butyl 10-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 10-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (166 mg, 0.45 mmol) in N, N-dimethylformamide (4.5 mL ) Solution of bispinacol diborane (230 mg, 0.91 mmol), 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (56 mg, 0.068 mmol) and potassium acetate (133 mg, 1 .4 mmol) was added and stirred at 80 ° C. for 13 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was dissolved in THF (4.5 mL), 1N aqueous sodium hydroxide solution (0.90 mL) and hydrogen peroxide solution (0.26 mL) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate = 89 / 11- 68/32) to give the title compound (108 mg, white solid, yield 79%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.01 (1H, t, J = 7.9 Hz), 6.95 (1H, t, J = 9.9 Hz), 6.50 (1H, dd, J = 10.0, 7.8 Hz), 3.71 -3.66 (4H, m), 3.26 (1H, t, J = 5.1 Hz), 3.16 (1H, t, J = 5.5 Hz), 3.07 (1H, t, J = 5.0 Hz), 3.02 (1H, t, J = 5.7 Hz), 1.49 (9H, s).
MS (ESI): 248 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル ７−ヒドロキシ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（９．６ｍｇ、０．０３２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．３１ｍＬ）溶液に、炭酸カリウム（８．８ｍｇ、０．０６４ｍｍｏｌ）及びヨードメタン（３．０μＬ、０．０４７ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜８１／１９）で精製し、表題化合物（７．６ｍｇ、無色油状物、７５％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.13 (1H, t, J = 7.8 Hz), 7.01 (1H, d, J = 6.6 Hz), 6.76 (1H, d, J = 7.8 Hz), 4.00 (3H, s), 3.72-3.64 (4H, m), 3.14 (1H, t, J = 5.4 Hz), 3.09 (1H, t, J = 5.2 Hz), 2.86 (1H, t, J = 5.1 Hz), 2.81 (1H, t, J = 5.4 Hz), 1.49 (9H, s).
MS(ESI) : 262 (M-tBu+H)⁺. Reference Example 11 Synthesis of tert-butyl 7-methoxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 7-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (9.6 mg, 0.032 mmol) in N, N-dimethylformamide (0 .31 mL) solution was added potassium carbonate (8.8 mg, 0.064 mmol) and iodomethane (3.0 μL, 0.047 mmol) at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 81/19). Purification gave the title compound (7.6 mg, colorless oil, 75%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.13 (1H, t, J = 7.8 Hz), 7.01 (1H, d, J = 6.6 Hz), 6.76 (1H, d, J = 7.8 Hz), 4.00 (3H , s), 3.72-3.64 (4H, m), 3.14 (1H, t, J = 5.4 Hz), 3.09 (1H, t, J = 5.2 Hz), 2.86 (1H, t, J = 5.1 Hz), 2.81 (1H, t, J = 5.4 Hz), 1.49 (9H, s).
MS (ESI): 262 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル ８−ヒドロキシ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（７．０ｍｇ、０．０２３ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．２３ｍＬ）溶液に、炭酸カリウム（６．４ｍｇ、０．０４６ｍｍｏｌ）及びヨードメタン（２．２μＬ、０．０３５ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜８１／１９）で精製し、表題化合物（７．５ｍｇ、無色油状物、１００％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.24 (1H, d, J = 7.3 Hz), 6.93 (1H, s), 6.84 (1H, dd, J = 8.5, 2.2 Hz), 3.84 (3H, s), 3.71-3.64 (4H, m), 3.08 (1H, t, J = 5.5 Hz), 3.03 (1H, t, J = 5.1 Hz), 2.83 (1H, t, J = 5.1 Hz), 2.79 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS(ESI) : 262 (M-tBu+H)⁺. Reference Example 12 Synthesis of tert-butyl 8-methoxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 8-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (7.0 mg, 0.023 mmol) in N, N-dimethylformamide (0 .23 mL) solution was added potassium carbonate (6.4 mg, 0.046 mmol) and iodomethane (2.2 μL, 0.035 mmol) at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 81/19). Purification gave the title compound (7.5 mg, colorless oil, 100%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.24 (1H, d, J = 7.3 Hz), 6.93 (1H, s), 6.84 (1H, dd, J = 8.5, 2.2 Hz), 3.84 (3H, s) , 3.71-3.64 (4H, m), 3.08 (1H, t, J = 5.5 Hz), 3.03 (1H, t, J = 5.1 Hz), 2.83 (1H, t, J = 5.1 Hz), 2.79 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS (ESI): 262 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル ９−ヒドロキシ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（１５ｍｇ、０．０４９ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．４９ｍＬ）溶液に、炭酸カリウム（１４ｍｇ、０．０９９ｍｍｏｌ）及びヨードメタン（４．６μＬ、０．０７４ｍｍｏｌ）を０℃で加え、室温で６時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜８０／２０）で精製し、表題化合物（１２ｍｇ、無色油状物、７９％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.26 (1H, d, J = 9.0 Hz), 6.85 (1H, d, J = 2.4 Hz), 6.82 (1H, dd, J = 8.8, 2.7 Hz), 3.84 (3H, s), 3.72-3.64 (4H, m), 3.09 (1H, t, J = 5.1 Hz), 3.04 (1H, t, J = 5.1 Hz), 2.83 (1H, t, J = 5.2 Hz), 2.80 (1H, t, J = 5.0 Hz), 1.49 (9H, s).
MS(ESI) : 262 (M-tBu+H)⁺. Reference Example 13 Synthesis of tert-butyl 9-methoxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 9-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (15 mg, 0.049 mmol) in N, N-dimethylformamide (0.49 mL ) To the solution were added potassium carbonate (14 mg, 0.099 mmol) and iodomethane (4.6 μL, 0.074 mmol) at 0 ° C., and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 80/20). Purification gave the title compound (12 mg, colorless oil, 79%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.26 (1H, d, J = 9.0 Hz), 6.85 (1H, d, J = 2.4 Hz), 6.82 (1H, dd, J = 8.8, 2.7 Hz), 3.84 (3H, s), 3.72-3.64 (4H, m), 3.09 (1H, t, J = 5.1 Hz), 3.04 (1H, t, J = 5.1 Hz), 2.83 (1H, t, J = 5.2 Hz) , 2.80 (1H, t, J = 5.0 Hz), 1.49 (9H, s).
MS (ESI): 262 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル １０−ヒドロキシ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（９０ｍｇ、０．３０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２．９ｍＬ）溶液に、炭酸カリウム（８２ｍｇ、０．５９ｍｍｏｌ）及びヨードメタン（２８μＬ、０．４５ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜８０／２０）で精製し、表題化合物（８９ｍｇ、無色油状物、９４％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.11 (1H, t, J = 8.2 Hz), 6.99 (1H, d, J = 8.3 Hz), 6.60 (1H, d, J = 8.0 Hz), 3.88 (3H, d, J = 6.6 Hz), 3.69-3.62 (4H, m), 3.19 (1H, t, J = 5.2 Hz), 3.15 (1H, t, J = 4.9 Hz), 3.07 (1H, t, J = 5.6 Hz), 3.02 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS(ESI) : 262 (M-tBu+H)⁺. Reference Example 14 Synthesis of tert-butyl 10-methoxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 10-hydroxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (90 mg, 0.30 mmol) in N, N-dimethylformamide (2.9 mL) ) To the solution were added potassium carbonate (82 mg, 0.59 mmol) and iodomethane (28 μL, 0.45 mmol) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 80/20). Purification gave the title compound (89 mg, colorless oil, 94%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.11 (1H, t, J = 8.2 Hz), 6.99 (1H, d, J = 8.3 Hz), 6.60 (1H, d, J = 8.0 Hz), 3.88 (3H , d, J = 6.6 Hz), 3.69-3.62 (4H, m), 3.19 (1H, t, J = 5.2 Hz), 3.15 (1H, t, J = 4.9 Hz), 3.07 (1H, t, J = 5.6 Hz), 3.02 (1H, t, J = 5.2 Hz), 1.49 (9H, s).
MS (ESI): 262 (M-tBu + H) ⁺ .

７−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（７．６ｍｇ、０．０２４ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（４．５ｍｇ、白色固体、収率７４％、以下、実施例１の化合物）を得た。
¹H NMR (400MHz, DMSO-d₆) δ: 9.31 (1H, brs), 7.17 (1H, t, J = 7.8 Hz), 7.11 (1H, dd, J = 7.8, 1.0 Hz), 6.90 (1H, d, J = 7.8 Hz), 3.91 (3H, s), 3.36 (4H, t, J = 5.6 Hz), 3.23 (2H, t, J = 5.1 Hz), 2.99 (2H, t, J = 5.1 Hz).
MS(ESI) : 218 (M+H)⁺. Example 1 Synthesis of 7-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a 1,4-dioxane solution of 7-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (7.6 mg, 0.024 mmol) was added 4N hydrogen chloride / 1,4. -The dioxane solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (4.5 mg, white solid, yield 74%, hereinafter, the compound of Example 1).
¹ H NMR (400MHz, DMSO-d ₆ ) δ: 9.31 (1H, brs), 7.17 (1H, t, J = 7.8 Hz), 7.11 (1H, dd, J = 7.8, 1.0 Hz), 6.90 (1H, d, J = 7.8 Hz), 3.91 (3H, s), 3.36 (4H, t, J = 5.6 Hz), 3.23 (2H, t, J = 5.1 Hz), 2.99 (2H, t, J = 5.1 Hz) .
MS (ESI): 218 (M + H) ⁺ .

８−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（７．５ｍｇ、０．０２３ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（４．５ｍｇ、白色固体、収率７４％、以下、比較例１の化合物）を得た。
¹H NMR (400MHz, CD₃OD) δ: 7.35 (1H, dd, J = 8.5, 2.0 Hz), 7.00 (1H, t, J = 2.2 Hz), 6.87 (1H, dt, J = 8.5, 2.3 Hz), 3.85 (3H, d, J = 2.4 Hz), 3.49 (4H, q, J = 5.8 Hz), 3.27 (2H, t, J = 5.7 Hz), 3.06 (2H, t, J = 5.6 Hz).
MS(ESI) : 218 (M+H)⁺. Comparative Example 1 Synthesis of 8-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a 1,4-dioxane solution of 8-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (7.5 mg, 0.023 mmol) 4N hydrogen chloride / 1,4 -The dioxane solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (4.5 mg, white solid, yield 74%, hereinafter, the compound of Comparative Example 1).
¹ H NMR (400MHz, CD ₃ OD) δ: 7.35 (1H, dd, J = 8.5, 2.0 Hz), 7.00 (1H, t, J = 2.2 Hz), 6.87 (1H, dt, J = 8.5, 2.3 Hz) ), 3.85 (3H, d, J = 2.4 Hz), 3.49 (4H, q, J = 5.8 Hz), 3.27 (2H, t, J = 5.7 Hz), 3.06 (2H, t, J = 5.6 Hz).
MS (ESI): 218 (M + H) ⁺ .

９−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（１２ｍｇ、０．０３９ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（８．９ｍｇ、白色固体、収率９０％、以下、実施例２の化合物）を得た。
¹H NMR (400MHz, DMSO-d₆) δ: 9.23 (1H, brs), 7.39 (1H, d, J = 8.9 Hz), 7.09 (1H, d, J = 2.4 Hz), 6.85 (1H, dd, J = 9.0, 2.7 Hz), 3.78 (3H, s), 3.38-3.35 (4H, m), 3.21 (2H, t, J = 5.5 Hz), 3.00 (2H, t, J = 5.6 Hz).
MS(ESI) : 218 (M+H)⁺. Example 2 Synthesis of 9-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a 1,4-dioxane solution of 9-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (12 mg, 0.039 mmol), 4N hydrogen chloride / 1,4-dioxane. The solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (8.9 mg, white solid, yield 90%, hereinafter, the compound of Example 2).
¹ H NMR (400MHz, DMSO-d ₆ ) δ: 9.23 (1H, brs), 7.39 (1H, d, J = 8.9 Hz), 7.09 (1H, d, J = 2.4 Hz), 6.85 (1H, dd, J = 9.0, 2.7 Hz), 3.78 (3H, s), 3.38-3.35 (4H, m), 3.21 (2H, t, J = 5.5 Hz), 3.00 (2H, t, J = 5.6 Hz).
MS (ESI): 218 (M + H) ⁺ .

１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（６．３ｍｇ、０．０２０ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（３．３ｍｇ、白色固体、収率６５％、以下、実施例３の化合物）を得た。
¹H NMR (400MHz, CD₃OD) δ: 7.18 (1H, t, J = 8.2 Hz), 7.00 (1H, t, J = 8.3 Hz), 6.72 (1H, d, J = 8.0 Hz), 3.90 (3H, s), 3.49-3.46 (4H, m), 3.39 (2H, t, J = 5.7 Hz), 3.25 (2H, t, J = 5.7 Hz).
MS(ESI) : 218 (M+H)⁺. Example 3 Synthesis of 10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a 1,4-dioxane solution of 10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (6.3 mg, 0.020 mmol) 4N hydrogen chloride / 1,4 -The dioxane solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (3.3 mg, white solid, yield 65%, hereinafter, the compound of Example 3).
¹ H NMR (400MHz, CD ₃ OD) δ: 7.18 (1H, t, J = 8.2 Hz), 7.00 (1H, t, J = 8.3 Hz), 6.72 (1H, d, J = 8.0 Hz), 3.90 ( 3H, s), 3.49-3.46 (4H, m), 3.39 (2H, t, J = 5.7 Hz), 3.25 (2H, t, J = 5.7 Hz).
MS (ESI): 218 (M + H) ⁺ .

ｔｅｒｔ−ブチル ７−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（９０ｍｇ、０．２５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２．５ｍＬ）溶液に、メチルメルカプタンナトリウム（６９ｍｇ、０．９８ｍｍｏｌ）及び１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（４０ｍｇ、０．０４９ｍｍｏｌ）を加え、１５０℃で１５時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９４／６）で精製し、ｔｅｒｔ−ブチル ７−（メチルチオ）−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート及びｔｅｒｔ−ブチル ４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラートの混合物（７４ｍｇ）を得た。得られた混合物をジクロロメタン（２．０ｍＬ）に溶解し、トリフルオロ酢酸（０．１７ｍＬ）を加え、室温で１３時間撹拌した。反応混合物に飽和重曹水を加え中和し、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９６／４〜８６／１４）で精製し、表題化合物（２１ｍｇ、無色油状物、収率３６％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.26-7.24 (1H, m), 7.18-7.13 (2H, m), 3.13-3.08 (6H, m), 2.76 (2H, t, J = 5.4 Hz), 2.58 (3H, s).
MS(ESI) : 234 (M+H)⁺. Reference Example 15 Synthesis of 7- (methylthio) -2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine:

tert-Butyl 7-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (90 mg, 0.25 mmol) in N, N-dimethylformamide (2.5 mL ) To the solution were added methyl mercaptan sodium (69 mg, 0.98 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (40 mg, 0.049 mmol), and 15 ° C. at 15 ° C. Stir for hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 94/6). Purified, tert-butyl 7- (methylthio) -4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate and tert-butyl 4,5-dihydro-1H-benzofuro A mixture of [2,3-d] azepine-3 (2H) -carboxylate (74 mg) was obtained. The obtained mixture was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (0.17 mL) was added, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform / methanol = 96/4 to 86/14), The title compound (21 mg, colorless oil, yield 36%) was obtained.
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.26-7.24 (1H, m), 7.18-7.13 (2H, m), 3.13-3.08 (6H, m), 2.76 (2H, t, J = 5.4 Hz), 2.58 (3H, s).
MS (ESI): 234 (M + H) ⁺ .

ｔｅｒｔ−ブチル ９−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（４５ｍｇ、０．１２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１．２ｍＬ）溶液に、メチルメルカプタンナトリウム（３４ｍｇ、０．４９ｍｍｏｌ）及び１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（１２ｍｇ、０．０１４ｍｍｏｌ）を加え、１５０℃で１２時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９３／７）で精製し、表題化合物（８．３ｍｇ、無色油状物、収率２０％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.36 (1H, s), 7.30 (1H, d, J = 8.5 Hz), 7.21 (1H, dd, J = 8.5, 1.7 Hz), 3.68 (4H, dt, J = 18.0, 6.5 Hz), 3.10 (1H, t, J = 5.4 Hz), 3.05 (1H, t, J = 5.2 Hz), 2.85 (1H, t, J = 5.6 Hz), 2.80 (1H, t, J = 5.2 Hz), 2.51 (3H, s), 1.49 (9H, s).
MS(ESI) : 278 (M-tBu+H)⁺. Reference Example 16 Synthesis of tert-butyl 9- (methylthio) -4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 9-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (45 mg, 0.12 mmol) in N, N-dimethylformamide (1.2 mL ) To the solution were added methyl mercaptan sodium (34 mg, 0.49 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (12 mg, 0.014 mmol), and 12 at 150 ° C. Stir for hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 93/7). Purification gave the title compound (8.3 mg, colorless oil, 20% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.36 (1H, s), 7.30 (1H, d, J = 8.5 Hz), 7.21 (1H, dd, J = 8.5, 1.7 Hz), 3.68 (4H, dt, J = 18.0, 6.5 Hz), 3.10 (1H, t, J = 5.4 Hz), 3.05 (1H, t, J = 5.2 Hz), 2.85 (1H, t, J = 5.6 Hz), 2.80 (1H, t, J = 5.2 Hz), 2.51 (3H, s), 1.49 (9H, s).
MS (ESI): 278 (M-tBu + H) ⁺ .

ｔｅｒｔ−ブチル １０−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（２０ｍｇ、０．０５５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．５５ｍＬ）溶液に、メチルメルカプタンナトリウム（１５ｍｇ、０．２２ｍｍｏｌ）及び１，１’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム（ＩＩ）ジクロリド-ジクロロメタン錯体（８．９ｍｇ、０．０１１ｍｍｏｌ）加え、１５０℃で２０時間撹拌した。反応混合物を室温まで冷却後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜９３／７）で精製し、表題化合物（６．５ｍｇ、無色油状物、収率３６％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.19 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 7.7 Hz), 7.02 (1H, d, J = 7.1 Hz), 3.73-3.62 (4H, m), 3.39 (1H, t, J = 5.4 Hz), 3.33 (1H, t, J = 5.0 Hz), 3.09 (1H, t, J = 5.2 Hz), 3.05 (1H, t, J = 5.4 Hz), 2.51 (3H, s), 1.49 (9H, s).
MS(ESI) : 234 (M-Boc+H)⁺. Reference Example 17 Synthesis of tert-butyl 10- (methylthio) -4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 10-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (20 mg, 0.055 mmol) in N, N-dimethylformamide (0.55 mL) ) To the solution was added methyl mercaptan sodium (15 mg, 0.22 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (8.9 mg, 0.011 mmol) at 150 ° C. Stir for 20 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 93/7). Purification gave the title compound (6.5 mg, colorless oil, 36% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.19 (1H, d, J = 8.8 Hz), 7.15 (1H, t, J = 7.7 Hz), 7.02 (1H, d, J = 7.1 Hz), 3.73-3.62 (4H, m), 3.39 (1H, t, J = 5.4 Hz), 3.33 (1H, t, J = 5.0 Hz), 3.09 (1H, t, J = 5.2 Hz), 3.05 (1H, t, J = 5.4 Hz), 2.51 (3H, s), 1.49 (9H, s).
MS (ESI): 234 (M-Boc + H) ⁺ .

７−（メチルチオ）−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（２１ｍｇ、０．０８９ｍｍｏｌ）の酢酸エチル溶液に、１０％塩化水素／メタノール溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（１９ｍｇ、白色固体、収率８０％、以下、実施例４の化合物）を得た。
¹H NMR (400MHz, D₂O) δ: 7.30-7.28 (1H, m), 7.18-7.16 (2H, m), 3.39 (4H, t, J = 5.6 Hz), 3.19 (2H, d, J = 5.6 Hz), 2.96 (2H, t, J = 5.6 Hz), 2.44 (3H, s).
MS(ESI) : 234 (M+H)⁺. Example 4 Synthesis of 7- (methylthio) -2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a solution of 7- (methylthio) -2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (21 mg, 0.089 mmol) in ethyl acetate was added a 10% hydrogen chloride / methanol solution at room temperature. Added and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (19 mg, white solid, yield 80%, hereinafter, the compound of Example 4).
¹ H NMR (400MHz, D ₂ O) δ: 7.30-7.28 (1H, m), 7.18-7.16 (2H, m), 3.39 (4H, t, J = 5.6 Hz), 3.19 (2H, d, J = 5.6 Hz), 2.96 (2H, t, J = 5.6 Hz), 2.44 (3H, s).
MS (ESI): 234 (M + H) ⁺ .

ｔｅｒｔ−ブチル ９−（メチルチオ）−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（８．３ｍｇ、０．０２５ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（５．４ｍｇ、白色固体、収率８０％、以下、実施例５の化合物）を得た。
¹H NMR (400MHz, D₂O) δ: 7.37 (1H, d, J = 2.0 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.17 (1H, dd, J = 8.7, 1.8 Hz), 3.41-3.38(4H, m), 3.16 (2H, t, J = 5.7 Hz), 2.95 (2H, t, J = 5.6 Hz), 2.39 (3H, s).
MS(ESI) : 234 (M+H)⁺. Example 5 Synthesis of 9- (methylthio) -2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

1,4-Dioxane solution of tert-butyl 9- (methylthio) -4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (8.3 mg, 0.025 mmol) 4N hydrogen chloride / 1,4-dioxane solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (5.4 mg, white solid, yield 80%, hereinafter, the compound of Example 5).
¹ H NMR (400MHz, D ₂ O) δ: 7.37 (1H, d, J = 2.0 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.17 (1H, dd, J = 8.7, 1.8 Hz), 3.41-3.38 (4H, m), 3.16 (2H, t, J = 5.7 Hz), 2.95 (2H, t, J = 5.6 Hz), 2.39 (3H, s).
MS (ESI): 234 (M + H) ⁺ .

ｔｅｒｔ−ブチル １０−（メチルチオ）−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（５．５ｍｇ、０．０１６ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（３．２ｍｇ、白色固体、収率７５％、以下、実施例６の化合物）を得た。
¹H NMR (400MHz, D₂O) δ: 7.20 (1H, d, J = 8.3 Hz), 7.16 (1H, t, J = 7.7 Hz), 7.04 (1H, d, J = 7.1 Hz), 3.42-3.39 (6H, m), 3.16 (2H, t, J = 5.7 Hz), 2.41 (3H, s).
MS(ESI) : 234 (M+H)⁺. Example 6 Synthesis of 10- (methylthio) -2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

1,4-Dioxane solution of tert-butyl 10- (methylthio) -4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (5.5 mg, 0.016 mmol) 4N hydrogen chloride / 1,4-dioxane solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (3.2 mg, white solid, yield 75%, hereinafter, the compound of Example 6).
¹ H NMR (400MHz, D ₂ O) δ: 7.20 (1H, d, J = 8.3 Hz), 7.16 (1H, t, J = 7.7 Hz), 7.04 (1H, d, J = 7.1 Hz), 3.42- 3.39 (6H, m), 3.16 (2H, t, J = 5.7 Hz), 2.41 (3H, s).
MS (ESI): 234 (M + H) ⁺ .

ｔｅｒｔ−ブチル １０−メトキシ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（８８ｍｇ、０．２８ｍｍｏｌ）のジクロロメタン（１．４ｍＬ）溶液に、トリフルオロ酢酸（０．２１ｍＬ、２．８ｍｍｏｌ）を０℃で加え、室温で２時間撹拌した。反応混合物に飽和炭酸水素ナトリウムを加え中和し、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、表題化合物（６０ｍｇ、無色油状物、収率１００％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.10 (1H, t, J = 8.2 Hz), 6.99 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 7.8 Hz), 3.88 (3H, s), 3.10 (4H, s), 3.08-3.05 (2H, m), 3.01-2.98 (2H, m).
MS(ESI) : 218 (M+H)⁺. Reference Example 18 Synthesis of 10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine:

tert-Butyl 10-methoxy-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (88 mg, 0.28 mmol) in dichloromethane (1.4 mL) Fluoroacetic acid (0.21 mL, 2.8 mmol) was added at 0 ° C. and stirred at room temperature for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (60 mg, colorless oil, yield 100%).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.10 (1H, t, J = 8.2 Hz), 6.99 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 7.8 Hz), 3.88 (3H , s), 3.10 (4H, s), 3.08-3.05 (2H, m), 3.01-2.98 (2H, m).
MS (ESI): 218 (M + H) ⁺ .

１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（５０ｍｇ、０．２２ｍｍｏｌ）の１，２−ジクロロエタン（２．３ｍＬ）溶液に、パラホルムアルデヒド（４２ｍｇ、１．４ｍｍｏｌ）及びトリアセトキシ水素化ホウ素ナトリウム（２９４ｍｇ、１．４ｍｍｏｌ）を加え、７０℃で１．５時間撹拌した。反応混合物を室温まで冷却後、飽和炭酸水素ナトリウムを加え中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をアミノシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム）で精製し、１０−メトキシ−３−メチル−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（４７ｍｇ）を得た。得られた１０−メトキシ−３−メチル−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピンを酢酸エチルに溶解し、１０％塩化水素／メタノール溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（４４ｍｇ、白色固体、収率７７％、以下、実施例７の化合物）を得た。
¹H NMR (400MHz, D₂O) δ: 7.14 (1H, t, J = 8.2 Hz), 7.00 (1H, d, J = 8.3 Hz), 6.71 (1H, d, J = 8.0 Hz), 3.79 (3H, s), 3.36 (4H, dd, J = 8.9, 5.0 Hz), 3.22 (2H, t, J = 5.4 Hz), 3.13 (2H, t, J = 5.6 Hz), 2.82 (3H, s).
MS(ESI) : 232 (M+H)⁺. Example 7 Synthesis of 10-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a solution of 10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (50 mg, 0.22 mmol) in 1,2-dichloroethane (2.3 mL) was added paraformaldehyde (42 mg 1.4 mmol) and sodium triacetoxyborohydride (294 mg, 1.4 mmol) were added and stirred at 70 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, neutralized with saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by amino silica gel column chromatography (eluent: chloroform) to give 10-methoxy-3-methyl-2. , 3,4,5-Tetrahydro-1H-benzofuro [2,3-d] azepine (47 mg) was obtained. The obtained 10-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine was dissolved in ethyl acetate, and a 10% hydrogen chloride / methanol solution was added at room temperature. , Stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (44 mg, white solid, yield 77%, hereinafter, the compound of Example 7).
¹ H NMR (400MHz, D ₂ O) δ: 7.14 (1H, t, J = 8.2 Hz), 7.00 (1H, d, J = 8.3 Hz), 6.71 (1H, d, J = 8.0 Hz), 3.79 ( 3H, s), 3.36 (4H, dd, J = 8.9, 5.0 Hz), 3.22 (2H, t, J = 5.4 Hz), 3.13 (2H, t, J = 5.6 Hz), 2.82 (3H, s).
MS (ESI): 232 (M + H) ⁺ .

１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（１０ｍｇ、０．０４１ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．２３ｍＬ）溶液に、水素化ナトリウム（２．４ｍｇ、０．０５１ｍｍｏｌ、５０ｗｔ％）を０℃で加え、０℃で３０分間撹拌した。反応混合物に、ヨードエタン（４．５μＬ、０．０５５ｍｍｏｌ）を０℃で加え、室温で１時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をアミノシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝８８／１２〜６７／３３）で精製し、３−エチル−１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（７．５ｍｇ）を得た。得られた３−エチル−１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピンを酢酸エチルに溶解し、１０％塩化水素／メタノール溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（６．０ｍｇ、白色固体、収率４６％、以下、実施例８の化合物）を得た。
¹H NMR (400MHz, D₂O) δ: 7.13 (1H, t, J = 8.0 Hz), 6.98 (1H, d, J = 8.0 Hz), 6.69 (1H, d, J = 8.0 Hz), 3.77 (3H, s), 3.47-3.44 (4H, m), 3.25-3.19 (4H, m), 3.13 (2H, t, J = 5.1 Hz), 1.24 (2H, t, J = 7.2 Hz).
MS(ESI) : 246 (M+H)⁺. Example 8 Synthesis of 3-ethyl-10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a solution of 10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (10 mg, 0.041 mmol) in N, N-dimethylformamide (0.23 mL) was added sodium hydride. (2.4 mg, 0.051 mmol, 50 wt%) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. To the reaction mixture was added iodoethane (4.5 μL, 0.055 mmol) at 0 ° C. and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was subjected to amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 88/12 to 67/33). To give 3-ethyl-10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (7.5 mg). The obtained 3-ethyl-10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine was dissolved in ethyl acetate, and a 10% hydrogen chloride / methanol solution was added at room temperature. , Stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (6.0 mg, white solid, yield 46%, hereinafter, the compound of Example 8).
¹ H NMR (400MHz, D ₂ O) δ: 7.13 (1H, t, J = 8.0 Hz), 6.98 (1H, d, J = 8.0 Hz), 6.69 (1H, d, J = 8.0 Hz), 3.77 ( 3H, s), 3.47-3.44 (4H, m), 3.25-3.19 (4H, m), 3.13 (2H, t, J = 5.1 Hz), 1.24 (2H, t, J = 7.2 Hz).
MS (ESI): 246 (M + H) ⁺ .

１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（１１ｍｇ、０．０４８ｍｍｏｌ）のジクロロメタン（０．４８ｍＬ）溶液に、アセトン（１８μＬ、０．２４ｍｍｏｌ）、トリアセトキシ水素化ホウ素ナトリウム（５１ｍｇ、０．２４ｍｍｏｌ）を加え、室温で１４時間撹拌した。反応混合物に飽和炭酸水素ナトリウムを加え中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をアミノシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝８３／１７〜６９／３１）で精製し、３−イソプロピル−１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン（１１ｍｇ）を得た。得られた３−イソプロピル−１０−メトキシ−２，３，４，５−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピンを酢酸エチルに溶解し、１０％塩化水素／メタノール溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（９．７ｍｇ、白色固体、収率６８％、以下、比較例２の化合物）を得た。
¹H NMR (400MHz, D₂O) δ: 7.14 (1H, t, J = 7.6 Hz), 6.99 (1H, d, J = 8.8 Hz), 6.70 (1H, d, J = 8.0 Hz), 3.78 (3H, s), 3.65-3.58 (1H, m), 3.44 (4H, brs), 3.27 (2H, brs), 3.15 (2H, d, J = 5.6 Hz), 1.25 (6H, d, J = 6.6 Hz).
MS(ESI) : 260 (M+H)⁺. Comparative Example 2 Synthesis of 3-isopropyl-10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

To a solution of 10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (11 mg, 0.048 mmol) in dichloromethane (0.48 mL), acetone (18 μL, 0.24 mmol). , Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was subjected to amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 83/17 to 69/31). To give 3-isopropyl-10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine (11 mg). The obtained 3-isopropyl-10-methoxy-2,3,4,5-tetrahydro-1H-benzofuro [2,3-d] azepine was dissolved in ethyl acetate, and a 10% hydrogen chloride / methanol solution was added at room temperature. , Stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (9.7 mg, white solid, yield 68%, hereinafter, the compound of Comparative Example 2).
¹ H NMR (400MHz, D ₂ O) δ: 7.14 (1H, t, J = 7.6 Hz), 6.99 (1H, d, J = 8.8 Hz), 6.70 (1H, d, J = 8.0 Hz), 3.78 ( 3H, s), 3.65-3.58 (1H, m), 3.44 (4H, brs), 3.27 (2H, brs), 3.15 (2H, d, J = 5.6 Hz), 1.25 (6H, d, J = 6.6 Hz ).
MS (ESI): 260 (M + H) ⁺ .

ｔｅｒｔ−ブチル ７−ブロモ−４，５−ジヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（１７ｍｇ、０．０４１ｍｍｏｌ）のエタノール（０．２ｍＬ）／酢酸（０．２ｍＬ）／水（０．２ｍＬ）溶液に、水酸化パラジウム／炭素（１５ｍｇ、パラジウム２０重量％）を加え、反応系内を水素置換し、室温で１日間撹拌した。反応系内をアルゴン置換した後、反応混合物をメタノールでろ過した。ろ液を濃縮後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液：ｎ−ヘキサン／酢酸エチル＝１００／０〜７５／２５）で精製し、表題化合物（５．４ｍｇ、無色油状物、収率４３％）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.13 (1H, td, J = 8.0, 0.7 Hz), 7.09 (1H, d, J = 7.3 Hz), 6.86 (1H, td, J = 7.4, 0.8 Hz), 6.77 (1H, d, J = 8.0Hz), 5.04 (1H, td, J = 12.4, 4.8 Hz), 3.72-3.67 (1H, m), 3.55-3.43 (3H, m), 3.27-3.20 (1H, m), 2.20-2.11 (2H, m), 2.01-1.94 (2H, m), 1.46 (9H, s).
MS(ESI) : 234 (M-tBu +H)⁺. Reference Example 19 Synthesis of (5aS, 10bS) -tert-butyl 4,5,5a, 10b-tetrahydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate:

tert-Butyl 7-bromo-4,5-dihydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (17 mg, 0.041 mmol) in ethanol (0.2 mL) / acetic acid (0 .2 mL) / water (0.2 mL) solution was added palladium hydroxide / carbon (15 mg, palladium 20% by weight), and the reaction system was purged with hydrogen, followed by stirring at room temperature for 1 day. After substituting the inside of the reaction system with argon, the reaction mixture was filtered with methanol. The filtrate was concentrated, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100/0 to 75/25). Purification gave the title compound (5.4 mg, colorless oil, 43% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.13 (1H, td, J = 8.0, 0.7 Hz), 7.09 (1H, d, J = 7.3 Hz), 6.86 (1H, td, J = 7.4, 0.8 Hz) , 6.77 (1H, d, J = 8.0Hz), 5.04 (1H, td, J = 12.4, 4.8 Hz), 3.72-3.67 (1H, m), 3.55-3.43 (3H, m), 3.27-3.20 (1H , m), 2.20-2.11 (2H, m), 2.01-1.94 (2H, m), 1.46 (9H, s).
MS (ESI): 234 (M-tBu + H) ⁺ .

（５ａＳ，１０ｂＳ）−ｔｅｒｔ−ブチル ４，５，５ａ，１０ｂ−テトラヒドロ−１Ｈ−ベンゾフロ［２，３−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（５．４ｍｇ、０．０１９ｍｍｏｌ）の１，４−ジオキサン溶液に、４Ｎ塩化水素／１，４−ジオキサン溶液を室温で加え、撹拌した。析出した固体をろ取し、室温で減圧乾燥し、表題化合物（２．１ｍｇ、白色固体、収率５０％、以下、比較例３の化合物）を得た。
¹H NMR (400MHz, CDCl₃) δ: 7.17 (1H, t, J = 7.8 Hz), 7.06 (1H, d, J = 7.6 Hz), 6.90 (1H, td, J = 7.4, 0.9 Hz), 6.80 (1H, d, J = 8.0 Hz), 5.11 (1H, dt, J = 9.8, 4.4 Hz), 3.86-3.81 (1H, m), 3.37-3.27 (2H, m), 3.22-3.16 (1H, m), 2.69 (1H, t, J = 11.1 Hz), 2.54-2.46 (3H, m), 2.20 (1H, ddd, J = 16.1, 7.1, 5.1 Hz).
MS(ESI) : 190 (M+H)⁺. Comparative Example 3 Synthesis of (5aS, 10bS) -2,3,4,5,5a, 10b-Hexahydro-1H-benzofuro [2,3-d] azepine hydrochloride:

1, (5aS, 10bS) -tert-butyl 4,5,5a, 10b-tetrahydro-1H-benzofuro [2,3-d] azepine-3 (2H) -carboxylate (5.4 mg, 0.019 mmol) To the 4-dioxane solution, 4N hydrogen chloride / 1,4-dioxane solution was added at room temperature and stirred. The precipitated solid was collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (2.1 mg, white solid, yield 50%, hereinafter, the compound of Comparative Example 3).
¹ H NMR (400MHz, CDCl ₃ ) δ: 7.17 (1H, t, J = 7.8 Hz), 7.06 (1H, d, J = 7.6 Hz), 6.90 (1H, td, J = 7.4, 0.9 Hz), 6.80 (1H, d, J = 8.0 Hz), 5.11 (1H, dt, J = 9.8, 4.4 Hz), 3.86-3.81 (1H, m), 3.37-3.27 (2H, m), 3.22-3.16 (1H, m ), 2.69 (1H, t, J = 11.1 Hz), 2.54-2.46 (3H, m), 2.20 (1H, ddd, J = 16.1, 7.1, 5.1 Hz).
MS (ESI): 190 (M + H) ⁺ .

Example 9 Human 5-HT2C receptor agonist activity:
Using a cell that stably expresses human 5-HT2C receptor (hereinafter, human 5-HT2C receptor-expressing cell), the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable one thereof The acid addition salts were evaluated for human 5-HT2C receptor agonist activity.

  PCI-neo-HTR2C prepared by cloning the human 5-HT2C receptor gene into the expression vector pCI-neo (Promega) was introduced into HEK-293 cells (American Type Culture Collection), and the limit from the introduced cells. A single clone was obtained by the dilution method to prepare human 5-HT2C receptor-expressing cells.

Human 5-HT2C receptor expressing cells are 10% fetal bovine serum (dialyzed), 1% MEM non-essential amino acids, 100 U / mL penicillin, 100 μg / mL streptomycin and 500 μg / mL Geneticin Dulbecco's Modified Eagle The culture medium was maintained in a 5% CO ₂ incubator at 37 ° C. using 's Medium as a culture solution.

Human 5-HT2C receptor-expressing cells are suspended in a culture medium for seeding, seeded at 8 × 10 ⁴ cells in each well of 96-well black plate (Corning), and cultured overnight at 37 ° C. and 5% CO _2. And used for the following evaluation. As a culture medium for seeding, human 5-HT2C receptor-expressing cells include Dulbecco's containing 10% fetal bovine serum (dialyzed), 1% non-essential amino acid for MEM, 100 U / mL penicillin and 100 μg / mL streptomycin. Modified Eagle's Medium was used.

  Evaluation of human 5-HT2C receptor agonistic activity was performed by measuring an increase in intracellular calcium concentration due to activation of human 5-HT2C receptor.

  For the measurement of intracellular calcium concentration, FLIPR (registered trademark) Calcium 5 Assay Kit (Molecular Devices) was used. As the assay buffer, Hank's balanced salt solution containing 20 mmol / L HEPES (pH 7.3) added with 2.5 mmol / L probenecid (SIGMA) was used.

The medium of the plate seeded with human 5-HT2C receptor-expressing cells was removed, and FLIPR (registered trademark) Calcium5 Assay Reagent (included in the Kit) 150 μL / well dissolved in the assay buffer according to the instructions attached to the Kit In addition, the cells were incubated at 37 ° C. and 5% CO ₂ for 60 minutes under light shielding, and further allowed to stand at room temperature for 15 minutes under light shielding. Using FLIPR (registered trademark) TETRA (Molecular Devices), 50 μL / well of a test compound was automatically added, and the fluorescence intensity was measured at an excitation wavelength of 470-495 nm and a fluorescence wavelength of 515-575 nm for 5 minutes.

Evaluation of each test compound was carried out by triplicate at each concentration at a common ratio of 3. As a control, lorcaserin (Selleck Chemicals), which is a 5-HT2C receptor agonist sold as a pharmaceutical, was used. The fluorescence intensity at the time of assay buffer addition was defined as 0% response value, and the maximum fluorescence intensity when serotonin (Nacalai Tesque), which is a human 5-HT2 receptor agonist, was added instead of the test compound was defined as 100% response value. The reaction rate (%) at each concentration of the test compound was determined. The EC ₅₀ value of each test compound (concentration showing 50% response to 100% response value of serotonin) was determined by linear regression using the reaction rate (%) at each concentration of each test compound. Each test compound and serotonin were dissolved in DMSO and then diluted with an assay buffer.

The EC ₅₀ values for each test compound are shown in Table 2. As shown in Table 2, the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is a potent human 5-HT2C receptor equivalent to or equivalent to lorcaserine. It was shown to have agonist activity.

(Example 10) Effect on pressure during leakage of rats under anesthesia:
Using an anesthetized rat leakage pressure measurement method, the effect of tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof on stress urinary incontinence was evaluated.

  SD female rats (Nippon Charles River) weighing 215 to 365 g were anesthetized with isoflurane (Mylan Pharmaceutical), and the spinal cord was cut at the T8-T9 level for the purpose of eliminating the micturition reflex. Next, the lower abdomen was incised, the ureters on both sides were ligated, and the kidney side was cut. In addition, two catheters (PE-90 and PE-50; Becton & Dickinson) were placed in the bladder. Immediately before waking up from anesthesia, urethane (SIGMA) was additionally anesthetized in the abdominal cavity, and then the abdominal muscles and skin incisions were sutured. The PE-50 type intravesical catheter was connected to a pressure transducer, and the PE-90 type catheter was connected to a 60 mL syringe filled with physiological saline. The transducer signal was sent to a computer via an amplifier (blood pressure amplification unit AP-641G; Nihon Kohden) and a data analyzer (PowerLab; AD Instruments Inc.), recorded on a hard disk, and analyzed. The physiological saline was injected into the bladder by vertically raising a 60 mL syringe filled with physiological saline, and the maximum intravesical pressure (leakage pressure) when physiological saline leaked from the urethral orifice was measured. After confirming that the physiological saline solution leaked from the urethral orifice, the bladder infusion of the physiological saline solution was stopped, and the physiological saline solution retained in the bladder was discharged.

  The bladder was infused and excreted with physiological saline, and the test compound was administered into the tail vein immediately after a stable leak pressure was obtained three times. Saline solution was injected into the urinary bladder 5 minutes after administration of the test compound, and the leakage pressure was measured. The rate of change (%) in leakage pressure after administration with respect to the average value of leakage pressure three times immediately before test compound administration was used as the evaluation value.

  The compound of Example 7 was used as the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof. The compound of Example 7 was dissolved in physiological saline and administered once at a dose of 1 mg / kg (hereinafter, the compound administration group of Example 7). As a control, lorcaserin (Selleck Chemicals), which is a 5-HT2C receptor agonist sold as a pharmaceutical, was used. Lorcaserin was dissolved in physiological saline and administered once at a dose of 1 mg / kg (hereinafter referred to as lorcaserin administration group). As a control, a group to which the same dose of physiological saline was administered was provided (hereinafter, control group).

  The evaluation results of the compound of Example 7 are shown in FIG. The vertical axis | shaft of FIG. 1 shows the change rate (%) of the pressure at the time of leakage after test compound administration (average value +/- standard error; N = 4-6). In FIG. 1, “physiological saline” indicates a control group, “lorcaserine” indicates a lorcaserine administration group, and “compound of Example 7” indicates a compound administration group of Example 7. “*” In FIG. 1 indicates a statistically significant difference (p <0.05, Dunnett's test) in comparison with the control group (“saline solution” in the figure).

  The rate of change in leakage pressure in the compound administration group of Example 7 and the lorcaserine administration group was statistically significantly higher than the rate of change in leakage pressure in the control group.

  From this result, it was shown that the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof exhibits a therapeutic or preventive effect on stress urinary incontinence.

Since the tetrahydrobenzoflozepine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has potent 5-HT2C receptor agonistic activity, it is particularly useful for the treatment of stress urinary incontinence. It can be used as an agent or a preventive agent.

Claims (6)

A hexahydrobenzoflozepine derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[In the formula, any one of R ^{1 to} R ³ represents a methoxy group or a methylthio group, the other represents a hydrogen atom, and when R ³ represents a methoxy group, R ⁴ represents a hydrogen atom, a methyl group, or When it represents an ethyl group and R ³ represents a hydrogen atom or a methylthio group, R ⁴ represents a hydrogen atom. ] One of R ¹ and R ³ is a methoxy group or a methylthio group, and the other is a hydrogen atom;
R ² is a hydrogen atom,
When R ³ represents a methoxy group, R ⁴ is a hydrogen atom or a methyl group,
The tetrahydrobenzoflozepine derivative according to claim 1 or a pharmacologically acceptable acid addition salt thereof. R ¹ and R ² are hydrogen atoms;
R ³ is a methoxy group,
R ⁴ is a methyl group,
The tetrahydrobenzoflozepine derivative according to claim 1 or a pharmacologically acceptable acid addition salt thereof.   The pharmaceutical which contains the tetrahydro benzo floor zepine derivative as described in any one of Claims 1-3, or its pharmacologically acceptable acid addition salt as an active ingredient.   A 5-HT2C receptor agonist containing the tetrahydrobenzoflozepine derivative or pharmacologically acceptable acid addition salt thereof according to any one of claims 1 to 3 as an active ingredient. The therapeutic agent or preventive agent of stress urinary incontinence which contains the tetrahydro benzo floor zepine derivative as described in any one of Claims 1-3, or its pharmacologically acceptable acid addition salt as an active ingredient.

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